Palladium-catalyzed methylene c-h lactamization and cyclic amination of carboxylic acids

Abstract

The reactions disclosed in this application convert linear ω-amino acids into valuable cyclic β -amino acids with γ- and δ-lactam, pyrrolidine and tetrahydroquinoline scaffolds relevant to drug discovery. The disclosed methods establish a general synthetic platform for the synthesis of multiple classes of lactams, pyrrolidines and piperidines under the same catalytic system. The synthetic utility of the reaction is demonstrated by the synthesis of a form of sertraline.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 551,249, filed February 8, 2024, which is incorporated herein by reference in its entirety.

[0002] Government support This invention was completed with government support under license number GM084019 granted by the National Institutes of Health in the United States. The government holds certain rights to this invention. Technical Field

[0003] The reactions disclosed in this application convert straight-chain ω-amino acids into valuable cyclic β-amino acids with γ- and δ-lactams, pyrrolidines, and tetrahydroquinoline skeletons relevant to drug discovery. The disclosed methods establish a general synthetic platform for the synthesis of multiple classes of lactams, pyrrolidines, and piperidines under the same catalytic manifold. The synthetic practicality of this reaction is demonstrated by the synthesis of Stemona japonica in the form of amide. Background Technology

[0004] By forming sp 3 The development of cyclization reactions to prepare saturated heterocycles from C–N bonds is one of the cornerstones of modern synthetic chemistry, due to the ubiquitous presence of lactams and cyclic amines in natural products and pharmaceuticals. Figure 1 A). 1,2 sp 3 The advent of the C–H amination method ushered in a new era, in which sp24-p- ... 3 C–N bonding has become a viable synthetic strategy. 3–6 Despite relying on nitrogen olefins, 7–10 free radicals 11–14 Activation of allyl C–H bonds 15,16 In sp 3 Significant progress has been made in the development of C–H amination reactions, but progress on the amination of ubiquitous unactivated methylene and methyl C–H bonds remains slow. Palladium-catalyzed amination of methyl and methylene sp... 3 Activation of the C–H bond provides a complementary strategy for solving this problem. 17,18 However, under this catalytic system, via sp 3 Most cyclization reactions that form C–N bonds require the use of custom-designed directing groups. 19–22 Achieving challenging palladium-catalyzed sp from natural substrates without the installation of directing groups. 3 C–H amination reactions are only just beginning to gain momentum. To this end, palladium-catalyzed intramolecular amination of methyl C–H bonds in spatially crowded substrates has been reported. 23–26 Therefore, there is a need in the field to develop natural amide-directed methyl C–H bond activation for synthesis. N - Protected β- and γ-lactams. 27,28 Summary of the Invention

[0005] Recent developments in bifunctional ligands have rapidly advanced palladium-catalyzed sp24-phosphorus synthesis guided by natural carboxylic acids. 3 C–H activation reactions. However, this method can be used to achieve intermolecular or intramolecular sp. 3 C–H amination has encountered a fundamental challenge: nitrogen coordination often overrides the directing effect of the native carboxyl group. This challenge has been overcome through the discovery and design of novel chloropyridine-pyridone ligands. N - The unique carboxylic acid-directed lactamation and cycloamination of protected ω-amino acids becomes possible. The directed C–H activation and C–N bond formation separation in this reaction differs from existing sp... 3 C–H amination methods, in which both processes are nitrogen-directed. The scheme described in this application converts straight-chain ω-amino acids into valuable cyclic β-amino acids with γ- and δ-lactam, pyrrolidine, and tetrahydroquinoline skeletons relevant to drug discovery. The synthetic practicality of this reaction is demonstrated by the synthesis of Stemona japonica in the form of amide.

[0006] This application provides a palladium-catalyzed method for methylene C–H lactamation or cycloamination, which includes treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source.

[0007] This application provides the above method, wherein the pyridine-pyridone ligand is a chloropyridine-pyridone ligand selected from the group consisting of: .

[0008] This application also provides the above-described method, wherein the carboxylic acid is... N - Protected ω-amino acids.

[0009] This application also provides the above method according to the following scheme: in: R 3 R 4 R 5 and R 6 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1.

[0010] This application also provides the above method according to the following reaction scheme: in: R 3 R 4 R 5 R 6 R 7 and R 8 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1. Attached Figure Description

[0011] Figure 1 Natural products and drug molecules that can be synthesized through methylene C–H amidation and amination.

[0012] Figure 2 A. Ligand discovery and design optimization of reaction conditions. B. Preliminary study of reaction behavior. C. Ligand design for recalcitrant substrates.

[0013] Figure 3 Substrate range for carboxylic acid-directed β-C–H γ- and δ-lactamization reactions.

[0014] Figure 4 Substrate range for carboxylic acid-directed β-C–H cyclic amination reactions.

[0015] Figure 5 Synthesis of bicyclic lactam skeletons associated with Stemona japonica alkaloids.

[0016] Figure 6. A. Natural products and drug molecules synthesized via methylene C–H amidation and amination. B. Novel reaction designs for palladium-catalyzed methylene C–H lactamation and cycloamination. C. Construction of γ- and δ-lactams, pyrrolidines, and tetrahydroquinolines by β-methylene C–H activation with novel chlorinated ligands.

[0017] Figure 7. A. Optimization of reaction conditions through ligand discovery and design. B. Preliminary study of reaction behavior. C. Ligand design for recalcitrant substrates.

[0018] Figure 8. Substrate range for carboxylic acid-directed β-C–H γ- and δ-lactamization reactions. Reaction conditions: Pd(OAc)2 (10 mol%), ligand (12 mol%), 2,5-dimethyl-p-benzoquinone (2.0 equivalents), Ag2CO3 (2.0 equivalents), K2HPO4 (0.35 equivalents), CsOAc (0.4 equivalents), HFIP, 100 °C, 36 h. a Unless otherwise stated, the yield is the isolated yield of methyl ester. b Pd(OAc)2 (15 mol%), ligand (17 mol%). c Separate in the form of carboxylic acids. d It was separated in the form of benzyl ester.

[0019] Figure 9. Substrate range for carboxylic acid-directed β-C–H cycloamination. Reaction conditions: Pd(OAc)2 (10 mol%), ligand (12 mol%), 2,5-dimethyl-p-benzoquinone (2.0 equivalents), Ag2CO3 (2.0 equivalents), K2HPO4 (0.35 equivalents), CsOAc (0.4 equivalents), HFIP, 100 °C, 36 h. a Unless otherwise stated, the yield is the isolated yield of methyl ester. b Pd(OAc)2 (15 mol%), ligand (17 mol%). c Separate in the form of carboxylic acids.

[0020] Figure 10. A. Synthesis of the bicyclic lactam skeleton associated with Stemona japonica alkaloids; see Examples for details of reaction conditions. B. Excellent reactivity of chlorinated ligands in dicarboxylate lactone chemistry. Detailed Implementation

[0021] Despite progress in this research direction, the formation of sp at the unactivated methylene carbon using palladium-catalyzed C–H activation guided by natural functional groups remains a challenge. 3 The C–N bond remains unbreakable. Recent successes in carboxylic acid-directed methylene C–H activation reactions have inspired the design of [reactions for sp]. 3Inspired by alternative strategies for C–H amination. Theoretically, using a carboxylic acid as a directing group can separate directed methylene C–H activation from C–N bond formation. This contrasts sharply with conventional reaction designs that use the nitrogen moiety as both a directing group for C–H activation and a nucleophile for C–N bond formation. 22,29 This separation of the interaction between the two functional groups eliminates the need for a custom directing group at nitrogen to accommodate palladium catalysts used in both processes, thus potentially enabling the use of natural substrates for the desired transformation. Figure 1 B). Therefore, it was decided to study N The reactivity of protected ω-amino acids was investigated to determine the feasibility of intramolecular carboxylic acid-directed β-methylene C–H amination. However, the use of carboxylic acid-directed methylene C–H dehydrogenation was anticipated. 30,31 lactone 32 Deuteration 33 And arylization 34–36 Existing methods are ineffective for the proposed amination reaction because the coordinating amino group is rarely included in previous optimization activities. Therefore, the ability of existing catalysts for the desired methylene C–H activation and C–N bond formation processes is unknown. Furthermore, the use of… N Protected ω-amino acids exhibit unique reaction profiles, which contrast sharply with known reaction systems employing only one type of directing group. Specifically, N - Protected ω-amino acids have two competing directing groups, which can lead to two different reactive modes. 37 One pathway is the desired carboxylic acid-directed C–N bond formation, and the other is the undesirable and potentially dominant amine and amide-directed C–O bond formation pathway. Therefore, these issues present three challenges to overcome in developing the desired C–H amination reactions: achieving carboxylic acid-directed β-methylene C–H activation in the presence of a coordinating amino group; promoting sp... 3 C–N bond formation; inhibition of competitive amine and amide-directed processes. Methods to overcome the mentioned challenges depend on ligand discovery and design, ultimately developing general strategies for obtaining a range of skeletons (such as γ- and δ-lactams, pyrrolidines, and tetrahydroquinolines) sought in drug discovery. The synthetic practicality of C–H amidation reactions was demonstrated by the formal synthesis of Stemona japonica amide via the construction of a bicyclic lactam skeleton. Figure 1 C).

[0022] N The reactivity of protected ω-amino acid 1 was first benchmarked against lactone conditions developed for α,ω-dicarboxylic acids, due to the similarity between the two reaction systems. Figure 2 A). 32Using the best-in-class ligand L1 for β-directed γ-lactoneization of dicarboxylic acids only yielded a 25% NMR yield of the desired γ-lactam product 1a for C–N bond formation, thus validating concerns about reduced reactivity when using existing catalytic systems. Satisfactorily, no CO bond formation reactivity was observed. The suboptimal reactivity of L1 prompted a switch to simpler pyridine-pyridone ligands L2–L8 to first plot preliminary structure-reactivity relationships for further optimization. Thus, initial optimization of reaction conditions began with an investigation of a series of pyridine-pyridone ligands with various substituents at the 6-position of pyridine. The 6-chloropyridine-pyridone compound L3 was subsequently identified as a promising ligand skeleton, in which the use of this ligand yielded the desired γ-lactam product 1a in 55% NMR yield. Substituting chlorine substituents with other functional groups such as fluorine and bromine (L2, L4), methyl (L8), methoxy (L6), hydroxyl (L5), and trifluoromethyl (L7) groups all resulted in decreased catalytic activity (8%–26% NMR yield in 1a). Using benzo[…] with a more extended π-system… g The quinoline skeleton (L9) did not lead to any improvement in reaction efficiency (15% NMR yield of 1a). Besides ligand L3, ligands with electron-donating substituents such as L6 and L8 were observed to perform slightly better than ligands with electron-withdrawing substituents such as L7, which facilitated further fine-tuning of the electronic properties of ligand L3. It is speculated that adding additional electron-donating substituents to the pyridine moiety of the ligand could further improve its reactivity, while adding additional electron-withdrawing substituents would lead to the opposite result. Further investigation following this reasoning yielded 6-chloro-4-methylpyridine-pyridone compound L14, which was found to be superior to ligand L3, thus providing γ-lactam product 1a in 65% NMR yield. The 4-methoxy-substituted ligand L16 performed slightly worse than ligand L3, while ligands L10-L13 with additional electron-withdrawing substituents were found to consistently perform worse. The ligand L15 with a 4-tert-butyl substituent appears to be an outlier in this case, the reason for which is unclear. Perturbation of other reaction parameters at this stage did not lead to a significant increase in reaction yield.

[0023] Although it has been determined that quinoline / pyridine-pyridone ligands such as L1 and L14, which form 5-membered chelates with palladium, preferentially undergo the carboxylic acid-directed β-C–H activation pathway, 30,32 However, their activity with amides as potential directing groups remains unclear; therefore, product 1a can be formed via carboxylic acid-directed β-C–H γ-lactamization or amide-directed γ-C–H γ-lactamization. To distinguish between these two pathways, the reactivity of substrate 2 was investigated to gather preliminary mechanistic insights into the C–H functionalization process. Figure 2B). Specifically, substrate 2 can yield δ-lactam product 2b via a carboxylic acid-directed β-C–H δ-lactamization pathway, or γ-lactam product 2a via an amide-directed γ-C–H γ-lactamization pathway. The lactamation reaction of 2 was found to specifically produce δ-lactam product 2b with 75% NMR yield, which favors the carboxylic acid-directed β-C–H δ-lactamization pathway. The amide-directed δ-C–H activation pathway involving the seven-membered palladium ring is considered unlikely. Furthermore, γ-lactam product 2a was not observed, indicating that the observed C–N bond formation reactivity is inconsistent with the amide-directed pathway. Consistent with this hypothesis, N - Protected ω-aminomethyl esters 3 and 4 did not show C–N bond formation reactivity under the same reaction conditions, suggesting that the presence of a carboxylic acid in the substrate is crucial for reactivity, and that the toluenesulfonylformamide moiety alone does not appear to provide observable C–H functionalization reactivity.

[0024] Given that toluenesulfonylformamide is known to participate in sp as a directing group 2 The observation that the current catalytic system cannot achieve the C–H activation reaction directed by toluenesulfonylformamide is somewhat surprising. 38–40 Therefore, the careful matching of directing groups and ligands was explored as a strategy to achieve site-selective conversion. Figure 2 B). Wasa amide-carboxylic acid substrate 5 was prepared to test the possibility of selecting between carboxylic acid-directed and amide-directed reactivity using known ligands developed for methylene C–H activation reactions. The use of the known APAQ ligand L17 resulted in an unoptimized 14% NMR yield of the proposed amide-directed lactone product 5c. 41 Using ligand L14, a 60% NMR yield was obtained for the carboxylic acid-directed lactamylation product 5a. These preliminary findings suggest that it is possible to select directing groups for site-specific C–H functionalization through careful pairing between the directing group and the ligand, and that the order of directing strength may be overturned by ligand effects. 37 With the acquisition of ligand L14 and preliminary mechanistic knowledge, the development of a broad substrate range for this C–H lactamation reaction has begun. However, when investigating... N - A stumbling block arises when the reactivity of protected ω-amino acids with substituents on alkyl chains. Substrate 6, with its α-spirocyclic amide, only offers a 12% NMR yield for δ-lactam 6b with ligand L14. Figure 2(C) This observation is surprising because the α-spirocyclic center is expected to facilitate lactamation reactions via the Throp-Ingold effect. This counterintuitive result prompts questions about whether quaternization of the substrate around the toluenesulfonylformamide reduces the efficiency of carboxylic acid-directed C–H functionalization. It is hypothesized that the additional β-methylene C–H bond pair available around the toluenesulfonylformamide could promote toluenesulfonylformamide-directed C–H activation, which is not contradictory to the higher reactivity of the quaternized substrate relative to its less substituted counterpart in directed C–H functionalization reactions. 28 Compared to carboxylic acids, the larger size of the toluenesulfonylformamide moiety led to the hypothesis that increasing the steric hindrance of the ligand could favor carboxylic acid-directed lactamation of substrate 6, rather than the non-productive coordination between the toluenesulfonylformamide and the palladium catalyst. Testing this hypothesis with the sterically more hindrance-prone quinoline-pyridone ligand L1 compared to ligand L14 yielded slightly better results, providing δ-lactam 6b in 20% NMR yield. Therefore, it was decided to combine the steric properties of the quinoline-pyridone ligand L1 with a chlorinated substituent that imparts reactivity to pyridinium-pyridone ligands L3 and L14 to produce the 4-chloroquinoline-pyridone ligand L18, which was proposed to impart greater steric hindrance around the main coordination range of the palladium catalyst while retaining the electronic benefits provided by the chlorinated substituent. The use of this new ligand L18 did indeed immediately increase the NMR yield of 6b to 47%.

[0025] Therefore, the substrate scope for γ- and δ-lactamization reactions was developed using ligands L14 and L18. Figure 3 Ligand L14 is the preferred ligand for lactamation reactions, while ligand L18 is used only when L14 fails to achieve a significant degree of lactamation. In some cases, using L14 as a ligand to slightly increase the catalyst loading to 15 mol% is necessary to improve reaction yield. The substrate scope design focuses on generating different classes of spirocyclic and fused-ring systems relevant to medicinal chemistry. 42,43 Furthermore, examples of products offering excellent levels of diastereoselectivity that provide readily manageable synthetic utility were preferred. Unless otherwise specified, all products were isolated as methyl esters. For γ-lactamization, fully unsubstituted γ-lactam 1a was isolated as a free carboxylic acid in 61% yield. NSubstitution at both the α- and β-terminal positions is permissible, thus providing a series of γ-lactams with various types of molecular skeletons. These lactams include α-quaternary γ-lactam 7a with gem-dimethyl substitution, isolated in 40% yield, and α-spirocyclic γ-lactams 8a-10a with cyclobutyl, cyclopentyl, and 4-tetrahydropyranyl systems, isolated in 40%-60% yield. Lactamation of α-monosubstituted substrates is feasible, but is not shown here due to low levels of diastereoselectivity (see Examples). Substitution at the β-terminal position provides γ-lactams 11a-13a with methyl (as free carboxylic acid), tert-butyl (as free carboxylic acid), and phenyl groups generated primarily as trans diastereomeric isomers (trans:cis >20:1, see Examples on stereochemical partitioning) in 78%-93% yield. β-spirocyclic γ-lactams 14a and 15a, containing cyclobutyl and cyclopentyl groups, were also successfully synthesized in yields of 81% and 50%, respectively. In addition to spirocyclic systems, fused-ring systems such as the 5,5-fused 20a were prepared as benzyl esters in 22% yield, and the benzofused γ-lactam 23a was assembled as a methyl ester in 60% yield. It is noteworthy that… N The successful synthesis of 25a-methoxyγ-lactam, isolated as a benzyl ester in 61% yield, demonstrates that another class of simple amides can also be used for this γ-lactamization scheme.

[0026] The development of the scope for δ-lactamization reactions is similar to that of γ-lactamization reactions as described above. Completely unsubstituted δ-lactam 2b was isolated in 70% yield as free carboxylic acid. N Substitution at both the α- and β-terminal positions is permissible, thus providing δ-lactams such as α-quaternary δ-lactam 16b with gem-dimethyl substitution in 60% yield; α-spirocyclic δ-lactams with cyclobutyl (17b), cyclopentyl (6b), and 4-tetrahydropyranyl (18b) systems in 40%–66% yield; and β-spirocyclic δ-lactam 19b in 73% yield. Fused ring systems are also feasible targets for δ-lactamization reactions, thus providing 5,6-fused 21b (in the form of benzyl ester), 6,6-fused 22b (in the form of benzyl ester), and benzo-fused 24b in approximately 60% separate yield.

[0027] After investigating the scope of the lactamation reaction with toluenesulfonylformamide, we considered whether this C–N bond formation scheme could address the challenges of achieving the C–H cycloamination reaction with toluenesulfonylformamide. Besides the expected difference in directing strength, 37 The presence of the α-methylene unit at the amine site opens up the possibility of β-hydride elimination, thereby complicating the reaction by introducing the undesirable toluenesulfonylimide formation pathway. 44Despite concerns about the feasibility of the reaction, it was found that the cycloamination reaction proceeded smoothly using ligands L14 and L18, thus providing a series of [potentially different reactions]. N - Protected pyrrolidine, although typically requires a higher catalyst loading of 15 mol% ( Figure 4 Unless otherwise specified, all products were isolated as methyl esters. Completely unsubstituted pyrrolidine 26a was isolated in 65% yield with no indication of toluenesulfonyl imide formation. Using this scheme, pyrrolidines with substitutions at the α-, β-, and γ-positions can be readily prepared, providing α-monosubstituted pyrrolidines 27a and 28a as cis-diastereomers in 55%–67% yield as free carboxylic acids (see supporting information on stereochemical partitioning); α-quaternary pyrrolidine 29a with gem-dimethyl substitution in 60% yield; and α-spirocyclic pyrrolidines with cyclobutyl (30a), cyclopentyl (31a), and 4-tetrahydropyranyl (32a) systems in 50%–67% yield; β-Pyrrolidines and spirocyclic pyrrolidines having gem-dimethyl (33a), cyclobutyl (34a), and cyclopentyl (35a) systems are provided in 0%–50% yield; γ-monosubstituted pyrrolidines, such as 36a–38a having methyl, tert-butyl, and phenyl groups, are provided in 70%–82% yield as trans diastereomers (trans:cis > 20:1, see supporting information on stereochemical partitioning), and γ-spirocyclic pyrrolidines 39a–49a having cyclobutyl and cyclopentyl systems are provided in 27%–35% yield. Fused bicyclic pyrrolidines, such as 41a having a 5,5-fused system, are produced in 30% yield, while 42a having a 5,6-fused system is prepared in 60% yield, and tetrahydroquinoline 43b is synthesized in 53% yield. It was also found that the cycloamination reaction was resistant to the substitution of the toluenesulfonyl protecting group for the 2-p-nitrobenzenesulfonyl protecting group, and 44a was successfully obtained, although the yield was reduced.

[0028] To demonstrate the synthetic practicality of C–H amidation reactions in complex molecular synthesis contexts, the following synthetic route was developed for the preparation of 5,7-fused bicyclic lactams related to Stemona japonica alkaloids. Figure 5 A). 45,46 γ-lactam 1a was prepared in gram-scale with a 57% isolated yield. Deprotection of the toluenesulfonyl group was then carried out by titration of a cold (-40°C) DME solution of γ-lactam 1a (as a solution of approximately 2.0 M DME) with sodium naphthylene followed by quenching with excess allyl bromide (added as a DMF solution), yielding diallylated lactam 47 in 51% yield. The Ireland-Claisen rearrangement converted diallylated lactam 47 to diallylated carboxylic acid 48 (the major diastereomer plotted) in 73% yield and at a diastereomeric ratio of approximately 5:1.47 It then undergoes a ring-closure metathesis-hydrogenation sequence to give the target 5,7-fused bicyclic lactam acid 49 in 85% yield. The target bicyclic lactam acid 49 is then subjected to another test by photoredox decarboxylation-oxygenation to provide bicyclic ketolactam 50 in 60% yield, which constitutes the synthesis of racemic buspiramic acid 51. 48,49 Alternatively, the closed-ring mesothesis product 52 can be combined with... N - Bromosuccinimide was brominated to yield a complex polycyclic compound 53. In summary, the preparation of 50 and 53 from 1 demonstrates the feasibility of converting simple linear bifunctional compounds into various complex skeletons via C–H amidation reactions as described in this disclosure.

[0029] Ultimately, the discovery and design of ligands L14 and L18 could also benefit existing dicarboxylate lactone chemistry. Figure 5 B). Given that ligands L14 and L18 are optimized for tolerance to carboxylic acids and N -Reactions involving protected amines and amides, using ligand L18, which has the greatest similarity to ligand L1, to address previously difficult reactions. N - Lactonelation of the protected dicarboxylic acid substrate 50 immediately increased the reaction yield from 25% to 60%. 32 It is worth noting that no other reaction parameters need to be changed, so the improvement in reaction yield is entirely due to ligand optimization.

[0030] In summary, it has been developed for N Two novel chlorinated ligands, L14 and L18, for the palladium-catalyzed, carboxylic acid-directed methylene lactamation and cycloamination of protected ω-amino acids. The C–N bond-forming reaction reported here provides a method for constructing a variety of cyclic lactams and amines with diverse ring sizes and structures relevant to chemical synthesis and medicinal chemistry, utilizing C–H activation.

[0031] References: Implementation Plan This application provides the following implementation scheme: Implementation Scheme 1. A palladium-catalyzed method for methylene C–H lactamation or cycloamination, comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source; and ii) adding 2,5-dimethyl-p-benzoquinone, an Ag salt, and K2HPO4 to a reaction vessel.

[0032] Implementation Scheme 2. The method of Implementation Scheme 1, wherein the pyridine-pyridone ligand is a chloropyridine-pyridone ligand selected from the group consisting of: .

[0033] Implementation Scheme 3. The method as described in Implementation Scheme 1 or Implementation Scheme 2, wherein the carboxylic acid is N - Protected ω-amino acids.

[0034] Implementation Scheme 4. The method of any one of Implementation Schemes 1 to 3, wherein the Pd source is Pd(OAc)2.

[0035] Implementation Scheme 5. The method of any one of Implementation Schemes 1 to 4, wherein the Ag salt is Ag2CO3.

[0036] Implementation Scheme 6. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L10.

[0037] Implementation Scheme 7. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L11.

[0038] Implementation Scheme 8. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L12.

[0039] Implementation Scheme 9. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L13.

[0040] Implementation Scheme 10. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L14.

[0041] Implementation Scheme 11. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L15.

[0042] Implementation Scheme 12. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L16.

[0043] Implementation Scheme 13. The method of any one of Implementation Schemes 1 to 5, wherein the chloropyridine-pyridone ligand is L18.

[0044] Implementation Scheme 14. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is selected from the group consisting of: .

[0045] Implementation Scheme 15. The method of any one of Implementation Schemes 1 to 5, wherein the quinoline-pyridone ligand is L1.

[0046] Implementation Scheme 16. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is L2.

[0047] Implementation Scheme 17. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is L3.

[0048] Implementation Scheme 18. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is L4.

[0049] Implementation Scheme 19. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is L5.

[0050] Implementation Scheme 20. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is L6.

[0051] Implementation Scheme 21. The method of any one of Implementation Schemes 1 to 5, wherein the quinoline-pyridone ligand is L7.

[0052] Implementation Scheme 22. The method of any one of Implementation Schemes 1 to 5, wherein the quinoline-pyridone ligand is L8.

[0053] Implementation Scheme 23. The method of any one of Implementation Schemes 1 to 5, wherein the pyridine-pyridone ligand is L9.

[0054] Implementation Scheme 24. A method for methylene C–H lactamation or cycloamineation, comprising i) treating a carboxylic acid substrate with any of ligands L1-L18 in the presence of a Pd source; and ii) adding a base.

[0055] Implementation Scheme 25. The method of Implementation Scheme 24, further comprising the addition of 2,5-dimethyl-p-benzoquinone.

[0056] Implementation Scheme 26. The method as described in Implementation Scheme 24 or Implementation Scheme 25, further comprising adding an Ag salt.

[0057] Implementation Scheme 27. The method as described in Implementation Scheme 26, wherein the Ag salt is Ag2CO3.

[0058] Implementation Scheme 28. The method of any one of Implementation Schemes 24 to 27, wherein the Pd source is Pd(OAc)2.

[0059] Implementation Scheme 29. The method of any one of Implementation Schemes 24 to 28, wherein the Pd source catalyst loading is 5-20 mol.

[0060] Implementation Scheme 30. The method as described in Implementation Scheme 29, wherein the Pd source catalyst loading is 10 mol.

[0061] Implementation Scheme 31. The method of any one of Implementation Schemes 24 to 29, further comprising adding CsOAc.

[0062] Implementation Scheme 32. The method of any one of Implementation Schemes 24 to 31, wherein the solvent is HFIP.

[0063] Implementation Scheme 33. The method of any one of Implementation Schemes 1 to 32, wherein the reaction temperature is approximately 90-110°C.

[0064] Implementation Scheme 34. The method as described in Implementation Scheme 33, wherein the reaction temperature is approximately 100°C.

[0065] Implementation Scheme 35. The method as described in any one of Implementation Schemes 1 to 34, wherein the reaction time is approximately 36 hours.

[0066] Implementation Scheme 36. The method of any one of Implementation Schemes 24 to 35, wherein the base is K2HPO4.

[0067] Implementation Scheme 37. The method of any one of Implementation Schemes 24 to 36, wherein the ligand L is L14.

[0068] Implementation Scheme 38. The method of any one of Implementation Schemes 24 to 36, wherein the ligand L is L18.

[0069] Implementation Scheme 39. The method described in Implementation Scheme 1, wherein the method is based on the following scheme: in: Z is -C(=O)- or -C(R) 1 (R) 2 )-; R 1 and R 2 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; R is N - Protecting group; and n is 1 or 2.

[0070] Implementation Scheme 40. The method as described in Implementation Scheme 39, wherein Z is -C(=O)-.

[0071] Implementation Scheme 41. The method as described in Implementation Scheme 39, wherein Z is -C(R 1 (R) 2 )-.

[0072] Implementation Scheme 42. The method as described in Implementation Scheme 41, wherein R 1 For H.

[0073] Implementation Scheme 43. The method as described in Implementation Scheme 41, wherein R 1 It is a (C1-C6) alkyl group.

[0074] Implementation Scheme 44. The method as described in Implementation Scheme 41, wherein R 1 For (C6-C) 10 Aryl.

[0075] Implementation Scheme 45. The method as described in any one of Implementation Schemes 39 to 44, wherein R 2 For H.

[0076] Implementation Scheme 46. The method as described in any one of Implementation Schemes 39 to 44, wherein R 2 It is a (C1-C6) alkyl group.

[0077] Implementation Scheme 47. The method as described in any one of Implementation Schemes 39 to 44, wherein R 2 For (C6-C) 10 Aryl.

[0078] Implementation Scheme 48. The method as described in any one of Implementation Schemes 39 to 47, wherein L is L14.

[0079] Implementation Scheme 49. The method as described in any one of Implementation Schemes 39 to 47, wherein L is L18.

[0080] Implementation scheme 50. The method as described in any one of implementation schemes 39 to 47, wherein L is L1.

[0081] Implementation Scheme 51. The method described in Implementation Scheme 39, which is based on the following scheme: in: Z is -C(=O)- or -C(R) 1 (R) 2 )-; R 1 and R 2 Independently H, (C1-C6)alkyl, (C6-C10 aryl or (C1-C6)alkyl (C6-C 10 aryl; R is N - Protecting group; and n is 1 or 2.

[0082] Implementation Scheme 52. The method described in Implementation Scheme 1, wherein the method is based on the following scheme: in: R 3 R 4 R 5 and R 6 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1.

[0083] Implementation Scheme 53. The C–H cyclic amination reaction as described in Implementation Scheme 1, which is based on the following reaction scheme: in: R 3 R 4 R 5 R 6 R 7 and R 8 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1.

[0084] Implementation Scheme 54. The method as described in any one of Implementation Scheme 52 or Implementation Scheme 53, wherein R is Ts.

[0085] Implementation scheme 55. The method as described in any one of implementation schemes 52 to 54, wherein L is L14.

[0086] Implementation Scheme 56. The method as described in any one of Implementation Schemes 52 to 54, wherein L is L18.

[0087] Implementation Scheme 57. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 4 For H.

[0088] Implementation Scheme 58. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 4 It is a (C1-C6) alkyl group.

[0089] Implementation Scheme 59. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 4 Together they form (C3-C7) cycloalkyl groups.

[0090] Implementation Scheme 60. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 4 Together they form (C3-C7) heterocyclic alkyl groups.

[0091] Implementation Scheme 61. The method as described in any one of Implementation Schemes 57 to 60, wherein R 5 and R 6 For H.

[0092] Implementation Scheme 62. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 5 Together they form (C6-C) 10 Aryl.

[0093] Implementation Scheme 63. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 5 Together they form (C3-C7) cycloalkyl groups.

[0094] Implementation Scheme 64. The method as described in any one of Implementation Schemes 52 to 56, wherein R 3 and R 5 Together they form (C3-C7) heterocyclic alkyl groups.

[0095] Implementation Scheme 65. The method as described in any one of Implementation Schemes 62 to 64, wherein R 4 and R 6 For H.

[0096] Implementation Scheme 66. The method of any one of Implementation Schemes 52 to 65, further comprising the addition of 2,5-dimethyl-p-benzoquinone.

[0097] Implementation Scheme 67. The method of Implementation Scheme 66 further includes the addition of Ag2CO3.

[0098] Implementation Scheme 68. The method as described in Implementation Scheme 67, wherein the Pd source is Pd(OAc)2.

[0099] Implementation Scheme 69. The method as described in Implementation Scheme 68, further comprising adding CsOAc.

[0100] Implementation Scheme 70. The method as described in Implementation Scheme 69, wherein the solvent is HFIP.

[0101] Implementation Scheme 71. The method as described in Implementation Scheme 70, wherein the reaction temperature is approximately 90-110°C.

[0102] Implementation Scheme 72. The method as described in Implementation Scheme 71, wherein the reaction temperature is approximately 100°C.

[0103] Implementation Scheme 73. The method as described in Implementation Scheme 72, wherein the reaction time is approximately 36 hours.

[0104] Implementation Scheme 74. The method as described in Implementation Scheme 73, wherein the base is K2HPO4.

[0105] Implementation Scheme 75. The method as described in Implementation Scheme 74, wherein the ligand L is L14.

[0106] Implementation Scheme 76. The method as described in Implementation Scheme 74, wherein the ligand L is L18.

[0107] Implementation Scheme 77. The method as described in Implementation Scheme 1, wherein the carboxylic acid is N - Protected ω-amino acids.

[0108] Implementation Scheme 78. A method for synthesizing Stemona amide, comprising a lactamation reaction as described in Implementation Scheme 52.

[0109] Implementation Scheme 79. Any method disclosed in this application.

[0110] Implementation Scheme 80. A palladium-catalyzed method for methylene C–H lactamation or cycloamineation, comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source; and ii) adding 2,5-dimethyl-p-benzoquinone, an Ag salt, and K2HPO4 to a reaction vessel.

[0111] Implementation Scheme 81. The method of Implementation Scheme 80, wherein the pyridine-pyridone ligand is a chloropyridine-pyridone ligand selected from the group consisting of: .

[0112] Implementation Scheme 82. The method as described in Implementation Scheme 80 or Implementation Scheme 81, wherein the carboxylic acid is N - Protected ω-amino acids.

[0113] Implementation Scheme 83. The method of any one of Implementation Schemes 80 to 82, wherein the Pd source is Pd(OAc)2.

[0114] Implementation Scheme 84. The method of any one of Implementation Schemes 80 to 83, wherein the Ag salt is Ag2CO3.

[0115] Implementation Scheme 85. The method of any one of Implementation Schemes 80 to 84, wherein the chloropyridine-pyridone ligand is L1, L14 or L18.

[0116] Implementation Scheme 86. The method described in Implementation Scheme 80 is based on the following scheme: in: Z is -C(=O)- or -C(R) 1 (R) 2 )-; R 1 and R 2 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; R is N - Protecting group; and n is 1 or 2.

[0117] Implementation Scheme 87. The method as described in Implementation Scheme 7, comprising the following schemes: in: Z is -C(=O)- or -C(R) 1 (R)2 )-; R 1 and R 2 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; R is N - Protecting group; and n is 1 or 2.

[0118] Implementation Scheme 88. The method as described in Implementation Scheme 80, comprising the following schemes: in: R 3 R 4 R 5 and R 6 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1.

[0119] Implementation Scheme 89. The C–H cyclic amination reaction as described in Implementation Scheme 1, comprising the following reaction scheme: in: R 3 R 4 R 5 R 6 R 7 and R 8 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10aryl; R is N - Protecting group; and n is 0 or 1.

[0120] Implementation Scheme 90. A method for synthesizing Stemona amide, comprising a lactamation reaction as described in Implementation Scheme 80.

[0121] Implementation Scheme 91. A method for synthesizing Stemona amide, comprising a lactamation reaction as described in Implementation Scheme 90.

[0122] Implementation Scheme 92. The method as described in any one of Implementation Schemes 80 to 91, wherein L is L1.

[0123] Implementation Scheme 93. The method as described in any one of Implementation Schemes 80 to 91, wherein L is L14.

[0124] Implementation Scheme 94. The method as described in any one of Implementation Schemes 80 to 91, wherein L is L18.

[0125] definition As used herein, the phrase “an” or “a” refers to one or more of the same entity; for example, “a compound” refers to one or more compounds or at least one compound. Therefore, the terms “an” (or “a”), “one or more”, and “at least one” are used interchangeably herein.

[0126] The phrase "as defined above" refers to the broadest definition of each group provided in the summary, detailed description, experiment, or the broadest claims. In all other embodiments provided below, substituents that may be present in each embodiment and are not explicitly defined retain the broadest definition provided in the summary.

[0127] As used herein, the term "comprising" is to be interpreted in an open-ended sense, whether in transitional phrases or in the body of the claims. That is, the term is to be interpreted as synonymous with the phrases "having at least" or "comprising at least". When used in the context of a method, the term "comprising" means that the method includes at least the listed steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the listed features or components, but may also include additional features or components.

[0128] As used herein, unless otherwise explicitly stated, the word "or" is used in an inclusive sense of "and / or" rather than in an exclusive sense of "either / or".

[0129] This document uses the term "independently" to mean that a variable is applied in any given case, regardless of the presence or absence of variables with the same or different definitions within the same compound. Therefore, in compounds where "R" appears twice and is defined as "independently selected," it means that each occurrence of the R group is individually identified as a member of the set conforming to the definition of that R group. For example, "each R..." 1 and R 2 "Independently selected from carbon and nitrogen" means R 1 and R 2 Both can be carbon, R 1 and R 2 Both can be nitrogen, or R 1 Or R 2 It could be carbon and the other could be nitrogen, or vice versa.

[0130] When any variable appears more than once in any part or chemical formula of a compound used in or claimed in the description and illustration of this invention, its definition for each occurrence is independent of its definition for each subsequent occurrence. Furthermore, combinations of substituents and / or variables are permitted only if the resulting compound is a stable compound.

[0131] The symbol “*” at the end of a bond, or the line or “~~~~” that passes through a bond, respectively indicates the connection point between a functional group or other chemical part and the rest of the molecule to which it belongs.

[0132] A bond drawn into a ring system (as opposed to a bond attached to a specific vertex) indicates that the bond can be attached to any suitable ring atom.

[0133] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may occur but does not have to occur, and the description includes instances where the event or situation occurs and instances where it does not occur. For example, “optionally substituted” means that the “optionally substituted” portion may contain hydrogen or substituents.

[0134] The phrase "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds. If a substituent is specified as "bonded" or "not present," the atom attached to the substituent is directly connected.

[0135] The term "about" in this document means approximately, roughly, roughly, or about. When the term "about" is used in conjunction with a numerical range, it modifies the range by expanding the upper and lower boundaries of the listed numerical value. Generally, the term "about" is used in this document to modify a value that fluctuates by 20%.

[0136] Some of the disclosed compounds exhibit tautomerism. Tautomers can exist in the form of two or more interconvertible substances. Proton transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers typically exist in equilibrium, and attempts to separate individual tautomers usually yield mixtures with chemical and physical properties consistent with those of the mixture of compounds. The position of equilibrium depends on the intramolecular chemical signature. For example, in many aliphatic aldehydes and ketones (such as acetaldehyde), the ketone form is dominant; while in phenols, the enol form is dominant. Common proton transfer tautomers include ketone / enol (-C(=O)-CH- -C(-OH)=CH-), amide / imino acid (-C(=O)-NH-) -C(-OH)=N-) and amidine (-C(=NR)-NH-) -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic compounds, and this invention covers all tautomer forms of the compounds.

[0137] Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Various methods and substances known to those skilled in the art are mentioned herein. Standard references explaining the general principles of pharmacology include Goodman and Gilman's works. The Pharmacological Basis of Therapeutics 10th Edition, McGraw Hill Companies Inc., New York (2001). Any suitable substances and / or methods known to those skilled in the art can be used to carry out this invention. However, preferred substances and methods are described herein. Unless otherwise stated, the substances, reagents, etc. mentioned in the following description and examples are available from commercial sources.

[0138] The definitions described herein can be appended to form chemically related combinations, such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclic,” “alkylcarbonyl,” “alkoxyalkyl,” etc. When the term “alkyl” is used as a suffix following another term, such as in “phenylalkyl” or “hydroxyalkyl,” this is intended to refer to an alkyl group as defined above that is substituted with one or two substituents selected from other specifically named groups. Thus, for example, “phenylalkyl” refers to an alkyl group having one or two phenyl substituents, and therefore includes benzyl, phenethyl, and biphenyl. “alkylaminoalkyl” is an alkyl group having one or two alkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, etc. Therefore, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups as defined below. The term -(aryl)alkyl refers to an unsubstituted alkyl or arylalkyl group. The term "(hetero)aryl" refers to aryl or heteroaryl.

[0139] As used herein, the term "acyl" denotes a group of the formula -C(=O)R, where R is hydrogen or a lower alkyl group as defined herein. The term "alkylcarbonyl" as used herein denotes a group of the formula C(=O)R, where R is an alkyl group as defined herein. The term C... 1-6 An acyl group is a group -C(=O)R containing 6 carbon atoms. As used herein, the term "aryl carbonyl" refers to a group of the formula C(=O)R, where R is an aryl group; and the term "benzoyl" refers to an aryl carbonyl group, where R is a phenyl group.

[0140] As used herein, the term "alkyl" refers to a non-branched or branched saturated monovalent hydrocarbon residue containing 1 to 12 carbon atoms. As used herein, the terms "lower alkyl" or "C1-C6 alkyl" refer to straight-chain or branched hydrocarbon residues containing 1 to 6 carbon atoms. 12 "Alkyl" means an alkyl group consisting of 1 to 12 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

[0141] When the term "alkyl" is used as a suffix following another term, such as in "phenylalkyl" or "hydroxyalkyl," it is intended to refer to an alkyl group as defined above, substituted with one or two substituents selected from other specifically named groups. Thus, for example, "phenylalkyl" indicates the group R'R"-, where R' is phenyl and R" is an alkylene group as defined herein, and it should be understood that the phenylalkyl moiety will be connected at the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, and 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly, except that R' is aryl. The terms "(hetero)arylalkyl" or "(hetero)arylalkyl" are interpreted similarly, except that R' is optionally aryl or heteroaryl.

[0142] When listing a range of values, it is intended to cover every value within that range and its subranges. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0143] "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 15 carbon atoms (“C15”). 1-15 Alkyl group). In some embodiments, the alkyl group has 1 to 14 carbon atoms (“C14”). 1-14 Alkyl group). In some embodiments, the alkyl group has 1 to 13 carbon atoms (“C13”). 1-13 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 11 carbon atoms (“C1”). 1-11 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc.

[0144] "Alkenyl" or "olefin" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds ("C"). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octtrienyl (C8).

[0145] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group ("alkynyl group"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("alkynyl group"). C2-4 The alkynyl group ("alkynyl group"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("alkynyl group"). C2-3 The alkynyl group (“C2-alkynyl”) is used in some embodiments. The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0146] The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refer to straight-chain or branched hydrocarbon residues containing 1 to 6 carbon atoms, wherein one or more carbon atoms are replaced by one or more halogen atoms.

[0147] Unless otherwise stated, the terms "alkylene" or "alkanediol" as used herein refer to a divalent saturated straight-chain hydrocarbon group of 1 to 10 carbon atoms (e.g., (CH2)). n ) or branched saturated divalent hydrocarbon groups of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH). i-Pr)CH2-). Except for the case of methylene, the free valences of alkylene groups are not attached to the same atom. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, and 2-ethylbutylene.

[0148] As used herein, the term "alkoxy" means -O-alkyl, where the alkyl group is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, including their isomers. As used herein, "lower alkoxy" refers to an alkoxy group having a "lower alkyl group" as previously defined. As used herein, "C1- 10 "Alkoxy" refers to -O-alkyl, where the alkyl group is C. 1-10 .

[0149] As used herein, the term "hydroxyalkyl" means an alkyl group as defined herein, in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxyl groups.

[0150] As used herein, the terms “alkylsulfonyl” and “arylsulfonyl” refer to a group of the formula -S(=O)2R, where R is either alkyl or aryl, and alkyl and aryl are as defined herein. As used herein, the term “heteroalkylsulfonyl” denotes a group of the formula -S(=O)2R, where R is a “heteroalkyl” as defined herein.

[0151] As used herein, the terms "alkylsulfonylamino" and "arylsulfonylamino" refer to groups of the formula -NR'S(=O)2R, where R is either alkyl or aryl, and R' is hydrogen or C. 1-3 Alkyl groups, and alkyl and aryl groups as defined herein.

[0152] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, namely cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. As used herein, "C 3-7 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 7 carbons in its carbon ring.

[0153] As used herein, the term carboxyl-alkyl refers to an alkyl moiety in which one hydrogen atom has been replaced by a carboxyl group. It is important to understand that heteroalkyl groups are connected via carbon atoms. The term "carboxy" refers to the –CO2H moiety.

[0154] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a monocyclic or bicyclic group having 5 to 12 ring atoms having at least one aromatic ring, each ring containing four to eight atoms, incorporating one or more N, O, or S heteroatoms, with the remaining ring atoms being carbon. It should be understood that the heteroaryl group's linkage will be on the aromatic ring. As is well known to those skilled in the art, the aromatic properties of heteroaryl rings are weaker than their all-carbon counterparts. Therefore, for the purposes of this invention, heteroaryl groups only need to possess a certain degree of aromaticity. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including but not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyrroleyl, pyrazolyl, imidazolyl, oxazole, isoxazole, thiazole, isothiazole, triazoline, thiadiazole, and oxadiazoline, which may optionally be substituted by one or more, preferably one or two, substituents selected from hydroxyl, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, benzoxazole, benzoisoxazole, benzothiazole, and benzoisothiazole. The bicyclic moieties may optionally be substituted on either ring; however, the bonding point is on the ring containing the heteroatom.

[0155] Unless otherwise stated, as used herein, the terms “heterocyclic group,” “heterocyclic alkyl group,” or “heterocyclic” refer to a monovalent saturated cyclic group consisting of one or more rings, preferably one or two rings, including spirocyclic systems with three to eight atoms per ring, incorporating one or more cyclic heteroatoms (selected from N, O, or S(O)). 0-2 It may optionally be independently substituted by one or more, preferably one or two, substituents selected from hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, and arylcarbonylamino. Examples of heterocyclic groups include, but are not limited to, aziridine, pyrrolidinyl, hexahydroaziridine, oxadiazinyl, tetrahydrofuranyl, tetrahydrophenylthio, oxazolidinyl, thiazolyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quininecycloyl, and imidazolinyl.

[0156] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 14-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence state allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused ring, bridged ring, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and can be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic systems may include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring, or a ring system in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members still refers to the number of ring members in the heterocyclic ring system.

[0157] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0158] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxetane, and thiopyrane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridanebutane, oxetanebutane, and thiopyranebutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopentyl, oxothiopentanyl, and dithiopentanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiadialkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphridyl, decahydro-1,8-naphridyl, octahydropyrrolo[3,2-b]pyrrole, indololinyl, phthalimide, naphthalimide, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyranolo[3,4-b]pyrrole, 5, 6-Dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-Dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-Dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-Dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-Dihydrofurano[2,3-b]pyridyl, 4,5,6,7-Tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-Tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-Tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-Tetrahydro-1,6-naphthidyl, etc.

[0159] "Aryl" refers to a monocyclic or polycyclic aromatic ring (e.g., bicyclic or tricyclic) group having 6-14 ring carbon atoms and no heteroatoms in the aromatic ring system (e.g., a 4n+2 aromatic ring system in which 6, 10, or 14 π electrons are enjoyed in a ring array). 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl (α-naphthyl) and 2-naphthyl (β-naphthyl)). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system.

[0160] "Heteroaryl" refers to a 5-14 member monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., a ring array with 6, 10, or 14 π electrons) having a ring carbon atom and providing 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence state allows. Heteroaryl polycyclic systems may include one or more heteroatoms in one or two rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the ring membership number still refers to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, wherein the linking point is on the aryl or heteroaryl ring, and in such cases, the ring membership number still refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl rings (e.g., indolyl, quinolinyl, carbazolyl, etc.) where one ring does not contain a heteroatom, the linking point can be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0161] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0162] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and phenylthioyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aziryl, oxazinyl, and thioazinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzobenzylthio, isobenzobenzylthio, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridine, dibenzofuranyl, carbazole, acridineyl, phenothiazinyl, phenotoxazinyl, and phenothiazinyl.

[0163] "Saturation" refers to a ring portion that does not contain double or triple bonds, meaning that the ring contains only single bonds.

[0164] Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted. Optional substitution refers to groups that can be substituted or are not substituted. Generally, the term "substituted" means that at least one hydrogen atom present on the group is replaced by a non-hydrogen substituent, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo transformations such as through rearrangement, cyclization, elimination, or other reactions. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents that satisfy the heteroatom's valence state and lead to the formation of a stable compound.

[0165] As used herein, an exemplary non-hydrogen substituent where a portion is "optionally substituted" means that the portion may be substituted by any other portion selected from, but not limited to, the following: halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR aa –N(R) bb 2. –N(OR) cc )R bb –SH, –SR aa –C(=O)R aa –CO2H, –CHO, –CO2R aa –OC(=O)R aa –OCO2R aa –C(=O)N(R) bb )2、–OC(=O)N(R bb )2、–NR bb C(=O)R aa –NR bb CO2R aa –NR bb C(=O)N(R bb )2、–C(=NR bb )R aa –C(=NR) bb OR aa –OC(=NR) bb )R aa –OC(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–OC(=NR bb )N(R bb )2、–NR bb C(=NR bb )N(R bb )2、–C(=O)NR bb SO2R aa –NR bb SO2R aa –SO2N(R) bb)2、–SO2R aa –S(=O)R aa –OS(=O)R aa -B(OR) cc 2. C 1–10 Alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 Aryl and 5 to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, or the replacement of two hydrogen atoms on a carbon atom by the =O group; each R that appears aa Selected independently from C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; each R that appears bb Independently selected from hydrogen, –OH, –OR aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –SO2N(R) cc )2、–SOR aa C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; each R that appears cc Independently selected from hydrogen and C 1–10 Alkyl, C1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; and each R that appears dd Independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(OC) 1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C 1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl group, –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6 Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)(C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC(=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups), –OC(NH)NH2, –NHC(NH)N(C 1–6Alkyl)2, –NHC(=NH)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –SO2NH2, –SO2C 1–6 Alkyl group, -B(OH)2, -B(OC) 1–6 Alkyl)2, C 1–6 Alkyl, C 1–6 All-halogenated alkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 aryl, 3- to 10-membered heterocyclic and 5- to 10-membered heteroaryl; or two geminal R groups on a carbon atom. dd Substituents can connect to form =O.

[0166] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0167] As used herein, the term "composition" is intended to cover products that contain the specified ingredients and any products produced directly or indirectly from combinations of the specified ingredients.

[0168] “Salt” includes any and all salts. “Pharmaceutically acceptable salts” are those salts that, within reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in… J. Pharmaceutical SciencesPharmaceutically acceptable salts are described in detail in (1977) 66:1–19. Pharmaceutically acceptable salts include salts derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed by amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods employed in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and nitrogen salts. + (C 1–4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed, where appropriate, with the use of counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0169] Unless otherwise stated, the compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC). The compounds described herein may be in the form of individual isomers substantially free of other isomers, or in mixtures of various isomers.

[0170] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the invention but with hydrogen replaced by deuterium or tritium... 19 F was18 F replacement, carbon bedding 13 C- or 14 C-enrichment carbon substitution and / or oxygen atoms being... 18 O-substituted compounds are within the scope of this disclosure. Other examples of isotopes include... 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I. Compounds with such isotopically enriched atoms can be used as analytical tools or probes, for example, in bioassays.

[0171] Some isotope-labeled compounds (e.g., with) 3 H and 14 C-labeled compounds can be used for the determination of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0172] Certain isotope-labeled compounds of formula (I) can be used for medical imaging purposes, such as positron-emitting isotopes. 11 C or 18 F-labeled compounds can be used in positron emission tomography (PET) applications and to emit isotopes using gamma rays, such as... 123 I-labeled compounds can be used in single-photon emission computed tomography (SPECT) applications. Furthermore, heavier isotopes such as deuterium (i.e.,...) can be used... 2 H) substitution can offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. Furthermore, the use of heavier isotopes such as deuterium (i.e., 2 H) substitution can offer certain therapeutic advantages due to increased metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. Additionally, isotopic substitution at the site of epimerization can slow down or weaken the epimerization process, thereby maintaining the more active or more potent form of the compound for a longer period. Isotopically labeled compounds of formula (I), particularly those containing a longer half-life (t), can generally be prepared by replacing the non-isotopically labeled reagent with a suitable isotopically labeled reagent according to a procedure similar to that disclosed in the schemes and / or examples herein. 1 / 2 Compounds of isotopes with a concentration greater than 1 day.

[0173] Example abbreviation Commonly used abbreviations include: acetyl (Ac), azo... pair Isobutyronitrile (AIBN), atmospheric pressure (Atm), 9-boronbicyclo[3.3.1]nonane (9-BBN or BBN), tert-butyloxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Service Registry Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DAB) CO), diethylaminosulfur trifluoride (DAST), dibenzylacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarbonate (DEAD), di(2,3-dichloroethane) different propyl acetate (DIAD), dipropyl acetate different Butyl aluminum hydride (DIBAL or DIBAL-H), 1,3-diisopropylcarbodiimide (DIC), diisopropylethylamine (DIPEA), N,N-dimethylacetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1'- pair -(diphenylphosphine)ethane (dppe), 1,1'- pair 1-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2 H 1-Quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylureon hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high-performance liquid chromatography (HPLC) different Propanol (IPA), lithium hexamethyldisilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (methanesulfonyl or Ms), methyl (Me), acetonitrile (MeCN) betweenChloroperoxybenzoic acid (MCPBA), mass spectrometry (ms), methyl tert-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxylic anhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr) different propyl ( i -Pr), psi, pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t -BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO), trifluoromethanesulfonate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'- pair -2,2,6,6-Tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethylureon tetrafluoroborate (TBTU), thin-layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS) right Toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or toluenesulfonyl (Ts), N-urethane-N-carboxylic anhydride (UNCA). (Including prefixes) just ( n ), different ( i- ), Zhong ( sec- Uncle tert- ) and new ( neo Conventional nomenclature, including ), has its usual meaning when used with alkyl moieties. (J. Rigaudy and DP Klesney, Nomenclature in Organic Chemistry IUPAC 1979 Pergamon Press, Oxford.).

[0174] General considerations The compounds of the present invention can be prepared by a variety of methods depicted in the exemplary synthetic reactions described below in the Examples section.

[0175] General information. Pd(OAc) 2 购自Strem。溶剂从Sigma-Aldrich、Alfa-AeserAcros and other reagents are obtained and used directly without further purification. Unless otherwise specified, other reagents are purchased at the highest commercial quality and used without further purification. Analytical thin-layer chromatography is performed on 0.25 mm silica gel 60F254 or Merck pre-coated aluminum-backed silica gel F254 plates. 1 1H NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 instruments. The following abbreviations (or combinations thereof) are used to interpret multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. Coupling constant. J Report in Hertz (Hz). 13 C NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 and fully decoupled by broadband proton decoupling. 19 F{ 1 ¹H NMR spectra were recorded on a Bruker AMX-400. Chemical shifts were referenced to appropriate residual solvent peaks. Column chromatography was performed using E. Merck silica gel (60, particle size 0.043–0.063 mm), and pTLC was performed on Merck silica gel plates (60F254). High-resolution mass spectrometry (HRMS) was recorded on an Agilent mass spectrometer using ESI-TOF (electrospray ionization-time-of-flight).

[0176] Experimental section for lactamation and cyclic amination reactions Preparation of ligands Ligands L1, L3, L6, L8, and L17 have been reported elsewhere. 1–4 Ligand L5 is commercially available. Ligands L2, L4, L6-L8, and L10-L18 were synthesized according to the general procedure described below. Ligand L9 was prepared using a different method, and its synthesis will be described immediately following the general procedure for the other ligands.

[0177] Figure S11. Molecular structures of the ligands (L1-L18) reported in this disclosure.

[0178] General procedure for synthesizing ligands L2, L4, L6-L8, and L10-L18: Figure S12. General procedure for synthesizing ligands L2, L4, L6-L8 and L10-L18.

[0179] Synthesis of S2: Adopting the improved procedures reported by Wang and his collaborators. 1 A stirred mixture of 2,6-dibromopyridine 23 (11.7 g, 50 mmol, 1.0 equivalent), 4-methoxybenzyl alcohol (14.7 g, 50 mmol, 1.0 equivalent), potassium hydroxide (3.37 g, 60 mmol, 1.2 equivalent), 18-crown-6 (1.32 g, 5 mmol, 0.1 equivalent), and toluene (200 mL) was heated under reflux for 12 hours. The cooled solution was evaporated under vacuum, and then 200 mL of DCM was added. The organic layer was washed twice with brine and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and purified by rapid column chromatography (5% EA / hexane to 10% EA / hexane) to give the desired compound S2 in 90% yield (13.2 g, 45 mmol), which was a viscous liquid that solidified into a white solid upon standing.

[0180] S3 Synthesis: Adopting the improved procedures reported by Wang and his collaborators. 1 Add 2-bromo-6-((4-methoxybenzyl)oxy)pyridine S2 (14.6 g, 50 mmol, 1.0 equivalent) to a solution of THF (200 mL) n -BuLi (22 mL, 55 mmol, 1.1 equivalents) was added, and the mixture was stirred at -78 °C for 30 min under a nitrogen atmosphere. Then, the following was added: n -Bu3SnCl (19.5 g, 60 mmol, 1.2 equivalents) was added, and the mixture was stirred at the same temperature for another 2 h. A saturated ammonium chloride solution (150 mL) was added to the solution and extracted with ethyl acetate (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude S3 was used as is in the next step without further purification (it was found that S3 decomposed on silica gel).

[0181] Synthesis of ligands L2, L4, L6-L8 and L10-L18: Adopting the improved procedures reported by Wang and his collaborators. 1A mixture of crude 2-((4-methoxybenzyl)oxy)-6-(tributyltinyl)pyridine 25 (assumed to be 10 mmol), various 2-halopyridines / quinolines (10 mmol), and tetra(triphenylphosphine)-palladium(0) (1.15 g, 1.0 mmol) in 20 mL toluene was refluxed under nitrogen for 48 h. The resulting brown mixture was evaporated under vacuum, and the dark mixture was purified by rapid chromatography (hexane / EA) to give the corresponding quinoline-pyridine / bipyridine compound S4 of moderate purity. The corresponding quinoline-pyridine / bipyridine compound S4 was dissolved in DCM, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h, then 10 mL of saturated NaHCO3 was added and stirred overnight. The mixture was then extracted with CHCl3 (30 mL x 3), and the organic layers were combined and concentrated under vacuum. The crude product was purified by rapid chromatography (DCM:methanol = 20:1, then 10:1) and the desired compounds L2, L4, L6-L8 and L10-L18 were given as white or pale yellow solids in two steps by S4 with an average yield of 40% (about 4 mmol).

[0182] Note: For DMSO- d 6 ligands 13 C NMR spectra tend to exhibit several very broad resonances, sometimes invisible. For ligands in CDCl3... 13 C NMR spectra, all expected 13 Both C NMR resonances are visible.

[0183] 6'-Fluoro-[2,2'-Bipyridine]-6(1 H )-Ketone (L2): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.36 – 8.03 (m, 2H), 7.67(dd, J = 8.7, 7.2 Hz, 1H), 7.34 (s, 1H), 7.25 (dd, J = 7.9, 2.3 Hz, 1H), 6.60 (d, J = 8.7 Hz, 1H).

[0184] 13 C NMR (151 MHz, DMSO- d6) δ 162.8, 162.4 (d, J = 237.2 Hz), 143.4 (d, J =7.7 Hz), 140.6, 118.3, 110.1 (d, J = 37.0 Hz). (Due to wide resonance, 4 expected...) 13 C resonance is invisible.

[0185] 1 H NMR (600 MHz, CDCl3) δ 7.93 (q, J = 7.8 Hz, 1H), 7.71 (dd, J = 7.6, 2.3Hz, 1H), 7.48 (dd, J = 9.2, 6.9 Hz, 1H), 7.00 (dd, J = 8.2, 2.8 Hz, 1H), 6.83(dd, J = 6.9, 0.9 Hz, 1H), 6.66 (dd, J = 9.2, 0.9 Hz, 1H).

[0186] 13 C NMR (151 MHz, CDCl3) δ 163.2 (d, J = 244.5 Hz), 162.8, 147.3 (d, J =12.1 Hz), 142.6 (d, J = 7.7 Hz), 140.6, 140.5, 123.0 (d, J = 5.0 Hz), 117.1 (d, J =7.7 Hz), 110.8 (d, J = 36.0 Hz), 103.9. (All expected resonances are visible).

[0187] 19 F{ 1 H} NMR (376 MHz, DMSO- d 6) δ -67.0, -73.4. (The ratio of the integrals is 18:1).

[0188] HRMS (ESI-TOF) m / z : Regarding C 10 H8FN2O + [M+H] +Calculated value: 191.0621, measured value: 191.0617.

[0189] 6'-Bromo-[2,2'-Bipyridine]-6(1 H )-Ketone (L4): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO- d 6) δ 11.10 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.7, 7.1 Hz, 1H),7.34 (s, 1H), 6.60 (d, J = 8.7 Hz, 1H).

[0190] 13 C NMR (151 MHz, DMSO- d 6) δ 162.7, 153.1, 141.0, 140.7, 140.6, 128.5, 119.9. (Due to wide resonance, 3 expected values...) 13 C resonance is invisible.

[0191] 1 H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 7.77 (dd, J = 7.8, 0.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.52 (dd, J = 7.8, 0.8 Hz, 1H), 7.48 (dd, J = 9.2, 6.9Hz, 1H), 6.79 (dd, J = 6.9, 0.9 Hz, 1H), 6.65 (dd, J = 9.2, 0.9 Hz, 1H).

[0192] 13C NMR (100 MHz, CDCl3) δ 162.8, 149.1, 142.1, 140.6, 140.4, 139.7, 129.1, 123.1, 118.6, 103.7. (All expected resonances were visible).

[0193] HRMS (ESI-TOF) m / z : Regarding C 10 H8 79 BrN2O + [M+H] + Calculated value: 250.9821, measured value: 250.9815.

[0194] 6'-Methoxy-[2,2'-Bipyridine]-6(1 H )-Ketone (L6): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO- d 6) δ 11.08 (s, 1H), 7.84 (dd, J = 8.3, 7.4 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.60 (dd, J = 8.9, 7.0 Hz, 1H), 7.16 (s, 1H), 7.04– 6.81 (m, 1H), 6.48 (d, J = 8.9 Hz, 1H), 3.99 (s, 3H).

[0195] 13 C NMR (151 MHz, DMSO- d 6) δ 163.1, 162.4, 140.8, 140.3, 113.7, 111.7, 53.3. (Due to wide resonance, 4 expected values...) 13 C resonance is invisible.

[0196] 1 H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 7.69 (dd, J = 8.3, 7.5 Hz, 1H), 7.48 (dd, J= 9.2, 7.0 Hz, 1H), 7.42 (dd, J = 7.6, 0.7 Hz, 1H), 6.82 (dd, J = 8.2, 0.7 Hz, 1H), 6.79 (dd, J = 7.0, 0.9 Hz, 1H), 6.62 (dd, J = 9.2, 0.9 Hz, 1H), 4.02(s, 3H).

[0197] 13 C NMR (100 MHz, CDCl3) δ 163.9, 163.0, 145.6, 141.9, 140.9, 139.9, 121.7, 112.9, 112.9, 103.1, 54.0. (All expected resonances were visible.) HRMS (ESI-TOF) m / z : Regarding C 11 H 11 N2O2 + [M+H] + Calculated value: 203.0821, measured value: 203.0807.

[0198] 6'-(trifluoromethyl)-[2,2'-bipyridine]-6(1 H )-Ketone (L7): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO- d 6) δ 11.14 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.25 (t, J = 7.9 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.72 (dd, J = 8.6, 7.2 Hz, 1H),7.49 (s, 1H), 6.66 (d, J = 8.6 Hz, 1H).

[0199] 13 C NMR (151 MHz, DMSO- d 6) δ 162.9, 146.2 (q,J = 34.3 Hz), 140.7,140.0, 123.9, 121.8 (q, J = 274.5 Hz), 120.9. (Due to wide resonance, 4 expected...) 13 C resonance is invisible.

[0200] 1 H NMR (400 MHz, CDCl3) δ 8.12 – 7.94 (m, 2H), 7.74 (dd, J = 6.4, 2.1Hz, 1H), 7.51 (dd, J = 9.2, 6.9 Hz, 1H), 6.88 (dd, J = 6.9, 0.9 Hz, 1H), 6.70(dd, J = 9.2, 0.9 Hz, 1H).

[0201] 13 C NMR (100 MHz, CDCl3) δ 162.8, 148.8, 148.16 (q, J = 35.3 Hz), 140.5,140.3, 139.3, 123.6, 122.4, 121.18 (q, J = 2.6 Hz), 104.2. (One expected resonance is invisible.) Resonance in 19 F{ 1 H} NMR (376 MHz, DMSO- d 6) Not visible above.

[0202] HRMS (ESI-TOF) m / z : Regarding C 11 H8F3N2O + [M+H] + Calculated value: 241.0589, measured value: 241.0590.

[0203] 6'-Methyl-[2,2'-bipyridine]-6(1 H )-Ketone (L8): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO- d6) δ 10.95 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.59 (dd, J = 9.0, 7.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.0 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 2.55 (s, 3H).

[0204] 13 C NMR (151 MHz, DMSO- d 6) δ 162.1, 157.8, 148.5, 140.9, 137.9, 124.1, 119.0, 117.6, 104.7, 24.0. (Due to wide resonance, one expected...) 13 C resonance is invisible.

[0205] 1 H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.47 (dd, J = 9.2, 6.9 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.78 (dd, J = 6.9, 0.9 Hz, 1H), 6.61 (dd, J = 9.2, 0.9 Hz, 1H), 2.57 (s, 3H).

[0206] 13 C NMR (100 MHz, CDCl3) δ 163.0, 158.6, 147.0, 142.0, 140.8, 137.7, 124.4, 121.9, 116.8, 102.7, 24.4. (All expected resonances are visible).

[0207] HRMS (ESI-TOF) m / z : Regarding C 11 H 11 N2O+ [M+H] + Calculated value: 187.0872, measured value: 187.0867.

[0208] 6'-Chloro-4'-(trifluoromethyl)-[2,2'-bipyridine]-6(1 H )-Ketone (L10): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO- d 6) δ 11.21 (s, 1H), 8.49 (d, J = 1.4 Hz, 1H),8.07 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.63 (s, 1H), 6.74 (d, J = 8.5 Hz, 1H).

[0209] 13 C NMR (151 MHz, DMSO- d 6) δ 163.2, 151.2, 140.76 (q, J = 33.9 Hz), 140.6, 123.08 (q, J = 273.7 Hz), 121.3, 115.2. (Due to the wide resonance, 4 expected...) 13 C resonance is invisible.

[0210] 19 F{ 1 H} NMR (376 MHz, DMSO- d 6) δ -63.2.

[0211] 1 H NMR (600 MHz, CDCl3) δ 7.92 (s, 1H), 7.60 (s, 1H), 7.53 (dd, J = 9.2, 6.9 Hz, 1H), 6.91 (dd, J = 6.9, 0.9 Hz, 1H), 6.74 (dd, J = 9.2, 0.9 Hz, 1H).

[0212] 13C NMR (151 MHz, CDCl3) δ 162.5, 152.8, 150.3, 142.7 (q, J = 34.7 Hz),140.4, 139.5, 124.3, 121.9 (q, J = 274.0 Hz), 121.2 (q, J = 4.0 Hz), 114.3 (q, J =3.4 Hz), 104.9. (All expected resonances are visible).

[0213] HRMS (ESI-TOF) m / z : Regarding C 11 H7 35 ClF3N2O + [M+H] + Calculated value: 275.0200, measured value: 275.0188.

[0214] methyl 6-chloro-6'-oxo-1',6'-dihydro-[2,2'-bipyridine]-4-carboxylate (L11): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, CDCl3) δ 8.27 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 1.0 Hz, 1H), 7.51 (dd, J = 9.2, 6.9 Hz, 1H), 6.93 (dd, J = 7.0, 0.9 Hz, 1H), 6.70 (dd, J =9.2, 0.9 Hz, 1H), 4.01 (s, 3H).

[0215] 13 C NMR (151 MHz, CDCl3) δ 163.8, 162.6, 152.5, 149.7, 141.8, 140.6, 140.0, 124.7, 123.7, 117.9, 104.6, 53.6. (All expected values) 13 C resonances are all visible.

[0216] HRMS (ESI-TOF) m / z : Regarding C12 H 10 35 ClN2O3 + [M+H] + Calculated value: 265.0380, measured value: 265.0380.

[0217] 5',6'-Dichloro-[2,2'-Bipyridine]-6(1 H )-Ketone (L12): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 9.2, 6.9 Hz, 1H), 6.81 (d, J = 6.9 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H).

[0218] 13 C NMR (151 MHz, CDCl3) δ 162.7, 149.4, 146.5, 140.7, 140.1, 139.9, 131.8, 123.2, 119.1, 104.3. (All expected values) 13 C resonances are all visible.

[0219] HRMS (ESI-TOF) m / z : Regarding C 10 H7 35 Cl2N2O + [M+H] + Calculated value: 240.9936, measured value: 240.9940.

[0220] 4',6'-Dichloro-[2,2'-Bipyridine]-6(1 H )-Ketone (L13): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, CDCl3) δ 7.73 (d, J= 0.8 Hz, 1H), 7.49 (dd, J = 9.1, 6.8Hz, 1H), 7.40 (d, J = 0.7 Hz, 1H), 6.81 (d, J = 6.9 Hz, 0H), 6.70 (d, J = 9.2 Hz, 1H).

[0221] 13 C NMR (151 MHz, CDCl3) δ 162.6, 152.3, 149.7, 147.3, 140.5, 139.7, 125.0, 123.7, 119.0, 104.5. (All expected values) 13 C resonances are all visible.

[0222] HRMS (ESI-TOF) m / z : Regarding C 10 H7 35 Cl2N2O + [M+H] + Calculated value: 240.9936, measured value: 240.9944.

[0223] 6'-Chloro-4'-methyl-[2,2'-bipyridine]-6(1 H )-Ketone (L14): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, DMSO) δ 11.04 (s, 1H), 8.02 (t, J = 1.0 Hz, 1H), 7.66(dd, J = 8.7, 7.1 Hz, 1H), 7.44 (t, J = 1.0 Hz, 1H), 7.32 (s, 1H), 6.58 (d, J = 8.7Hz, 1H), 2.40 (s, 3H).

[0224] 13 C NMR (151 MHz, DMSO) δ 162.7, 152.4, 149.9, 140.6, 125.0, 120.6, 20.4. (Due to the wide resonance, 4 expected values ​​are present.) 13 C resonance is invisible.

[0225] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 1.0 Hz, 0H), 7.48 (dd, J = 9.2, 6.9Hz, 0H), 7.20 (d, J = 1.0 Hz, 0H), 6.78 (dd, J = 7.0, 0.9 Hz, 0H), 6.65 (dd, J =9.3, 0.9 Hz, 0H), 2.43 (d, J = 0.6 Hz, 1H).

[0226] 13 C NMR (100 MHz, CDCl3) δ 162.8, 152.0, 151.6, 148.4, 140.7, 140.6, 125.9, 122.9, 119.3, 103.4, 21.2. (All expected resonances were visible).

[0227] HRMS (ESI-TOF) m / z : Regarding C 11 H 10 35 ClN2O + [M+H] + Calculated value: 221.0482, measured value: 221.0478.

[0228] 4'-(tert-butyl)-6'-chloro-[2,2'-bipyridine]-6(1 H )-Ketone (L15): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 1.4 Hz, 1H), 7.49 (dd, J = 9.2, 6.9Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 6.84 (d, J = 6.9 Hz, 1H), 6.65 (d, J = 9.2 Hz, 1H), 1.36 (s, 9H).

[0229] 13 C NMR (151 MHz, CDCl3) δ 165.3, 162.9, 151.8, 148.5, 141.2, 140.6, 122.6, 122.5, 115.6, 103.6, 35.6, 30.6. (All expected values) 13 C resonances are all visible.

[0230] HRMS (ESI-TOF) m / z : Regarding C 14 H 16 35 ClN2O + [M+H] + Calculated value: 263.0952, measured value: 263.0955.

[0231] 6'-Chloro-4'-methoxy-[2,2'-bipyridine]-6(1 H )-Ketone (L16): Structure of 2-halopyridine coupling coupler: 1 H NMR (600 MHz, CDCl3) δ 7.57 – 7.38 (m, 1H), 7.24 (d, J = 1.9 Hz, 1H), 6.87 (d, J = 1.9 Hz, 1H), 6.77 (dd, J = 7.0, 0.9 Hz, 1H), 6.64 (dd, J = 9.2, 0.9Hz, 1H), 3.93 (s, 3H).

[0232] 13 C NMR (151 MHz, CDCl3) δ 168.5, 162.8, 152.7, 149.4, 140.8, 140.6, 122.8, 110.1, 106.1, 103.6, 56.3. (All expected values) 13 C resonances are all visible.

[0233] HRMS (ESI-TOF) m / z : Regarding C 11 H 10 35 ClN2O2 + [M+H]+ Calculated value: 237.0431, measured value: 237.0430.

[0234] 6-(4-chloroquinoline-2-yl)pyridine-2(1 H )-Ketone (L18): Structure of 2-haloquinoline coupling coupler: 1 H NMR (600 MHz, CDCl3) δ 8.24 (dt, J = 8.5, 1.0 Hz, 1H), 8.12 (dt, J =8.3, 0.9 Hz, 1H), 7.95 (s, 1H), 7.85 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.71(ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.55 (dd, J = 9.2, 6.9 Hz, 1H), 6.93 (dd, J = 6.9, 0.9 Hz, 1H), 6.73 (dd, J = 9.2, 0.9 Hz, 1H).

[0235] 13 C NMR (151 MHz, CDCl3) δ 162.9, 147.9, 147.3, 144.4, 140.9, 140.7, 131.8, 130.1, 129.0, 126.5, 124.3, 123.5, 117.1, 104.8. (All expected values) 13 C resonances are all visible.

[0236] HRMS (ESI-TOF) m / z : Regarding C 14 H 10 35 ClN2O + [M+H] + Calculated value: 257.0482, measured value: 257.0480.

[0237] L9 synthesis: Figure S13. Synthesis of ligand L9 from compounds S5 and S6.

[0238] Compound S5 was synthesized according to the procedure reported by Taffarel and collaborators. 5 The improved procedure reported by Wang and his collaborators was adopted. 1 Compounds S5 (250 mg, 1.46 mmol) and S6 (220 mg, 1.46 mmol) were mixed in EtOH (12 mL), and KOH (82 mg, 1.46 mmol) was added. The reaction mixture was heated to 90 °C and stirred overnight at this temperature. After cooling to room temperature, all volatiles were removed, and the crude product was redissolved in DCM and extracted three times with water. The organic layers were collected, dried over anhydrous MgSO4, and concentrated to give S7 of sufficient purity, which was used directly in the next step.

[0239] Sufficiently pure S7 was suspended in 6M HCl and heated to reflux with stirring overnight. After cooling to room temperature, the reaction mixture was neutralized to pH ~ 7 and extracted three times with EtOAc. The organic layer was collected, dried over anhydrous MgSO4, and concentrated to give crude L9. Crude L9 was purified by rapid column chromatography (EA:methanol = 20:1 to 10:1) to give pure L9 as a yellow solid (62% yield after two steps).

[0240] 6-(benzo[ g Quinoline-2-yl)pyridine-2(1 H )-Ketone (L9): 1 H NMR (600 MHz, DMSO- d 6) δ 11.11 (s, 1H), 8.83 (s, 1H), 8.76 – 8.61 (m, 2H), 8.25 (d, J = 8.9 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.66 – 7.55 (m, 2H), 7.49 (s, 1H), 6.63 (d, J =8.8 Hz, 1H).

[0241] 13 C NMR (151 MHz, DMSO- d6) δ 162.1, 143.0, 140.8, 138.1, 133.8, 131.8, 128.3, 128.2, 127.2, 126.9, 126.9, 126.7, 125.8, 117.5. (Due to wide resonance, 4 expected values...) 13 C resonance is invisible.

[0242] 1 H NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.66 (s, 1H), 8.41 (dd, J =9.0, 1.8 Hz, 2H), 8.12 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.81 (dd, J =8.9, 1.9 Hz, 1H), 7.66 – 7.43 (m, 3H), 6.99 (dd, J = 7.0, 1.8 Hz, 1H), 6.73(dd, J = 9.0, 1.8 Hz, 1H).

[0243] 13 C NMR (100 MHz, CDCl3) δ 163.0, 147.8, 143.3, 141.7, 140.6, 138.2, 134.7, 132.7, 128.8, 128.3, 128.0, 127.1, 127.0, 126.8, 126.0, 123.5, 116.1, 104.9. (All expected resonances were visible).

[0244] HRMS (ESI-TOF) m / z : Regarding C 18 H 13 N2O + [M+H] + Calculated value: 273.1028, measured value: 273.1023.

[0245] Optimization data for lactamation and cycloamination reactions Studies on ligand types and reaction conditions used in lactamation and cycloamination reactions:

[0246] Table S1. Ligand studies for lactamation reactions.

[0247] Based on the ligand survey in Table S1, ligand L14 was selected as the optimal ligand. Changes in other experimental parameters did not lead to a significant increase in the NMR yield of the lactamation reaction. However, in some cases, increasing the catalyst loading to 15 mol% Pd(OAc)₂ and 17 mol% ligand resulted in increased reaction yields. This was found to be uncommon, as not every substrate benefits from this increase in catalyst loading. Extending this strategy to another type of reaction (e.g., dicarboxylate lactoneation) did not result in any increase in reaction yield.

[0248] The reaction conditions for the γ-lactamization of compound 1 using ligand L14 are also applicable to the δ-lactamization of compound 2: Figure S14. Reaction conditions for the δ-lactamization of compound 2 Similarly, the same set of reaction conditions can be applied to the cycloamination reaction with compound 26: Figure S15. Reaction conditions for the cycloamination of compound 26.

[0249] For substrates that are found to be resistant to lactamation or cycloamination using ligand L14, as first observed in compound 6, ligand L18 is required to provide an improvement in reaction yield.

[0250] Figure S16. Effect of using ligand L18 on the lactamation of 6.

[0251] Reaction procedures for lactamation and cycloamination General procedures for lactamation and cycloamination reactions The illustrated guide to dicarboxylate lactoneation provided in previous publications also applies to this reaction, including gram-scale reactions. 6 Add the substrate (0.1 mmol), Pd(OAc)2 (10 mol%, 0.01 mmol or 15 mol%, 0.015 mmol), ligand (12 mol%, 0.012 mmol or 17 mol%, 0.017 mmol), 2,5-dimethyl-p-benzoquinone (0.2 mmol), Ag2CO3 (0.2 mmol), K2HPO4 (0.035 mmol), and CsOAc (0.04 mmol, preferably added from a stock solution of HFIP, as CsOAc is hygroscopic) to two vials. Then add HFIP (1.0 mL, or to the required volume of 1.0 mL if a stock solution of CsOAc is used) and a stir bar, and then seal the reaction vessel with a PTFE diaphragm inserted between the vial and its cap. (Note: Pd(OAc)2, the ligand, 2,5-dimethyl-p-benzoquinone, CsOAc, and the substrate can all be prepared as stock solutions for HFIP. It is recommended to use stock solutions to set up a series of reactions to maximize working efficiency.) The reaction mixture was sonicated for 30 seconds and then stirred at 200 rpm and 100 °C (heat block temperature) for 36 hours. The reaction mixture was then cooled to room temperature and diluted with dichloromethane (1.0 mL), followed by the addition of deionized water (2.0 mL), 6M HCl aqueous solution (0.3 mL), and brine (1.0 mL), and then shaken vigorously. The lower organic layer was carefully aspirated and filtered through a short Celite® stopper. The remaining aqueous layer was extracted twice with CH2Cl2 (1.0 mL), and the organic layer was aspirated and filtered as mentioned. The combined organic layers were then evaporated to dryness. The crude product was then dissolved in CDCl3 (0.6 mL) with CH2Br2 (10.0 µL) as an internal standard to pass through… 1 The yield of the reaction was determined by ¹H NMR spectroscopy. The product was separated by aqueous extraction of the organic layer (in 0.6 mL of CDCl3 diluted with 2.0 mL CH₂Cl₂) with saturated NaHCO₃ aqueous solution (1.0 mL each time, 3 times). The collected aqueous layer was then acidified to pH ~ 2 with 6M HCl aqueous solution and extracted with EtOAc (1.0 mL, 3 times). The combined EtOAc layers were dried over anhydrous MgSO₄, filtered, and evaporated to dryness. If purification of the free acid was not found to be direct, the product was further purified by pTLC (with the precise eluent composition mentioned below for each example) or further derivatized to methyl or benzyl esters for separation.

[0252] General procedure for benzyl ester formation At room temperature, anhydrous CH2Cl2 (2.0 mL), BnOH (1.2 equivalents), DMAP (1.2 equivalents), and EDCI (1.2 equivalents) were added sequentially to the product obtained after aqueous extraction with saturated NaHCO3 solution as mentioned above. The reaction mixture was stirred overnight at room temperature, and the completion of the reaction was confirmed by TLC analysis of the reaction mixture. The reaction mixture was then quenched with water and extracted with CH2Cl2 (3 times), and the desired product was purified by pTLC (with the precise eluent composition mentioned below for each example).

[0253] General procedure for methyl ester formation The product obtained after aqueous extraction with saturated NaHCO3 solution as mentioned above was redissolved in MeOH and then titrated with a solution of TMSCHN2 in hexane until effervescence ceased. The reaction mixture was stirred overnight at room temperature, and the completion of the reaction was confirmed by TLC analysis of the reaction mixture. All volatiles were removed under reduced pressure, and the desired product was then purified by pTLC (with the precise eluent composition mentioned below for each example).

[0254] Characterization data of the products obtained from the lactamation reaction 2-(5-oxo-1-toluenesulfonylpyrrolidine-2-yl)acetic acid 1a Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, the compound was subjected to pTLC (EA + 1% AcOH, R... f = 0.6) was purified in acid, with a separation yield of 61% (18.0 mg, 0.061 mmol, white solid).

[0255] 1 H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.70 (t, J = 9.2 Hz, 1H), 3.24 (dd, J = 16.7, 3.2 Hz, 1H), 2.77 (dd, J = 16.6,9.7 Hz, 1H), 2.64 – 2.52 (m, 1H), 2.44 (s, 3H), 2.41 – 2.26 (m, 2H), 1.95(dt, J= 14.4, 8.7 Hz, 1H).

[0256] 13 C NMR (151 MHz, CDCl3) δ 173.9, 173.4, 145.5, 135.6, 129.8, 128.5, 56.0, 38.9, 30.3, 24.6, 21.9.

[0257] HRMS (ESI-TOF): For C 13 H 14 NO5S - [MH] - Calculated value: 296.0593, measured value: 296.0586.

[0258] 2-(4,4-Dimethyl-5-oxo-1-toluenesulfonylpyrrolidine-2-yl)methyl acetate 7a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 40% (13.7 mg, 0.04 mmol, white solid).

[0259] 1 H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 4.52 (q, J = 8.9 Hz, 1H), 3.71 (s, 3H), 3.47 (dd, J = 16.4, 3.3 Hz, 1H), 2.62 (dd, J = 16.4, 9.0 Hz, 1H), 2.43 (s, 3H), 2.25 (dd, J = 13.4, 7.9 Hz, 1H), 1.68 (dd, J = 13.5, 6.6 Hz, 1H), 1.16 (s, 3H), 0.95 (s, 3H).

[0260] 13C NMR (151 MHz, CDCl3) δ 179.1, 170.9, 145.3, 135.3, 129.7, 128.4, 53.3, 52.0, 41.1, 41.0, 40.3, 25.2, 25.1, 21.8.

[0261] HRMS (ESI-TOF): For C 16 H 22 NO5S + [M+H] + Calculated value: 340.1219, measured value: 340.1230.

[0262] 2-(5-oxo-6-toluenesulfonyl-6-azaspiro[3.4]oct-7-yl)methyl acetate 8a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 40% (14.2 mg, 0.04 mmol, white solid).

[0263] 1 H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.55 (ddt, J = 10.4, 8.1, 3.3 Hz, 1H), 3.71 (s, 3H), 3.27 (dd, J = 16.0, 3.6Hz, 1H), 2.49 (dd, J = 16.0, 10.3 Hz, 1H), 2.43 (s, 3H), 2.42 – 2.36 (m, 1H), 2.32 (dd, J = 13.3, 8.1 Hz, 1H), 2.31 – 2.27 (m, 1H), 2.08 (dd, J = 13.5, 2.9 Hz,1H), 2.06 – 2.01 (m, 1H), 2.01 – 1.97 (m, 1H), 1.94 – 1.87 (m, 1H), 1.87 –1.80 (m, 1H).

[0264] 13 C NMR (151 MHz, CDCl3) δ 177.4, 170.8, 145.3, 135.7, 129.8, 128.4, 54.2, 52.1, 45.7, 40.2, 38.7, 32.6, 29.8, 21.8, 16.3.

[0265] HRMS (ESI-TOF): For [M+H] + Regarding C 17 H 22 NO5S + The calculated value is 352.1219, and the measured value is 352.1220.

[0266] 2-(1-oxo-2-toluenesulfonyl-2-azaspiro[4.4]non-3-yl)methyl acetate 9a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.35) was purified as methyl ester. The product was separated in two steps, yielding 54% (19.6 mg, 0.054 mmol, white solid).

[0267] 1 H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.55 (tt, J = 9.3, 4.2 Hz, 1H), 3.71 (s, 3H), 3.44 (dd, J = 16.2, 3.7 Hz, 1H), 2.61 (dd, J = 16.3, 9.9 Hz, 1H), 2.43 (s, 3H), 2.28 (dd, J = 13.4, 7.9 Hz, 1H), 1.98 (dt, J = 13.7, 7.5 Hz, 1H), 1.77 (dd, J= 13.2, 4.5 Hz, 1H), 1.74 –1.65 (m, 3H), 1.65 – 1.59 (m, 1H), 1.55 – 1.49 (m, 2H), 1.46 – 1.35 (m, 1H).

[0268] 13 C NMR (151 MHz, CDCl3) δ 179.3, 170.9, 145.3, 135.6, 129.7, 128.4, 54.0, 52.0, 51.0, 40.6, 40.1, 37.9, 37.9, 25.9, 25.5, 21.8.

[0269] HRMS (ESI-TOF): For C 18 H 24 NO5S + [M+H] + Calculated value: 366.1375, measured value: 366.1386.

[0270] 2-(1-oxo-2-toluenesulfonyl-8-oxa-2-azaspiro[4.5]dec-3-yl)methyl acetate 10a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (50% EA / hexane, R... f = 0.20) was purified as methyl ester. The product was separated in two steps, yielding 60% (23.0 mg, 0.06 mmol, white solid).

[0271] 1 H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.55 (dddd, J = 9.6, 8.2, 6.2, 3.6 Hz, 1H), 3.92 (dt, J = 11.9, 4.5 Hz, 1H), 3.79 (dt, J = 12.0, 4.5 Hz, 1H), 3.70 (s, 3H), 3.48 – 3.37 (m, 3H), 2.62 (dd, J=16.4, 9.3 Hz, 1H), 2.48 – 2.38 (m, 4H), 1.96 (ddd, J = 13.9, 9.8, 4.2 Hz, 1H),1.77 (dd, J = 13.5, 6.2 Hz, 1H), 1.63 (ddd, J = 13.7, 9.7, 4.9 Hz, 1H), 1.40 (dp, J = 13.4, 2.6 Hz, 1H), 1.22 (ddt, J = 13.6, 4.9, 2.6 Hz, 1H).

[0272] 13 C NMR (151 MHz, CDCl3) δ 177.2, 170.7, 145.5, 135.4, 129.8, 128.4, 63.7, 63.4, 53.3, 52.1, 42.7, 41.0, 36.9, 33.6, 33.1, 21.8.

[0273] HRMS (ESI-TOF): For C 18 H 24 NO6S + [M+H] + Calculated value: 382.1324, measured value: 382.1337.

[0274] 2-((2 R* ,3 S* 11a-3-methyl-5-oxo-1-toluenesulfonylpyrrolidine-2-yl)acetic acid Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, the compound was subjected to pTLC (75% EA / hexane + 1% AcOH R) f = 0.50) was purified in acid. The isolated product was 78% (24.4 mg, 0.078 mmol, light brown solid).

[0275] 1 H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 4.23 (dd, J= 10.0, 3.9 Hz, 1H), 3.20 (dd, J = 16.8, 3.3 Hz, 1H), 2.81 –2.76 (m, 1H), 2.76 – 2.71 (m, 1H), 2.44 (s, 3H), 2.26 (p, J = 8.2 Hz, 1H), 1.96(d, J = 17.7 Hz, 1H), 0.99 (d, J = 7.0 Hz, 3H).

[0276] 13 C NMR (151 MHz, CDCl3) δ 175.0, 172.8, 145.6, 135.3, 129.8, 128.4, 63.3, 38.9, 38.1, 32.2, 21.9, 20.6.

[0277] HRMS (ESI-TOF): For C 14 H 16 NO5S - [MH] - Calculated value: 310.0749, measured value: 310.0738.

[0278] 2-((2 R* ,3 R *)-3-(tert-butyl)-5-oxo-1-toluenesulfonylpyrrolidine-2-yl)acetic acid 12a Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, the compound was subjected to pTLC (50% EA / hexane + 1% AcOH R) f = 0.30) was purified in acid. The separation yield was 93% (33.0 mg, 0.093 mmol, pale yellow solid).

[0279] 1 H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 4.49 (dd, J = 8.2, 3.4 Hz, 1H), 3.10 – 2.83 (m, 2H), 2.73 (dd, J= 18.6, 9.7Hz, 1H), 2.42 (s, 3H), 2.28 (d, J = 18.5 Hz, 1H), 1.91 (d, J = 9.6 Hz, 1H), 0.77 (s, 9H).

[0280] 13 C NMR (151 MHz, CDCl3) δ 175.5, 173.8, 145.5, 135.6, 135.4, 129.7, 128.6, 57.8, 46.9, 40.4, 33.3, 33.2, 26.3, 21.8.

[0281] HRMS (ESI-TOF): For C 17 H 22 NO5S - [MH] - Calculated value: 352.1219, measured value: 352.1205.

[0282] 2-((2 R* ,3 R* 5-oxo-3-phenyl-1-toluenesulfonylpyrrolidine-2-yl)methyl acetate 13a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 78% (30.1 mg, 0.078 mmol, white solid).

[0283] 1 H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.0 Hz,2H), 7.23 – 7.18 (m, 1H), 7.18 – 7.12 (m, 2H), 6.92 (d, J = 7.2 Hz, 2H), 4.49(ddd, J = 9.9, 3.3, 1.6 Hz, 1H), 3.73 (s, 3H), 3.38 (dt, J = 8.6, 1.9 Hz, 1H), 3.21 (dd,J = 16.4, 3.3 Hz, 1H), 3.04 (dd, J = 17.9, 8.7 Hz, 1H), 2.88 (dd, J =16.4, 9.9 Hz, 1H), 2.48 (dd, J = 17.9, 2.0 Hz, 1H), 2.45 (s, 3H).

[0284] 13 C NMR (151 MHz, CDCl3) δ 172.8, 170.7, 145.4, 142.3, 135.0, 129.6,129.1, 128.3, 127.5, 126.3, 64.8, 52.1, 42.1, 39.5, 37.1, 21.8.

[0285] HRMS (ESI-TOF): For C 20 H 22 NO5S + [M+H] + Calculated value: 388.1219, measured value: 388.1230.

[0286] 2-(7-oxo-6-toluenesulfonyl-6-azaspiro[3.4]oct-5-yl)methyl acetate 14a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.42) was purified as methyl ester. The product was separated in two steps, yielding 81% (28.4 mg, 0.081 mmol, white solid).

[0287] 1 H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 6.6 Hz, 2H), 7.31 (d, J = 7.4 Hz, 2H), 4.61 (d, J = 6.6 Hz, 1H), 3.69 (s, 3H), 2.84 (d, J = 16.2 Hz, 1H), 2.70 (dd, J = 16.2, 8.0 Hz, 1H), 2.62 (d, J= 17.1 Hz, 1H), 2.43 (d, J = 13.5 Hz, 1H), 2.42(s, 3H), 2.08 – 1.99 (m, 1H), 1.91 (q, J = 8.5 Hz, 1H), 1.88 – 1.79 (m, 3H), 1.78 – 1.72 (m, 1H).

[0288] 13 C NMR (151 MHz, CDCl3) δ 172.0, 171.1, 145.3, 135.7, 129.7, 128.3, 65.9, 52.2, 43.7, 43.3, 36.3, 35.8, 27.3, 21.8, 15.3.

[0289] HRMS (ESI-TOF): For C 17 H 22 NO5S + [M+H] + Calculated value: 352.1219, measured value: 352.1218.

[0290] 2-(3-oxo-2-toluenesulfonyl-2-azaspiro[4.4]non-1-yl)methyl acetate 15a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.50) was purified as methyl ester. The product was separated in two steps, yielding 50% (18.3 mg, 0.05 mmol, white solid).

[0291] 1 H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 9.4 Hz, 2H), 4.45 (dd, J = 8.0, 3.7 Hz, 1H), 3.69 (s, 3H), 2.90 (dd, J = 16.3, 3.7 Hz, 1H), 2.84 (dd, J = 16.3, 8.0 Hz, 1H), 2.51 (d, J= 16.8 Hz, 1H), 2.44 (s, 3H), 2.10 (d, J = 16.9 Hz, 1H), 1.74 – 1.64 (m, 2H), 1.63 – 1.53 (m, 3H), 1.53 –1.46 (m, 1H), 1.46 – 1.40 (m, 1H), 1.37 – 1.30 (m, 1H).

[0292] 13 C NMR (151 MHz, CDCl3) δ 172.5, 171.1, 145.3, 135.6, 129.7, 128.4, 65.2, 52.2, 49.2, 42.8, 39.4, 37.5, 32.3, 23.7, 22.7, 21.8.

[0293] HRMS (ESI-TOF): For C 18 H 24 NO5S + [M+H] + Calculated value: 366.1375, measured value: 366.1374.

[0294] 2-(6-oxo-1-toluenesulfonylpiperidin-2-yl)acetic acid 2b Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, the compound was subjected to pTLC (EA + 1% AcOH R) f = 0.27) was purified in acid. The separation yield was 70% (22.0 mg, 0.07 mmol, pale yellow solid).

[0295] 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.02 (d, J = 10.6 Hz, 1H), 3.12 (dd, J = 16.4, 3.3 Hz, 1H), 2.82 (dd, J=16.4, 10.6 Hz, 1H), 2.58 – 2.46 (m, 1H), 2.43 (s, 3H), 2.41 – 2.30 (m, 1H), 2.16 – 2.06 (m, 1H), 1.97 – 1.84 (m, 2H), 1.84 – 1.74 (m, 1H).

[0296] 13 C NMR (100 MHz, CDCl3) δ 175.0, 170.1, 145.1, 136.3, 129.4, 129.1, 53.2, 38.9, 33.4, 27.0, 21.8, 16.1.

[0297] HRMS (ESI-TOF): For C 14 H 18 NO5S + [M+H] + Calculated value: 312.0906, measured value: 312.0917.

[0298] 2-(5,5-dimethyl-6-oxo-1-toluenesulfonylpiperidin-2-yl)methyl acetate 16b Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.40) was purified as methyl ester. The product was separated in two steps, yielding 60% (21.0 mg, 0.06 mmol, white solid).

[0299] 1 H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.01 (ddd, J = 11.1, 5.8, 3.0 Hz, 1H), 3.71 (s, 3H), 3.03 (dd, J = 15.9, 3.4Hz, 1H), 2.75 (ddd, J= 16.1, 10.9, 2.1 Hz, 1H), 2.41 (s, 3H), 2.22 – 2.04 (m,1H), 1.96 – 1.90 (m, 1H), 1.90 – 1.82 (m, 1H), 1.58 – 1.44 (m, 1H), 1.17 (s,3H), 1.03 (s,3H).

[0300] 13 C NMR (151 MHz, CDCl3) δ 176.5, 170.6, 144.7, 136.5, 129.4, 128.8, 54.0, 52.1, 40.7, 39.3, 31.3, 27.6, 27.0, 23.8, 21.8.

[0301] HRMS (ESI-TOF): For C 17 H 24 NO5S + [M+H] + Calculated value: 354.1375, measured value: 354.1381.

[0302] 2-(5-oxo-6-toluenesulfonyl-6-azaspiro[3.5]non-7-yl)methyl acetate 17b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.40) was purified as methyl ester. The product was separated in two steps, yielding 66% (24.0 mg, 0.066 mmol, white solid).

[0303] 1 H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.3 Hz,2H), 5.18 – 4.76 (m, 1H), 3.71 (s, 3H), 3.01 (dd, J = 16.0, 3.3 Hz, 1H), 2.77 –2.60 (m, 2H), 2.42 (s, 3H), 2.02 (td, J= 10.2, 7.3 Hz, 1H), 1.98 – 1.92 (m,4H), 1.92 – 1.84 (m, 2H), 1.83 – 1.72 (m, 1H), 1.66 – 1.60 (m, 1H).

[0304] 13 C NMR (151 MHz, CDCl3) δ 174.9, 170.7, 144.7, 136.6, 129.4, 128.8, 53.7, 52.1, 45.5, 39.3, 33.7, 29.0, 28.4, 23.9, 21.8, 15.4.

[0305] HRMS (ESI-TOF): For C 18 H 24 NO5S + [M+H] + Calculated value: 366.1375, measured value: 366.1381.

[0306] 2-(6-oxo-7-toluenesulfonyl-7-azaspiro[4.5]dec-8-yl)methyl acetate 6b Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.47) was purified as methyl ester. The product was separated in two steps, yielding 40% (15.2 mg, 0.04 mmol, white solid).

[0307] 1 H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 5.02 (ddd, J = 11.1, 5.5, 2.9 Hz, 1H), 3.71 (s, 3H), 3.04 (dd, J = 15.9, 3.4Hz, 1H), 2.76 (ddd, J = 15.8, 10.7, 1.7 Hz, 1H), 2.42 (s, 3H), 2.25 (dt, J=13.4, 7.3 Hz, 1H), 2.13 – 2.01 (m, 1H), 1.94 (d, J = 14.4 Hz, 1H), 1.84 (td, J =13.9, 3.0 Hz, 1H), 1.76 – 1.68 (m, 1H), 1.63 – 1.60 (m, 1H), 1.60 – 1.55 (m,3H), 1.53 (d, J = 7.5 Hz, 1H), 1.51 (d, J = 10.7 Hz, 1H), 1.34 (dt, J = 13.2, 6.2Hz, 1H).

[0308] 13 C NMR (151 MHz, CDCl3) δ 177.0, 170.7, 144.6, 136.6, 129.3, 128.8,53.7, 52.1, 51.4, 40.2, 39.4, 38.1, 30.3, 26.1, 25.6, 24.8, 21.8.

[0309] HRMS (ESI-TOF): For C 19 H 26 NO5S + [M+H] + Calculated value: 380.1532, measured value: 380.1544.

[0310] 2-(1-oxo-2-toluenesulfonyl-9-oxa-2-azaspiro[5.5]undecane-3-yl)methyl acetate 18b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (50% EA / hexane, R... f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 50% (19.8 mg, 0.05 mmol, white solid).

[0311] 1 H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 4.98 (tt, J= 6.1, 3.0 Hz, 1H), 3.89 (dt, J = 11.3, 5.0 Hz, 1H), 3.71 (s,3H), 3.55 – 3.48 (m, 2H), 3.48 – 3.41 (m, 1H), 3.02 (dt, J = 16.0, 2.7 Hz, 1H),2.83 – 2.64 (m, 1H), 2.42 (s, 3H), 2.18 – 2.01 (m, 2H), 2.00 – 1.88 (m, 2H),1.87 – 1.76 (m, 1H), 1.76 – 1.66 (m, 1H), 1.41 – 1.29 (m, 2H).

[0312] 13 C NMR (151 MHz, CDCl3) δ 175.3, 170.5, 144.9, 136.3, 129.4, 128.9, 63.6, 62.8, 53.4, 52.1, 41.5, 39.2, 34.9, 33.7, 27.6, 23.1, 21.8.

[0313] HRMS (ESI-TOF): For C 19 H 26 NO6S + [M+H] + Calculated value: 396.1481, measured value: 396.1491.

[0314] 2-(9-oxo-8-toluenesulfonyl-8-azaspiro[4.5]dec-7-yl)methyl acetate 19b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.44) was purified as methyl ester. The product was separated in two steps, yielding 73% (27.5 mg, 0.073 mmol, white solid).

[0315] 1 H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.79 (qd, J= 8.1, 3.1 Hz, 1H), 3.68 (s, 3H), 3.06 (dd, J = 16.4, 3.1 Hz, 1H), 2.89 (dd, J = 16.4, 8.6 Hz, 1H), 2.42 (s, 3H), 2.36 (d, J = 16.9 Hz, 1H), 2.24 (dd, J = 16.9, 2.9 Hz, 1H), 2.17 (ddd, J = 13.7, 8.0, 2.9 Hz, 1H), 1.76 (dd, J = 13.7, 7.8 Hz, 1H), 1.72 – 1.52 (m, 4H), 1.49 – 1.38 (m, 3H), 1.19 (ddd, J =13.4, 8.0, 5.4 Hz, 1H).

[0316] 13 C NMR (151 MHz, CDCl3) δ 171.0, 170.8, 144.9, 136.6, 129.3, 129.1,52.4, 51.9, 46.0, 41.4, 40.8, 40.4, 40.1, 35.8, 24.6, 24.0, 21.8.

[0317] HRMS (ESI-TOF): For C 19 H 26 NO5S + [M+H] + Calculated value: 380.1532, measured value: 380.1537.

[0318] 2-((1 S* ,3 aS* 6 aR* 20a methyl 3-oxo-2-toluenesulfonyl octahydrocyclopentadienyl[c]pyrrolo-1-yl)acetate Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 22% (7.8 mg, 0.022 mmol, white solid).

[0319] 1 H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 4.34 (ddd, J = 9.5, 3.2, 1.2 Hz, 1H), 3.67 (s, 3H), 3.15 (dd, J = 16.3, 3.2Hz, 1H), 2.98 (td, J = 8.7, 3.3 Hz, 1H), 2.73 (dd, J = 16.3, 9.5 Hz, 1H), 2.44(s, 4H), 1.98 (dh, J = 14.2, 5.2 Hz, 1H), 1.91 – 1.73 (m, 2H), 1.52 – 1.42 (m,1H), 1.37 – 1.21 (m, 2H).

[0320] 13 C NMR (126 MHz, CDCl3) δ 176.7, 170.8, 145.3, 135.5, 129.7, 128.4, 61.3, 52.0, 46.8, 43.0, 40.4, 33.9, 29.7, 25.4, 21.8.

[0321] HRMS (ESI-TOF): For C 17 H 22 NO5S + [M+H] + Calculated value: 352.1219, measured value: 352.1219.

[0322] 2-((3 R* 4 aS* 7 aS *)-1-oxo-2-toluenesulfonyl octahydro-1H-cyclopentadienyl[c]pyridin-3-yl)benzyl acetate 21b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, benzyl ester formation was subsequently performed, and the compound was analyzed by pTLC (40% EA / hexane, R...). f= 0.50) was purified as benzyl ester. The product was separated in two steps, yielding 60% (26.5 mg, 0.060 mmol, white solid).

[0323] 1 H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.41 – 7.33 (m, 5H), 7.29 (d, J = 8.3 Hz, 2H), 5.28 – 5.14 (m, 2H), 4.99 (dq, J = 11.1, 4.0 Hz, 1H), 3.07 (dd, J = 15.3, 4.4 Hz, 1H), 2.81 (dd, J = 15.5, 10.6 Hz, 1H), 2.81 – 2.75(m, 1H), 2.51 (ttd, J = 13.0, 6.7, 4.6 Hz, 1H), 2.42 (s, 3H), 2.18 (ddd, J =14.3, 6.0, 2.9 Hz, 1H), 1.95 – 1.86 (m, 2H), 1.87 – 1.79 (m, 1H), 1.62 – 1.54(m, 2H), 1.47 – 1.35 (m, 2H), 1.17 (ddt, J = 13.0, 8.5, 6.7 Hz, 1H).

[0324] 13 C NMR (151 MHz, CDCl3) δ 173.5, 170.0, 144.8, 136.6, 135.6, 129.5,128.8, 128.6, 67.0, 53.9, 46.0, 38.7, 34.0, 33.5, 29.5, 25.2, 21.8.

[0325] HRMS (ESI-TOF): For C 24 H 28 NO5S + [M+H] + Calculated value: 442.1688, measured value: 442.1689.

[0326] 2-((3 R* 4 aS* 8 aS* -1-oxo-2-toluenesulfonyldecahydroisoquinoline-3-yl)benzyl acetate 22b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, benzyl ester formation was subsequently performed, and the compound was analyzed by pTLC (40% EA / hexane, R...). f = 0.50) was purified as benzyl ester. The product was separated in two steps, yielding 60% (27.2 mg, 0.060 mmol, white solid).

[0327] 1 H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.3 Hz, 2H), 7.36 (m, 5H), 7.27(d, J = 8.3 Hz, 2H), 5.14 (s, 2H), 4.99 (ddt, J = 10.0, 7.0, 3.7 Hz, 1H), 3.06(dd, J = 16.1, 3.3 Hz, 1H), 2.83 (dd, J = 16.1, 9.9 Hz, 1H), 2.51 – 2.35 (m, 4H), 2.24 – 2.18 (m, 1H), 2.18 – 2.13 (m, 1H), 1.73 (dt, J = 13.5, 3.7 Hz, 1H), 1.62(qd, J = 9.4, 3.8 Hz, 1H), 1.52 (td, J = 10.8, 4.7 Hz, 1H), 1.45 (dd, J = 13.4, 5.7Hz, 1H), 1.39 – 1.33 (m, 3H), 1.34 – 1.29 (m, 1H), 1.29 – 1.20 (m, 1H).

[0328] 3 C NMR (151 MHz, CDCl3) δ 173.5, 170.1, 144.7, 136.6, 135.6, 129.2,129.0, 128.8, 128.5, 128.5, 66.8, 52.4, 44.2, 40.5, 29.7, 29.3, 28.8, 26.3,24.2, 22.1, 21.8.

[0329] HRMS (ESI-TOF): For C 25 H 30 NO5S + [M+H] + Calculated value: 456.1845, measured value: 456.1853.

[0330] 2-(3-oxo-2-toluenesulfonylisoindoline-1-yl)methyl acetate 23a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 60% (21.6 mg, 0.060 mmol, white solid).

[0331] 1 H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 8.2 Hz, 2H), 7.33 (d, J = 7.3 Hz, 2H), 5.60 (dt, J = 8.3, 2.7 Hz, 1H), 3.66 (s, 3H), 3.57 (dt, J = 16.6, 2.9 Hz, 1H),2.91 (ddd, J = 16.7, 8.5, 2.1 Hz, 1H), 2.41 (s, 3H).

[0332] 13 C NMR (151 MHz, CDCl3) δ 170.4, 166.5, 145.4, 135.8, 134.4, 129.8,129.4, 129.3, 128.5, 125.2, 123.2, 58.5, 52.1, 39.4, 21.8.

[0333] HRMS (ESI-TOF): For C 18 H 18NO5S + [M+H] + Calculated value: 360.0906, measured value: 360.0897.

[0334] 2-(1-oxo-2-toluenesulfonyl-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl acetate 24b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, benzyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as benzyl ester. The product was separated in two steps, yielding 65% (24.2 mg, 0.065 mmol, white solid).

[0335] 1 H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 7.8 Hz, 1H), 7.49 (td, J = 7.5, 1.4 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 5.39 (dddd, J = 10.7, 5.5, 3.5, 1.9 Hz, 1H), 3.67 (s, 3H), 3.42 (dd, J =16.5, 5.7 Hz, 1H), 3.13 (dd, J = 16.5, 1.9 Hz, 1H), 2.79 (ddd, J = 16.1, 3.6, 1.4Hz, 1H), 2.61 (dd, J = 16.1, 10.6 Hz, 1H), 2.42 (s, 3H).

[0336] 13 C NMR (100 MHz, CDCl3) δ 170.6, 162.7, 145.1, 136.5, 136.3, 134.1,129.6, 129.1, 128.7, 127.9, 127.9, 52.1, 52.0, 37.9, 32.6, 21.8.

[0337] HRMS (ESI-TOF): For C 19 H 20 NO5S + [M+H] + Calculated value: 374.1062, measured value: 374.1070.

[0338] 2-(1-Methoxy-5-oxopyrrolidone-2-yl)benzyl acetate 25a Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, benzyl ester formation was subsequently performed, and the compound was analyzed by pTLC (75% EA / hexane, R...). f = 0.30) was purified as benzyl ester. The product was separated in two steps with a yield of 61% (16.0 mg, 0.061 mmol, colorless oil).

[0339] 1 H NMR (600 MHz, CDCl3) δ 7.73 – 7.29 (m, 5H), 5.15 (q, J = 12.2 Hz, 2H), 4.18 (p, J = 6.9 Hz, 1H), 3.73 (s, 3H), 2.86 (dd, J = 15.8, 5.4 Hz, 1H), 2.50 (dd, J = 15.8, 7.6 Hz, 1H), 2.43 – 2.22 (m, 3H), 1.79 – 1.70 (m, 1H).

[0340] 13 C NMR (151 MHz, CDCl3) δ 171.1, 170.5, 135.6, 128.8, 128.6, 128.6, 66.9, 62.8, 53.8, 38.3, 26.9, 22.1.

[0341] HRMS (ESI-TOF): For C 14 H 18 NO4 [M+H] + Calculated value: 264.1236, measured value: 264.1239.

[0342] Characterization data of products obtained from cycloamination reactions 2-(1-Toluenesulfonylpyrrolidone-2-yl)methyl acetate 26a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (50% EA / hexane, R... f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 65% (19.3 mg, 0.065 mmol, white solid).

[0343] 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.95 (ddt, J = 10.7, 7.4, 3.9 Hz, 1H), 3.69 (s, 3H), 3.45 (ddd, J = 10.7,6.4, 5.1 Hz, 1H), 3.22 – 2.97 (m, 2H), 2.50 (ddd, J = 16.1, 10.0, 0.9 Hz, 1H), 2.43 (s, 3H), 1.89 – 1.70 (m, 2H), 1.70 – 1.61 (m, 1H), 1.58 – 1.46 (m, 1H).

[0344] 13 C NMR (100 MHz, CDCl3) δ 171.9, 143.7, 134.2, 129.9, 127.8, 56.7, 51.8, 49.3, 41.3, 31.8, 23.9, 21.7.

[0345] HRMS (ESI-TOF): For C 14 H 20 NO4S + [M+H] + Calculated value: 298.1114, measured value: 298.1110.

[0346] 2-((2 S* 5 R* )-5-(tert-butyl)-1-toluenesulfonylpyrrolidine-2-yl)acetic acid 27a Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, the compound was subjected to pTLC (EA + 1% AcOH, R... f = 0.40) was purified in acid. The isolated product was 55% (18.6 mg, 0.055 mmol, white solid).

[0347] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.86 (qd, J = 8.4, 3.7 Hz, 1H), 3.60 (dd, J = 8.9, 1.5 Hz, 1H), 3.33 (dd, J =16.4, 3.8 Hz, 1H), 2.57 (dd, J = 16.5, 10.4 Hz, 1H), 2.44 (s, 3H), 1.95 (dtd, J =13.1, 8.2, 1.9 Hz, 1H), 1.71 (ddt, J = 13.3, 7.4, 1.9 Hz, 1H), 1.56 (tt, J =12.6, 7.8 Hz, 1H), 1.12 (tt, J = 13.1, 8.7 Hz, 1H), 0.98 (s, 9H).

[0348] 13 C NMR (151 MHz, CDCl3) δ 177.4, 143.8, 134.2, 129.9, 128.3, 70.9, 58.5, 42.0, 35.1, 31.9, 28.2, 26.6, 21.7.

[0349] HRMS (ESI-TOF): For C 17 H 26 NO4S + [M+H] + Calculated value: 340.1583, measured value: 340.1597.

[0350] 2-((2 S* 5 R*28a-5-phenyl-1-toluenesulfonylpyrrolidine-2-yl)acetic acid Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, the compound was subjected to pTLC (EA + 1% AcOH, R... f = 0.40) was purified in acid. The isolated product was 67% (24.1 mg, 0.067 mmol, light brown solid).

[0351] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.43 – 7.29 (m, 6H), 7.27 – 7.22 (m, 1H), 4.85 – 4.51 (m, 1H), 4.15 (ddd, J = 10.3, 6.4, 4.2 Hz,1H), 3.36 (dd, J = 16.3, 3.9 Hz, 1H), 2.67 (dd, J = 16.3, 10.1 Hz, 1H), 2.44 (s,3H), 2.03 – 1.77 (m, 3H), 1.61 (tt, J = 9.8, 4.1 Hz, 1H).

[0352] 13 C NMR (151 MHz, CDCl3) δ 176.9, 144.0, 142.2, 134.4, 129.9, 128.6, 127.9, 127.3, 126.2, 64.8, 58.2, 41.5, 34.0, 30.6, 21.7.

[0353] HRMS (ESI-TOF): For C 19 H 22 NO4S + [M+H] + Calculated value: 360.1270, measured value: 360.1285.

[0354] 2-(5,5-Dimethyl-1-toluenesulfonylpyrrolidine-2-yl)methyl acetate 29a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (50% EA / hexane, R...f = 0.50) was purified as methyl ester. The product was separated in two steps, yielding 60% (19.5 mg, 0.06 mmol, white solid).

[0355] 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 4.18 (t, J = 9.3 Hz, 1H), 3.67 (s, 3H), 3.05 (d, J = 15.8 Hz, 1H), 2.46 (dd, J = 15.4, 10.2 Hz, 1H), 2.41 (s, 3H), 2.07 – 1.78 (m, 2H), 1.76 – 1.67 (m,1H), 1.67 – 1.52 (m, 5H), 1.30 (s, 3H).

[0356] 13 C NMR (151 MHz, CDCl3) δ 172.0, 143.0, 139.0, 129.6, 127.6, 66.5, 58.2, 51.7, 40.6, 40.3, 31.7, 28.4, 26.5, 21.6.

[0357] HRMS (ESI-TOF): For C 16 H 24 NO4S + [M+H] + Calculated value: 326.1426, measured value: 326.1436.

[0358] 2-(5-Toluenesulfonyl-5-azaspiro[3.4]oct-6-yl)methyl acetate 30a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (50% EA / hexane, R... f = 0.57) was purified as methyl ester. The product was separated in two steps, yielding 67% (22.5 mg, 0.067 mmol, white solid).

[0359] 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 4.18 (ddt, J = 10.9, 7.4, 3.9 Hz, 1H), 3.67 (s, 3H), 3.12 – 3.07 (m, 1H), 3.07 – 3.01 (m, 1H), 2.79 (q, J = 10.3 Hz, 1H), 2.43 (dd, J = 15.9, 10.3 Hz, 1H), 2.41 (s, 3H), 2.00 (ddd, J = 11.7, 8.5, 5.9 Hz, 1H), 1.97 – 1.88 (m, 2H), 1.82(dt, J = 11.8, 6.1 Hz, 1H), 1.74 (qt, J = 10.0, 2.3 Hz, 1H), 1.67 (dddd, J = 10.7,7.7, 5.3, 2.4 Hz, 1H), 1.62 – 1.53 (m, 2H).

[0360] 13 C NMR (151 MHz, CDCl3) δ 171.9, 143.1, 138.9, 129.7, 127.2, 66.9, 58.6, 51.7, 41.5, 37.7, 37.5, 33.4, 28.3, 21.6, 14.9.

[0361] HRMS (ESI-TOF): For C 17 H 24 NO4S + [M+H] + Calculated value: 338.1426, measured value: 338.1424.

[0362] 2-(1-Toluenesulfonyl-1-azaspiro[4.4]non-2-yl)methyl acetate 31a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f= 0.40) was purified as methyl ester. The product was separated in two steps, yielding 50% (17.5 mg, 0.05 mmol, white solid).

[0363] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.0 Hz, 2H), 4.22 (ddd, J = 10.6, 7.5, 3.0 Hz, 1H), 3.67 (s, 3H), 3.04 (dd, J = 16.1, 3.5Hz, 1H), 2.54 – 2.47 (m, 1H), 2.47 – 2.42 (m, 1H), 2.41 (s, 3H), 2.31 (q, J =9.6 Hz, 1H), 1.90 (ddd, J = 19.3, 11.2, 7.5 Hz, 1H), 1.84 – 1.69 (m, 4H), 1.69 – 1.60 (m, 2H), 1.54 – 1.36 (m, 2H), 1.33 – 1.17 (m, 1H).

[0364] 13 C NMR (151 MHz, CDCl3) δ 172.0, 143.0, 139.3, 129.7, 127.3, 75.3, 58.0, 51.7, 40.7, 40.3, 39.1, 34.8, 28.8, 23.5, 22.6, 21.6.

[0365] HRMS (ESI-TOF): For C 18 H 26 NO4S + [M+H] + Calculated value: 352.1583, measured value: 352.1584.

[0366] 2-(1-Toluenesulfonyl-8-oxa-1-azaspiro[4.5]dec-2-yl)methyl acetate 32a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (50% EA / hexane, R... f= 0.27) was purified as methyl ester. The product was separated in two steps, yielding 51% (18.7 mg, 0.051 mmol, white solid).

[0367] 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.25 (ddd, J = 10.7, 6.7, 3.4 Hz, 1H), 4.07 – 3.82 (m, 2H), 3.68 (s, 3H), 3.46 – 3.25 (m, 2H), 3.07 (dd, J = 16.0, 3.5 Hz, 1H), 2.92 (td, J = 13.0, 5.0 Hz, 1H), 2.64 (td, J = 12.6, 5.1 Hz, 1H), 2.44 (dd, J = 16.1, 10.7 Hz, 1H), 2.41 (s,3H), 2.27 – 2.19 (m, 1H), 1.92 – 1.76 (m, 2H), 1.75 – 1.66 (m, 1H), 1.52 (dq, J = 13.3, 2.2 Hz, 1H), 1.12 (dq, J = 12.7, 2.2 Hz, 1H).

[0368] 13 C NMR (151 MHz, CDCl3) δ 171.8, 143.2, 139.5, 129.7, 127.3, 67.8, 66.5, 66.3, 58.0, 51.8, 41.5, 40.7, 34.2, 33.5, 28.3, 21.6.

[0369] HRMS (ESI-TOF): For C 18 H 26 NO5S + [M+H] + Calculated value: 368.1532, measured value: 368.1534.

[0370] 2-(4,4-Dimethyl-1-toluenesulfonylpyrrolidone-2-yl)methyl acetate 33a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.41) was purified as methyl ester. The product was separated in two steps, yielding 50% (16.3 mg, 0.05 mmol, white solid).

[0371] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 3.92 (qd, J = 8.3, 3.8 Hz, 1H), 3.68 (s, 3H), 3.34 (dt, J = 16.3, 3.0 Hz, 1H), 3.18 (dd, J = 10.5, 2.0 Hz, 1H), 3.03 (d, J = 10.5 Hz, 1H), 2.56 (ddd, J =16.5, 9.3, 2.1 Hz, 1H), 2.43 (s, 3H), 1.86 (dd, J = 12.9, 7.4 Hz, 1H), 1.50(dd, J = 12.6, 8.5 Hz, 1H), 1.03 (s, 3H), 0.48 (s, 3H).

[0372] 13 C NMR (151 MHz, CDCl3) δ 172.1, 143.7, 134.5, 129.8, 127.8, 61.6, 56.5, 51.7, 46.9, 41.7, 37.4, 26.5, 25.8, 21.7.

[0373] HRMS (ESI-TOF): For C 16 H 24 NO4S + [M+H] + Calculated value: 326.1426, measured value: 326.1437.

[0374] 2-(6-Toluenesulfonyl-6-azaspiro[3.4]oct-7-yl)methyl acetate 34a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.33) was purified as methyl ester. The product was separated in two steps, yielding 50% (16.8 mg, 0.05 mmol, white solid).

[0375] 1 H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 3.88 (dddd, J = 9.9, 7.6, 5.9, 4.0 Hz, 1H), 3.69 (s, 3H), 3.43 (d, J = 10.3Hz, 1H), 3.23 (dd, J = 16.2, 4.0 Hz, 1H), 3.10 (d, J = 10.3 Hz, 1H), 2.52 (dd, J =16.2, 9.8 Hz, 1H), 2.43 (s, 3H), 2.04 – 1.98 (m, 1H), 1.95 (dd, J = 12.8, 7.7Hz, 1H), 1.93 – 1.87 (m, 1H), 1.80 – 1.71 (m, 2H), 1.68 (dd, J = 12.8, 6.0 Hz,1H), 1.51 (ddd, J = 17.4, 8.5, 1.6 Hz, 1H), 1.36 (ddd, J = 17.8, 8.7, 2.0 Hz, 1H).

[0376] 13 C NMR (151 MHz, CDCl3) δ 172.1, 143.7, 134.1, 129.8, 127.9, 59.9, 56.4, 51.8, 44.2, 44.0, 41.7, 31.4, 31.2, 21.7, 16.2.

[0377] HRMS (ESI-TOF): For C 17 H 24 NO4S + [M+H] + Calculated value: 338.1426, measured value: 338.1427.

[0378] 2-(2-Toluenesulfonyl-2-azaspiro[4.4]non-3-yl)methyl acetate 35a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.42) was purified as methyl ester. The product was separated in two steps, yielding 40% (14.0 mg, 0.04 mmol, white solid).

[0379] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.8 Hz,2H), 4.07 – 3.84 (m, 1H), 3.68 (s, 3H), 3.32 (dd, J = 16.4, 3.9 Hz, 1H), 3.28(d, J = 10.2 Hz, 1H), 3.02 (d, J = 10.3 Hz, 1H), 2.57 (dd, J = 16.3, 9.5 Hz, 1H), 2.44 (s, 3H), 1.93 (dd, J = 12.9, 7.6 Hz, 1H), 1.66 – 1.50 (m, 4H), 1.50 – 1.35(m, 3H), 1.00 (dt, J = 14.3, 7.7 Hz, 1H), 0.85 – 0.77 (m, 1H).

[0380] 13 C NMR (151 MHz, CDCl3) δ 172.2, 143.7, 134.3, 129.8, 127.8, 60.0, 56.7, 51.7, 48.6, 44.7, 41.7, 36.7, 36.5, 24.6, 24.4, 21.7.

[0381] HRMS (ESI-TOF): For C 18 H 26 NO4S + [M+H] + Calculated value: 352.1583, measured value: 352.1591.

[0382] 2-((2 R* ,3 S* 3-Methyl-1-toluenesulfonylpyrrolidone-2-yl)methyl acetate 36a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 82% (25.5 mg, 0.082 mmol, white solid).

[0383] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.47 – 7.19 (m, 2H), 3.69 (s, 3H), 3.52 (dt, J = 9.3, 3.7 Hz, 1H), 3.44 (ddd, J = 10.0, 7.3, 4.5 Hz,1H), 3.17 (ddd, J = 10.0, 8.5, 6.9 Hz, 1H), 2.98 (dd, J = 16.1, 3.9 Hz, 1H), 2.53(dd, J = 16.1, 9.3 Hz, 1H), 2.43 (s, 3H), 2.04 (ddt, J = 10.2, 6.9, 3.4 Hz, 1H),1.99 – 1.84 (m, 1H), 1.23 (ddt, J = 12.6, 6.9, 4.4 Hz, 1H), 0.54 (d, J = 6.9 Hz, 3H).

[0384] 13C NMR (151 MHz, CDCl3) δ 171.9, 143.7, 134.0, 129.7, 127.8, 63.6, 51.7, 47.5, 41.0, 39.1, 31.0, 21.7, 18.3.

[0385] HRMS (ESI-TOF): For C 15 H 22 NO4S + [M+H] + Calculated value: 312.1270, measured value: 312.1277.

[0386] 2-((2 R* ,3 R* 3-(tert-butyl)-1-toluenesulfonylpyrrolidine-2-yl)methyl acetate 37a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.45) was purified as methyl ester. The product was separated in two steps, yielding 70% (24.7 mg, 0.07 mmol, white solid).

[0387] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.7 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 3.82 (q, J = 5.6 Hz, 1H), 3.69 (s, 3H), 3.42 – 3.34 (m, 2H), 2.80 (ddd, J =15.1, 4.4, 1.8 Hz, 1H), 2.73 (ddd, J = 15.2, 6.0, 2.1 Hz, 1H), 2.42 (s, 3H), 2.05 – 1.92 (m, 1H), 1.82 (dq, J = 13.8, 6.7 Hz, 1H), 1.47 – 1.34 (m, 1H), 0.63 (s, 9H).

[0388] 13C NMR (151 MHz, CDCl3) δ 171.8, 143.5, 135.7, 129.8, 127.7, 57.9, 55.4, 51.8, 48.9, 42.6, 32.5, 27.7, 26.7, 21.7.

[0389] HRMS (ESI-TOF): For C 18 H 28 NO4S + [M+H] + Calculated value: 354.1739, measured value: 354.1730.

[0390] 2-((2 R* ,3 R* 3-Phenylacetyl-1-toluenesulfonylpyrrolidone-2-yl)methyl acetate 38a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.30) was purified as methyl ester. The product was separated in two steps, yielding 70% (26.1 mg, 0.07 mmol, white solid).

[0391] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 7.8 Hz,2H), 7.19 – 7.01 (m, 3H), 6.90 – 6.68 (m, 2H), 3.96 (ddd, J = 7.9, 6.4, 4.0 Hz,1H), 3.74 – 3.45 (m, 5H), 3.26 (dt, J = 8.4, 6.6 Hz, 1H), 3.01 (dd, J = 15.6, 4.0Hz, 1H), 2.71 (dd, J = 15.6, 8.0 Hz, 1H), 2.46 (s, 3H), 2.09 (dtd, J = 12.8, 6.4, 5.0 Hz, 1H), 1.64 – 1.58 (m, 1H).

[0392] 13C NMR (151 MHz, CDCl3) δ 171.5, 143.8, 140.7, 134.6, 129.9, 128.7,127.7, 127.3, 127.0, 63.8, 51.7, 50.7, 49.0, 40.4, 32.5, 21.7.

[0393] HRMS (ESI-TOF): For C 20 H 24 NO4S + [M+H] + Calculated value: 374.1426, measured value: 374.1439.

[0394] 2-(6-Toluenesulfonyl-6-azaspiro[3.4]oct-5-yl)methyl acetate 39a Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.35) was purified as methyl ester. The product was separated in two steps, yielding 35% (12.0 mg, 0.035 mmol, white solid).

[0395] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 3.86 (ddd, J = 7.4, 4.4, 1.8 Hz, 1H), 3.73 (s, 3H), 3.52 – 3.38 (m, 1H), 2.95 (qd, J = 8.9, 1.9 Hz, 1H), 2.78 – 2.64 (m, 1H), 2.42 (s, 3H), 2.44 – 2.36(m, 1H), 2.11 – 1.88 (m, 1H), 1.87 – 1.77 (m, 2H), 1.77 – 1.53 (m, 3H), 1.25– 0.96 (m, 3H).

[0396] 13C NMR (151 MHz, CDCl3) δ 172.2, 143.6, 134.0, 129.7, 127.8, 64.6, 52.0, 48.5, 46.1, 39.0, 34.9, 33.4, 26.9, 21.7, 15.7.

[0397] HRMS (ESI-TOF): For C 17 H 24 NO4S + [M+H] + Calculated value: 338.1426, measured value: 338.1436.

[0398] 2-(2-Toluenesulfonyl-2-azaspiro[4.4]non-1-yl)methyl acetate 40a Following the general procedure of its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.42) was purified as methyl ester. The product was separated in two steps, yielding 27% (9.5 mg, 0.027 mmol, white solid).

[0399] 1 H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.7 Hz, 2H), 3.80 (dd, J = 7.6, 4.1 Hz, 1H), 3.71 (s, 3H), 3.48 (t, J = 8.6 Hz, 1H), 3.01(td, J = 9.7, 6.7 Hz, 1H), 2.82 (dd, J = 15.9, 4.1 Hz, 1H), 2.55 (dd, J = 16.2, 8.2Hz, 1H), 2.43 (s, 3H), 1.75 (td, J = 11.7, 8.5 Hz, 1H), 1.55 – 1.52 (m, 1H), 1.52 – 1.49 (m, 1H), 1.49 – 1.39 (m, 4H), 1.39 – 1.31 (m, 1H), 0.80 (dt, J=13.8, 7.0 Hz, 1H), 0.68 (dt, J = 13.7, 7.5 Hz, 1H).

[0400] 13 C NMR (151 MHz, CDCl3) δ 172.3, 143.6, 134.2, 129.7, 127.8, 64.0, 53.9, 51.9, 46.7, 40.1, 36.7, 35.1, 32.4, 24.0, 23.5, 21.7.

[0401] HRMS (ESI-TOF): For C 18 H 26 NO4S + [M+H] + Calculated value: 352.1583, measured value: 352.1595.

[0402] 2-((1 S* ,3 aS* 6 aR* )-2-Toluenesulfonyloctahydrocyclopentadiene[ c 41a pyrrolo-1-yl)methyl acetate Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.35) was purified as methyl ester. The product was separated in two steps, yielding 30% (10.0 mg, 0.03 mmol, white solid).

[0403] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 3.73 (ddd, J = 9.6, 4.0, 2.8 Hz, 1H), 3.68 (s, 3H), 3.60 (dd, J = 10.1, 8.2Hz, 1H), 3.05 (dd, J = 15.9, 4.0 Hz, 1H), 2.81 (dd, J = 10.0, 6.9 Hz, 1H), 2.66(pd, J= 7.8, 3.7 Hz, 1H), 2.53 (dd, J = 15.8, 9.7 Hz, 1H), 2.44 (s, 3H), 2.31(qd, J = 7.9, 2.8 Hz, 1H), 1.72 – 1.60 (m, 2H), 1.43 – 1.30 (m, 1H), 1.19 (ddt, J = 13.5, 6.8, 3.4 Hz, 1H), 0.85 (dq, J = 13.0, 7.7 Hz, 1H).

[0404] 13 C NMR (151 MHz, CDCl3) δ 171.9, 143.6, 134.4, 129.7, 127.7, 62.8, 54.2, 51.8, 51.0, 41.7, 41.4, 31.4, 30.6, 24.9, 21.7.

[0405] HRMS (ESI-TOF): For C 17 H 24 NO4S + [M+H] + Calculated value: 338.1426, measured value: 338.1437.

[0406] 2-((2 S* ,3 aS* 7 aS* )-1-Toluenesulfonyloctahydro-1 H 42a Indole-2-yl)methyl acetate Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.41) was purified as methyl ester. The product was separated in two steps, yielding 60% (21.0 mg, 0.06 mmol, white solid).

[0407] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 3.83 (tdd, J= 9.6, 7.2, 4.0 Hz, 1H), 3.69 (s, 3H), 3.57 (dt, J = 12.2, 6.4Hz, 1H), 3.34 (dd, J = 16.0, 4.1 Hz, 1H), 2.55 (dd, J = 16.1, 9.8 Hz, 1H), 2.43(s, 3H), 1.97 (dt, J = 12.9, 6.5 Hz, 2H), 1.74 (td, J = 12.8, 9.4 Hz, 1H), 1.66(d, J = 13.7 Hz, 1H), 1.61 – 1.54 (m, 1H), 1.51 (h, J = 6.6 Hz, 1H), 1.46 – 1.37(m, 2H), 1.37 – 1.26 (m, 1H), 1.20 (ddt, J = 12.7, 8.3, 3.1 Hz, 1H), 1.13 (qt, J = 13.2, 2.8 Hz, 1H).

[0408] 13 C NMR (151 MHz, CDCl3) δ 172.1, 143.5, 135.1, 129.9, 127.6, 61.0, 57.2, 51.7, 43.3, 36.4, 34.7, 31.4, 25.9, 24.5, 21.7, 20.4.

[0409] HRMS (ESI-TOF): For C 18 H 26 NO4S + [M+H] + Calculated value: 352.1583, measured value: 352.1577.

[0410] 2-(1-Toluenesulfonyl-1,2,3,4-tetrahydroquinoline-2-yl)methyl acetate 43b Following the general procedure of its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (20% EA / hexane, R...). f= 0.25) was purified as methyl ester. The product was separated in two steps, yielding 53% (19.0 mg, 0.053 mmol, pale yellow solid).

[0411] 1 H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 6.4 Hz, 2H), 7.24 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.61 (p, J = 6.9 Hz, 1H), 3.67 (s, 3H), 2.86 (dd, J =15.5, 5.3 Hz, 1H), 2.56 – 2.43 (m, 1H), 2.37 (s, 3H), 2.37 – 2.28 (m, 1H), 1.97 (dq, J = 12.7, 6.2 Hz, 1H), 1.70 (dt, J = 15.0, 6.9 Hz, 1H), 1.43 (dt, J =14.6, 7.1 Hz, 1H).

[0412] 13 C NMR (151 MHz, CDCl3) δ 171.3, 143.7, 136.0, 135.1, 133.8, 129.6,128.0, 128.0, 127.3, 127.0, 126.1, 53.2, 51.9, 40.8, 28.4, 24.7, 21.7.

[0413] HRMS (ESI-TOF): For C 19 H 22 NO4S + [M+H] + Calculated value: 360.1270, measured value: 360.1288.

[0414] 2-(1-((2-nitrophenyl)sulfonyl)pyrrolidine-2-yl)methyl acetate 44a Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, methyl ester formation was subsequently performed, and the compound was analyzed by pTLC (30% EA / hexane, R...). f = 0.20) was purified as methyl ester. The product was separated in two steps, yielding 40% (13.1 mg, 0.04 mmol, yellow solid).

[0415] 1 H NMR (500 MHz, CDCl3) δ 8.08 – 8.00 (m, 1H), 7.75 – 7.65 (m, 2H), 7.63 – 7.56 (m, 1H), 4.29 (ddt, J = 9.9, 7.5, 3.7 Hz, 1H), 3.68 (s, 3H), 3.54 –3.36 (m, 2H), 2.96 (dd, J = 16.0, 3.9 Hz, 1H), 2.50 (dd, J = 16.0, 9.8 Hz, 1H), 2.06 (dq, J = 12.2, 7.5 Hz, 1H), 1.98 – 1.87 (m, 1H), 1.86 – 1.75 (m, 2H).

[0416] 13 C NMR (126 MHz, CDCl3) δ 171.5, 148.7, 133.8, 131.8, 131.6, 131.0,124.1, 56.9, 51.9, 49.2, 40.4, 32.0, 24.0.

[0417] HRMS (ESI-TOF): For C 13 H 27 N2O6S + [M+H] + Calculated value: 329.0808, measured value: 329.0811.

[0418] Synthesis and characterization of substrates for lactamation reactions General procedure A for the preparation of α-substituted amic acids (unless otherwise specified): Figure S17. General procedure for preparing α-substituted amide acids.

[0419] Step 1: At 0℃, nA solution of BuLi (2.5 M hexane, 2.1 equivalences) was added to a solution of DIPA (2.0 equivalences) in THF (0.1 M). The resulting solution was stirred at 0 °C for 30 min. Ordinary carboxylic acid S8 (10.0 mmol, 1.0 equivalences) was dissolved in THF (5.0 mL) and added dropwise to the LDA solution at 0 °C, while the solution was warmed to room temperature and stirred for 2 h. The reaction mixture was then cooled to 0 °C, and a solution of a haloalkene (10.0 mmol, 1.0 equivalences) in THF (5.0 mL) was added. The reaction mixture was warmed to room temperature and stirred overnight. The completion of the reaction was confirmed by TLC analysis of the reaction mixture. The reaction mixture was then quenched with aqueous HCl (1.0 M) and extracted three times with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product is filtered through a short silica stopper to remove polar impurities (usually orange in color), concentrated to obtain a light yellow oil, and then used in the next step without further purification.

[0420] Step 2: At room temperature, dissolve the ordinary crude carboxylic acid S9 or S10 obtained in the previous step in anhydrous THF (0.1 M), followed by the addition of Et3N (1.1 equivalents), and then TsNCO (1.1 equivalents). The reaction mixture is then stirred overnight at room temperature using a needle outlet (gas escaping is observed as the reaction proceeds). The completion of the reaction is confirmed by TLC analysis of the reaction mixture. The reaction mixture is then saturated with NaHCO3. 3(水溶液) The extract was quenched and extracted three times with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The desired common amide olefin S11 or S12 was obtained after purification by silica gel rapid column chromatography (elution polarity range: 20% EA / hexane to 50% EA / hexane). The average yield of this two-step sequence was approximately 60%.

[0421] Step 3: Dissolve common amide olefins S11 or S12 in DMF (0.1 M) and add OsO4 (1 mol%, 2.5 wt% tert-butanol solution) to the reaction mixture, observing a color change from colorless to light brown. Stir the reaction mixture for 5 minutes, then add Oxone® (4.0 equivalents). The reaction mixture is then stirred vigorously overnight. The completion of the reaction is confirmed by TLC analysis. The reactants are diluted with deionized water and extracted three times with EtOAc. The organic layers are combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel rapid column chromatography to give the desired common amide acids S13 and S14 (elution polarity range: 50% EA / hexane + 1% AcOH to EA + 1% AcOH). The average yield of this oxidative cleavage step is approximately 80%.

[0422] General procedure B for the preparation of α,β-disubstituted and β-substituted amide acids (unless otherwise specified): Figure S18. General procedure for preparing α,β-disubstituted and β-substituted amide acids.

[0423] Step 1: Dissolve the common α,β-unsaturated compound S15 (10.0 mmol) in anhydrous THF (0.1 M), then add CuI (10 mol%), and cool the reaction mixture to -15°C with vigorous stirring. Add TMSCl (2.0 equivalents) to the reaction mixture, followed by the Grignard reagent. The color of the reaction mixture changes from pale yellow to deep blue when the Grignard reagent addition is complete. Stir the reaction mixture and heat to room temperature overnight. Confirm the completion of the reaction by TLC analysis. Flush the reaction mixture with saturated NH4Cl. (水溶液) Quenching and extraction with EtOAc three times. The combined organic layers were dried with anhydrous MgSO4, concentrated under reduced pressure to remove all volatiles, and filtered through a short silica gel stopper to remove polar impurities.

[0424] Step 2: The crude addition products S16 and S17 were suspended in a 15% NaOH aqueous solution, heated to reflux, and stirred overnight at this temperature. The reaction mixture was cooled to room temperature and extracted three times with Et2O. The aqueous layer was collected and acidified to pH ~ 2 by adding an aqueous solution of HCl (6.0 M). The aqueous layer was then extracted three times with EtOAc. The combined EtOAc layers were dried over anhydrous MgSO4, concentrated under reduced pressure, and filtered through a short silica gel stopper to remove polar impurities, yielding crude ordinary carboxylic acids S18 and S19, which were used in the next step without further purification.

[0425] Step 3: At room temperature, dissolve the common crude carboxylic acid S18 or S19 obtained in the previous step in anhydrous THF (0.1 M), followed by the addition of Et3N (1.1 equivalents), and then TsNCO (1.1 equivalents). The reaction mixture is then stirred overnight at room temperature using a needle outlet (gas escaping is observed as the reaction proceeds). The completion of the reaction is confirmed by TLC analysis of the reaction mixture. The reaction mixture is then saturated with NaHCO3. 3(水溶液) The extract was quenched and extracted three times with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The desired common amide olefin S20 or S21 was obtained after purification by silica gel rapid column chromatography (elution polarity range: 20% EA / hexane to 50% EA / hexane). The average yield of this three-step sequence was approximately 42%.

[0426] Step 4: Dissolve common amide olefin S20 or S21 in DMF (0.1 M) and add OsO4 (1 mol%, 2.5 wt% tert-butanol solution) to the reaction mixture, observing a color change from colorless to light brown. Stir the reaction mixture for 5 minutes, then add Oxone® (4.0 equivalents). The reaction mixture is then stirred vigorously overnight. The completion of the reaction is confirmed by TLC analysis. The reactants are diluted with deionized water and extracted three times with EtOAc. The organic layers are combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel rapid column chromatography to give the desired amyl acids S22 and S23 (elution polarity range: 50% EA / hexane + 1% AcOH to EA + 1% AcOH). The average yield of this oxidative cleavage step is approximately 80%.

[0427] N -Toluenesulfonylhept-6-enamide SS1 The compound was prepared from commercially available hept-6-enoic acid according to step 2 of general procedure A.

[0428] 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 5.70 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.22 – 4.55 (m, 2H), 2.44 (s, 3H), 2.25 (t, J = 7.5 Hz, 2H), 2.14 – 1.86 (m, 2H), 1.56 (p, J = 7.4 Hz, 2H), 1.44 –1.22 (m, 2H).

[0429] 13 C NMR (100 MHz, CDCl3) δ 171.1, 145.3, 138.2, 135.6, 129.8, 128.4, 115.0, 36.2, 33.3, 28.1, 23.8, 21.8.

[0430] HRMS (ESI-TOF): For C 14 H 20 NO3S + [M+H] +Calculated value: 282.1164, measured value: 282.1157.

[0431] 6-((4-methylphenyl)sulfinylamino)-6-oxohexanoic acid 1 The compound was prepared from SS1 according to step 3 of general procedure A.

[0432] 1 H NMR (400 MHz, MeOD) δ 8.03 – 7.61 (m, 2H), 7.50 – 7.16 (m, 2H), 2.43 (s, 3H), 2.34 – 2.10 (m, 4H), 1.65 – 1.41 (m, 4H).

[0433] 13 C NMR (151 MHz, MeOD) δ 177.1, 173.5, 146.1, 138.0, 130.5, 129.2, 36.6, 34.4, 25.2, 25.1, 21.5, 21.5.

[0434] HRMS (ESI-TOF): For C 13 H 16 NO5S - [MH] - Calculated value: 298.0749, measured value: 298.0757.

[0435] 2,2-Dimethyl- N -Toluenesulfonylhept-6-enamide SS7 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0436] 1 H NMR (600 MHz, CDCl3) δ 8.25 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.33(d, J = 7.8 Hz, 2H), 5.65 (ddt, J = 17.0, 10.5, 6.7 Hz, 1H), 5.07 – 4.79 (m, 2H), 2.43 (s, 3H), 1.91 (qt, J= 7.2, 1.4 Hz, 2H), 1.55 – 1.37 (m, 2H), 1.17 – 1.03 (m, 8H).

[0437] 13 C NMR (151 MHz, CDCl3) δ 175.4, 145.2, 138.1, 135.6, 129.7, 128.6,115.2, 43.5, 40.4, 33.9, 24.8, 23.8, 21.8.

[0438] HRMS (ESI-TOF): For C 16 H 24 NO3S + [M+H] + Calculated value: 310.1477, measured value: 310.1477.

[0439] 5,5-Dimethyl-6-((4-methylphenyl)sulfinamide)-6-oxohexanoic acid 7 The compound was prepared by SS7 according to general procedure A.

[0440] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.1 Hz,2H), 2.43 (s, 3H), 2.15 (t, J = 7.3 Hz, 2H), 1.55 – 1.39 (m, 2H), 1.28 – 1.19 (m, 2H), 1.09 (s, 6H).

[0441] 13 C NMR (151 MHz, MeOD) δ 178.2, 176.9, 146.1, 137.9, 130.4, 129.3, 44.5, 40.3, 34.9, 24.7, 21.6, 21.1.

[0442] HRMS (ESI-TOF): For C 15 H 20 NO5S - [MH] - Calculated value: 326.1062, measured value: 326.1064.

[0443] 1-(pent-4-en-1-yl)- N -Toluenesulfonylcyclobutane-1-formamide SS8 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0444] 1 H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.33(d, J = 8.1 Hz, 2H), 5.61 (ddt, J = 17.0, 10.4, 6.6 Hz, 1H), 5.12 – 4.68 (m, 2H), 2.43 (s, 3H), 2.33 (qt, J = 7.1, 1.6 Hz, 2H), 1.94 – 1.87 (m, 2H), 1.87 – 1.82(m, 1H), 1.82 – 1.77 (m, 2H), 1.74 (ddd, J = 14.8, 9.3, 4.3 Hz, 1H), 1.69 –1.60 (m, 2H), 1.13 – 0.86 (m, 2H).

[0445] 13 C NMR (151 MHz, CDCl3) δ 174.9, 145.2, 138.0, 135.6, 129.7, 128.5, 115.1, 48.9, 37.7, 33.6, 29.3, 23.6, 21.8, 15.1.

[0446] HRMS (ESI-TOF): For C 17 H 24 NO3S + [M+H] + Calculated value: 322.1477, measured value: 322.1479.

[0447] 4-(1-(toluenesulfonylcarbamoyl)cyclobutyl)butyric acid 8 The compound was prepared by SS8 according to general procedure A.

[0448] 1H NMR (600 MHz, MeOD) δ 7.88 (d, J = 8.4 Hz, 2H), 7.47 – 7.21 (m, 2H), 2.43 (s, 3H), 2.33 – 2.24 (m, 2H), 2.12 (t, J = 7.3 Hz, 2H), 1.91 – 1.78 (m, 3H), 1.78 – 1.61 (m, 3H), 1.13 – 1.05 (m, 2H).

[0449] 13 C NMR (151 MHz, MeOD) δ 177.7, 176.7, 146.1, 137.9, 130.5, 129.2, 50.2, 38.1, 34.6, 30.3, 21.6, 20.9, 15.8.

[0450] HRMS (ESI-TOF): For C 16 H 20 NO5S - [MH] - Calculated value: 338.1062, measured value: 338.1065.

[0451] 1-(pent-4-en-1-yl)- N -Toluenesulfonylcyclopentane-1-formamide SS9 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0452] 1 H NMR (600 MHz, CDCl3) δ 8.59 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.33(d, J = 8.1 Hz, 2H), 5.61 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), 5.30 – 4.68 (m, 2H), 2.43 (s, 3H), 2.11 – 1.94 (m, 2H), 1.94 – 1.79 (m, 2H), 1.62 – 1.48 (m, 6H), 1.48 – 1.33 (m, 2H), 1.13 – 0.87 (m, 2H).

[0453] 13 C NMR (151 MHz, CDCl3) δ 175.2, 145.1, 138.0, 135.6, 129.7, 128.5, 115.0, 55.6, 38.9, 35.2, 33.8, 24.7, 24.5, 21.8.

[0454] HRMS (ESI-TOF): For C 18 H 26 NO3S + [M+H] + Calculated value: 322.1477, measured value: 322.1477.

[0455] 4-(1-(toluenesulfonylcarbamoyl)cyclopentyl)butyric acid 9 The compound was prepared from SS9 according to general procedure A.

[0456] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.56 – 7.29 (m, 2H), 2.43 (s, 3H), 2.12 (t, J = 7.3 Hz, 2H), 2.07 – 2.00 (m, 2H), 1.65 – 1.55 (m,4H), 1.53 – 1.34 (m, 4H), 1.12 (dtd, J = 12.1, 8.2, 5.9 Hz, 2H).

[0457] 13 C NMR (151 MHz, MeOD) δ 177.6, 176.7, 146.1, 137.9, 130.4, 129.3, 56.9, 39.1, 35.9, 34.9, 25.4, 22.0, 21.5.

[0458] HRMS (ESI-TOF): For C 17 H 22 NO5S - [MH] - Calculated value: 352.1219, measured value: 352.1219.

[0459] 4-(pent-4-en-1-yl)- N-Toluenesulfonyltetrahydro-2 H -Pyran-4-carboxamide SS10 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0460] 1 H NMR (600 MHz, CDCl3) δ 8.74 (d, J = 4.3 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.59 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 4.97 –4.77 (m, 2H), 3.71 (dt, J = 12.0, 4.0 Hz, 2H), 3.38 (ddd, J = 11.9, 10.6, 2.3 Hz,2H), 2.45 (s, 3H), 1.91 (dq, J = 11.9, 2.1 Hz, 2H), 1.87 (dtd, J = 7.2, 5.8, 1.4Hz, 2H), 1.55 – 1.46 (m, 2H), 1.46 – 1.41 (m, 2H), 1.15 – 0.80 (m, 2H).

[0461] 13 C NMR (151 MHz, CDCl3) δ 173.7, 145.5, 137.7, 135.5, 129.8, 128.5,115.3, 64.8, 45.9, 39.5, 33.8, 33.7, 22.4, 21.8.

[0462] HRMS (ESI-TOF): For C 18 H 26 NO4S + [M+H] + Calculated value: 352.1583, measured value: 352.1590.

[0463] 4-(4-(toluenesulfonylcarbamoyl)tetrahydro-2- H 10-pyran-4-yl)butyric acid The compound was prepared by SS10 according to general procedure A.

[0464] 1 H NMR (600 MHz, MeOD) δ 7.89 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 3.71 (dt, J = 11.9, 3.9 Hz, 2H), 3.49 – 3.18 (m, 2H), 2.43 (s, 3H), 2.09(t, J = 7.3 Hz, 2H), 1.98 (dp, J = 14.1, 2.3 Hz, 2H), 1.66 – 1.49 (m, 2H), 1.46(ddd, J = 14.7, 11.0, 4.3 Hz, 2H), 1.24 – 0.89 (m, 2H).

[0465] 13 C NMR (151 MHz, MeOD) δ 176.5, 176.0, 146.3, 137.8, 130.4, 129.4, 65.8, 46.8, 39.6, 34.7, 34.6, 21.6, 19.7.

[0466] HRMS (ESI-TOF): For C 17 H 22 NO6S - [MH] - Calculated value: 368.1168, measured value: 368.1178.

[0467] 3-Methyl- N -Toluenesulfonylhept-6-enamide SS11 The compound was obtained commercially from a commercially available source according to general procedure B. Prepared.

[0468] 1 H NMR (600 MHz, CDCl3) δ 8.55 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.34(d, J = 8.1 Hz, 2H), 5.70 (ddt, J= 16.9, 10.2, 6.6 Hz, 1H), 5.03 – 4.79 (m, 2H), 2.44 (s, 3H), 2.23 (dd, J = 14.9, 6.0 Hz, 1H), 2.04 (dd, J = 14.9, 8.1 Hz, 1H),2.04 – 1.98 (m, 1H), 1.98 – 1.87 (m, 2H), 1.37 – 1.26 (m, 1H), 1.25 – 1.16(m, 1H), 0.85 (d, J = 6.6 Hz, 3H).

[0469] 13 C NMR (151 MHz, CDCl3) δ 170.4, 145.3, 138.3, 135.6, 129.8, 128.5,114.9, 43.9, 35.7, 31.1, 29.9, 21.8, 19.4.

[0470] HRMS (ESI-TOF): For C 15 H 22 NO3S + [M+H] + Calculated value: 296.1321, measured value: 296.1314.

[0471] 4-Methyl-6-((4-methylphenyl)sulfinamide)-6-oxohexanoic acid 11 The compound was prepared by SS11 according to general procedure B.

[0472] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H), 2.29 – 2.14 (m, 3H), 2.02 (dd, J = 14.5, 8.1 Hz, 1H), 1.86(ddt, J = 14.3, 8.1, 6.3 Hz, 1H), 1.52 (ddt, J = 13.7, 9.4, 6.1 Hz, 1H), 1.40(dddd, J= 13.8, 9.4, 7.8, 6.1 Hz, 1H), 0.82 (d, J = 6.7 Hz, 3H).

[0473] 13 C NMR (151 MHz, MeOD) δ 177.2, 173.0, 146.1, 137.9, 130.5, 129.2, 44.1, 32.5, 32.4, 31.2, 21.6, 19.3.

[0474] HRMS (ESI-TOF): For C 14 H 18 NO5S - [MH] - Calculated value: 312.0906, measured value: 312.0912.

[0475] 3-(tert-butyl)- N -Toluenesulfonylhept-6-enamide SS12 The compound was obtained according to general procedure B from a known... Prepared.

[0476] 1 H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.33(d, J = 7.8 Hz, 2H), 5.64 (ddt, J = 17.0, 10.5, 6.6 Hz, 1H), 5.05 – 4.68 (m, 2H), 2.43 (s, 3H), 2.35 (dd, J = 16.2, 5.2 Hz, 1H), 1.99 (dd, J = 16.1, 6.5 Hz, 1H),1.85 (dtdd, J = 13.0, 8.0, 4.0, 2.6 Hz, 1H), 1.81 – 1.71 (m, 1H), 1.66 (dddd, J =9.4, 6.4, 5.2, 2.8 Hz, 1H), 1.53 (dddd, J = 13.4, 10.2, 6.4, 2.9 Hz, 1H), 1.01(dtd, J= 13.7, 9.8, 5.1 Hz, 1H), 0.76 (s, 9H).

[0477] 13 C NMR (151 MHz, CDCl3) δ 171.4, 145.3, 138.6, 135.5, 129.7, 128.6, 114.8, 44.0, 38.2, 33.6, 32.8, 30.4, 27.4, 21.8.

[0478] HRMS (ESI-TOF): For C 18 H 28 NO3S + [M+H] + Calculated value: 338.1790, measured value: 338.1802.

[0479] 4-(tert-butyl)-6-((4-methylphenyl)sulfinylamino)-6-oxohexanoic acid 12 The compound was prepared by SS12 according to general procedure B.

[0480] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.2 Hz,2H), 2.43 (s, 3H), 2.37 (dd, J = 16.3, 5.4 Hz, 1H), 2.09 – 1.91 (m, 3H), 1.79(dddd, J = 13.6, 10.6, 6.3, 2.8 Hz, 1H), 1.61 (dddd, J = 9.4, 6.4, 5.4, 2.8 Hz,1H), 1.23 – 1.14 (m, 1H), 0.79 (s, 9H).

[0481] 13 C NMR (151 MHz, MeOD) δ 177.2, 174.0, 146.2, 137.7, 130.5, 129.3, 45.1, 38.2, 34.4, 34.0, 27.6, 27.3, 21.6.

[0482] HRMS (ESI-TOF): For C 17H 24 NO5S - [MH] - Calculated value: 354.1375, measured value: 354.1375.

[0483] 3-Phenyle N -Toluenesulfonylhept-6-enamide SS13 The compound was obtained commercially from a commercially available source according to general procedure B. Prepared.

[0484] 1 H NMR (600 MHz, CDCl3) δ 8.58 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.34 –7.22 (m, 2H), 7.23 – 7.14 (m, 3H), 7.12 – 6.92 (m, 2H), 5.65 (ddt, J = 16.9,10.3, 6.6 Hz, 1H), 5.02 – 4.76 (m, 2H), 3.00 (ddd, J = 15.0, 8.6, 6.4 Hz, 1H),2.55 (dd, J = 14.9, 6.6 Hz, 1H), 2.51 – 2.45 (m, 1H), 2.44 (s, 3H), 1.81 (q, J =7.1 Hz, 2H), 1.62 (tdd, J = 8.3, 6.3, 3.1 Hz, 2H).

[0485] 13 C NMR (151 MHz, CDCl3) δ 169.7, 142.7, 137.9, 135.4, 129.7, 128.8,128.3, 127.5, 126.9, 115.1, 44.0, 41.6, 35.1, 31.3, 21.8.

[0486] HRMS (ESI-TOF): For C 20 H 24 NO3S + [M+H] + Calculated value: 358.1477, measured value: 358.1475.

[0487] 6-((4-methylphenyl)sulfinamide)-6-oxo-4-phenylhexanoic acid 13 The compound was prepared by SS13 according to general procedure B.

[0488] 1 H NMR (600 MHz, MeOD) δ 7.68 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.7 Hz,2H), 7.23 – 7.10 (m, 3H), 7.08 – 6.98 (m, 2H), 2.99 (dddd, J = 10.1, 8.7, 6.5,5.0 Hz, 1H), 2.56 (dd, J = 14.7, 6.5 Hz, 1H), 2.49 (dd, J = 14.7, 8.8 Hz, 1H), 2.42 (s, 3H), 2.09 – 1.94 (m, 2H), 1.86 (dddd, J = 13.8, 8.9, 7.2, 5.0 Hz, 1H),1.77 (dddd, J = 13.6, 10.2, 9.1, 5.7 Hz, 1H).

[0489] 13 C NMR (151 MHz, MeOD) δ 176.9, 172.1, 145.9, 143.5, 137.7, 130.5, 129.6, 129.0, 128.6, 127.8, 44.1, 42.8, 32.7, 32.1, 21.6.

[0490] HRMS (ESI-TOF): For C 19 H 20 NO5S - [MH] - Calculated value: 374.1062, measured value: 374.1067.

[0491] 2-(1-(but-3-en-1-yl)cyclobutyl)- N -Toluenesulfonylacetamide SS14 The compound was obtained according to general procedure B from a known... Prepared.

[0492] 1 H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.34(d, J = 7.9 Hz, 2H), 5.71 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.13 – 4.78 (m, 2H), 2.44 (s, 3H), 2.34 (s, 2H), 2.02 – 1.68 (m, 8H), 1.60 – 1.41 (m, 2H).

[0493] 13 C NMR (151 MHz, CDCl3) δ 169.4, 145.3, 138.8, 135.7, 129.8, 128.5, 114.5, 44.8, 40.7, 37.7, 31.8, 28.7, 21.8, 15.5.

[0494] HRMS (ESI-TOF): For C 17 H 24 NO3S + [M+H] + Calculated value: 322.1477, measured value: 322.1480.

[0495] 3-(1-(2-((4-methylphenyl)sulfinylamino)-2-oxoethyl)cyclobutyl)propionic acid 14 The compound was prepared by SS14 according to general procedure B.

[0496] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H), 2.30 (s, 2H), 2.17 – 2.03 (m, 2H), 2.00 – 1.85 (m, 2H), 1.85 – 1.46 (m, 6H).

[0497] 13C NMR (151 MHz, MeOD) δ 177.5, 172.0, 146.1, 137.9, 130.5, 129.2, 44.5, 41.5, 35.0, 32.1, 30.1, 21.6, 15.9.

[0498] HRMS (ESI-TOF): For C 16 H 20 NO5S - [MH] - Calculated value: 338.1062, measured value: 338.1070.

[0499] 2-(1-(but-3-en-1-yl)cyclopentyl)- N -Toluenesulfonylacetamide SS15 The compound was obtained according to general procedure B from a known... Prepared.

[0500] 1 H NMR (600 MHz, CDCl3) δ 8.77 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.33(d, J = 8.1 Hz, 2H), 5.69 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 5.08 – 4.79 (m, 2H), 2.44 (s, 3H), 2.20 (s, 2H), 1.91 (dddd, J = 13.0, 6.3, 2.8, 1.4 Hz, 2H), 1.65 –1.50 (m, 4H), 1.50 – 1.26 (m, 6H).

[0501] 13 C NMR (151 MHz, CDCl3) δ 169.8, 145.2, 139.0, 135.7, 129.7, 128.5, 114.4, 45.1, 44.4, 37.7, 37.6, 29.4, 24.3, 21.8.

[0502] HRMS (ESI-TOF): For C 18 H 26 NO3S + [M+H] +Calculated value: 336.1634, measured value: 336.1630.

[0503] 3-(1-(2-((4-methylphenyl)sulfinamide)-2-oxoethyl)cyclopentyl)propionic acid 15 The compound was prepared by SS15 according to general procedure B.

[0504] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 7.7 Hz,2H), 2.44 (s, 3H), 2.26 – 2.04 (m, 4H), 1.65 – 1.54 (m, 6H), 1.54 – 1.42 (m,2H), 1.42 – 1.25 (m, 2H).

[0505] 13 C NMR (151 MHz, MeOD) δ 177.7, 172.2, 146.1, 137.9, 130.5, 129.2, 45.9, 44.3, 38.2, 34.8, 30.9, 25.1, 21.6.

[0506] HRMS (ESI-TOF): For C 17 H 22 NO5S - [MH] - Calculated value: 352.1219, measured value: 352.1225.

[0507] N -Toluenesulfonyloctyl-7-enamide SS2 The compound was prepared from commercially available oct-7-enoic acid according to step 2 of general procedure A.

[0508] 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.34(d, J = 8.1 Hz, 2H), 5.73 (ddt, J= 16.9, 10.2, 6.6 Hz, 1H), 5.39 – 4.35 (m, 2H), 2.44 (s, 3H), 2.24 (t, J = 7.5 Hz, 2H), 2.11 – 1.80 (m, 2H), 1.55 (p, J = 7.6 Hz, 2H), 1.47 – 1.07 (m, 4H).

[0509] 13 C NMR (100 MHz, CDCl3) δ 171.2, 145.3, 138.7, 135.6, 129.8, 128.4,114.6, 36.3, 33.5, 28.5, 28.4, 24.2, 21.8.

[0510] HRMS (ESI-TOF): For C 15 H 22 NO3S + [M+H] + Calculated value: 296.1322, measured value: 296.1321.

[0511] 7-((4-methylphenyl)sulfinylamino)-7-oxoheptanoic acid 2 The compound was prepared from SS2 according to general procedure A.

[0512] 1 H NMR (400 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.8 Hz,2H), 2.44 (s, 3H), 2.21 (t, J = 7.4 Hz, 4H), 1.64 – 1.43 (m, 4H), 1.30 – 1.11 (m, 2H).

[0513] 13 C NMR (151 MHz, MeOD) δ 177.4, 173.7, 146.1, 138.0, 130.5, 129.2, 36.7, 34.6, 29.3, 25.6, 25.3, 21.5.

[0514] HRMS (ESI-TOF): For C 14 H 18 NO5S- [MH] - Calculated value: 312.0906, measured value: 312.0902.

[0515] 2,2-Dimethyl- N -Toluenesulfonyloctyl-7-enamide SS16 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0516] 1 H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.33(d, J = 8.1 Hz, 2H), 5.70 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.19 – 4.73 (m, 2H), 2.44 (s, 3H), 1.92 (tdd, J = 6.7, 5.3, 1.4 Hz, 2H), 1.49 – 1.36 (m, 2H), 1.24(p, J = 7.6 Hz, 2H), 1.11 (s, 6H), 1.02 (dtd, J = 9.4, 7.9, 5.2 Hz, 2H).

[0517] 13 C NMR (151 MHz, CDCl3) δ 175.5, 145.1, 138.6, 135.6, 129.7, 128.6,114.7, 43.6, 40.8, 33.6, 29.2, 24.8, 24.0, 21.8.

[0518] HRMS (ESI-TOF): For C 17 H 26 NO3S + [M+H] + Calculated value: 324.1635, measured value: 324.1637.

[0519] 6,6-Dimethyl-7-((4-methylphenyl)sulfinylamino)-7-oxoheptanoic acid 16 The compound was prepared by SS16 according to general procedure A.

[0520] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 7.8 Hz,2H), 2.44 (s, 3H), 2.12 (t, J = 7.5 Hz, 2H), 1.53 – 1.36 (m, 4H), 1.07 (s, 6H), 0.92 (dtd, J = 12.1, 8.7, 6.4 Hz, 2H).

[0521] 13 C NMR (151 MHz, MeOD) δ 178.3, 177.3, 146.1, 138.0, 130.4, 129.3, 44.5, 40.7, 34.6, 26.3, 25.2, 24.8, 21.5.

[0522] HRMS (ESI-TOF): For C 16 H 22 NO5S - [MH] - Calculated value: 340.1219, measured value: 340.1222.

[0523] 1-(hex-5-en-1-yl)- N -Toluenesulfonylcyclobutane-1-formamide SS17 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0524] 1 H NMR (600 MHz, CDCl3) δ 8.18 – 8.02 (m, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.69 (ddt, J= 17.0, 10.3, 6.7 Hz, 1H), 5.18 – 4.71 (m,2H), 2.44 (s, 3H), 2.39 – 2.21 (m, 2H), 2.05 – 1.82 (m, 3H), 1.82 – 1.72 (m,3H), 1.72 – 1.62 (m, 2H), 1.24 (p, J = 7.6 Hz, 2H), 0.92 (qd, J = 10.1, 6.3 Hz, 2H).

[0525] 13 C NMR (151 MHz, CDCl3) δ 174.7, 145.2, 138.5, 135.7, 129.7, 128.6, 114.7, 48.9, 38.4, 33.5, 29.3, 29.0, 24.0, 21.8, 15.1.

[0526] HRMS (ESI-TOF): For C 18 H 26 NO3S + [M+H] + Calculated value: 336.1625, measured value: 336.1629.

[0527] 5-(1-(toluenesulfonylcarbamoyl)cyclobutyl)valerate 17 The compound was prepared by SS17 according to general procedure A.

[0528] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H), 2.38 – 2.20 (m, 2H), 2.08 (t, J = 7.5 Hz, 2H), 1.99 – 1.77(m, 3H), 1.77 – 1.59 (m, 3H), 1.41 (p, J = 7.6 Hz, 2H), 1.05 – 0.65 (m, 2H).

[0529] 13C NMR (151 MHz, MeOD) δ 177.8, 177.2, 146.1, 138.0, 130.5, 129.2, 50.3, 38.6, 34.6, 30.3, 26.0, 25.0, 21.6, 15.8.

[0530] HRMS (ESI-TOF): For C 17 H 22 NO5S - [MH] - Calculated value: 352.1219, measured value: 352.1223.

[0531] 1-(hex-5-en-1-yl)- N -Toluenesulfonylcyclopentane-1-formamide SS6 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0532] 1 H NMR (600 MHz, CDCl3) δ 8.48 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.33(d, J = 8.1 Hz, 2H), 5.69 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.08 – 4.70 (m, 2H), 2.44 (s, 3H), 1.99 (dt, J = 12.9, 5.7 Hz, 2H), 1.88 (q, J = 7.2 Hz, 2H), 1.60 –1.44 (m, 6H), 1.47 – 1.33 (m, 2H), 1.22 (p, J = 7.6 Hz, 2H), 0.94 (qd, J = 10.2, 6.3 Hz, 2H).

[0533] 13 C NMR (151 MHz, CDCl3) δ 175.2, 145.1, 138.6, 135.7, 129.7, 128.5,114.7, 55.6, 39.5, 35.3, 33.5, 29.2, 24.9, 24.8, 21.8.

[0534] HRMS (ESI-TOF): For C 19 H 28 NO3S + [M+H] + Calculated value: 350.1791, measured value: 350.1780.

[0535] 5-(1-(toluenesulfonylcarbamoyl)cyclopentyl)valerate 6 The compound was prepared by SS6 according to general procedure A.

[0536] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.9 Hz,2H), 2.44 (s, 3H), 2.08 (t, J = 7.5 Hz, 2H), 2.02 (dddd, J = 13.1, 6.7, 2.9, 1.4Hz, 2H), 1.57 (ddt, J = 9.4, 4.8, 3.4 Hz, 4H), 1.51 – 1.31 (m, 6H), 0.82 (dddd, J = 12.0, 9.6, 6.7, 5.0 Hz, 2H).

[0537] 13 C NMR (151 MHz, MeOD) δ 177.8, 177.2, 146.1, 138.0, 130.4, 129.3, 57.0, 39.6, 35.9, 34.6, 26.3, 26.1, 25.4, 21.5.

[0538] HRMS (ESI-TOF): For C 18 H 24 NO5S - [MH] - Calculated value: 366.1375, measured value: 366.1373.

[0539] 4-(hex-5-en-1-yl)- N -Toluenesulfonyltetrahydro-2 H -Pyran-4-formamide SS18 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0540] 1 H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.38(d, J = 8.1 Hz, 2H), 5.71 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.13 – 4.83 (m, 2H), 3.75 (dt, J = 12.0, 4.0 Hz, 2H), 3.41 (ddd, J = 12.2, 10.6, 2.3 Hz, 2H), 2.48 (s,3H), 2.04 – 1.80 (m, 4H), 1.53 (ddd, J = 14.4, 10.6, 4.1 Hz, 2H), 1.48 – 1.40 (m, 2H), 1.27 – 1.18 (m, 2H), 0.95 – 0.81 (m, 2H).

[0541] 13 C NMR (151 MHz, CDCl3) δ 173.4, 145.5, 138.4, 135.5, 129.7, 128.6,114.9, 64.8, 45.9, 40.2, 34.0, 33.5, 29.1, 22.8, 21.9.

[0542] HRMS (ESI-TOF): For C 19 H 28 NO4S + [M+H] + Calculated value: 366.1741, measured value: 366.1741.

[0543] 5-(4-(toluenesulfonylcarbamoyl)tetrahydro-2- H 18-pyran-4-yl)valeric acid The compound was prepared by SS18 according to general procedure A.

[0544] 1 H NMR (600 MHz, MeOD) δ 7.89 (d, J= 8.4 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 3.71 (dt, J = 11.9, 3.9 Hz, 2H), 3.42 – 3.30 (m, 2H), 2.45 (s, 3H), 2.06(t, J = 7.5 Hz, 2H), 2.00 – 1.88 (m, 2H), 1.59 – 1.32 (m, 6H), 0.78 (tt, J = 9.6, 7.9 Hz, 2H).

[0545] 13 C NMR (151 MHz, MeOD) δ 177.1, 176.2, 146.2, 138.0, 130.5, 129.4, 65.9, 46.9, 40.1, 34.7, 34.5, 26.2, 23.8, 21.6.

[0546] HRMS (ESI-TOF): For C 18 H 24 NO6S - [MH] - Calculated value: 382.1336, measured value: 382.1333.

[0547] 2-(1-(pent-4-en-1-yl)cyclopentyl)- N -Toluenesulfonylacetamide SS19 The compound was obtained according to general procedure B from a known... Prepared.

[0548] 1 H NMR (600 MHz, CDCl3) δ 8.69 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.34(d, J = 7.8 Hz, 2H), 5.71 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.02 – 4.76 (m, 2H), 2.44 (s, 3H), 2.19 (s, 2H), 1.92 (qt, J= 6.8, 1.4 Hz, 2H), 1.66 – 1.49 (m, 4H), 1.49 – 1.34 (m, 4H), 1.34 – 1.10 (m, 4H).

[0549] 13 C NMR (151 MHz, CDCl3) δ 169.9, 145.2, 138.8, 135.7, 129.7, 128.5,114.6, 114.6, 45.2, 44.5, 38.1, 37.6, 34.4, 24.3, 24.3, 21.8.

[0550] HRMS (ESI-TOF): For C 19 H 28 NO3S + [M+H] + Calculated value: 350.1791, measured value: 350.1795.

[0551] 4-(1-(2-((4-methylphenyl)sulfinamide)-2-oxoethyl)cyclopentyl)butyric acid 19 The compound was prepared by SS19 according to general procedure B.

[0552] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.1 Hz,2H), 2.44 (s, 3H), 2.19 (s, 2H), 2.12 (t, J = 7.4 Hz, 2H), 1.54 (qd, J = 4.4, 1.7Hz, 4H), 1.46 (dqd, J = 15.1, 7.6, 3.3 Hz, 4H), 1.43 – 1.32 (m, 2H), 1.30 –1.20 (m, 2H).

[0553] 13 C NMR (151 MHz, MeOD) δ 177.4, 172.5, 146.1, 138.0, 130.5, 129.2, 46.2, 44.5, 39.4, 38.4, 35.4, 25.1, 21.5.

[0554] HRMS (ESI-TOF): For C 18 H 26 NO5S - [M+H] + Calculated value: 368.1532, measured value: 368.1537.

[0555] The ratio of diastereomers is approximately 1:1 2-(But-3-en-1-yl)- N -Toluenesulfonylcyclopentane-1-formamide SS20 The compound was obtained commercially from a commercially available source according to general procedure B. Prepared.

[0556] 1 H NMR (600 MHz, CDCl3) δ 8.74 – 8.53 (m, 2H), 8.09 – 7.81 (m, 4H), 7.35 – 7.30 (m, 4H), 5.67 (ddt, J = 16.1, 9.4, 6.2 Hz, 1H), 5.60 (ddt, J = 16.1,9.4, 6.2 Hz, 1H), 4.97 – 4.70 (m, 4H), 2.62 (td, J = 7.8, 6.1 Hz, 1H), 2.43 (s,6H), 2.17 (q, J = 8.3 Hz, 1H), 2.13 – 2.00 (m, 2H), 2.00 – 1.91 (m, 2H), 1.91 –1.80 (m, 6H), 1.80 – 1.65 (m, 5H), 1.65 – 1.55 (m, 3H), 1.55 – 1.46 (m, 1H),1.46 – 1.41 (m, 1H), 1.41 – 1.31 (m, 1H), 1.31 – 1.23 (m, 1H), 1.23 – 1.12(m, 2H), 1.02 (dtd, J = 13.4, 9.7, 5.4 Hz, 1H).

[0557] 13C NMR (151 MHz, CDCl3) δ 173.9, 173.0, 145.2, 145.2, 138.4, 138.3,135.7, 135.6, 129.7, 129.7, 128.6, 128.5, 114.7, 114.7, 52.5, 49.3, 43.7,43.5, 34.3, 32.6, 32.5, 32.4, 31.0, 30.5, 29.7, 28.0, 24.8, 23.8, 21.8, 21.8.

[0558] HRMS (ESI-TOF): For C 17 H 24 NO3S - [M+H] + Calculated value: 322.1478, measured value: 322.1473.

[0559] The ratio of diastereomers is approximately 1:1 3-(2-(toluenesulfonylcarbamoyl)cyclopentyl)propionic acid 20 The compound was prepared by SS20 according to general procedure B.

[0560] 1 H NMR (600 MHz, MeOD) δ 8.04 – 7.66 (m, 4H), 7.38 (dd, J = 8.1, 6.1Hz, 4H), 2.71 (td, J = 7.8, 5.6 Hz, 1H), 2.43 (s, 6H), 2.24 (td, J = 8.6, 7.2 Hz,1H), 2.20 – 2.03 (m, 5H), 2.03 – 1.95 (m, 1H), 1.95 – 1.83 (m, 2H), 1.83 –1.70 (m, 4H), 1.68 – 1.55 (m, 4H), 1.55 – 1.45 (m, 2H), 1.42 (dddd, J = 14.1,9.0, 6.9, 5.2 Hz, 1H), 1.36 – 1.26 (m, 1H), 1.25 – 1.16 (m, 1H), 1.12 (dddd, J = 13.5, 9.9, 8.9, 5.9 Hz, 1H).

[0561] 13 C NMR (151 MHz, MeOD) δ 177.1, 176.9, 176.6, 175.6, 146.2, 146.1,137.8, 137.8, 130.5, 130.5, 129.3, 129.1, 53.0, 49.5, 44.9, 44.8, 33.9, 33.7,33.2, 31.9, 31.6, 31.0, 29.0, 27.1, 25.5, 24.7, 21.6, 21.6.

[0562] HRMS (ESI-TOF): For C 16 H 20 NO5S - [MH] - Calculated value: 338.1062, measured value: 338.1064.

[0563] The ratio of diastereomers is approximately 1:1 2-(pent-4-en-1-yl)- N -Toluenesulfonylcyclopentane-1-formamide SS21 The compound was obtained commercially from a commercially available source according to general procedure B. Prepared.

[0564] 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 2H), 7.95 (dd, J = 8.4, 4.7Hz, 4H), 7.34 (d, J = 8.1 Hz, 4H), 6.01 – 5.52 (m, 2H), 5.03 – 4.83 (m, 4H), 2.61 (td, J = 7.7, 6.1 Hz, 1H), 2.44 (s, 6H), 2.20 – 2.09 (m, 1H), 2.09 – 1.98(m, 2H), 1.93 (p, J = 6.7 Hz, 1H), 1.89 – 1.79 (m, 6H), 1.72 (dddd, J= 19.6,12.0, 7.7, 4.2 Hz, 5H), 1.65 – 1.54 (m, 3H), 1.54 – 1.43 (m, 1H), 1.42 – 1.23(m, 4H), 1.23 – 0.99 (m, 5H), 0.92 (dtd, J = 13.1, 10.3, 4.8 Hz, 1H).

[0565] 13 C NMR (100 MHz, CDCl3) δ 174.0, 172.9, 145.2, 145.2, 138.7, 138.7,135.7, 135.6, 129.8, 129.7, 128.6, 128.5, 114.7, 114.6, 52.6, 49.4, 44.2,44.0, 34.6, 33.9, 33.9, 32.5, 31.1, 30.6, 30.0, 28.0, 27.9, 27.6, 24.8, 23.8,21.8, 21.8.

[0566] HRMS (ESI-TOF): For C 18 H 26 NO3S - [M+H] + Calculated value: 336.1634, measured value: 336.1628.

[0567] The diastereomeric ratio is approximately 2:1. Racemization may occur under oxidative cleavage conditions.

[0568] 4-(2-(toluenesulfonylcarbamoyl)cyclopentyl)butyric acid 21 The compound was prepared by SS21 according to general procedure B.

[0569] 1 H NMR (600 MHz, MeOD) δ 8.08 – 7.59 (m, 3H), 7.51 – 7.25 (m, 3H), 2.70 (td, J= 8.0, 5.9 Hz, 1H), 2.50 – 2.35 (m, 4H), 2.26 – 2.18 (m, 0.5H), 2.18 – 2.09 (m, 1H), 2.08 – 1.94 (m, 3H), 1.92 – 1.83 (m, 1H), 1.83 – 1.69 (m, 4H), 1.67 – 1.56 (m, 1H), 1.55 – 1.24 (m, 6H), 1.22 – 1.14 (m, 0.5H), 1.02 (ddt, J = 13.2, 10.8, 5.2 Hz, 1H), 0.80 (dtd, J = 13.1, 10.5, 4.9 Hz, 1H).

[0570] 13 C NMR (151 MHz, MeOD) δ 175.9, 175.8, 175.6, 174.3, 144.8, 144.7,136.6, 136.5, 129.1, 128.0, 127.8, 51.7, 48.1, 43.7, 34.0, 33.4, 32.2, 30.9,30.5, 29.9, 27.6, 24.3, 23.6, 23.6, 23.3, 20.2, 20.2.

[0571] HRMS (ESI-TOF): For C 17 H 22 NO5S - [MH] - Calculated value: 352.1219, measured value: 352.1220.

[0572] Apparent single diastereomer (1 R* ,2 R* )-2-(pent-4-en-1-yl)- N -Toluenesulfonylcyclohexane-1-formamide SS22 The compound was obtained commercially from a commercially available source according to general procedure B. Prepared.

[0573] 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.33(d, J= 8.1 Hz, 2H), 5.69 (ddt, J = 16.9, 10.1, 6.6 Hz, 1H), 5.03 – 4.76 (m, 2H), 2.44 (s, 3H), 2.35 (dt, J = 8.7, 4.3 Hz, 1H), 1.84 (dddd, J = 14.5, 7.9, 4.5, 1.4Hz, 2H), 1.80 – 1.50 (m, 6H), 1.44 – 1.19 (m, 6H), 1.19 – 1.00 (m, 1H), 0.83(ddt, J = 15.9, 8.0, 4.5 Hz, 1H).

[0574] 13 C NMR (100 MHz, CDCl3) δ 172.5, 145.2, 138.7, 135.8, 129.7, 128.5,114.6, 47.5, 37.5, 33.8, 28.2, 28.1, 26.9, 25.5, 24.2, 23.9, 21.8.

[0575] HRMS (ESI-TOF): For C 19 H 28 NO3S - [M+H] + Calculated value: 350.1790, measured value: 350.1792.

[0576] The diastereomeric ratio is approximately 4:1. Racemization may occur under oxidative cleavage conditions.

[0577] 4-(2-(toluenesulfonylcarbamoyl)cyclohexyl)butyric acid 22 The compound was prepared by SS22 according to general procedure B.

[0578] 1 H NMR (600 MHz, MeOD) δ 7.87 (d, J = 8.4 Hz, 2.5H), 7.39 (d, J= 8.2 Hz,2.5H), 2.44 (s, 5H), 2.14 – 1.97 (m, 2.5H), 1.95 – 1.88 (m, 0.25H), 1.85 –1.79 (m, 0.25H), 1.70 (dddd, J = 16.3, 10.2, 6.5, 2.8 Hz, 3H), 1.58 (dddd, J =20.4, 13.5, 8.0, 3.5 Hz, 2.5H), 1.53 – 1.37 (m, 4.5H), 1.36 – 1.13 (m, 5H), 1.00 – 0.90 (m, 0.25H), 0.90 – 0.84 (m, 0.25H), 0.76 (ddd, J = 12.9, 8.8, 4.0Hz, 1H).

[0579] 13 C NMR (151 MHz, MeOD) δ 177.3, 175.5, 146.1, 138.1, 130.5, 129.2, 47.4, 38.6, 35.0, 29.9, 29.1, 25.9, 24.5, 24.0, 23.2, 21.6.

[0580] HRMS (ESI-TOF): For C 18 H 24 NO5S - [MH] - Calculated value: 366.1375, measured value: 366.1380.

[0581] 3-(2-(toluenesulfonylcarbamoyl)phenyl)propionic acid 23 The compound was obtained commercially from a commercially available source according to general procedure A. Prepared.

[0582] 1 H NMR (600 MHz, MeOD) δ 7.97 (d, J = 8.4 Hz, 2H), 7.60 – 7.37 (m, 4H), 7.29 (d, J = 7.6 Hz, 2H), 2.81 (t, J = 7.9 Hz, 2H), 2.46 (s, 3H), 2.32 (dd, J=8.4, 7.3 Hz, 2H).

[0583] 13 C NMR (151 MHz, MeOD) δ 176.1, 169.8, 146.4, 140.8, 137.7, 134.9, 132.4, 131.5, 130.6, 129.3, 128.7, 127.5, 36.2, 29.2, 21.6.

[0584] HRMS (ESI-TOF): For C 17 H 16 NO5S - [MH] - Calculated value: 346.0749, measured value: 346.0757.

[0585] 4-(2-(toluenesulfonylcarbamoyl)phenyl)butyric acid 24 The compound was obtained commercially from a commercially available source according to general procedure A. The reaction of the divalent anion of benzoic acid starting material with 4-bromobut-1-ene was found to have a rather low yield (approximately 20%). It is speculated that the competitive E2 elimination of 4-bromobut-1-ene to butadiene is more readily achieved than the desired alkylation reaction.

[0586] 1 H NMR (600 MHz, MeOD) δ 8.21 – 7.64 (m, 2H), 7.48 – 7.32 (m, 4H), 7.32 – 7.13 (m, 2H), 2.78 – 2.50 (m, 2H), 2.47 (s, 3H), 2.13 – 1.89 (m, 2H),1.54 (q, J = 7.8 Hz, 2H).

[0587] 13 C NMR (151 MHz, MeOD) δ 176.9, 170.3, 146.3, 141.7, 138.0, 135.2, 132.1, 131.5, 130.6, 129.4, 128.6, 127.3, 34.4, 33.2, 27.8, 21.6.

[0588] HRMS (ESI-TOF): For C 18 H 18 NO5S - [MH]- Calculated value: 360.0906, measured value: 360.0906.

[0589] 6-(methoxyamino)-6-oxohexanoic acid 25 Note: This compound was found to have considerable water solubility. Therefore, the following synthetic sequence was designed for its synthesis.

[0590] Figure S19. Procedure for preparing 25.

[0591] According to the program reported by Robert and his collaborators 7 The acid anhydride S25 was prepared by stirring adipic acid S24 (10 mmol), MgCl2 (2 mol%), and Boc2O (10 mmol) in THF (10 mL) at 40 °C for 1 hour. Crude acid anhydride S25 was obtained by evaporating the evaporator under reduced pressure and immediately redissolved in anhydrous DCM (0.1 M), followed by the addition of benzyl alcohol (11 mmol), Et3N (11 mmol), and DMAP (1 mmol) and stirring overnight. The reaction mixture was then diluted with 1 M HCl. (水溶液) Quenching with 1M HCl (水溶液) Wash three times. Collect the organic layer, dry with anhydrous MgSO4, filter and concentrate to obtain crude monobenzyl ester S26. Purify crude ester S26 by rapid column chromatography (20% EA / hexane to 50% EA / hexane) in two steps to obtain known pure ester S26 (1.4 g, 6.1 mmol) in 61% yield. 8 Ester S26 (5.0 mmol) was then dissolved in DCM (0.1 M), followed by the sequential addition of MeONH2·HCl (5.5 mmol), Et3N (5.5 mmol), and EDCI (5.5 mmol) and stirring at room temperature for 2 hours. The reaction mixture was then diluted with 1 M HCl. (水溶液) Quenching with 1M HCl (水溶液) The mixture was washed three times. The organic layer was collected, dried over anhydrous MgSO4, filtered, and concentrated to give crude amide ester S27. Crude S27 was purified by rapid column chromatography (50% EA / hexane to 70% EA / hexane) to give S27 (1.3 g, 4.8 mmol) in 96% yield. Compound S27 was then hydrogenolyzed in EtOH with Pd / C and H2 (balloon pressure) to give 25 in quantitative yield after removal of volatiles.

[0592] 6-(methoxyamino)-6-oxohexanoic acid benzyl ester S27 1 H NMR (600 MHz, CDCl3) δ 7.58 – 7.29 (m, 5H), 5.11 (s, 2H), 3.74 (s,3H), 2.51 – 2.27 (m, 2H), 2.09 (s, 2H), 1.81 – 1.54 (m, 4H).

[0593] 13 C NMR (151 MHz, CDCl3) δ 173.5, 170.5, 136.0, 128.7, 128.4, 128.4, 66.4, 64.6, 33.9, 32.9, 24.8, 24.3.

[0594] HRMS (ESI-TOF): For C 14 H 20 NO4 + [M+H] + Calculated value: 266.1394, measured value: 266.1399.

[0595] 6-(methoxyamino)-6-oxohexanoic acid 25 1 H NMR (600 MHz, MeOD) δ 3.68 (s, 3H), 2.31 (t, J = 6.9 Hz, 2H), 2.10(t, J = 6.9 Hz, 2H), 1.70 – 1.55 (m, 4H).

[0596] 13 C NMR (151 MHz, MeOD) δ 177.2, 172.4, 64.3, 34.5, 33.4, 26.0, 25.4.

[0597] HRMS (ESI-TOF): For C7H 12 NO4 - [MH] - Calculated value: 174.0766, measured value: 174.0773.

[0598] Synthesis and characterization of substrates used in cyclic amination reactions General procedure C for the preparation of α-substituted amino acids (unless otherwise specified): Figure S20. General procedure for preparing α-substituted amino acids.

[0599] Step 1: Intermediate S10 is prepared according to the general procedure A as described above.

[0600] Step 2: Dissolve intermediate S10 in toluene (0.1 M) and add Et3N (1.1 equivalents), followed by DPPA (1.1 equivalents). Stir the reaction mixture at room temperature for 30 minutes, then heat to reflux and stir under reflux for 2 hours (Note: a large amount of gas escapes). Cool the reaction mixture to room temperature and quench it by adding deionized water. Wash the organic layer three times with deionized water, then dry it with anhydrous MgSO4, filter and concentrate under reduced pressure to give crude isocyanate S28.

[0601] Steps 3 and 4: Crude isocyanate S28 was then dissolved in 1,4-dioxane (0.1 M) and stirred at room temperature. HCl aqueous solution (6 M) was added dropwise until the pH of the reaction mixture was approximately 1. The reaction mixture was stirred overnight and then alkalized with NaOH aqueous solution (3.75 M) to pH ~ 12. The reaction mixture was then diluted with deionized water and extracted three times with Et₂O. The organic layers were collected, dried over anhydrous MgSO₄, filtered, and concentrated to give crude amine. The crude amine was dissolved in DCM at room temperature, followed by the addition of Et₃N (1.1 equivalents) and TsCl (1.1 equivalents) and stirred overnight. The reaction mixture was then quenched with saturated NaHCO₃ and extracted three times with DCM. The organic layers were combined, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure to give crude toluenesulfonyl-protected amine S29. The crude toluenesulfonyl-protected amine S29 was purified by rapid column chromatography (elution polarity range: 20% EA / hexane to 50% EA / hexane). For this four-step sequence, the average yield of S29 was approximately 35%.

[0602] Step 5: Perform oxidative pyrolysis as described in general procedure A.

[0603] General procedure D for the preparation of β-substituted amino acids (unless otherwise specified): Figure S21. General procedure for preparing β-substituted amino acids.

[0604] Step 1: Intermediate S11 is prepared according to general procedure A as described above.

[0605] Step 2: Dissolve intermediate S11 in anhydrous THF (0.1 M) and cool to 0°C. Add LiAlH4 solution (2.0 M Et2O solution, 4 equivalents) dropwise to the reaction mixture (Note: a large amount of gas will escape). After addition, gradually warm the reaction mixture to room temperature and stir overnight. Then, post-process the reaction mixture using the Fisher workup program (dilute the reaction mixture with Et2O and cool to 0°C. For x g of LiAlH4, add x mL of water, followed by x mL of 15% NaOH aqueous solution, then add 3x mL of water. After addition, warm the reaction mixture to room temperature and stir for 15 min, then add anhydrous MgSO4, stir for another 15 min, and filter). Purify crude S31 by rapid column chromatography (elution polarity range: 20% EA / hexane to 50% EA / hexane). The average yield of S31 for this reduction is approximately 60%.

[0606] Step 3: Perform oxidative pyrolysis as described in general procedure A.

[0607] General procedure E for the preparation of γ-substituted amic acids (unless otherwise specified): Figure S22. General procedure for preparing γ-substituted ammonic acids.

[0608] Step 1: Intermediate S20 is prepared according to general procedure B as described above.

[0609] Step 2: Intermediate S33 is prepared according to the general procedure D as described above.

[0610] Step 3: Perform oxidative pyrolysis as described in general procedure B.

[0611] 6-((4-methylphenyl)sulfinylamino)hexanoic acid 26 The known compound was prepared from commercially available 6-aminohexanoic acid according to a method reported by Pavlidis and collaborators. 9 N -(2,2-Dimethylnon-8-en-3-yl)-4-methylbenzenesulfonamide SS27 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0612] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J= 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.69 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 – 4.79 (m, 2H), 4.29 (td, J =9.0, 3.8 Hz, 1H), 3.02 (td, J = 9.6, 2.9 Hz, 1H), 2.41 (s, 3H), 1.95 – 1.77 (m,2H), 1.53 (dddd, J = 14.6, 11.3, 6.4, 3.5 Hz, 1H), 1.31 – 1.20 (m, 1H), 1.20 –1.01 (m, 3H), 0.96 (dtd, J = 15.4, 12.0, 6.6 Hz, 1H), 0.82 (s, 9H).

[0613] 13 C NMR (151 MHz, CDCl3) δ 143.0, 139.5, 138.9, 129.5, 127.1, 114.4, 63.7, 35.2, 33.7, 31.8, 29.0, 26.9, 26.7, 21.6.

[0614] HRMS (ESI-TOF): For C 18 H 30 NO2S + [M+H] + Calculated value: 324.1999, measured value: 324.2002.

[0615] 7,7-Dimethyl-6-((4-methylphenyl)sulfinylamino)octanoic acid 27 The compound was prepared by SS27 according to general procedure C.

[0616] 1 H NMR (600 MHz, MeOD) δ 7.72 (d, J = 8.3 Hz, 2H), 7.49 – 7.12 (m, 2H), 2.94 (dd, J= 10.3, 2.8 Hz, 1H), 2.42 (s, 3H), 2.13 – 1.89 (m, 2H), 1.51 (dddd, J = 13.7, 10.5, 6.1, 2.8 Hz, 1H), 1.46 – 1.34 (m, 1H), 1.34 – 1.23 (m, 1H), 1.18 (dtd, J = 14.1, 10.4, 4.7 Hz, 1H), 0.86 (s, 10H), 0.79 (ddt, J = 15.4, 12.4, 5.1 Hz, 1H).

[0617] 13 C NMR (151 MHz, MeOD) δ 177.3, 144.1, 141.6, 130.5, 127.9, 64.6, 36.1, 34.7, 31.7, 28.1, 27.4, 25.8, 21.4.

[0618] HRMS (ESI-TOF): For C 17 H 26 NO4S - [MH] - Calculated value: 340.1583, measured value: 340.1581.

[0619] 4-Methyl- N -(1-Phenylacetyl-6-en-1-yl)benzenesulfonamide SS28 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0620] 1 H NMR (600 MHz, CDCl3) δ 7.65 – 7.49 (m, 2H), 7.17 – 7.06 (m, 5H), 7.06 – 6.85 (m, 2H), 5.70 (ddt, J = 17.0, 9.6, 6.6 Hz, 1H), 5.25 – 5.08 (m,1H), 5.05 – 4.79 (m, 2H), 4.25 (q, J = 7.4 Hz, 1H), 2.35 (s, 3H), 1.93 (q, J=7.1 Hz, 2H), 1.86 – 1.71 (m, 1H), 1.71 – 1.62 (m, 1H), 1.37 – 1.19 (m, 3H), 1.11 (dp, J = 15.7, 4.3 Hz, 1H).

[0621] 13 C NMR (151 MHz, CDCl3) δ 143.0, 141.1, 138.7, 137.8, 129.4, 128.5,127.4, 127.2, 126.6, 114.6, 58.4, 37.6, 33.5, 28.5, 25.4, 21.6.

[0622] HRMS (ESI-TOF): For C 20 H 26 NO2S + [M+H] + Calculated value: 344.1686, measured value: 344.1679.

[0623] 6-((4-methylphenyl)sulfinylamino)-6-phenylhexanoic acid 28 The compound was prepared by SS28 according to general procedure C.

[0624] 1 H NMR (600 MHz, MeOD) δ 7.65 – 7.41 (m, 2H), 7.20 – 7.00 (m, 7H), 4.21 (t, J = 7.4 Hz, 1H), 2.33 (s, 3H), 2.15 (t, J = 7.4 Hz, 2H), 1.69 (dddd, J =13.5, 9.7, 6.2, 4.1 Hz, 1H), 1.66 – 1.55 (m, 1H), 1.49 (dddd, J = 13.1, 8.9,7.2, 5.7 Hz, 2H), 1.27 (dddd, J = 21.9, 14.2, 10.9, 6.3 Hz, 1H), 1.13 (dddd, J =19.2, 12.9, 9.6, 6.1 Hz, 1H).

[0625] 13C NMR (151 MHz, MeOD) δ 177.3, 144.0, 143.3, 139.9, 130.2, 130.2,129.2, 127.9, 127.9, 127.7, 59.3, 38.4, 34.7, 26.8, 25.5, 21.4.

[0626] HRMS (ESI-TOF): For C 19 H 22 NO4S - [MH] - Calculated value: 360.1270, measured value: 360.1281.

[0627] 4-Methyl- N -(2-Methyloct-7-en-2-yl)benzenesulfonamide SS29 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0628] 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.74 (ddt, J = 16.9, 9.9, 6.8 Hz, 1H), 5.08 – 4.87 (m, 2H), 4.83 (s, 1H), 2.40 (s, 3H), 2.07 – 1.84 (m, 2H), 1.54 – 1.38 (m, 2H), 1.25 – 1.21 (m, 4H),1.15 (s, 6H).

[0629] 13 C NMR (151 MHz, CDCl3) δ 142.9, 140.8, 138.9, 129.5, 127.1, 114.5, 57.2, 42.8, 33.7, 29.1, 27.8, 23.4, 21.6.

[0630] HRMS (ESI-TOF): For C 16 H 26 NO2S + [M+H] + Calculated value: 296.1686, measured value: 296.1688.

[0631] 6-Methyl-6-((4-methylphenyl)sulfinylamino)heptanoic acid 29 The compound was prepared by SS29 according to general procedure C.

[0632] 1 H NMR (600 MHz, MeOD) δ 7.75 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.1 Hz,2H), 2.42 (s, 3H), 2.20 (t, J = 7.5 Hz, 2H), 1.62 – 1.35 (m, 4H), 1.26 (ttd, J =10.4, 6.6, 2.8 Hz, 2H), 1.13 (s, 6H).

[0633] 13 C NMR (151 MHz, MeOD) δ 177.5, 144.1, 142.7, 130.5, 127.9, 57.4, 43.2, 34.8, 28.2, 26.3, 24.6, 21.4.

[0634] HRMS (ESI-TOF): For C 15 H 22 NO4S - [MH] - Calculated value: 312.1270, measured value: 312.1275.

[0635] N -(1-(hex-5-en-1-yl)cyclobutyl)-4-methylbenzenesulfonamide SS30 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0636] 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.72 (ddt, J= 16.9, 9.9, 6.7 Hz, 1H), 5.17 – 4.84 (m, 2H), 4.77 (s, 1H), 2.41 (s, 3H), 2.15 (qd, J = 9.6, 2.7 Hz, 2H), 1.99 – 1.82 (m, 4H), 1.82 – 1.72(m, 1H), 1.72 – 1.58 (m, 3H), 1.31 – 1.04 (m, 4H).

[0637] 13 C NMR (151 MHz, CDCl3) δ 143.1, 140.2, 138.9, 129.6, 127.1, 114.5, 59.8, 37.8, 33.8, 33.7, 29.0, 23.1, 21.6, 15.0.

[0638] HRMS (ESI-TOF): For C 17 H 26 NO2S + [M+H] + Calculated value: 308.1686, measured value: 308.1686.

[0639] 5-(1-((4-methylphenyl)sulfinylamino)cyclobutyl)valeric acid 30 The compound was prepared by SS30 according to general procedure C.

[0640] 1 H NMR (600 MHz, MeOD) δ 7.75 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz,2H), 2.42 (s, 3H), 2.26 – 2.04 (m, 4H), 1.89 – 1.79 (m, 2H), 1.79 – 1.58 (m,4H), 1.34 (p, J = 7.6 Hz, 2H), 1.14 (tt, J = 9.6, 5.9 Hz, 2H).

[0641] 13C NMR (151 MHz, MeOD) δ 177.5, 144.3, 142.2, 130.6, 127.9, 60.4, 38.6, 35.0, 34.4, 26.1, 24.2, 21.4, 15.8.

[0642] HRMS (ESI-TOF): For C 16 H 22 NO4S - [MH] - Calculated value: 324.1270, measured value: 324.1270.

[0643] N -(1-(hex-5-en-1-yl)cyclopentyl)-4-methylbenzenesulfonamide SS31 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0644] 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 6.7 Hz, 2H), 5.73 (ddt, J = 16.9, 9.9, 6.7 Hz, 1H), 5.10 – 4.80 (m, 2H), 4.48 (s, 1H), 2.41 (s, 3H), 1.93 (q, J = 7.0 Hz, 2H), 1.83 (ddd, J = 12.1, 5.4, 2.8 Hz, 2H), 1.63 – 1.39 (m, 8H), 1.32 – 1.05 (m, 4H).

[0645] 13 C NMR (151 MHz, CDCl3) δ 142.9, 140.5, 139.0, 129.6, 127.0, 114.4, 68.6, 38.9, 38.3, 33.8, 29.2, 24.3, 22.9, 21.6.

[0646] HRMS (ESI-TOF): For C 18 H 28 NO2S + [M+H] +Calculated value: 322.1842, measured value: 322.1840.

[0647] 5-(1-((4-methylphenyl)sulfinylamino)cyclopentyl)valerate 31 The compound was prepared by SS31 according to general procedure C.

[0648] 1 H NMR (600 MHz, MeOD) δ 7.76 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz,2H), 2.42 (s, 3H), 2.12 (t, J = 7.5 Hz, 2H), 1.95 – 1.83 (m, 2H), 1.65 – 1.48 (m, 6H), 1.48 – 1.35 (m, 2H), 1.31 (p, J = 7.4 Hz, 2H), 1.22 (dddd, J = 16.6,10.7, 6.6, 3.1 Hz, 2H).

[0649] 13 C NMR (151 MHz, MeOD) δ 177.5, 144.1, 142.6, 130.5, 127.8, 69.0, 39.9, 39.0, 35.0, 26.3, 25.4, 23.7, 21.4.

[0650] HRMS (ESI-TOF): For C 17 H 24 NO4S - [MH] - Calculated value: 338.1426, measured value: 338.1428.

[0651] N -(4-(hex-5-en-1-yl)tetrahydro-2 H -pyran-4-yl)-4-methylbenzenesulfonamide SS32 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0652] 1 H NMR (600 MHz, CDCl3) δ 7.79 (d,J = 8.3 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 5.70 (ddt, J = 16.9, 9.8, 6.7 Hz, 1H), 5.08 – 4.80 (m, 3H), 3.79 – 3.37(m, 4H), 2.41 (s, 3H), 1.89 (q, J = 7.2 Hz, 2H), 1.82 (dt, J = 14.1, 2.7 Hz, 2H), 1.65 – 1.46 (m, 4H), 1.24 – 0.96 (m, 4H).

[0653] 13 C NMR (151 MHz, CDCl3) δ 143.3, 140.4, 138.8, 129.7, 127.0, 114.5,114.5, 63.5, 57.4, 39.6, 36.2, 33.8, 28.9, 22.1, 21.6.

[0654] HRMS (ESI-TOF): For C 18 H 28 NO3S + [M+H] + Calculated value: 338.1790, measured value: 338.1799.

[0655] 5-(4-((4-methylphenyl)sulfinylamino)tetrahydro-2H-pyran-4-yl)valeric acid 32 The compound was prepared by SS32 according to general procedure C.

[0656] 1 H NMR (600 MHz, MeOD) δ 7.78 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 3.60 (dd, J = 8.7, 2.5 Hz, 4H), 2.42 (s, 3H), 2.06 (t, J = 7.4 Hz, 2H), 1.93(dq, J = 14.3, 2.7 Hz, 2H), 1.49 (ddd, J= 14.6, 8.7, 6.6 Hz, 2H), 1.46 – 1.35(m, 2H), 1.23 – 1.13 (m, 2H), 1.10 (tdd, J = 10.9, 6.0, 2.6 Hz, 2H).

[0657] 13 C NMR (151 MHz, MeOD) δ 177.3, 144.5, 142.5, 130.6, 127.9, 64.5, 57.7, 40.9, 37.1, 34.9, 26.1, 23.1, 21.4.

[0658] HRMS (ESI-TOF): For C 17 H 24 NO5S - [MH] - Calculated value: 354.1375, measured value: 354.1374.

[0659] N -(2,2-Dimethylhept-6-en-1-yl)-4-methylbenzenesulfonamide SS33 The compound was obtained commercially from a commercially available source according to general procedure D. Prepared.

[0660] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.74 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.16 – 4.80 (m, 2H), 4.61 (t, J =6.8 Hz, 1H), 2.67 (d, J = 6.8 Hz, 2H), 2.42 (s, 3H), 2.09 – 1.83 (m, 2H), 1.30 – 1.20 (m, 2H), 1.20 – 1.09 (m, 2H), 0.83 (s, 6H).

[0661] 13C NMR (151 MHz, CDCl3) δ 143.4, 138.8, 137.1, 129.8, 127.2, 114.7, 53.1, 39.0, 34.4, 33.8, 25.0, 23.2, 21.6.

[0662] HRMS (ESI-TOF): For C 16 H 26 NO2S + [M+H] + Calculated value: 296.1685, measured value: 296.1682.

[0663] 5,5-Dimethyl-6-((4-methylphenyl)sulfinylamino)hexanoic acid 33 The compound was prepared by SS33 according to general procedure D.

[0664] 1 H NMR (600 MHz, MeOD) δ 7.72 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.1 Hz,2H), 2.59 (s, 2H), 2.42 (s, 3H), 2.22 (t, J = 7.3 Hz, 2H), 1.48 (dtd, J = 14.7,7.4, 4.3 Hz, 2H), 1.28 – 1.17 (m, 2H), 0.85 (s, 6H).

[0665] 13 C NMR (151 MHz, MeOD) δ 177.6, 144.5, 139.1, 130.7, 128.0, 53.8, 39.8, 35.3, 34.8, 25.3, 21.4, 20.3.

[0666] HRMS (ESI-TOF): For C 15 H 22 NO4S - [MH] - Calculated value: 312.1270, measured value: 312.1273.

[0667] 4-Methyl- N-((1-(pent-4-en-1-yl)cyclobutyl)methyl)benzenesulfonamide SS34 The compound was obtained commercially from a commercially available source according to general procedure D. Prepared.

[0668] 1 H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.73 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.11 – 4.82 (m, 2H), 4.42 (t, J =6.4 Hz, 1H), 2.90 (d, J = 6.4 Hz, 2H), 2.43 (s, 3H), 1.96 (q, J = 7.2 Hz, 2H),1.89 – 1.74 (m, 2H), 1.68 (dd, J = 8.3, 6.2 Hz, 4H), 1.45 – 1.31 (m, 2H), 1.23 – 1.06 (m, 2H).

[0669] 13 C NMR (151 MHz, CDCl3) δ 143.5, 138.8, 137.0, 129.8, 127.3, 114.8, 49.4, 41.2, 36.6, 34.2, 29.3, 23.0, 21.7, 15.1.

[0670] HRMS (ESI-TOF): For C 17 H 26 NO2S + [M+H] + Calculated value: 308.1686, measured value: 308.1680.

[0671] 4-(1-(((4-methylphenyl)sulfinylamino)methyl)cyclobutyl)butyric acid 34 The compound was prepared by SS34 according to general procedure D.

[0672] 1 H NMR (600 MHz, MeOD) δ 7.74 (d, J= 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz,2H), 2.83 (s, 2H), 2.43 (s, 3H), 2.23 (t, J = 7.1 Hz, 2H), 1.90 – 1.65 (m, 6H), 1.49 – 1.42 (m, 2H), 1.40 (qd, J = 6.5, 2.1 Hz, 2H).

[0673] 13 C NMR (151 MHz, MeOD) δ 177.5, 144.5, 139.1, 130.7, 128.0, 50.2, 42.5, 37.6, 35.1, 30.1, 21.4, 20.1, 15.6.

[0674] HRMS (ESI-TOF): For C 16 H 22 NO4S - [MH] - Calculated value: 324.1270, measured value: 324.1272.

[0675] 4-Methyl- N -((1-(pent-4-en-1-yl)cyclopentyl)methyl)benzenesulfonamide SS35 The compound was obtained commercially from a commercially available source according to general procedure D. Prepared.

[0676] 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.49 – 7.28 (m, 2H), 5.72 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.19 – 4.81 (m, 2H), 4.28 (t, J = 6.5 Hz, 1H), 2.75 (d, J= 6.6 Hz, 2H), 2.43 (s, 3H), 2.20 – 1.83 (m, 2H), 1.65 – 1.46(m, 4H), 1.44 – 1.30 (m, 4H), 1.30 – 1.24 (m, 2H), 1.24 – 1.08 (m, 2H).

[0677] 13 C NMR (100 MHz, CDCl3) δ 143.5, 138.8, 136.9, 129.9, 127.3, 114.8, 49.7, 45.4, 37.0, 35.7, 34.4, 25.0, 23.8, 21.7.

[0678] HRMS (ESI-TOF): For C 18 H 28 NO2S + [M+H] + Calculated value: 322.1842, measured value: 322.1841.

[0679] 4-(1-(((4-methylphenyl)sulfinylamino)methyl)cyclopentyl)butyric acid 35 The compound was prepared by SS35 according to general procedure D.

[0680] 1 H NMR (600 MHz, MeOD) δ 7.73 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz,2H), 2.67 (s, 2H), 2.42 (s, 3H), 2.22 (t, J = 7.1 Hz, 2H), 1.60 – 1.47 (m, 4H), 1.47 – 1.39 (m, 4H), 1.39 – 1.24 (m, 4H).

[0681] 13 C NMR (151 MHz, MeOD) δ 177.6, 144.5, 139.0, 130.7, 128.0, 50.4, 46.8, 37.9, 36.4, 35.2, 25.7, 21.4, 20.9.

[0682] HRMS (ESI-TOF): For C 17 H24 NO4S - [MH] - Calculated value: 338.1426, measured value: 338.1430.

[0683] 4-Methyl- N -(3-Methylhept-6-en-1-yl)benzenesulfonamide SS36 The compound was obtained commercially available according to general procedure E. Prepared.

[0684] 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 5.73 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), 5.20 – 4.80 (m, 2H), 4.42 (t, J =6.2 Hz, 1H), 3.41 – 2.78 (m, 2H), 2.43 (s, 3H), 2.18 – 1.82 (m, 2H), 1.54 –1.38 (m, 2H), 1.38 – 1.23 (m, 2H), 1.15 (dddd, J = 13.5, 9.6, 7.5, 5.8 Hz, 1H),0.81 (d, J = 6.3 Hz, 3H).

[0685] 13 C NMR (100 MHz, CDCl3) δ 143.5, 138.9, 137.0, 129.8, 127.2, 114.6, 41.3, 36.6, 35.9, 31.2, 29.7, 21.7, 19.2.

[0686] HRMS (ESI-TOF): For C 15 H 24 NO2S + [M+H] + Calculated value: 282.1528, measured value: 282.1528.

[0687] 4-Methyl-6-((4-methylphenyl)sulfinylamino)hexanoic acid 36 The compound was prepared by SS36 according to general procedure E.

[0688] 1 H NMR (600 MHz, MeOD) δ 7.72 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 2.86 (ddd, J = 14.9, 7.7, 5.8 Hz, 2H), 2.43 (s, 3H), 2.33 – 2.14 (m, 2H),1.54 (dddd, J = 13.2, 9.1, 6.5, 5.2 Hz, 1H), 1.51 – 1.41 (m, 2H), 1.35 (dddd, J =13.4, 9.0, 7.4, 6.0 Hz, 1H), 1.29 – 1.18 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H).

[0689] 13 C NMR (151 MHz, MeOD) δ 177.7, 144.6, 139.0, 130.7, 128.1, 41.9, 37.3, 32.8, 32.5, 30.9, 21.4, 19.2.

[0690] HRMS (ESI-TOF): For C 14 H 20 NO4S - [MH] - Calculated value: 298.1113, measured value: 298.1112.

[0691] N -(3-(tert-butyl)hept-6-en-1-yl)-4-methylbenzenesulfonamide SS37 This compound was obtained according to general procedure E from a known... Prepared.

[0692] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 5.71 (ddt,J = 16.9, 10.1, 6.7 Hz, 1H), 5.19 – 4.80 (m, 2H), 4.44 (t, J =5.9 Hz, 1H), 2.97 (ddt, J = 11.9, 9.5, 5.8 Hz, 1H), 2.89 (ddt, J = 12.6, 9.1, 6.5Hz, 1H), 2.42 (s, 3H), 1.98 (dq, J = 14.9, 6.6 Hz, 1H), 1.89 (dq, J = 14.6, 7.2Hz, 1H), 1.65 – 1.56 (m, 1H), 1.52 (dddd, J = 13.4, 9.7, 6.3, 3.2 Hz, 1H), 1.22– 1.13 (m, 1H), 1.07 – 0.96 (m, 1H), 0.84 (tt, J = 7.4, 3.5 Hz, 1H), 0.79 (s,9H).

[0693] 13 C NMR (151 MHz, CDCl3) δ 143.5, 139.0, 137.1, 129.8, 127.3, 114.8, 45.2, 43.5, 33.9, 33.7, 31.7, 30.6, 27.6, 21.6.

[0694] HRMS (ESI-TOF): For C 18 H 30 NO2S + [M+H] + Calculated value: 324.1998, measured value: 324.1993.

[0695] 5,5-Dimethyl-4-(2-((4-methylphenyl)sulfinylamino)ethyl)hexanoic acid 37 The compound was prepared by SS37 according to general procedure E.

[0696] 1 H NMR (600 MHz, MeOD) δ 7.73 (d, J = 8.3 Hz, 2H), 7.37 (d, J= 8.0 Hz,2H), 2.93 – 2.77 (m, 2H), 2.42 (s, 3H), 2.29 (ddd, J = 15.6, 9.9, 5.5 Hz, 1H),2.17 (ddd, J = 16.0, 9.7, 6.6 Hz, 1H), 1.79 (dddd, J = 13.6, 10.0, 6.6, 3.5 Hz,1H), 1.71 – 1.54 (m, 1H), 1.33 – 1.20 (m, 1H), 1.20 – 1.08 (m, 1H), 0.90 (dp, J = 10.2, 3.8 Hz, 1H), 0.83 (s, 9H).

[0697] 13 C NMR (151 MHz, MeOD) δ 177.5, 144.6, 139.0, 130.7, 128.1, 46.3, 44.4, 34.6, 34.5, 32.4, 27.9, 27.7, 21.4.

[0698] HRMS (ESI-TOF): For C 17 H 26 NO4S - [MH] - Calculated value: 340.1583, measured value: 340.1586.

[0699] 4-Methyl- N -(3-Phenylacetyl-6-en-1-yl)benzenesulfonamide SS38 The compound was obtained commercially available according to general procedure E. Prepared.

[0700] 1 H NMR (600 MHz, CDCl3) δ 7.86 – 7.43 (m, 2H), 7.39 – 7.24 (m, 4H), 7.24 – 7.11 (m, 1H), 7.04 (d, J = 7.4 Hz, 2H), 5.70 (ddt, J = 17.3, 12.8, 5.5 Hz,1H), 5.08 – 4.67 (m, 2H), 4.37 (t, J= 6.0 Hz, 1H), 2.78 (tt, J = 13.1, 6.1 Hz,2H), 2.54 (ddd, J = 11.0, 7.6, 4.7 Hz, 1H), 2.42 (s, 3H), 1.98 – 1.77 (m, 3H), 1.69 (ddt, J = 13.3, 10.3, 6.7 Hz, 1H), 1.62 (q, J = 7.6 Hz, 2H).

[0701] 13 C NMR (151 MHz, CDCl3) δ 143.8, 143.4, 138.4, 137.0, 129.8, 128.7,127.7, 127.2, 126.6, 114.9, 114.8, 42.7, 41.6, 36.6, 35.9, 31.6, 21.6.

[0702] HRMS (ESI-TOF): For C 20 H 26 NO2S + [M+H] + Calculated value: 344.1685, measured value: 344.1688.

[0703] 6-((4-methylphenyl)sulfinylamino)-4-phenylhexanoic acid 38 The compound was prepared by SS38 according to general procedure E.

[0704] 1 H NMR (600 MHz, MeOD) δ 7.63 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.22 – 7.10 (m, 1H), 7.10 – 7.00 (m, 2H), 2.65(t, J = 7.5 Hz, 2H), 2.57 (tt, J = 10.0, 4.9 Hz, 1H), 2.41 (s, 3H), 2.12 – 1.94(m, 2H), 1.88 (dddd, J= 13.7, 8.8, 7.3, 4.9 Hz, 1H), 1.83 – 1.63 (m, 3H).

[0705] 13 C NMR (151 MHz, MeOD) δ 177.3, 144.8, 144.5, 138.8, 130.7, 129.6, 128.7, 128.0, 127.6, 43.6, 42.2, 37.4, 32.8, 32.7, 21.4.

[0706] HRMS (ESI-TOF): For C 19 H 22 NO4S - [MH] - Calculated value: 360.1270, measured value: 360.1270.

[0707] N -(2-(1-(but-3-en-1-yl)cyclobutyl)ethyl)-4-methylbenzenesulfonamide SS39 This compound was obtained according to general procedure E from a known... Prepared.

[0708] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.75 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 5.22 – 4.77 (m, 2H), 4.50 – 4.31(m, 1H), 2.96 – 2.70 (m, 2H), 2.43 (s, 3H), 1.91 – 1.73 (m, 4H), 1.73 – 1.63 (m, 4H), 1.63 – 1.53 (m, 2H), 1.43 – 1.30 (m, 2H).

[0709] 13 C NMR (151 MHz, CDCl3) δ 143.6, 139.0, 137.0, 129.9, 127.3, 114.4, 40.2, 39.4, 38.1, 37.5, 31.8, 28.4, 21.7, 15.4.

[0710] HRMS (ESI-TOF): For C 17 H 26 NO2S + [M+H] + Calculated value: 308.1685, measured value: 308.1677.

[0711] 3-(1-(2-((4-methylphenyl)sulfinylamino)ethyl)cyclobutyl)propionic acid 39 The compound was prepared by SS39 according to general procedure E.

[0712] 1 H NMR (600 MHz, MeOD) δ 7.73 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.0 Hz,2H), 2.85 – 2.58 (m, 2H), 2.42 (s, 3H), 2.23 – 2.04 (m, 2H), 1.92 – 1.77 (m,2H), 1.77 – 1.62 (m, 6H), 1.62 – 1.47 (m, 2H).

[0713] 13 C NMR (151 MHz, MeOD) δ 177.7, 144.7, 138.8, 130.7, 128.1, 40.9, 39.8, 38.5, 34.1, 32.2, 29.8, 21.4, 15.9.

[0714] HRMS (ESI-TOF): For C 16 H 22 NO4S - [MH] - Calculated value: 324.1269, measured value: 324.1275.

[0715] N -(2-(1-(but-3-en-1-yl)cyclopentyl)ethyl)-4-methylbenzenesulfonamide SS40 This compound was obtained according to general procedure E from a known... Prepared.

[0716] 1 H NMR (600 MHz, CDCl3) δ 7.75 (d, J= 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.73 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 5.13 – 4.69 (m, 2H), 4.34 (t, J =5.9 Hz, 1H), 3.29 – 2.65 (m, 2H), 2.43 (s, 3H), 1.98 – 1.73 (m, 2H), 1.66 –1.51 (m, 4H), 1.51 – 1.38 (m, 2H), 1.38 – 1.31 (m, 2H), 1.31 – 1.11 (m, 4H).

[0717] 13 C NMR (151 MHz, CDCl3) δ 143.5, 139.2, 137.1, 129.9, 127.3, 114.2, 44.0, 40.1, 38.4, 37.9, 37.6, 29.2, 24.6, 21.7.

[0718] HRMS (ESI-TOF): For C 18 H 28 NO2S + [M+H] + Calculated value: 322.1841, measured value: 322.1840.

[0719] 3-(1-(2-((4-methylphenyl)sulfinylamino)ethyl)cyclopentyl)propionic acid 40 The compound was prepared by SS40 according to general procedure E.

[0720] 1 H NMR (600 MHz, MeOD) δ 7.73 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz,2H), 2.95 – 2.62 (m, 2H), 2.43 (s, 3H), 2.33 – 2.02 (m, 2H), 1.58 (dd, J = 9.4,6.7 Hz, 4H), 1.56 – 1.47 (m, 2H), 1.47 – 1.38 (m, 2H), 1.38 – 1.23 (m, 4H).

[0721] 13 C NMR (151 MHz, MeOD) δ 177.8, 144.7, 138.9, 130.8, 128.1, 44.7, 40.6, 38.7, 38.5, 34.2, 30.7, 25.4, 21.4.

[0722] HRMS (ESI-TOF): For C 17 H 24 NO4S - [MH] - Calculated value: 338.1426, measured value: 338.1426.

[0723] The diastereomeric ratio is approximately 1.7:1. N -((2-(but-3-en-1-yl)cyclopentyl)methyl)-4-methylbenzenesulfonamide SS41 The compound was obtained commercially available according to general procedure E. Prepared.

[0724] 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.41 – 7.12 (m, 2H), 5.92 – 5.60 (m, 1H), 5.11 (t, J = 6.2 Hz, 0.7H), 5.04 (t, J = 6.0 Hz, 0.4H), 4.99– 4.80 (m, 2H), 3.09 – 2.83 (m, 1H), 2.68 (ddd, J = 12.1, 8.7, 5.9 Hz, 1H),2.40 (s, 3H), 2.10 – 1.79 (m, 3H), 1.79 – 1.69 (m, 1H), 1.69 – 1.57 (m, 1H),1.57 – 1.38 (m, 3.5H), 1.38 – 1.25 (m, 1.3H), 1.25 – 1.04 (m, 2.6H).

[0725] 13C NMR (100 MHz, CDCl3) δ 143.3, 143.3, 138.9, 138.8, 137.0, 136.8,129.7, 129.7, 127.1, 114.4, 114.3, 47.4, 45.2, 43.5, 42.7, 42.0, 41.0, 34.4,32.6, 32.5, 32.2, 30.2, 30.0, 28.7, 28.6, 23.9, 22.4, 21.6.

[0726] HRMS (ESI-TOF): For C 17 H 26 NO2S + [M+H] + Calculated value: 308.1685, measured value: 308.1689.

[0727] The diastereomeric ratio is approximately 1.7:1. 3-(2-(((4-methylphenyl)sulfinylamino)methyl)cyclopentyl)propionic acid 41 The compound was prepared by SS41 according to general procedure E.

[0728] 1 H NMR (600 MHz, MeOD) δ 7.84 – 7.49 (m, 2H), 7.45 – 7.02 (m, 2H), 2.95 – 2.80 (m, 1H), 2.71 – 2.61 (m, 1H), 2.42 (s, 3H), 2.33 – 2.24 (m, 1H),2.24 – 2.14 (m, 1H), 2.00 (dp, J = 9.0, 6.4 Hz, 0.4H), 1.86 (dddd, J = 10.0, 7.4,4.9, 2.3 Hz, 0.4H), 1.83 – 1.77 (m, 0.7H), 1.77 – 1.67 (m, 0.7H), 1.67 – 1.61(m, 0.7H), 1.61 – 1.48 (m, 3H), 1.48 – 1.35 (m, 2H), 1.35 – 1.24 (m, 1.4H), 1.17 (dq, J = 12.6, 7.9 Hz, 0.7H).

[0729] 13C NMR (151 MHz, MeOD) δ 177.6, 177.6, 144.6, 144.5, 139.0, 138.8,130.7, 130.7, 128.1, 128.0, 128.0, 48.3, 46.6, 44.2, 43.8, 43.3, 42.4, 33.8,33.8, 33.1, 31.5, 31.2, 30.8, 29.6, 25.6, 24.9, 23.0, 21.4.

[0730] HRMS (ESI-TOF): For C 16 H 22 NO4S - [MH] - Calculated value: 324.1270, measured value: 324.1272.

[0731] Relative configuration derived from 42a 4-Methyl- N -((1 R* ,2 R* 2-(pent-4-en-1-yl)cyclohexyl)benzenesulfonamide SS42 The compound was obtained commercially according to steps 1 and 2 of general procedure B, followed by steps 2-4 of general procedure C. Prepared.

[0732] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 5.68 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.06 – 4.75 (m, 2H), 4.63 (d, J =8.4 Hz, 1H), 3.41 (dq, J = 8.2, 3.5 Hz, 1H), 2.41 (s, 3H), 2.08 – 1.73 (m, 2H), 1.72 – 1.53 (m, 2H), 1.53 – 1.37 (m, 4H), 1.37 – 1.25 (m, 1H), 1.25 – 1.14 (m, 2H), 1.14 – 0.94 (m, 4H).

[0733] 13 C NMR (100 MHz, CDCl3) δ 143.3, 138.9, 138.4, 129.7, 127.2, 114.4, 53.0, 40.3, 34.0, 31.0, 31.0, 27.5, 26.2, 24.4, 21.7, 21.1.

[0734] HRMS (ESI-TOF): For C 18 H 28 NO2S + [M+H] + Calculated value: 322.1841, measured value: 322.1845.

[0735] The relative configuration derived from 42a.

[0736] 4-((1 R *,2 R *)-2-((4-methylphenyl)sulfinylamino)cyclohexyl)butyric acid 42 This compound was prepared by SS42 according to general procedure C.

[0737] 1 H NMR (600 MHz, MeOD) δ 7.75 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz,2H), 3.39 (s, 1H), 2.42 (s, 3H), 2.07 (t, J = 7.5 Hz, 2H), 1.57 (d, J = 13.4 Hz, 1H), 1.49 (td, J = 11.1, 4.2 Hz, 2H), 1.46 – 1.37 (m, 3H), 1.32 (dd, J = 11.8,7.9 Hz, 2H), 1.30 – 1.19 (m, 4H), 1.17 – 1.06 (m, 2H).

[0738] 13 C NMR (151 MHz, MeOD) δ 177.6, 144.4, 140.6, 130.6, 128.0, 54.4, 41.5, 35.2, 31.8, 31.4, 28.3, 25.1, 23.6, 22.4, 21.4.

[0739] HRMS (ESI-TOF): For C 17 H 24 NO4S - [MH] - Calculated value: 338.1426, measured value: 338.1442.

[0740] N -(2-(hex-5-en-1-yl)phenyl)-4-methylbenzenesulfonamide SS43 This compound was obtained commercially from a commercially available source according to general procedure C. Prepared.

[0741] 1 H NMR (600 MHz, CDCl3) δ 7.79 – 7.48 (m, 2H), 7.34 (dd, J = 7.7, 1.4Hz, 1H), 7.27 – 7.19 (m, 2H), 7.19 – 6.99 (m, 3H), 5.75 (ddt, J = 16.9, 10.1,6.7 Hz, 1H), 5.20 – 4.75 (m, 2H), 2.38 (s, 3H), 2.36 – 2.20 (m, 2H), 2.11 –1.82 (m, 2H), 1.51 – 1.21 (m, 4H).

[0742] 13 C NMR (151 MHz, CDCl3) δ 143.9, 138.6, 136.8, 135.6, 134.1, 129.8,129.7, 127.3, 127.0, 126.3, 124.4, 114.9, 33.6, 30.7, 29.4, 28.7, 21.7.

[0743] HRMS (ESI-TOF): For C 19 H 24 NO2S + [M+H] + Calculated value: 330.1528, measured value: 330.1528.

[0744] 5-(2-((4-methylphenyl)sulfinylamino)phenyl)valeric acid 43 This compound was prepared from SS43 according to general procedure C.

[0745] 1 H NMR (600 MHz, MeOD) δ 7.78 – 7.49 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H),7.23 – 7.11 (m, 2H), 7.11 – 6.91 (m, 2H), 2.48 – 2.43 (m, 2H), 2.41 (s, 3H),2.21 (t, J = 7.5 Hz, 2H), 1.49 (p, J = 7.6 Hz, 2H), 1.44 – 1.22 (m, 2H).

[0746] 13 C NMR (151 MHz, MeOD) δ 177.5, 144.9, 140.1, 139.0, 135.6, 130.7,130.6, 128.4, 128.3, 128.0, 127.4, 34.7, 31.3, 30.7, 26.0, 21.5.

[0747] HRMS (ESI-TOF): For C 18 H 20 NO4S - [MH] - Calculated value: 346.1113, measured value: 346.1116.

[0748] 6-((2-nitrophenyl)sulfinylamino)hexanoic acid 44 The known compound was prepared from commercially available 6-aminohexanoic acid according to a method reported by Pavlidis and collaborators. 9 1 H NMR (600 MHz, MeOD) δ 8.07 (dd, J = 5.9, 3.4 Hz, 1H), 7.96 – 7.72(m, 3H), 3.04 (t, J = 7.0 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 1.80 – 1.41 (m, 4H), 1.41 – 1.12 (m, 2H).

[0749] 13C NMR (151 MHz, MeOD) δ 177.4, 149.6, 135.0, 134.9, 133.5, 131.5, 125.8, 44.1, 34.7, 30.4, 27.1, 25.5.

[0750] HRMS (ESI-TOF): For C 12 H 15 N2O6S - [MH] - Calculated value: 315.0651, measured value: 315.0653.

[0751] Preliminary study of response behavior The role of carboxylic acids: The protection of the carboxylic acid eliminates the reactivity of the lactamation reaction, indicating that the presence of the carboxylic acid is crucial for the lactamation reaction.

[0752] Reactivity of Figures S23.3 and 4.

[0753] Compounds 3 and 4 were synthesized from compounds 1 and 2, respectively, according to the general procedure for methyl ester formation as described above. Toluenesulfonylformamide does not undergo methylation under the mentioned reaction conditions.

[0754] 3-((4-methylphenyl)sulfinylamino)-6-oxohexanoate methyl ester 1 H NMR (400 MHz, CDCl3) δ 8.5 (s, 1H), 7.9 ( d , J = 8.4 Hz, 2H), 7.3 ( d , J = 8.3 Hz, 2H), 3.7 (s, 3H), 2.4 (s, 3H), 2.4 – 2.1 (m, 4H), 1.8 – 1.5 (m, 4H).

[0755] 13 C NMR (100 MHz, CDCl3) δ 174.1, 170.5, 145.3, 135.7, 129.8, 128.5, 51.9, 35.9, 33.6, 24.0, 23.8, 21.8.

[0756] HRMS (ESI-TOF): For C 14 H 20 NO5S + [M+H]+ Calculated value: 314.1063, measured value: 314.1064.

[0757] 4-((4-methylphenyl)sulfinylamino)-7-oxoheptanoate methyl ester 1 H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 7.9 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 7.9 Hz, 2H), 3.7 (s, 3H), 2.4 (s, 3H), 2.4 – 2.2 (m, 4H), 1.6 (p, J = 7.5 Hz, 4H), 1.4 – 1.1 (m, 2H).

[0758] 13 C NMR (100 MHz, CDCl3) δ 174.4, 170.9, 145.3, 135.7, 129.8, 128.5, 51.8, 36.0, 33.8, 28.3, 24.4, 24.0, 21.8.

[0759] HRMS (ESI-TOF): For C 15 H 22 NO5S + [M+H] + Calculated value: 328.1219, measured value: 328.1223.

[0760] α-Quaternization of carboxylic acids: Quaternization at the α-position of the carboxylic acid eliminated the lactamation reactivity. Performing the same experiment in HFIP-OD resulted in no deuterium incorporation at the β-methylene position (Fig. S15). Approximately 30% of the β-methyl position was deuterated. This indicates that quaternization at the α-position of the carboxylic acid can suppress C–H activation at the β-methylene position, resulting in the elimination of lactamation reactivity. Given the results obtained, alternative rationalizations for the lack of lactamation reactivity, where β-methylene C–H activation is effective but lactamation fails, are unlikely. This experiment suggests that α-quaternization of the substrate may not be a good way to rule out the α,β-desaturation pathway in related cyclization reactions.

[0761] Figure S24. Reactivity of α-quaternized compound S38.

[0762] Figure S25. MeOH- d Compound S38 in 4 1 H NMR, compound S38- d rough 1 1H NMR and compound S38- d rough 2 H NMR.

[0763] Figure S26. Procedure for synthesizing compound S38.

[0764] Compound S38 was synthesized according to the general procedure described above.

[0765] 2,2-Dimethyl-6-((4-methylphenyl)sulfinamide)-6-oxohexanoic acid S38 1 H NMR (400 MHz, MeOH- d 4) δ 7.9 (d, J = 8.3 Hz, 2H), 7.4 (d, J = 8.2 Hz,2H), 2.4 (s, 3H), 2.2 (t, J = 7.0 Hz, 2H), 1.6 – 1.4 (m, 2H), 1.4 – 1.3 (m, 2H), 1.1 (s, 6H).

[0766] 13 C NMR (100 MHz, MeOH- d 4) δ 181.5, 173.6, 146.1, 138.0, 130.5, 129.2, 42.7, 40.6, 37.3, 25.5, 21.5, 21.4.

[0767] HRMS (ESI-TOF): For C 15 H 20 NO5S - [MH] - Calculated value: 326.1062, measured value: 326.1060.

[0768] Ligand-controlled C–H lactamation and C–H lactoneation: Compound 5 was prepared according to the procedure described below: Figure S27. Preparation of substrate 5.

[0769] Intermediate S26 was prepared entirely according to the procedure described above (Figure S9). Compound S26 was dissolved in DCM (0.1 M), and oxaloyl chloride (1.1 equivalents) was added, followed by one drop of DMF (Note: a large amount of gas escapes). The reaction mixture was stirred overnight at room temperature, and concentrated under reduced pressure the next day. The crude acyl chloride was then dissolved in toluene (1.0 M), and Ar was added. F NH2 (1.1 equivalents) was added, followed by heating to reflux and stirring overnight. TLC analysis at this stage confirmed the disappearance of the starting material. All volatiles were removed under reduced pressure, and crude S39 was purified by rapid column chromatography (50% EA / hexane) to give pure S39 as a white solid (80% after two steps). Compound S39 was then hydrogenolyzed in EtOH (0.1 M) with Pd / C and H2 (balloon pressure) to quantitatively give compound 5.

[0770] 6-O-6-((2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)amino)hexanoic acid 5 1 H NMR (600 MHz, MeOD) δ 2.52 (t, J = 7.2 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 1.81 – 1.73 (m, 2H), 1.73 – 1.67 (m, 2H).

[0771] 13 C NMR (151 MHz, MeOD) δ 177.2, 173.9, 146.6, 144.9, 144.8, 143.2,143.1, 125.2, 123.4, 123.0, 122.9, 122.8, 121.6, 119.8, 107.7, 107.7, 107.6,107.5, 107.4, 107.3, 36.3, 34.5, 26.0, 25.5.

[0772] 19 F{ 1 H} NMR (376 MHz, MeOD) δ -57.5 (t, J = 21.9 Hz), -142.1 – -144.6(m), -144.6 – -146.1 (m).

[0773] HRMS (ESI-TOF): For C 13 H9F7NO3 - [MH] - Calculated value: 360.0470, expected m / z not found.

[0774] Compound 5a was isolated in its methyl ester form with a 57% separation yield.

[0775] 2-(5-oxo-1-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)pyrrolidine-2-yl)methyl acetate 5a 1 H NMR (600 MHz, CDCl3) δ 4.53 (p, J = 6.0 Hz, 1H), 3.61 (s, 3H), 2.73 –2.64 (m, 1H), 2.64 – 2.56 (m, 3H), 2.52 (dd, J = 16.0, 7.6 Hz, 1H), 2.13 – 2.05(m, 1H).

[0776] 13 C NMR (151 MHz, CDCl3) δ 174.2, 170.1, 56.6, 52.1, 38.8, 29.4, 26.0. (Ar F Partial 13 C resonance is invisible.

[0777] 19 F{ 1 H} NMR (376 MHz, CDCl3) δ -56.2 (t, J = 21.9 Hz), -138.4 – -139.8(m), -140.0, -143.0.

[0778] HRMS (ESI-TOF): For C 14 H 11 F7NO3 + [M+H] + Calculated value: 374.0628, measured value: 374.0635.

[0779] 2-(5-oxotetrahydrofuran-2-yl)-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)acetamide 5c 1 H NMR (600 MHz, CDCl3) δ 7.46 (s, 1H), 4.95 (dq, J = 8.5, 6.7 Hz, 1H), 3.04 – 2.82 (m, 2H), 2.75 – 2.61 (m, 2H), 2.54 (dq, J = 13.2, 6.6 Hz, 1H), 2.08(dq, J = 12.7, 9.5 Hz, 1H).

[0780] 13 C NMR (151 MHz, CDCl3) δ 176.0, 166.7, 76.4, 42.1, 28.6, 27.8. (Ar F Partial 13 C resonance is invisible.

[0781] 19 F{ 1 H} NMR (376 MHz, CDCl3) δ -56.0 (t, J = 21.7 Hz), -138.0 – -141.2(m), -141.6 – -145.5 (m).

[0782] HRMS (ESI-TOF): For C 13 H9F7NO3 + [M+H] + Calculated value: 360.0471, measured value: 360.0470.

[0783] α-Monosubstituted substrate lactamation 2-(5-oxo-4-phenyl-1-toluenesulfonylpyrrolidine-2-yl)methyl acetate S39 1 H NMR (600 MHz, CDCl3) δ 8.0 – 7.9 (m, 2.5H), 7.4 – 7.3 (m, 5.5H), 7.3 – 7.2 (m, 1.3H), 7.2 – 7.1 (m, 0.6H), 7.1 – 7.0 (m, 2H), 4.8 (dddd, J=9.9, 8.0, 3.3, 1.9 Hz, 1H), 4.6 (dtd, J = 9.0, 7.2, 3.7 Hz, 0.3H), 3.8 (dd, J =11.5, 8.8 Hz, 1H), 3.7 (s, 3H), 3.7 (s, 0.9H), 3.7 – 3.6 (m, 0.3H), 3.5 (dd, J = 16.5, 3.7 Hz, 0.3H), 3.2 (dd, J = 16.1, 3.3 Hz, 1H), 3.0 – 2.8 (m, 0.3H), 2.8(dd, J = 16.2, 10.0 Hz, 1H), 2.7 (dd, J = 16.5, 9.0 Hz, 0.3H), 2.5 – 2.4 (m, 6H), 2.1 – 2.0 (m, 0.3H).

[0784] 13 C NMR (151 MHz, CDCl3) δ 174.1, 173.3, 170.7, 170.7, 145.5, 145.5,136.9, 136.5, 135.6, 135.5, 129.8, 129.8, 129.0, 128.9, 128.6, 128.6, 128.1,128.0, 127.8, 127.8, 54.9, 54.2, 52.2, 52.0, 47.8, 46.8, 40.6, 38.8, 33.8,33.8, 29.8, 21.8.

[0785] HRMS (ESI-TOF): For C 20 H 22 NO5S + [M+H] + Calculated value: 388.1219, measured value: 388.1219.

[0786] 2-(4-(tert-butyl)-5-oxo-1-toluenesulfonylpyrrolidine-2-yl)methyl acetate S40 1 H NMR (600 MHz, CDCl3) δ 8.0 – 7.7 (m, 4H), 7.4 – 7.3 (m, 4H), 4.6(dddd,J = 10.2, 8.8, 3.3, 1.5 Hz, 1H), 4.4 (tdd, J = 8.6, 7.4, 3.8 Hz, 1H), 3.7(s, 3H), 3.7 (s, 3H), 3.5 (dd, J = 16.3, 3.8 Hz, 1H), 3.1 (dd, J = 16.1, 3.3 Hz,1H), 2.7 – 2.6 (m, 2H), 2.5 – 2.4 (m, 8H), 2.2 (dd, J = 11.3, 9.9 Hz, 1H), 2.1(ddd, J = 13.6, 11.6, 8.7 Hz, 1H), 1.9 (ddd, J = 13.4, 8.7, 1.5 Hz, 1H), 1.6(ddd, J = 13.2, 11.1, 8.4 Hz, 1H), 1.0 (s, 9H), 0.9 (s, 9H).

[0787] 13 C NMR (151 MHz, CDCl3) δ 175.0, 173.9, 171.0, 170.8, 145.2, 145.1,136.0, 135.7, 129.7, 129.7, 128.4, 128.4, 53.7, 53.4, 52.1, 52.0, 51.1, 49.8,41.2, 39.2, 32.7, 32.4, 28.7, 27.9, 27.3, 27.0, 21.8.

[0788] HRMS (ESI-TOF): For C 18 H 26 NO5S + [M+H] + Calculated value: 368.1532, measured value: 368.1535.

[0789] 2-(6-oxo-5-phenyl-1-toluenesulfonylpiperidin-2-yl)methyl acetate S41 11H NMR (600 MHz, CDCl3) δ 8.0 – 7.9 (m, 2H), 7.9 – 7.9 (m, 2H), 7.3 –7.3 (m, 2H), 7.3 – 7.3 (m, 4H), 7.3 – 7.2 (m, 1H), 7.2 (dd, J J = 5.1, 1.8 Hz, 3H), 7.1 – 7.0 (m, 2H), 6.9 – 6.7 (m, 2H), 5.2 – 5.1 (m, 1H), 5.1 (ddt, J J=9.9, 6.4, 3.3 Hz, 1H), 3.7 (d, J J = 14.7 Hz, 7H), 3.5 (t, J J = 9.1 Hz, 1H), 3.3 –3.2 (m, 1H), 3.1 (ddd, J J = 16.1, 3.3, 1.0 Hz, 1H), 2.9 (td, J J = 16.2, 10.5 Hz, 2H), 2.4 (s, 3H), 2.4 (s, 3H), 2.3 (ddd, J J = 17.0, 9.7, 4.8 Hz, 1H), 2.2 – 2.1(m, 1H), 2.1 (dt, J J = 10.4, 5.0 Hz, 1H), 2.1 – 2.1 (m, 3H), 1.9 – 1.8 (m, 2H).

[0790] 13 13C NMR (151 MHz, CDCl3) δ 171.6, 171.2, 170.6, 170.6, 145.1, 145.0, 140.4, 139.5, 136.4, 136.3, 129.5, 129.4, 129.3, 129.2, 129.0, 128.7, 128.3, 127.9, 127.4, 127.2, 54.0, 53.7, 52.2, 52.1, 51.3, 49.1, 39.7, 39.5, 29.8, 27.0, 26.4, 25.7, 24.3, 21.8.

[0791] HRMS (ESI-TOF): for C 21 H 24 NO5S + , [M+H] +Calculated value: 402.1376, measured value: 402.1371.

[0792] 2-(5-(tert-butyl)-6-oxo-1-toluenesulfonylpiperidin-2-yl)methyl acetate S42 1 H NMR (600 MHz, CDCl3) δ 8.1 – 7.8 (m, 2.8H), 7.4 – 7.3 (m, 2.8H), 4.9 – 4.8 (m, 1.3H), 3.7 (s, 1H), 3.7 (s, 3H), 3.2 (dd, J = 16.0, 3.5 Hz,0.3H), 3.0 (dd, J = 16.0, 3.5 Hz, 1H), 2.9 – 2.7 (m, 1.3H), 2.4 (s, 4.2H), 2.2(td, J = 8.3, 3.1 Hz, 0.3H), 2.1 (dd, J = 9.6, 7.4 Hz, 1H), 2.1 – 2.0 (m, 1.3H), 2.0 (dtd, J = 16.1, 7.5, 5.3 Hz, 1H), 1.8 (ddt, J = 13.2, 7.5, 5.6 Hz, 1.3H), 1.8– 1.7 (m, 0.7H), 1.6 – 1.6 (m, 1H), 1.0 (s, 3H), 0.9 (s, 9H).

[0793] 13 C NMR (151 MHz, CDCl3) δ 173.0, 172.6, 170.9, 170.7, 144.7, 144.6,137.0, 136.9, 129.4, 129.3, 128.9, 128.8, 54.2, 54.0, 53.0, 52.2, 52.1, 52.0,39.8, 38.9, 35.2, 34.2, 28.2, 27.1, 27.1, 26.7, 21.8, 21.8, 20.4, 19.3.

[0794] HRMS (ESI-TOF): For C 19 H 27 NO5S + [M+H] +Calculated value: 382.1689, measured value: 382.1690.

[0795] Synthetic applications of lactamation reaction Figure S28. Synthesis of the bicyclic lactam skeleton.

[0796] The synthesis of 1a on a 1-gram scale was carried out in a manner similar to that reported in our previous paper on dicarboxylic acid lactone formation. 6 Compound 1a was purified by column chromatography (50% EA / hexane + 1% AcOH to 75% EA / hexane + 1% AcOH) to give the desired product as a light brown solid (566 mg, 1.90 mmol, 57% yield).

[0797] 2-(1-Allyl-5-oxopyrrolidone-2-yl)acetic acid 47 Compound 1a (566 mg, 1.90 mmol) was dissolved in anhydrous dimethoxyethane (19 mL) and cooled to -40 °C. A sodium naphthalene solution (made by adding chopped Na...) (s) The reaction was prepared by sonicating 19.0 mmol of sodium naphthalene (19.0 mmol) in 20 mL of anhydrous dimethoxyethane for 30 minutes. Observation: The solution changed from colorless to dark green. The solution was then added dropwise to a solution of compound 1a until the light green color persisted for more than 5 minutes after the addition of the dark green sodium naphthalene solution. The solution was then warmed to room temperature, and a solution of allyl bromide (1.65 mL, 19.0 mmol) in anhydrous DMF (10 mL) was added to the reaction mixture. The reaction mixture was then heated to 40 °C and stirred overnight at this temperature. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was concentrated under reduced pressure, washed with hexane, and sonicated three times to remove most of the naphthalene. The residue was then suspended in water and washed three times with EtOAc. The EtOAc layer was collected, dried with anhydrous MgSO4, and concentrated under reduced pressure to give crude product 47. Compound 47 was purified by rapid column chromatography (50% EA / hexane to 100% EA) to give the desired compound 47 (216 mg, 0.97 mmol, 51%, R) as a yellow oil. f = 0.32 (100% EA)).

[0798] 1 H NMR (600 MHz, CDCl3) δ 5.90 (ddt, J = 16.6, 10.4, 5.9 Hz, 1H), 5.71(dddd, J= 16.9, 9.9, 6.9, 5.1 Hz, 1H), 5.32 (dq, J = 17.2, 1.5 Hz, 1H), 5.26(dd, J = 10.4, 1.4 Hz, 1H), 5.21 – 5.13 (m, 2H), 4.65 – 4.51 (m, 2H), 4.24(ddt, J = 15.6, 5.2, 1.7 Hz, 1H), 4.00 (tt, J = 8.5, 4.3 Hz, 1H), 3.55 (dd, J =15.7, 6.9 Hz, 1H), 2.74 (dd, J = 15.5, 4.2 Hz, 1H), 2.46 (ddd, J = 16.8, 9.7, 7.3Hz, 1H), 2.42 – 2.38 (m, 1H), 2.38 – 2.32 (m, 1H), 2.28 (ddt, J = 13.2, 9.9,7.6 Hz, 1H), 1.81 (ddt, J = 14.5, 9.9, 5.0 Hz, 1H).

[0799] 13 C NMR (151 MHz, CDCl3) δ 174.8, 170.3, 132.7, 131.8, 119.1, 118.1,77.4, 77.0, 65.7, 54.5, 43.5, 38.4, 29.7, 24.6.

[0800] HRMS (ESI-TOF): For C 12 H 18 NO3 + [M+H] + Calculated value: 224.1287, measured value: 224.1282.

[0801] Note 1: Using DMF as a co-solvent is crucial for alkylation with allyl bromide. Do not use lithium naphthylene for the deprotection / alkylation sequence, as lithium alkoxy / aminolithium has been found to be inefficient in achieving the desired alkylation with allyl bromide.

[0802] Note 2: Alternatively, the reactants can be quenched with formic acid, followed by evaporation of the evaporators, and then washed with hexane / ultrasonicated to obtain the compound. (Note: Water-soluble), this compound can be sequentially alkylated under oxygen and nitrogen conditions using different electrophilic reagents. Oxyalkylation conditions: alkyl bromide / alkyl iodide (10.0 equivalents), K₂CO₃ (10.0 equivalents), MeCN (0.5 M), 50 °C, overnight. Nitroalkylation conditions: alkyl bromide / alkyl iodide (2.0 equivalents), NaH (1.1 equivalents), DMF (0.5 M), 0 °C to room temperature, progress monitored by TLC.

[0803] The diastereomeric ratio is approximately 5:1, as shown in the figure for the main diastereomers, and the relative configurations derived from 49.

[0804] ( S *)-2-(( S* )-1-Allyl-5-oxopyrrolidone-2-yl)pent-4-enoic acid 48 Compound 47 (50.0 mg, 0.22 mmol) was dissolved in anhydrous THF (2.2 mL, 0.1 M) in a sealed tube and cooled to -78 °C. The sealed tube was briefly opened, and TMSCl (84 μL, 3.0 equivalent) was rapidly added, followed by LHMDS (0.51 mL, 3.0 equivalent of approximately 1.3 M THF solution). The reaction mixture was stirred at -78 °C for 10 min and then warmed to room temperature. The reaction mixture was then heated to 85 °C and stirred at this temperature for 1 h. TLC analysis at this stage confirmed the complete disappearance of the starting material. The reactants were then treated with saturated NH4Cl. (水溶液) Quenching and extraction three times with EtOAc. The organic layer was collected, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was redissolved in THF, and TBAF solution (1M THF solution) was added, followed by AcOH to desilylate any incidentally silylated material. Desilylation was carried out for 1 hour with stirring, quenched with 1M HCl, and extracted three times with EtOAc. The EtOAc layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure to give crude product 48, which was purified by rapid column chromatography (70% EA / hexane to 100% EA to EA + 1% AcOH) to give pure 48 (36.0 mg, 0.16 mmol, 73%, diastereomeric ratio approximately 5:1, R) as a colorless oil that solidifies upon standing. f = 0.30 (EA + 1% AcOH)).

[0805] 1 H NMR (600 MHz, MeOD) δ 5.97 – 5.66 (m, 2.4H), 5.26 (dq, J= 17.2, 1.5Hz, 1H), 5.22 (dq, J = 10.1, 1.4 Hz, 1H), 5.12 (dq, J = 17.1, 1.6 Hz, 0.2H), 5.08(dd, J = 17.1, 1.7 Hz, 1H), 5.05 (ddt, J = 10.2, 2.1, 1.2 Hz, 0.2H), 5.01 (dd, J =10.2, 1.8 Hz, 1H), 4.38 (ddt, J = 15.6, 4.0, 1.8 Hz, 0.2H), 4.26 (ddt, J = 15.6,5.2, 1.7 Hz, 1H), 4.12 (dt, J = 8.6, 4.2 Hz, 1H), 3.93 (dt, J = 9.3, 3.9 Hz,0.2H), 3.64 (ddd, J = 15.6, 7.6, 1.2 Hz, 0.2H), 3.57 (ddd, J = 15.6, 7.0, 1.2 Hz,1H), 2.93 (ddd, J = 8.5, 6.4, 3.8 Hz, 0.2H), 2.86 (dt, J = 10.3, 4.0 Hz, 1H),2.53 – 2.48 (m, 0.2H), 2.47 – 2.43 (m, 1H), 2.43 – 2.39 (m, 1H), 2.39 – 2.33(m, 1H), 2.31 (dd, J = 10.5, 4.7 Hz, 0.2H), 2.25 – 2.20 (m, 0.2H), 2.20 – 2.15(m, 0.2H), 2.15 – 2.08 (m, 1H), 2.06 – 1.97 (m, 2H)。

[0806] 13C NMR (151 MHz, MeOD) δ 177.9, 177.6, 175.9, 175.8, 136.7, 136.7,136.4, 136.4, 133.4, 133.3, 133.3, 118.8, 117.6, 117.0, 60.3, 60.2, 60.1, 48.1, 46.1, 44.5, 44.3, 33.7, 31.0, 30.8, 30.4, 21.1, 20.1.

[0807] HRMS (ESI-TOF): For C 12 H 16 NO3 - [MH] - Calculated value: 222.1130, measured value: 222.1135.

[0808] The diastereomer ratio is approximately 5:1, as shown in the figure for the main diastereomers.

[0809] (9 S* 9 aS* )-3-oxooctahydro-1 H -pyrrolo[1,2- a Azazo-9-carboxylic acid 49 Compound 48 (36.0 mg, 0.16 mmol) was dissolved in anhydrous DCM (3.2 mL, 0.05 M) in a 20 mL reaction vial, and Grubbs' 2 generation catalyst was added. nd The reaction mixture was then degassed by bubbling with argon and the vial was capped. The reaction mixture was then heated to reflux and stirred for 6 hours. TLC analysis at this stage confirmed the complete disappearance of the starting material. The reaction mixture was then cooled to room temperature and saturated with NaHCO3. 3(水溶液)The sample was extracted three times, the aqueous layer was collected and acidified to pH ~ 2 by adding 6M HCl, and then extracted three times with EtOAc. The EtOAc layers were combined, dried over anhydrous MgSO4, filtered and concentrated to give crude product 52 (characterized as listed below). Crude product 52 was then dissolved in EtOH (5.0 mL) and hydrogenated with Pd / C (50 mg) and H2 (balloon pressure). The reaction mixture was stirred overnight at room temperature and filtered through a Celite® stopper the next day to give crude product 49. Crude product 49 was purified by rapid column chromatography (EA + 1% AcOH to 95% EA + 5% MeOH + 1% AcOH) to give pure 49 (27.1 mg, 0.14 mmol, 85%, by 2 steps, diastereomeric ratio approximately 5:1, R) as a white solid. f = 0.4 (95% EA + 5% MeOH + 1% AcOH)).

[0810] 1 H NMR (600 MHz, CDCl3) δ 4.22 (q, J = 7.7 Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 2.91 (t, J = 7.7 Hz, 1H), 2.77 (t, J = 12.8 Hz, 1H), 2.46 – 2.36 (m, 2H), 2.12 – 2.04 (m, 1H), 2.00 (dd, J = 14.7, 6.5 Hz, 1H), 1.91 (dd, J = 13.5, 5.8 Hz,1H), 1.78 – 1.68 (m, 2H), 1.63 – 1.47 (m, 2H), 1.35 (q, J = 12.3 Hz, 1H).

[0811] 13 C NMR (100 MHz, CDCl3) δ 176.0, 175.7, 59.4, 48.8, 41.9, 30.5, 28.7, 28.6, 24.5, 22.3.

[0812] HRMS (ESI-TOF): For C 10 H 14 NO3 - [MH] -Calculated value: 196.0973, measured value: 196.0980.

[0813] The ratio of diastereomers is approximately 5:1. (9 S* 9 aS* )-3-Oxo-2,3,5,8,9,9 a -hexahydro-1 H -pyrrolo[1,2- a Azazo-9-carboxylic acid 52 Compound 52 could be obtained from compound 48 (12.0 mg, 0.053 mmol) via a cross-metathesis procedure using a Grubbs second-generation catalyst as described above. Compound 52 (9.6 mg, 0.049 mmol, 92%, diastereomeric ratio approximately 5:1, R) was isolated as a light brown solid. f = 0.4 (95% EA + 5% MeOH + 1% AcOH)).

[0814] 1 H NMR (600 MHz, MeOD) δ 5.79 – 5.67 (m, 1H), 5.62 (ddt, J = 10.8, 6.1,2.2 Hz, 1H), 4.51 – 4.27 (m, 2H), 3.58 (d, J = 16.9 Hz, 1H), 3.35 – 3.26 (m,1H), 2.50 – 2.42 (m, 2H), 2.42 – 2.32 (m, 1H), 2.13 (tdt, J = 9.8, 7.4, 3.4 Hz,1H), 1.76 (dtd, J = 13.2, 10.1, 8.0 Hz, 1H).

[0815] 13 C NMR (151 MHz, MeOD) δ 176.9, 176.8, 130.4, 128.1, 61.3, 49.0, 41.3, 31.4, 25.4, 21.6.

[0816] HRMS (ESI-TOF): For C 10 H 12 NO3 - [MH] - Calculated value: 194.0817, measured value: 194.0822.

[0817] Hexahydro-3 H -pyrrolo[1,2- a ] Azazo-3,9(2 H )-Diketone 50 According to the improved procedures reported by Faraggi and collaborators 10 Compound 49 (5.0 mg, 0.025 mmol), Na2CO3 (5.4 mg, 0.05 mmol), and Ir ( p -F(Me)ppy)2-(4,4'-dtbbpy)]PF6 (0.73 mg, 0.75 μmol, 3 mol%) and ethyl viologen diperchlorate (0.52 mg, 1.25 μmol, 5 mol%) were weighed into 2-dtbbpy vials. DMSO (1.25 mL) was added, followed by bubbling of the reaction mixture and headspace purging with O2. The vials were sealed with Teflon caps, and the reaction mixture was stirred for 10 min. Afterward, the reaction mixture was vigorously stirred (1250 rpm) and irradiated with a fan-cooled 34W blue LED at approximately 30°C for 24 h. TLC analysis at this stage confirmed the complete disappearance of the starting material. The reaction mixture was diluted with ethyl acetate, washed three times with brine, and the organic layer was dried over anhydrous MgSO4. All volatiles were evaporated, and crude product 50 was purified by rapid column chromatography (DCM + 1% MeOH to DCM + 2.5% MeOH). Compound 50 (2.5 mg, 0.015 mmol, 60% yield, R) was isolated as a pale yellow oil. f = 0.30 (DCM + 2.5% MeOH)).

[0818] Note: Attempts to scale up the reaction to 100 mg were unsuccessful. The 60% yield reported in this paper can only be replicated at a 5.0 mg scale.

[0819] 1 H NMR (600 MHz, CDCl3) δ 4.30 (ddt, J = 14.2, 3.6, 1.8 Hz, 1H), 4.03(dd, J = 8.7, 7.2 Hz, 1H), 2.67 (td, J = 12.6, 2.6 Hz, 1H), 2.63 – 2.55 (m, 1H), 2.51 – 2.46 (m, 1H), 2.46 – 2.41 (m, 2H), 2.35 (dtd, J= 13.3, 8.5, 6.4 Hz,1H), 2.03 (dd, J = 13.6, 4.7 Hz, 1H), 1.91 – 1.82 (m, 2H), 1.72 (qt, J = 14.5,3.7 Hz, 1H), 1.50 (dtdd, J = 14.9, 13.2, 3.6, 1.9 Hz, 1H).

[0820] 13 C NMR (151 MHz, CDCl3) δ 212.6, 175.0, 68.4, 44.0, 40.9, 30.1, 29.0,24.5, 22.4.

[0821] HRMS (ESI-TOF): For C9H 14 NO2 + [M+H] + Calculated value: 168.1025, measured value: 168.1025.

[0822] The ratio of diastereomers is approximately 5:1. (1 S* 4 R* 5 R* 10 aS* )-5-bromohexahydro-4 H -1,4-methylpyrrolo[2,1- d [1,5]oxazine-2,8-dione 53 Compound 52 (9.6 mg, 0.049 mmol) was dissolved in CHCl3 (1.0 mL, 0.05 M), and NBS (10.0 mg, 0.056 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and TLC analysis at this stage confirmed the complete disappearance of the starting material. The reactants were then thawed with saturated NaHCO3. 3(水溶液) Quenching and washing three times with DCM. The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated to give crude product 53. Crude product 53 was purified by rapid column chromatography (70% EA / hexane to 100% EA) to give product 53 as a white solid (9.3 mg, 0.034 mmol, 70% yield, diastereomeric ratio approximately 5:1, R). f = 0.30 (100% EA)).

[0823] 1H NMR (600 MHz, CDCl3) δ 5.02 (dd, J = 8.1, 1.3 Hz, 1H), 4.64 (ddd, J =14.6, 6.4, 1.2 Hz, 1H), 4.25 (ddt, J = 11.0, 6.4, 1.0 Hz, 1H), 3.83 – 3.73 (m,1H), 3.07 (dd, J = 14.6, 11.0 Hz, 1H), 2.81 (dd, J = 8.5, 2.1 Hz, 1H), 2.68 (dt, J = 14.3, 8.5 Hz, 1H), 2.55 – 2.46 (m, 1H), 2.43 (d, J = 14.1 Hz, 1H), 2.44 –2.36 (m, 1H), 2.34 – 2.29 (m, 1H), 2.29 – 2.23 (m, 1H).

[0824] 13 C NMR (151 MHz, CDCl3) δ 174.9, 174.8, 82.4, 63.2, 46.5, 44.9, 44.8, 29.4, 27.4, 20.8.

[0825] HRMS (ESI-TOF): For C 10 H 13 79 BrNO3 + [M+H] + Calculated value: 274.0079, measured value: 274.0085.

[0826] The features disclosed in the foregoing specification or the following claims or drawings are expressed in their specific form or according to the means for performing the disclosed functions or the methods or processes for obtaining the disclosed results. Where appropriate, such features may be used alone or in any combination thereof to implement the invention in its different forms.

[0827] For purposes of clarity and understanding, the foregoing invention has been described in detail to a certain extent by way of example and embodiments. It will be apparent to those skilled in the art that variations and modifications can be made within the scope of the appended claims. Therefore, it is to be understood that the foregoing description is intended to be illustrative rather than restrictive. Consequently, the scope of the invention should not be determined by reference to the foregoing description, but rather by reference to the following appended claims together with the full scope of their equivalents.

[0828] All patents, patent applications and publications cited in this application are incorporated herein by reference in their entirety for all purposes, as if each individual patent, patent application or publication were so individually indicated.

Claims

1. A palladium-catalyzed method for methylene C–H lactamation or cycloamination, comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source; and ii) adding 2,5-dimethyl-p-benzoquinone, an Ag salt, and K2HPO4 to a reaction vessel.

2. The method of claim 1, wherein the pyridine-pyridone ligand is a chloropyridine-pyridone ligand selected from the group consisting of: 。 3. The method of claim 1 or claim 2, wherein the carboxylic acid is N - Protected ω-amino acids.

4. The method according to any one of claims 1 to 3, wherein the Pd source is Pd(OAc)2.

5. The method according to any one of claims 1 to 4, wherein the Ag salt is Ag2CO3.

6. The method according to any one of claims 1 to 5, wherein the chloropyridine-pyridone ligand is L1, L14 or L18.

7. The method of claim 1, wherein it is based on the following scheme: in: Z is -C(=O)- or -C(R) 1 (R) 2 )-; R 1 and R 2 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; R is N - Protecting group; and n is 1 or 2.

8. The method of claim 7, comprising the following schemes: in: Z is -C(=O)- or -C(R) 1 (R) 2 )-; R 1 and R 2 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; R is N - Protecting group; and n is 1 or 2.

9. The method of claim 1, comprising the following schemes: in: R 3 R 4 R 5 and R 6 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7) heterocycloalkyl, or a (C6-C7) cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1.

10. The C–H cyclic amination reaction as described in claim 1, comprising the following reaction scheme: in: R 3 R 4 R 5 R 6 R 7 and R 8 Independently H, (C1-C6)alkyl, (C6-C 10 aryl or (C1-C6)alkyl (C6-C 10 aryl; Or R 3 R 4 R 5 and R 6 Any two of them together form a (C3-C7)cycloalkyl, a (C3-C7)heteroalkyl, or a (C6-C7)cycloalkyl. 10 aryl; R is N - Protecting group; and n is 0 or 1.

11. A method for synthesizing Stemona amide, comprising the lactamation reaction as described in claim 1.

12. A method for synthesizing Stemona amide, comprising the lactamation reaction as described in claim 9.

13. The method of any one of claims 1 to 12, wherein L is L1.

14. The method of any one of claims 1 to 12, wherein L is L14.

15. The method of any one of claims 1 to 12, wherein L is L18.

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