Palladium-catalyzed methylene c-h lactamization and cycloamination of carboxylic acids

Abstract

The reactions disclosed in this application transform linear co-amino acids into valuable cyclic β-amino acids possessing γ- and δ-lactam, pyrrolidine, and tetrahydroquinoline scaffolds pertinent 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 utility of this reaction was demonstrated by formal synthesis of Stemoamide.

Description

TSRI 2214.1PC PALLADIUM-CATALYZED METHYLENE C–H LACTAMIZATION AND CYCLOAMINATION OF CARBOXYLIC ACIDS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional patent application No. 63 / 551,249 which was filed on February 8, 2024, and which is hereby incorporated by reference in its entirety. GOVERNMENT SUPPORT

[0002] This invention was made with government support under GM084019 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION

[0003] The reactions disclosed in this application transform linear ω-amino acids into valuable cyclic β-amino acids possessing γ- and δ-lactam, pyrrolidine, and tetrahydroquinoline scaffolds pertinent 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 utility of this reaction was demonstrated by formal synthesis of Stemoamide. BACKGROUND OF THE INVENTION

[0004] The development of cyclization reactions to prepare saturated heterocycles through the formation of sp3C–N bonds is one of the cornerstones of modern synthetic chemistry due to the prevalence of lactams and cyclic amines in natural products and pharmaceuticals (Fig.1A).1,2The advent of sp3C–H amination methods has ushered in an era in which direct formation of sp3C–N bonds via C–H activation has become a viable synthetic strategy.3–6While the reliance on nitrene,7–10radical,11–14and activation of allylic C–H bonds15,16have made much headway in the development of sp3C–H amination reactions, the progress concerning amination of ubiquitous unactivated methylene and methyl C–H bondsTSRI 2214.1PC has remained sluggish. Palladium-catalyzed activation of methyl and methylene sp3C–H bonds offers a complementary strategy to tackle this problem.17,18However, the majority of cyclization reactions going through sp3C–N bond formation under this catalytic manifold require the use of bespoke directing groups.19–22The realization of challenging palladium- catalyzed sp3C–H amination reactions of native substrate without installing directing groups has only begun to gain momentum. To this end, palladium-catalyzed intramolecular amination of methyl C–H bonds in sterically congested substrates have been reported.23–26

[0005] Thus, there exists a need in the field for the development of native amide-directed methyl C–H bond activation for the synthesis of N-protected β- and γ-lactams.27,28BRIEF DESCRIPTION OF THE FIGURES

[0006] Figure 1. Natural products and drug molecules amenable to methylene C–H amidation and amination for their synthesis.

[0007] Figure 2. A. Optimization of reaction conditions through ligand discovery and design. B. Preliminary investigations of reaction behavior. C. Design of ligand for recalcitrant substrates.

[0008] Figure 3. Substrate scope for carboxylic acid-directed β-C–H γ- and δ- lactamization reaction.

[0009] Figure 4. Substrate scope for carboxylic acid-directed β-C–H cycloamination reaction.

[0010] Figure 5. Synthesis of bicyclic lactam scaffolds pertinent to Stemona alkaloids. SUMMARY OF THE INVENTION

[0011] Recent developments of bifunctional ligands have rapidly advanced palladium- catalyzed sp3C–H activation reactions directed by native carboxylic acids. However, exploiting this approach to achieve inter or intramolecular sp3C–H amination has met with a fundamental challenge: nitrogen coordination often overrides the directing effect of the native carboxyl group. Through the discovery and design of new chlorinated pyridine- pyridone ligands, this challenge has been overcome and has enabled exclusive carboxylic- acid directed lactamization and cycloamination of N-protected ω-amino acids. The compartmentalization of directed C–H activation and C–N bond formation in this reaction is distinct from existing sp3C–H amination approaches, in which both processes are directed by nitrogen. The protocols described in this application transform linear ω-aminoTSRI 2214.1PC acids into valuable cyclic β-amino acids possessing γ- and δ-lactam, pyrrolidine, and tetrahydroquinoline scaffolds pertinent to drug discovery. The synthetic utility of this reaction was demonstrated by formal synthesis of Stemoamide.

[0012] The application provides a method of Palladium-catalyzed methylene C–H lactamization, or cycloamination comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source.

[0013] The application provides the above methods, wherein the pyridine-pyridone ligand is a chlorinated pyridine-pyridone ligand selected from the group consisting of:.

[0014] The application further provides the above methods, wherein the carboxylic acid is a N-protected ω-amino acid.

[0015] The application further provides the above methods, according to the following schemeTSRI 2214.1PC wherein: R3, R4, R5, and R6are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1.

[0016] The application further provides the above methods, according to the following reaction schemewherein: R3, R4, R5, R6, R7, and R8are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1- C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1. DETAILED DESCRIPTION OF THE INVENTION

[0017] Despite the advances made in this line of research, the formation of sp3C–N bonds at unactivated methylene carbons using palladium-catalyzed C–H activation directed by native functional groups has remained impregnable. Recent successes with carboxylic acid-directed methylene C–H activation reactions have prompted the inspiration to design an alternative strategy for sp3C–H amination. It was theorized that the use of carboxylic-acid as the directing group could compartmentalize directed methylene C–H activation and C–N bond formation. This is in stark contrast to conventional reaction designs that the nitrogen motif functions as both the directing group for C–H activation and the nucleophile for C–NTSRI 2214.1PC bond formation.22,29This separation of roles among two functional groups may obviate the need for bespoke directing groups at nitrogen to accommodate the palladium catalyst for both of these processes, and thus could potentially enable the use of native substrate for the desired transformation (Fig.1B). Therefore, it was decided to investigate the reactivity of N- protected ω-amino acids to determine if an intramolecular carboxylic acid-directed β- methylene C–H amination reaction would be feasible. However, existing protocols for carboxylic acid-directed methylene C–H dehydrogenation,30,31lactonization,32deuteration33and arylations34–36are expected to be ineffective for the proposed amination reaction as coordinating amino groups were rarely included in previous optimization campaigns. Hence, the capabilities of existing catalysts for the desired methylene C–H activation and C–N bond formation processes are unknown. In addition, the use of N-protected ω-amino acids creates a unique reaction scenario that is in stark contrast to known reaction systems in which only one type of directing group was employed. Specifically, N-protected ω-amino acids possess two competing directing groups that could result in two distinct modes of reactivity,37one being the desired carboxylic-acid directed C–N bond formation, and the other being an undesired and potentially dominating amine and amide-directed C–O bond formation pathway. These issues therefore presented three challenges to overcome for the development of the desired C–H amination reaction: enabling carboxylic acid-directed β-methylene C–H activation in the presence of coordinating amino groups; promoting sp3C–N bond formation; suppressing competing amine and amide-directed processes. The approach to overcoming the challenges as mentioned hinges upon ligand discovery and design, culminating in the development of a general strategy to access a series of scaffolds such as γ- and δ-lactam, pyrrolidine, and tetrahydroquinoline that are highly sought after in drug discovery. The synthetic utility of the C–H amidation reaction was demonstrated by formal synthesis of Stemoamide via the construction of bicyclic lactam scaffolds (Fig.1C).

[0018] The reactivity of N-protected ω-amino acid 1 was first benchmarked with the lactonization conditions developed for α,ω-dicarboxylic acids owing to the similarities between the two reaction systems (Fig.2A).32The use of ligand L1 that is the best in class for β-directed γ-lactonization of dicarboxylic acid only provided 25 % NMR yield of the desired γ-lactam product 1a for the C–N bond formation reaction, validating the concerns with diminished reactivity using existing catalytic systems. Gratifyingly, no C–O bond formation reactivity was observed. The suboptimal reactivity of L1 prompted the reversion to using simple pyridine-pyridone ligands L2-L8 to first map out a preliminary structure- reactivity relationship of the ligands for further optimization. Therefore, initial optimizationTSRI 2214.1PC of the reaction conditions commenced with the investigation of a series of pyridine-pyridone ligands with various substituents at the pyridine 6-position. The 6-chloropyridine-pyridone compound L3 was subsequently identified as a promising ligand scaffold, in which the use of this ligand provided the desired γ-lactam product 1a in 55% NMR yield. Replacement of the chlorine substituent with other functional groups such as fluorine and bromine (L2, L4), methyl (L8), methoxy (L6), hydroxyl (L5), and trifluoromethyl (L7) group all led to diminished catalytic activity (8-26% NMR yield of 1a). The use of a benzo[g]quinoline scaffold with a more extended π-system (L9) did not lead to any improvements in reaction efficiency (15% NMR yield of 1a). Aside from ligand L3, it was observed that ligands with electron donating substituents such as L6 and L8 performed slightly better compared to ligands with electron withdrawing substituents such as L7, prompting the further fine-tuning of the electronic properties of ligand L3. It was surmised that installing extra electron donating substituents on the pyridine portion of the ligand might further improve its reactivity, whereas installing extra electron withdrawing substituents would result in the opposite. Further investigations following this reasoning provided the 6-chloro-4- methylpyridine-pyridone compound L14 that was found to be superior to ligand L3, providing the γ-lactam product 1a in 65% NMR yield. The 4-methoxy substituted ligand L16 performed slightly worse compared to ligand L3, whereas ligands L10-L13 having extra electron withdrawing substituents were found to be invariably inferior. Ligand L15 with a 4- tert-butyl substituent appears to be an outlier in this case for yet unclear reasons. Perturbation of other reaction parameters at this stage led to no significant improvements in reaction yields.

[0019] Although it has been established that quinoline / pyridine-pyridone ligands that form 5-membered chelate with palladium such as L1 and L14 prefer to undergo carboxylic acid-directed β-C–H activation pathways,30,32it is unclear regarding their activity with amide as a potential directing group, and thus the product 1a could be formed either through carboxylic acid-directed β-C–H γ-lactamization, or amide-directed γ-C–H γ-lactamization. To discern between these two pathways, the reactivity of substrate 2 to gather preliminary mechanistic insights regarding the course of C–H functionalization (Fig.2B) was investigated. Specifically, substrate 2 could follow a carboxylic acid-directed β-C–H δ- lactamization pathway to provide δ-lactam product 2b, or an amide-directed γ-C–H γ- lactamization pathway to give γ-lactam product 2a. It was found that the lactamization reaction of 2 generated δ-lactam product 2b exclusively in 75% NMR yield, favoring a carboxylic acid-directed β-C–H δ-lactamization pathway. An amide-directed δ-C–HTSRI 2214.1PC activation pathway that would have involved a seven-membered palladacycle is considered unlikely. In addition, the γ-lactam product 2a was not observed, suggesting the observed C–N bond formation reactivity is inconsistent with amide-directed pathways. In agreement with this hypothesis, N-protected ω-amino methyl esters 3 and 4 displayed no C–N bond formation reactivity under identical reaction conditions, suggesting that the presence of carboxylic acid in the substrate is crucial for reactivity, and the tosyl carboxamide moiety alone does not appear to provide observable C–H functionalization reactivity.

[0020] The observation that the current catalytic system does not enable tosyl carboxamide-directed reactivity is somewhat surprising given that tosyl carboxamides are known to participate as directing groups in sp2C–H activation reactions.38–40It was therefore probed whether judicial matching of directing groups and ligands could be employed as a strategy to achieve site selective transformations (Fig.2B). Wasa amide-carboxylic acid substrate 5 was prepared to test the possibility of selecting between carboxylic acid-directed reactivity and amide-directed reactivity using known ligands developed for directed 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 lactonization product 5c,41whereas the use of ligand L14 gave 60% NMR yield of the carboxylic acid-directed lactamization product 5a. These preliminary findings suggest selection of directing groups for site-specific C–H functionalization is achievable through judicial pairing between directing groups and ligands, and the order of directing strengths could possibly be overridden by ligand effects.37

[0021] With the acquisition of ligand L14 and preliminary mechanistic knowledge, the development of the substrate scope for this C–H lactamization reaction began. However, a stumbling block emerged as the reactivity of N-protected ω-amino acids with substituents on the alkyl chain was surveyed. The substrate 6 with an α-spirocyclic amide provided only 12% NMR yield of δ-lactam 6b with ligand L14 (Fig.2C). This observation was surprising as the α-spirocyclic center was expected to assist the lactamization reaction through Thrope-Ingold effect. This counterintuitive outcome prompted questioning if quaternization of the substrate around the tosyl carboxamide would reduce the efficiency of C–H functionalization directed by the carboxylic acid. It was hypothesized that the extra pairs of β-methylene C–H bonds available around the tosyl carboxamide may promote tosyl carboxamide directed C–H activation processes, which is not inconsistent with the higher reactivity of quaternized substrates over their less substituted counterparts in directed C–H functionalization reactions.28Cognizant of the larger size of the tosyl carboxamide moiety as compared to aTSRI 2214.1PC carboxylic acid, it was surmised that increasing the steric hindrance of the ligand may favor carboxylic acid-directed lactamization of substrate 6 over unproductive coordination between tosyl carboxamide and the palladium catalyst. Testing of this hypothesis with sterically more encumbered quinoline-pyridone ligand L1 gave marginally better results compared to ligand L14, providing δ-lactam 6b in 20% NMR yield. It was therefore decided to combine the steric attribute of quinoline-pyridone ligand L1 with the chloro substituent that imbued reactivity to the pyridine-pyridone ligands L3 and L14 to create a 4-chloroquinoline-pyridone ligand L18 that is proposed to confer greater steric hindrance around the primary coordination sphere of the palladium catalyst while retaining the electronic benefits provided by the chloro substituent. The use of this new ligand L18 indeed immediately provided an improvement of the NMR yield of 6b to 47%.

[0022] As such, the substrate scope of the γ- and δ-lactamization reaction was developed with ligands L14 and L18 (Fig.3). The ligand L14 is the primary ligand of choice for the lactamization reaction, whereas the ligand L18 would only be used in cases when L14 fails to achieve significant degrees of lactamization. In certain cases, a slight increase in catalyst loading to 15 mol% using L14 as the ligand is required to elevate reaction yields. The design of the substrate scope focuses on generation of different classes of spiro and fused rings systems that are relevant to medicinal chemistry,42,43and examples that provide excellent levels of diastereoselection in the products that offer tractable synthetic utility are preferentially selected. All products were isolated as the methyl ester unless otherwise specified. For γ-lactamization, the fully unsubstituted γ-lactam 1a was isolated in 61% yield as the free carboxylic acid. Substitutions at both the α- and β-positions of the N-terminal are tolerated, providing a series of γ-lactams with multiple types of molecular scaffolds. These include α-quaternary γ-lactam 7a with gem-dimethyl substitution which was isolated in 40% yield, α-spirocyclic γ-lactams 8a-10a with cyclobutyl, cyclopentyl, and 4-tetrahydropyranyl systems that were isolated in 40-60% yields. Lactamization of α-monosubstituted substrates are feasible but are not shown here due to low levels of diastereoselectivity (see Examples). Substitution at the β-position provided the γ-lactams 11a-13a with methyl (as free carboxylic acid), tert-butyl (as free carboxylic acid), and phenyl groups that were generated predominantly as the anti-diastereomer (anti:syn > 20:1, see Examples regarding stereochemical assignments) in 78-93% yields. β-Spirocyclic γ-lactams 14a and 15a with cyclobutyl and cyclopentyl groups were also successfully synthesized in 81% and 50% yields, respectively. Aside from spirocyclic systems, fused ring systems such as the 5,5-fused 20a was prepared in 22% yield as the benzyl ester, and the benzo-fused γ-lactam 23a wasTSRI 2214.1PC assembled in 60% yield as the methyl ester. Of note is the successful synthesis of N-methoxy γ-lactam 25a, which was isolated in 61% yield as the benzyl ester and suggesting that another class of simple amides could also be used for this γ-lactamization protocol.

[0023] The development of the scope for the δ-lactamization reaction is analogous to that of the γ-lactamization reaction as described above. The fully unsubstituted δ-lactam 2b was isolated in 70% yield as the free carboxylic acid. Substitutions at both the α- and β-positions of the N-terminal are tolerated, 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% yields; and β-spirocyclic δ-lactam 19b in 73% yield. Fused ring systems are also viable targets for the δ-lactamization reaction, providing 5,6-fused 21b (as benzyl ester), 6,6-fused 22b (as benzyl ester), and benzo-fused 24b in around 60% isolated yield.

[0024] Following investigation of the scope of the lactamization reaction with tosyl carboxamides, it was pondered if this C–N bond formation protocol could rise to the challenge of achieving C–H cycloamination reaction with tosyl amides. Aside from the differences in expected directing strengths,37the presence of an α-methylene unit at the amine opens up the possibility for β-hydride elimination to occur, complicating the reaction by introducing an undesired tosyl imine formation pathway.44Despite the concerns for the feasibility of the reaction, the cycloamination reactions were found to occur smoothly using ligands L14 and L18, providing a series of N-protected pyrrolidines albeit generally requiring a higher catalyst loading at 15 mol% (Fig.4). All products were isolated as the methyl ester unless otherwise specified. The fully unsubstituted pyrrolidine 26a was isolated in 65% yield with no sign of tosyl imine formation. Pyrrolidines with substitutions at the α-, β-, and γ- positions were readily prepared using this protocol, providing α-monosubstituted pyrrolidines 27a and 28a as the syn-diastereomer in 55-67% yield as the free carboxylic acid (see Supporting Information regarding stereochemical assignments); α-quaternary pyrrolidine 29a with gem-dimethyl substitution in 60% yield; α-spirocyclic pyrrolidines with cyclobutyl (30a), cyclopentyl (31a), and 4-tetrahydropyranyl (32a) systems in 50-67% yields; β- quaternary and spirocyclic pyrrolidines with gem-dimethyl (33a), cyclobutyl (34a), and cyclopentyl (35a) systems in 40-50% yields; γ-monosubstituted pyrrolidines such as 36a-38a with methyl, tert-butyl, and phenyl groups in 70-82% yields as the anti-diastereomer (anti:syn > 20:1, see Supporting Information regarding stereochemical assignments), and γ- spirocyclic pyrrolidines 39a-49a with cyclobutyl and cyclopentyl systems in 27-35% yields. Fused bicyclic pyrrolidines such as 41a with 5,5-fused system was generated in 30% yield,TSRI 2214.1PC whereas 42a with a 5,6-fused system was prepared in 60% yield, and the tetrahydroquinoline 43b was synthesized in 53% yield. The cycloamination reaction was also found to be tolerant to the replacement of the tosyl protecting group for the 2-nosyl protecting group, successfully giving 44a although with a diminished yield.

[0025] To demonstrate the synthetic utility of the C–H amidation reaction in the context of complex molecule synthesis, a synthetic route for the preparation of 5,7-fused bicyclic lactams that are pertinent to Stemona alkaloids was developed as follows (Fig.5A).45,46The γ-lactam 1a was prepared from 1 in 57% isolated yield on gram scale. Subsequent tosyl group deprotection by titration of a cold (-40 °C) DME solution of γ-lactam 1a with sodium naphthalenide (as a ~2.0 M DME solution) followed by quenching with an excess of allyl bromide (added as a solution in DMF) gave the diallylated lactam 47 in 51% yield. An Ireland-Claisen rearrangement transformed the diallylated lactam 47 to diallylated carboxylic acid 48 in 73% yield with a d.r. of around 5:1 (major diastereomer as drawn),47which then underwent a ring-closing metathesis-hydrogenation sequence to arrive at the target 5,7-fused bicyclic lactam acid 49 in 85% yield. Putting the target bicyclic lactam acid 49 through another hurdle, the use of a photoredox decarboxylative oxygenation reaction provided the bicyclic ketolactam 50 in 60% yield that constitutes a formal synthesis of racemic Stemoamide 51.48,49Alternatively, the ring-closing metathesis product 52 could undergo bromolactonization with N-bromosuccinimide to give complex polycyclic species 53. All in all, the preparation of 50 and 53 from 1 demonstrates the feasibility of converting simple linear bifunctional compounds into various complex scaffolds via the use of the C–H amidation reaction as described in this disclosure.

[0026] Ultimately, the discovery and design of ligands L14 and L18 could also benefit existing dicarboxylic acid lactonization chemistry (Fig.5B). Given that the ligands L14 and L18 were optimized for reactions that are tolerant of both carboxylic acids and N-protected amines and amides, the use of ligand L18 that bears the greatest resemblance to ligand L1 for the lactonization of a previously difficult N-protected dicarboxylic acid substrate 50 immediately elevated the reaction yield from 25% to 60%.32Worthy of note is that alteration of the rest of the reaction parameters is not required, and thus the improvement in reaction yield comes entirely from the result of ligand optimization.

[0027] In conclusion, two new chlorinated ligands L14 and L18 for palladium-catalyzed, carboxylic acid-directed methylene lactamization and cycloamination reactions of N- protected ω-amino acids have been developed. The C–N bond formation reactions reported herein provide a means to leverage C–H activation to construct a variety of cyclic lactamsTSRI 2214.1PC and amines with various ring sizes and structures that are relevant to chemical synthesis and medicinal chemistry. References: 1. Kittakoop, P., Mahidol, C. & Ruchirawat, S. Alkaloids as Important Scaffolds in Therapeutic Drugs for the Treatments of Cancer, Tuberculosis, and Smoking Cessation. Curr. Top. Med. Chem.14, 239–252 (2014). 2. Cushnie, T. P. T., Cushnie, B. & Lamb, A. J. Alkaloids: An overview of their antibacterial, antibiotic-enhancing and antivirulence activities. Int. J. Antimicrob. Agents.44, 377–386 (2014). 3. Roughley, S. D. & Jordan, A. M. 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Relative Strength of Common Directing Groups in Palladium-Catalyzed Aromatic C−H Activation. iScience 20, 373–391 (2019). 38. Zhu, C. & Falck, J. R. N-acylsulfonamide assisted tandem C−H olefination / annulation: Synthesis of isoindolinones. Org. Lett.13, 1214–1217 (2011). 39. Péron, F., Fossey, C., Cailly, T. & Fabis, F. N-tosylcarboxamide as a transformable directing group for Pd-catalyzed C−H ortho-arylation. Org. Lett.14, 1827–1829 (2012). 40. Péron, F., Fossey, C., Sopkova-Deoliveirasantos, J., Cailly, T. & Fabis, F. Room-temperature ortho-alkoxylation and -halogenation of N-tosylbenzamides by using palladium(II)-catalyzed C−H activation. Chem. Eur. J.20, 7507–7513 (2014). 41. Chen, G. et al. Ligand-accelerated enantioselective methylene C(sp3)–H bond activation. Science 353, 1023–1027 (2016). 42. Hiesinger, K., Dar’In, D., Proschak, E. & Krasavin, M. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem.64, 150–183 (2021). 43. Marson, C. M. New and unusual scaffolds in medicinal chemistry. Chem. Soc. Rev.40, 5514–5533 (2011). 44. Wang, J. R. et al. Palladium-catalyzed aerobic oxidation of amines. Tet. Lett. 47, 8293–8297 (2006). 45. Pilli, R. A. & Ferreira De Oliveira, M. da C. Recent progress in the chemistry of the Stemona alkaloids. Nat. Prod. Rep.17, 117–127 (2000).TSRI 2214.1PC 46. Pilli, R. A., Rosso, G. B. & Ferreira de Oliveira, M. D. C. The chemistry of Stemona alkaloids: An update. Nat. Prod. Rep.27, 1908–1937 (2010). 47. Davies, S. G. et al. Diastereoselective Ireland-Claisen rearrangements of substituted allyl β-amino esters: Applications in the asymmetric synthesis of C(5)-substituted transpentacins. Org. Biomol. Chem.12, 2702–2728 (2014). 48. Faraggi, T. M., Li, W. & MacMillan, D. W. C. Decarboxylative Oxygenation via Photoredox Catalysis. Isr. J. Chem.60, 410–415 (2020). 49. Chavan, S. P., Harale, K. R., Puranik, V. G. & Gawade, R. L. Formal synthesis of (-)-Stemoamide using a useful epimerization at C-8. Tet. Lett.53, 2647–2650 (2012). EMBODIMENTS

[0028] The application provides the following embodiments:

[0029] Embodiment 1. A method of Palladium-catalyzed methylene C–H lactamization, or cycloamination comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source; and ii) addition of p-xyloquinone, an Ag salt, and K2HPO4in a reaction vessel.

[0030] Embodiment 2. The method of embodiment 1, wherein the pyridine-pyridone ligand is a chlorinated pyridine-pyridone ligand selected from the group consisting of:TSRI 2214.1PC.

[0031] Embodiment 3. The method of either Embodiment 1 or Embodiment 2, wherein the carboxylic acid is a N-protected ω-amino acid.

[0032] Embodiment 4. The method of any one of Embodiments 1-3, wherein the Pd source is Pd(OAc)2.

[0033] Embodiment 5. The method of any one of Embodiments 1-4, wherein the Ag salt is Ag2CO3.

[0034] Embodiment 6. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L10.

[0035] Embodiment 7. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L11.

[0036] Embodiment 8. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L12.

[0037] Embodiment 9. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L13.

[0038] Embodiment 10. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L14.

[0039] Embodiment 11. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L15.

[0040] Embodiment 12. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L16.

[0041] Embodiment 13. The method of any one of Embodiments 1-5, wherein the chlorinated pyridine-pyridone ligand is L18.

[0042] Embodiment 14. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is selected from the group consisting of:TSRI 2214.1PC.

[0043] Embodiment 15. The method of any one of Embodiments 1-5, wherein the quinoline-pyridone ligand is L1.

[0044] Embodiment 16. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is L2.

[0045] Embodiment 17. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is L3.

[0046] Embodiment 18. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is L4.

[0047] Embodiment 19. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is L5.

[0048] Embodiment 20. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is L6.

[0049] Embodiment 21. The method of any one of Embodiments 1-5, wherein the quinoline-pyridone ligand is L7.

[0050] Embodiment 22. The method of any one of Embodiments 1-5, wherein the quinoline-pyridone ligand is L8.

[0051] Embodiment 23. The method of any one of Embodiments 1-5, wherein the pyridine-pyridone ligand is L9.

[0052] Embodiment 24. A method of methylene C–H lactamization or cycloamination comprising i) treating a carboxylic acid substrate with any one of ligands L1-L18 in the presence of a Pd source; and ii) addition of a base.

[0053] Embodiment 25. The method of Embodiment 24, further comprising addition of p-xyloquinone.

[0054] Embodiment 26. The method of either Embodiment 24 or Embodiment 25, further comprising addition of an Ag salt.TSRI 2214.1PC

[0055] Embodiment 27. The method of Embodiment 26, wherein the Ag salt is Ag2CO3.

[0056] Embodiment 28. The method of any one of Embodiments 24-27, wherein the Pd source is Pd(OAc)2.

[0057] Embodiment 29. The method of any one of Embodiments 24-28, wherein the Pd source catalyst loading is 5-20 mol%.

[0058] Embodiment 30. The method of Embodiment 29, wherein the Pd source catalyst loading is 10 mol%.

[0059] Embodiment 31. The method of any one of Embodiments 24-29, further comprising addition of CsOAc

[0060] Embodiment 32. The method of any one of Embodiments 24-31, wherein the solvent is HFIP.

[0061] Embodiment 33. The method of any one of Embodiments 1-32, wherein the reaction temperature is approximately 90-110 °C.

[0062] Embodiment 34. The method of Embodiment 33, wherein the reaction temperature is approximately 100 °C.

[0063] Embodiment 35. The method of any one of Embodiments 1-34, wherein the reaction time is approximately 36h.

[0064] Embodiment 36. The method of any one of Embodiments 24-35, wherein the base is K2HPO4.

[0065] Embodiment 37. The method of any one of Embodiments 24-36, wherein the ligand L is L14.

[0066] Embodiment 38. The method of any one of Embodiments 24-36, wherein the ligand L is L18.

[0067] Embodiment 39. The method of Embodiment 1, according to the following schemeR1and R2are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6)TSRI 2214.1PC alkyl (C6-C10) aryl; R is an N-protecting group; and n is 1 or 2.

[0068] Embodiment 40. The method of Embodiment 39, wherein Z is -C(=O)-.

[0069] Embodiment 41. The method of Embodiment 39, wherein Z is -C(R1)(R2)-.

[0070] Embodiment 42. The method of Embodiment 41, wherein R1is H.

[0071] Embodiment 43. The method of Embodiment 41, wherein R1is (C1-C6) alkyl.

[0072] Embodiment 44. The method of Embodiment 41, wherein R1is (C6-C10) aryl.

[0073] Embodiment 45. The method of any one of Embodiments 39-44, wherein R2is H.

[0074] Embodiment 46. The method of any one of Embodiments 39-44, wherein R2is (C1-C6) alkyl.

[0075] Embodiment 47. The method of any one of Embodiments 39-44, wherein R2is(C6-C10) aryl.

[0076] Embodiment 48. The method of any one of Embodiments 39-47, wherein L is L14.

[0077] Embodiment 49. The method of any one of Embodiments 39-47, wherein L is L18.

[0078] Embodiment 50. The method of any one of Embodiments 39-47, wherein L is L1.

[0079] Embodiment 51. The method of Embodiment 39, according to the following scheme 10 mol%TSRI 2214.1PC R1and R2are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6-C10) aryl; R is an N-protecting group; and n is 1 or 2.

[0080] Embodiment 52. The method of Embodiment 1, according to the following schemewherein: R3, R4, R5, and R6are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1.

[0081] Embodiment 53. The C–H cycloamination reaction of Embodiment 1, according to the following reaction schemewherein: R3, R4, R5, R6, R7, and R8are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1- C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; andTSRI 2214.1PC n is 0 or 1.

[0082] Embodiment 54. The method of either one of Embodiment 52 or Embodiment 53, wherein R is Ts.

[0083] Embodiment 55. The method of any one of Embodiments 52-54, wherein L is L14.

[0084] Embodiment 56. The method of any one of Embodiments 52-54, wherein L is L18.

[0085] Embodiment 57. The method of any one of Embodiments 52-56, wherein R3and R4are H.

[0086] Embodiment 58. The method of any one of Embodiments 52-56, wherein R3and R4are (C1-C6) alkyl.

[0087] Embodiment 59. The method of any one of Embodiments 52-56, wherein R3and R4together form (C3-C7) cycloalkyl.

[0088] Embodiment 60. The method of any one of Embodiments 52-56, wherein R3and R4together form (C3-C7) heterocycloalkyl.

[0089] Embodiment 61. The method of any one of Embodiments 57-60, wherein R5and R6are H.

[0090] Embodiment 62. The method of any one of Embodiments 52-56, wherein R3and R5together form (C6-C10) aryl.

[0091] Embodiment 63. The method of any one of Embodiments 52-56, wherein R3and R5together form (C3-C7) cycloalkyl.

[0092] Embodiment 64. The method of any one of Embodiments 52-56, wherein R3and R5together form (C3-C7) heterocycloalkyl.

[0093] Embodiment 65. The method of any one of Embodiments 62-64, wherein R4and R6are H.

[0094] Embodiment 66. The method of any one of Embodiments 52-65, further comprising addition of p-xyloquinone.

[0095] Embodiment 67. The method of Embodiment 66, further comprising addition of Ag2CO3.

[0096] Embodiment 68. The method of Embodiment 67, wherein the Pd source is Pd(OAc)2.

[0097] Embodiment 69. The method of Embodiment 68, further comprising addition of CsOAc.TSRI 2214.1PC

[0098] Embodiment 70. The method of Embodiment 69, wherein the solvent is HFIP.

[0099] Embodiment 71. The method of Embodiment 70, wherein the reaction temperature is approximately 90-110 °C.

[0100] Embodiment 72. The method of Embodiment 71, wherein the reaction temperature is approximately 100 °C.

[0101] Embodiment 73. The method of Embodiment 72, wherein the reaction time is approximately 36h.

[0102] Embodiment 74. The method of Embodiment 73, wherein the base is K2HPO4.

[0103] Embodiment 75. The method of Embodiment 74, wherein the ligand L is L14.

[0104] Embodiment 76. The method of Embodiment 74, wherein the ligand L is L18.

[0105] Embodiment 77. The method of Embodiment 1, wherein the carboxylic acid is an N-protected ω-amino acid.

[0106] Embodiment 78. A method of synthesis of Stemoamide, comprising the lactamiztion reaction of Embodiment 52.

[0107] Embodiment 79. Any method disclosed in the instant application.

[0108] Embodiment 80. A method of Palladium-catalyzed methylene C–H lactamization, or cycloamination comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source; and ii) addition of p-xyloquinone, an Ag salt, and K2HPO4in a reaction vessel.

[0109] Embodiment 81. The method of Embodiment 80, wherein the pyridine-pyridone ligand is a chlorinated pyridine-pyridone ligand selected from the group consisting of:TSRI 2214.1PC.

[0110] Embodiment 82. The method of either Embodiment 80 or Embodiment 81, wherein the carboxylic acid is a N-protected ω-amino acid.

[0111] Embodiment 83. The method of any one of Embodiments 80-82, wherein the Pd source is Pd(OAc)2.

[0112] Embodiment 84. The method of any one of Embodiments 80-83, wherein the Ag salt is Ag2CO3.

[0113] Embodiment 85. The method of any one of Embodiments 80-84, wherein the chlorinated pyridine-pyridone ligand is L1, L14, or L18.

[0114] Embodiment 86. The method of Embodiment 80, according to the following schemeR1and R2are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6-C10) aryl; R is an N-protecting group; and n is 1 or 2.

[0115] Embodiment 87. The method of Embodiment 7, comprising the following schemeTSRI 2214.1PC 10 mol%wherein: Z is -C(=O)- or -C(R1)(R2)-; R1and R2are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6- C10) aryl; R is an N-protecting group; and n is 1 or 2.

[0116] Embodiment 88. The method of Embodiment 80, comprising the following scheme Rwherein: R3, R4, R5, and R6are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1.

[0117] Embodiment 89. The C–H cycloamination reaction of Embodiment 1, comprising the following reaction schemeTSRI 2214.1PCwherein: R3, R4, R5, R6, R7, and R8are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1- C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1.

[0118] Embodiment 90. A method of synthesis of Stemoamide, comprising the lactamiztion reaction of Embodiment 80.

[0119] Embodiment 91. A method of synthesis of Stemoamide, comprising the lactamiztion reaction of Embodiment 90.

[0120] Embodiment 92. The method of any one of Embodiments 80-91, wherein L is L1.

[0121] Embodiment 93. The method of any one of Embodiments 80-91, wherein L is L14.

[0122] Embodiment 94. The method of any one of Embodiments 80-91, wherein L is L18. Definitions

[0123] The phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0124] The phrase "as defined herein above" refers to the broadest definition for each group as provided in the Summary of the Invention, the Detailed Description of theTSRI 2214.1PC Invention, the Experimentals, or the broadest claim. In all other embodiments provided below, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.

[0125] As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited 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 recited features or components, but may also include additional features or components.

[0126] As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and / or" and not the "exclusive" sense of "either / or".

[0127] The term "independently" is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which “R” appears twice and is defined as "independently selected from” means that each instance of that R group is separately identified as one member of the set which follows in the definition of that R group. For example, “each R1and R2is independently selected from carbon and nitrogen" means that both R1and R2can be carbon, both R1and R2can be nitrogen, or R1or R2can be carbon and the other nitrogen or vice versa.

[0128] When any variable occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such compounds result in stable compounds.

[0129] The symbols "*" at the end of a bond or a line drawn through a bond or “~~~~” drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part.

[0130] A bond drawn into ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.

[0131] The term “optional” or “optionally” as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. ForTSRI 2214.1PC example, “optionally substituted” means that the “optionally substituted” moiety may incorporate a hydrogen or a substituent.

[0132] The phrase “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated to be a "bond" or "absent", the atoms linked to the substituents are then directly connected.

[0133] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.

[0134] Certain compounds disclosed may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers includeacidC(-OH)=N-) and amidine (-C(=NR)-NH--C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.

[0135] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and / or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted.TSRI 2214.1PC

[0136] The definitions described herein may be appended to form chemically-relevant combinations, such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,” “alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents. “Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below. The term -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.

[0137] The term “acyl” as used herein denotes a group of formula -C(=O)R wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C(=O)R wherein R is alkyl as defined herein. The term C1-6acyl refers to a group -C(=O)R contain 6 carbon atoms. The term "arylcarbonyl" as used herein means a group of formula C(=O)R wherein R is an aryl group; the term "benzoyl" as used herein an "arylcarbonyl" group wherein R is phenyl.

[0138] The term “alkyl” as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 12 carbon atoms. The term “lower alkyl” or “C1-C6alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C1-12 alkyl" as used herein refers to an alkyl composed of 1 to 12 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0139] When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically- named group. Thus, for example, “phenylalkyl” denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. TheTSRI 2214.1PC terms “arylalkyl” or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.

[0140] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0141] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C1–15alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C1–14 alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C1–13 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C1–11alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n– pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n– octyl (C8) and the like.

[0142] “Alkenyl” or “olefin” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5 alkenyl”). In someTSRI 2214.1PC embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0143] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0144] The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.

[0145] The term "alkylene" or "alkylenyl" as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH2)n)or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH(i-Pr)CH2-), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom. Examples of alkylene radicals include, but are notTSRI 2214.1PC limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.

[0146] The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t- butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "C1-10alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C1-10.

[0147] The term "hydroxyalkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups.

[0148] The terms "alkylsulfonyl" and "arylsulfonyl" as used herein refers to a group of formula -S(=O)2R wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” as used herein refers herein denotes a group of formula -S(=O)2R wherein R is “heteroalkyl” as defined herein.

[0149] The terms "alkylsulfonylamino" and "arylsulfonylamino"as used herein refers to a group of formula -NR'S(=O)2R wherein R is alkyl or aryl respectively, R' is hydrogen or C1-3alkyl, and alkyl and aryl are as defined herein.

[0150] The term “cycloalkyl” as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7cycloalkyl" as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.

[0151] The term carboxy-alkyl as used herein refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom. The term “carboxy” or “carboxyl” refers to a –CO2H moiety.

[0152] The term "heteroaryl” or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. As well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl,TSRI 2214.1PC pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, 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, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.

[0153] The term "heterocyclyl", “heterocycloalkyl” or "heterocycle" as used herein denotes a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,O or S(O)0-2), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.

[0154] “Heterocyclyl” or “heterocyclic” refers to a group or radical of a 3– to 14– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein theTSRI 2214.1PC point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0155] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0156] Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groupsTSRI 2214.1PC containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][1,4]diazepinyl, 1,4,5,7–tetrahydropyrano[3,4–b]pyrrolyl, 5,6–dihydro–4H–furo[3,2–b]pyrrolyl, 6,7–dihydro– 5H–furo[3,2–b]pyranyl, 5,7–dihydro–4H–thieno[2,3–c]pyranyl, 2,3–dihydro–1H– pyrrolo[2,3–b]pyridinyl, 2,3–dihydrofuro[2,3–b]pyridinyl, 4,5,6,7–tetrahydro–1H–pyrrolo- [2,3–b]pyridinyl, 4,5,6,7–tetrahydrofuro[3,2–c]pyridinyl, 4,5,6,7–tetrahydrothieno[3,2– b]pyridinyl, 1,2,3,4–tetrahydro–1,6–naphthyridinyl, and the like.

[0157] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl (α-naphthyl) and 2–naphthyl (β-naphthyl)). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0158] “Heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” alsoTSRI 2214.1PC includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).

[0159] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided 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 has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0160] Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl,TSRI 2214.1PC benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0161] “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

[0162] Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.

[0163] Exemplary non-hydrogen substituents wherein a moiety is “optionally substituted” as used herein means the moiety may be substituted with any additional moiety selected from, but not limited to, the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, – OH, –ORaa, –N(Rbb)2, –N(ORcc)Rbb, –SH, –SRaa, –C(=O)Raa, –CO2H, –CHO, –CO2Raa, – OC(=O)Raa, –OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, – NRbbC(=O)N(Rbb)2, –C(=NRbb)Raa, –C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, – C(=NRbb)N(Rbb)2, –OC(=NRbb)N(Rbb)2, –NRbbC(=NRbb)N(Rbb)2, –C(=O)NRbbSO2Raa, – NRbbSO2Raa, –SO2N(Rbb)2, –SO2Raa, –S(=O)Raa, –OS(=O)Raa, -B(ORcc)2, C1–10alkyl, C2–10alkenyl, C2–10 alkynyl, C3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =O; each instance of Raais, independently, selected from the group consisting of C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Raagroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,TSRI 2214.1PC carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, – SO2N(Rcc)2, –SORaa, C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14 aryl, and 5– to 14- membered heteroaryl, or two Rccgroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, – OC1–6alkyl, –ON(C1–6alkyl)2, –N(C1–6alkyl)2, –N(OC1–6alkyl)(C1–6alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, –C(=O)(C1–6alkyl), –CO2H, –CO2(C1–6alkyl), – OC(=O)(C1–6 alkyl), –OCO2(C1–6 alkyl), –C(=O)NH2, –C(=O)N(C1–6 alkyl)2, – OC(=O)NH(C1–6alkyl), –NHC(=O)( C1–6alkyl), –N(C1–6alkyl)C(=O)( C1–6alkyl), – NHCO2(C1–6alkyl), –NHC(=O)N(C1–6alkyl)2, –NHC(=O)NH(C1–6alkyl), –NHC(=O)NH2, –C(=NH)O(C1–6 alkyl),–OC(=NH)(C1–6 alkyl), –OC(=NH)OC1–6 alkyl, –C(=NH)N(C1–6 alkyl)2, –C(=NH)NH(C1–6alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6alkyl)2, – OC(NH)NH(C1–6alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6alkyl)2, –NHC(=NH)NH2, – NHSO2(C1–6 alkyl), –SO2N(C1–6 alkyl)2, –SO2NH(C1–6 alkyl), –SO2NH2,–SO2C1–6 alkyl, - B(OH)2, -B(OC1–6 alkyl)2,C1–6 alkyl, C1–6 perhaloalkyl, C2–6 alkenyl, C2–6 alkynyl, C3–10 carbocyclyl, C6–10aryl, 3–to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =O.

[0164] “Halo” or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I).

[0165] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients.

[0166] “Salt” includes any and all salts. “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact withTSRI 2214.1PC the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed 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 using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0167] Unless otherwise indicated, compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC). Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.TSRI 2214.1PC

[0168] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, replacement of a carbon by a13C- or14C- enriched carbon, and / or replacement of an oxygen atom with18O, are within the scope of the disclosure. Other examples of isotopes include15N,18O,17O,31P,32P,35S,18F,36Cl and123I. Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.

[0169] Certain isotopically-labelled compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability.

[0170] Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like11C or18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like123I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half- lives (t1 / 2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. DETAILED DESCRIPTION OF THE DRAWINGS

[0171] Figure 6. A. Natural products and drug molecules amenable to methylene C–H amidation and amination for their synthesis. B. Novel reaction design for palladium-catalyzed methylene C–H lactamization and cycloamination reactions. C. Construction of γ- and δ-TSRI 2214.1PC lactams, pyrrolidines, and tetrahydroquinoline through β-methylene C–H activation with new chlorinated ligands.

[0172] Figure 7. A. Optimization of reaction conditions through ligand discovery and design. B. Preliminary investigations of reaction behavior. C. Design of ligand for recalcitrant substrates.

[0173] Figure 8. Substrate scope for carboxylic acid-directed β-C–H γ- and δ- lactamization reaction. Reaction conditions: Pd(OAc)2(10 mol%), Ligand (12 mol%), p- xyloquinone (2.0 eq.), Ag2CO3 (2.0 eq.), K2HPO4 (0.35 eq.), CsOAc (0.4 eq.), HFIP, 100 °C, 36h.aIsolated yields of methyl ester unless otherwise stated.bPd(OAc)2(15 mol%), Ligand (17 mol%).cIsolated as the carboxylic acid.dIsolated as the benzyl ester.

[0174] Figure 9. Substrate scope for carboxylic acid-directed β-C–H cycloamination reaction. Reaction conditions: Pd(OAc)2 (10 mol%), Ligand (12 mol%), p-xyloquinone (2.0 eq.), Ag2CO3(2.0 eq.), K2HPO4(0.35 eq.), CsOAc (0.4 eq.), HFIP, 100 °C, 36h.aIsolated yields of methyl ester unless otherwise stated.bPd(OAc)2 (15 mol%), Ligand (17 mol%).cIsolated as the carboxylic acid.

[0175] Figure 10. A. Synthesis of bicyclic lactam scaffolds pertinent to Stemona alkaloids, see Examples for details regarding the reaction conditions. B. Superior reactivity of chlorinated ligands in dicarboxylic acid lactonization chemistry. EXAMPLES Abbreviations

[0176] Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert- butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (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 azodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD), di-iso- butylaluminumhydride (DIBAL or DIBAL-H), 1,3-Diisopropylcarbodiimide (DIC), di-iso- propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N- dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxideTSRI 2214.1PC (DMSO), 1,1'-bis-(diphenylphosphino)ethane (dppe), 1,1'-bis-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole-1-yl)-N, N,N’N’-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), iso-propanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), , methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS), N- carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N- methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t-BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p- toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or tosyl (Ts), N- urethane-N-carboxyanhydride (UNCA),. Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.). General Considerations

[0177] Compounds of the invention can be made by a variety of methods depicted in the illustrative synthetic reactions described below in the Examples section. General Information.

[0178] Pd(OAc)2was purchased from Strem. Solvents were obtained from Sigma-Aldrich, Alfa-Aeser, and Acros, and used directly without further purification. Other reagentswere purchased at the highest commercial quality and used without further purification, unless otherwise stated. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60F254 or Merck pre-coated aluminium-backed silica gel F254 plates.1H NMR spectraTSRI 2214.1PC were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 instruments. The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants, J, were reported in Hertz unit (Hz).13C NMR spectra were recorded on Bruker AMX-400, Bruker AV-500, or Bruker DRX-600 and were fully decoupled by broad band proton decoupling.19F{1H} NMR spectra were recorded on Bruker AMX-400. Chemical shifts were referenced to the appropriate residual solvent peaks. Column chromatography was performed using E. Merck silica (60, particle size 0.043–0.063 mm), and pTLC was performed on Merck silica plates (60F254). High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of flight). Experimental Section for the lactamization and cycloamination reactions Preparation of ligands

[0179] The ligands L1, L3, L6, L8 and L17 have been reported elsewhere,1–4the ligand L5 is commercially available. The ligands L2, L4, L6-L8, and L10-L18 were synthesized according to the general procedure as described below. For the ligand L9, it was prepared using a different approach and its synthesis would be described right after the general procedure for the other ligands.TSRI 2214.1PC Figure S11. Molecular structures of ligands (L1-L18) reported in this disclosure.

[0180] General procedure for the synthesis of ligands L2, L4, L6-L8 and L10-L18:Figure S12. General procedure for the synthesis of ligands L2, L4, L6-L8, and L10-L18. Synthesis of S2:

[0181] Adopting a modified procedure reported by Wang and co-workers1: A stirred mixture of 2,6-dibromopyridine 23 (11.7 g, 50 mmol, 1.0 equiv), 4-methoxybenzyl alcohol (14.7 g, 50 mmol, 1.0 equiv), potassium hydroxide (3.37 g, 60 mmol, 1.2 equiv), 18-crown-6 (1.32 g, 5 mmol, 0.1 equiv) and toluene (200 mL) was heated under reflux for 12 hours. The cooled solution was evaporated under vacuum before 200 mL DCM was added. The organic layer was washed with brine twice and dried over anhydrous Na2SO4. The crude was concentrated under reduced pressure, and purified by flash column chromatography (5% EA / hexanes to 10% EA / hexanes) to give the desired compound S2 in 90% yield (13.2 g, 45 mmol) as a thick liquid that solidifies to a white solid upon standing. Synthesis of S3:

[0182] Adopting a modified procedure reported by Wang and co-workers1: To a solution of 2-bromo-6-((4-methoxybenzyl)oxy)pyridine S2 (14.6 g, 50 mmol, 1.0 equiv) in THF (200 mL) was added n-BuLi (22 mL, 55 mmol, 1.1 equiv) and the mixture was stirred at -78 °C for 30 min under nitrogen atmosphere. Then n-Bu3SnCl (19.5 g, 60 mmol, 1.2 equiv) was added and the mixture was stirred at the same temperature for another 2 h. 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 in vacuo. The crude S3 was used as is for the next step without further purification (S3 wasTSRI 2214.1PC found to undergo decomposition on silica gel). Synthesis of ligands L2, L4, L6-L8, and L10-L18:

[0183] Adopting a modified procedure reported by Wang and co-workers1: A mixture of crude 2-((4-methoxybenzyl)oxy)-6-(tributylstannyl)pyridine 25 (assumed 10 mmol), various 2-halopyridines / quinolines (10 mmol), and tetrakis(triphenylphosphine)-palladium(0) (1.15 g, 1.0 mmol) in 20 mL of toluene was refluxed under nitrogen for 48 h. The resulting brown mixture was evaporated in vacuo, and the dark mixture was purified over flash chromatography (hexane / EA) to afford the corresponding quinoline-pyridine / bipyridine compounds S4 in moderate purity. The corresponding quinoline-pyridine / bipyridine compounds S4 was dissolved in DCM and 1 mL of trifluoroacetic acid was added. The mixture was stirred under room temperature for 1 hour before 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 was purified by flash chromatography (DCM: methanol = 20:1 then 10:1) to give the desired compounds L2, L4, L6-L8, and L10- L18 in an average 40% yield (~4 mmol) over two steps from S4 as white or pale yellow solids. Note: For the13C NMR spectra of ligands in DMSO-d6, they tend to have several very broad resonances that are sometimes invisible. For the13C NMR spectra of ligands in CDCl3, all expected13C NMR resonances are visible.6'-Fluoro-[2,2'-bipyridin]-6(1H)-one (L2):Structure of 2-halopyridine coupling partner:1H NMR (600 MHz, DMSO-d6) 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).TSRI 2214.1PC13C 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). (4 expected13C resonances are not visible due to broad resonances).1H NMR (600 MHz, CDCl3) δ 7.93 (q, J = 7.8 Hz, 1H), 7.71 (dd, J = 7.6, 2.3 Hz, 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).13C 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).19F{1H} NMR (376 MHz, DMSO-d6) δ -67.0, -73.4. (Ratio of integral = 18:1). HRMS (ESI-TOF) m / z Calcd for C10H8FN2O+[M+H]+: 191.0621, found 191.0617.6'-Bromo-[2,2'-bipyridin]-6(1H)-one (L4):Structure of 2-halopyridine coupling partner:1H NMR (600 MHz, DMSO-d6) 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).13C NMR (151 MHz, DMSO-d6) δ 162.7, 153.1, 141.0, 140.7, 140.6, 128.5, 119.9. (3 expected13C resonances are not visible due to broad resonances).1H 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, 6.9 Hz, 1H), 6.79 (dd, J = 6.9, 0.9 Hz, 1H), 6.65 (dd, J = 9.2, 0.9 Hz, 1H).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 are visible).TSRI 2214.1PC HRMS (ESI-TOF) m / z Calcd for C10H879BrN2O+[M+H]+: 250.9821, found 250.9815.6'-Methoxy-[2,2'-bipyridin]-6(1H)-one (L6):Structure of 2-halopyridine coupling partner:1H NMR (600 MHz, DMSO-d6) 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).13C NMR (151 MHz, DMSO-d6) δ 163.1, 162.4, 140.8, 140.3, 113.7, 111.7, 53.3. (4 expected13C resonances are not visible due to broad resonances).1H 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).13C 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 are visible) HRMS (ESI-TOF) m / z Calcd for C11H11N2O2+[M+H]+: 203.0821, found: 203.0807.6'-(Trifluoromethyl)-[2,2'-bipyridin]-6(1H)-one (L7):Structure of 2-halopyridine coupling partner:TSRI 2214.1PC1H NMR (600 MHz, DMSO-d6) 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).13C NMR (151 MHz, DMSO-d6) 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. (4 expected13C resonances are not visible due to broad resonances).1H NMR (400 MHz, CDCl3) δ 8.12 – 7.94 (m, 2H), 7.74 (dd, J = 6.4, 2.1 Hz, 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).13C 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. (1 expected resonance was not visible.) No resonances were visible on19F{1H} NMR (376 MHz, DMSO-d6). HRMS (ESI-TOF) m / z Calcd for C11H8F3N2O+[M+H]+: 241.0589, found: 241.0590.1H 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).13C NMR (151 MHz, DMSO-d6) δ 162.1, 157.8, 148.5, 140.9, 137.9, 124.1, 119.0, 117.6, 104.7, 24.0. (1 expected13C resonance is not visible due to broad resonance).1H 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).13C 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).TSRI 2214.1PC HRMS (ESI-TOF) m / z Calcd for C11H11N2O+[M+H]+: 187.0872, found: 187.0867.6'-Chloro-4'-(trifluoromethyl)-[2,2'-bipyridin]-6(1H)-one (L10):Structure of 2-halopyridine coupling partner:1H NMR (600 MHz, DMSO-d6) 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).13C NMR (151 MHz, DMSO-d6) 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. (4 expected13C resonances are not visible due to broad resonances).19F{1H} NMR (376 MHz, DMSO-d6) δ -63.2.1H 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).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). HRMS (ESI-TOF) m / z Calcd for C11H735ClF3N2O+[M+H]+: 275.0200, found: 275.0188.Methyl 6-chloro-6'-oxo-1',6'-dihydro-[2,2'-bipyridine]-4-carboxylate (L11):TSRI 2214.1PCStructure of 2-halopyridine coupling partner:1H 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).13C 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 expected13C resonances are visible). HRMS (ESI-TOF) m / z Calcd for C12H1035ClN2O3+[M+H]+:265.0380, found 265.0380. Cl Cl N HN O 5',6'-Dichloro-[2,2'-bipyridin]-6(1H)-one (L12):Structure of 2-halopyridine coupling partner:1H 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).13C 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 expected13C resonances are visible). HRMS (ESI-TOF) m / z Calcd for C10H735Cl2N2O+[M+H]+: 240.9936, found: 240.9940.TSRI 2214.1PC 4',6'-Dichloro-[2,2'-bipyridin]-6(1H)-one (L13):Structure of 2-halopyridine coupling partner:1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 0.8 Hz, 1H), 7.49 (dd, J = 9.1, 6.8 Hz, 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).13C 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 expected13C resonances are visible). HRMS (ESI-TOF) m / z Calcd for C10H735Cl2N2O+[M+H]+: 240.9936, found: 240.9944.6'-Chloro-4'-methyl-[2,2'-bipyridin]-6(1H)-one (L14):Structure of 2-halopyridine coupling partner:1H 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 = 8.7 Hz, 1H), 2.40 (s, 3H).13C NMR (151 MHz, DMSO) δ 162.7, 152.4, 149.9, 140.6, 125.0, 120.6, 20.4. (4 expected13C resonances are not visible due to broad resonances).1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 1.0 Hz, 0H), 7.48 (dd, J = 9.2, 6.9 Hz, 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).TSRI 2214.1PC13C 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 are visible). HRMS (ESI-TOF) m / z Calcd for C11H1035ClN2O+[M+H]+: 221.0482, found: 221.0478.4'-(tert-Butyl)-6'-chloro-[2,2'-bipyridin]-6(1H)-one (L15):Structure of 2-halopyridine coupling partner:1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 1.4 Hz, 1H), 7.49 (dd, J = 9.2, 6.9 Hz, 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).13C 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 expected13C resonances are visible). HRMS (ESI-TOF) m / z Calcd for C14H1635ClN2O+[M+H]+263.0952, found: 263.0955.6'-Chloro-4'-methoxy-[2,2'-bipyridin]-6(1H)-one (L16):Structure of 2-halopyridine coupling partner:TSRI 2214.1PC1H 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, 0.9 Hz, 1H), 3.93 (s, 3H).13C 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 expected13C resonances are visible). HRMS (ESI-TOF) m / z Calcd for C11H1035ClN2O2+[M+H]+: 237.0431, found: 237.0430.6-(4-Chloroquinolin-2-yl)pyridin-2(1H)-one (L18):Structure of 2-haloquinoline coupling partner:1H 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).13C 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 expected13C resonances are visible). HRMS (ESI-TOF) m / z Calcd for C14H1035ClN2O+[M+H]+: 257.0482, found: 257.0480. Synthesis of L9:Figure S13. Synthesis of ligand L9 from compounds S5 and S6.

[0184] Compound S5 was synthesized according to the procedure reported by Taffarel and co-workers.5Adopting a modified procedure reported by Wang and co-workers1:TSRI 2214.1PC 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 down to room temperature, all volatiles were removed, and the crude was redissolved in DCM and extracted three times with water. The organic layer was collected, dried with anhydrous MgSO4, and concentrated to give sufficiently pure S7 that was used directly in the next step.

[0185] The sufficiently pure S7 was suspended in 6M HCl and was heated to reflux and stirred overnight. After cooling down to room temperature, the reaction mixture was neutralized to pH ~ 7 and extracted with EtOAc three times. The organic layers were collected, dried with anhydrous MgSO4, and concentrated to give crude L9. The crude L9 was purified by flash column chromatography (EA: methanol = 20:1 to 10:1) to give pure L9 as a yellow solid (62% yield over 2 steps).6-(Benzo[g]quinolin-2-yl)pyridin-2(1H)-one (L9):1H NMR (600 MHz, DMSO-d6) 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).13C 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. (4 expected13C resonances are not visible due to broad resonances).1H 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).13C 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 are visible).TSRI 2214.1PC HRMS (ESI-TOF) m / z Calcd for C18H13N2O+[M+H]+: 273.1028, found: 273.1023. Optimization data for the lactamization and cycloamination reaction Investigation of ligand type and reaction conditions for the lactamization and cycloamination reactions:Table S1. Ligand investigation for the lactamization reaction.

[0186] From the ligand survey in Table S1, the ligand L14 was selected as the optimal ligand. Alteration of other experimental parameters did not lead to significant improvements in reaction NMR yields of the lactamization reaction. However, increase in catalyst loading to 15 mol% Pd(OAc)2and 17 mol% ligand in some cases led to improved reaction yields. This was found not to be a general phenomenon, as not every substrate could benefit from thisTSRI 2214.1PC increase in catalyst loading. Extension of such a strategy to another type of reaction, e.g. dicarboxylic acid lactonization, did not result in any improvement in reaction yields.

[0187] The reaction conditions using ligand L14 for the γ-lactamization of compound 1 was also applicable for the δ-lactamization of compound 2:Figure S14. Reaction conditions for the δ-lactamization of compound 2

[0188] Similarly, the same set of reaction conditions could be applied to the cycloamination reaction with compound 26:Figure S15. Reaction conditions for the cycloamination of compound 26.

[0189] For substrates that were found to be recalcitrant towards lactamization or cycloamination with the use of ligand L14, as was first observed with the compound 6, the use of ligand L18 was required to provide an elevation of reaction yield.Figure S16. Effect of the use of ligand L18 on the lactamization of 6. Reaction procedures of the lactamization and cycloamination reaction General procedure for the lactamization and cycloamination reaction The pictorial guide provided in the previous publication regarding dicarboxylic acid lactonization is also applicable to the present reaction, including gram scale reaction.6

[0190] To a 2-dram vial was added 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), p- xyloquinone (0.2 mmol), Ag2CO3(0.2 mmol), K2HPO4(0.035 mmol) and CsOAc (0.04TSRI 2214.1PC mmol, preferably added from a stock solution in HFIP as CsOAc is hygroscopic). HFIP (1.0 mL, or the volume needed to make up to 1.0 mL if a stock solution of CsOAc was used) and a stir-bar was then added, followed by sealing the reaction vessel with a PTFE septum inserted between the vial and its cap. (Note: Pd(OAc)2, ligand, p-xyloquinone, CsOAc, and the substrate could all be prepared as a stock solution in HFIP. The use of stock solution is recommended for setting up a series of reactions to maximize work efficiency). The reaction mixture was sonicated for 30 seconds before stirring at 200 rpm and 100 °C (heating block temperature) for 36 hours. The reaction mixture was then cooled to room temperature and diluted with dichloromethane (1.0 mL), followed by addition of deionized water (2.0 mL), aq.6M HCl (0.3 mL), brine (1.0 mL) and then shaken vigorously. The lower organic layer was carefully pipetted and filtered through a short plug of Celite®. The remaining aqueous layer was extracted with CH2Cl2 (1.0 mL) twice and the organic layer was pipetted and filtered as mentioned. The combined organic layer was then evaporated to dryness. The crude was then taken into CDCl3 (0.6 mL) with CH2Br2 (10.0 µL) as the internal standard to determine the assay yield of the reaction by1H NMR spectroscopy. The isolation of the product was carried out with aqueous extractions of the organic layer (in 0.6 mL CDCl3diluted with 2.0 mL CH2Cl2) with sat. aq. NaHCO3solution (1.0 mL each, 3 times). The collected aqueous layer was then acidified by aq.6M HCl to pH ~ 2 and extracted with EtOAc (1.0 mL, 3 times). The combined EtOAc layers was dried with anhydrous MgSO4, filtered, and evaporated to dryness. The product was further purified by pTLC (exact eluent composition mentioned below for each example) or subject to further derivatization into methyl or benzyl esters for isolation if purification of the free acid was found to be not straightforward. General procedure for benzyl ester formation

[0191] To the product obtained after aqueous extraction with sat. NaHCO3 solution as mentioned above was added dry CH2Cl2(2.0 mL), BnOH (1.2 eq.), DMAP (1.2 eq.) and EDCI (1.2 eq.) sequentially at room temperature. The reaction mixture was stirred at room temperature overnight, and completion of the reaction was confirmed by TLC analysis of the reaction mixture. The reaction mixture was then quenched by the addition of water and extracted with CH2Cl2(3 times), and the desired product was purified by pTLC (exact eluent composition mentioned below for each example). General procedure for methyl ester formationTSRI 2214.1PC

[0192] To the product obtained after aqueous extraction with sat. NaHCO3 solution as mentioned above, it was redissolved in MeOH and subsequently titrated with a solution of TMSCHN2in hexanes until effervescence subsides. The reaction mixture was stirred at room temperature overnight, and 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 (exact eluent composition mentioned below for each example). Characterization data of products obtained from the lactamization reaction2-(5-Oxo-1-tosylpyrrolidin-2-yl)acetic acid 1a

[0193] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L14, the compound was purified as the acid by pTLC (EA + 1% AcOH, Rf = 0.6) Isolated yield 61% (18.0 mg, 0.061 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C13H14NO5S- [M-H]-: 296.0593, found 296.0586.Methyl 2-(4,4-dimethyl-5-oxo-1-tosylpyrrolidin-2-yl)acetate 7a

[0194] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.30). Isolated yield 40% over 2 steps (13.7 mg, 0.04 mmol, white solid).TSRI 2214.1PC1H 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).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. HRMS (ESI-TOF) Calculated for C16H22NO5S+[M+H]+: 340.1219, found 340.1230.Methyl 2-(5-oxo-6-tosyl-6-azaspiro[3.4]octan-7-yl)acetate 8a

[0195] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.30). Isolated yield 40% over 2 steps (14.2 mg, 0.04 mmol, white solid).1H 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, 3.6 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S+, for [M+H]+: 352.1219, found 352.1220.Methyl 2-(1-oxo-2-tosyl-2-azaspiro[4.4]nonan-3-yl)acetate 9aTSRI 2214.1PC

[0196] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.35). Isolated yield 54% over 2 steps (19.6 mg, 0.054 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO5S+[M+H]+: 366.1375, Found: 366.1386.Methyl 2-(1-oxo-2-tosyl-8-oxa-2-azaspiro[4.5]decan-3-yl)acetate 10a

[0197] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (50% EA / hexanes, Rf= 0.20). Isolated yield 60% over 2 steps (23.0 mg, 0.06 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO6S+[M+H]+: 382.1324, found 382.1337.TSRI 2214.1PC2-((2R*,3S*)-3-Methyl-5-oxo-1-tosylpyrrolidin-2-yl)acetic acid 11a

[0198] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14, the compound was purified as the acid by pTLC (75% EA / hexane + 1% AcOH Rf= 0.50). Isolated yield 78% (24.4 mg, 0.078 mmol, pale brown solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H16NO5S- [M-H]-: 310.0749, Found: 310.0738.2-((2R*,3R*)-3-(tert-Butyl)-5-oxo-1-tosylpyrrolidin-2-yl)acetic acid 12a

[0199] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, the compound was purified as the acid by pTLC (50% EA / hexane + 1% AcOH Rf= 0.30). Isolated yield 93% (33.0 mg, 0.093 mmol, pale yellow solid).TSRI 2214.1PC1H 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, 9.7 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S- [M-H]-: 352.1219, Found: 352.1205.Methyl 2-((2R*,3R*)-5-oxo-3-phenyl-1-tosylpyrrolidin-2-yl)acetate 13a

[0200] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.30). Isolated yield 78% over 2 steps (30.1 mg, 0.078 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C20H22NO5S+[M+H]+: 388.1219, Found: 388.1230.Methyl 2-(7-oxo-6-tosyl-6-azaspiro[3.4]octan-5-yl)acetate 14aTSRI 2214.1PC

[0201] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.42). Isolated yield 81% over 2 steps (28.4 mg, 0.081 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S+[M+H]+: 352.1219, Found: 352.1218.Methyl 2-(3-oxo-2-tosyl-2-azaspiro[4.4]nonan-1-yl)acetate 15a

[0202] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.50). Isolated yield 50% over 2 steps (18.3 mg, 0.05 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO5S+[M+H]+: 366.1375, Found: 366.1374.TSRI 2214.1PC2-(6-Oxo-1-tosylpiperidin-2-yl)acetic acid 2b

[0203] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14, the compound was purified as the acid by pTLC (EA + 1% AcOH Rf= 0.27). Isolated yield 70% (22.0 mg, 0.07 mmol, pale yellow solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H18NO5S+[M+H]+: 312.0906, Found: 312.0917.Methyl 2-(5,5-dimethyl-6-oxo-1-tosylpiperidin-2-yl)acetate 16b

[0204] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.40). Isolated yield 60% over 2 steps (21.0 mg, 0.06 mmol, white solid).1H 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, 3.4 Hz, 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).13C 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.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C17H24NO5S+[M+H]+: 354.1375, Found: 354.1381.Methyl 2-(5-oxo-6-tosyl-6-azaspiro[3.5]nonan-7-yl)acetate 17b

[0205] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.40). Isolated yield 66% over 2 steps (24.0 mg, 0.066 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO5S+[M+H]+: 366.1375, Found: 366.1381.Methyl 2-(6-oxo-7-tosyl-7-azaspiro[4.5]decan-8-yl)acetate 6b

[0206] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.47). Isolated yield 40% over 2 steps (15.2 mg, 0.04 mmol, white solid).1H 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, 3.4 Hz, 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 = 14.4TSRI 2214.1PC 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, 6.2 Hz, 1H).13C 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. HRMS (ESI-TOF) Calculated for C19H26NO5S+[M+H]+: 380.1532, Found: 380.1544.Methyl 2-(1-oxo-2-tosyl-9-oxa-2-azaspiro[5.5]undecan-3-yl)acetate 18b

[0207] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (50% EA / hexanes, Rf = 0.30). Isolated yield 50% over 2 steps (19.8 mg, 0.05 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H26NO6S+[M+H]+: 396.1481, Found: 396.1491.Methyl 2-(9-oxo-8-tosyl-8-azaspiro[4.5]decan-7-yl)acetate 19b

[0208] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methylTSRI 2214.1PC ester by pTLC (30% EA / hexanes, Rf = 0.44). Isolated yield 73% over 2 steps (27.5 mg, 0.073 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H26NO5S+[M+H]+: 380.1532, Found: 380.1537.Methyl 2-((1S*,3aS*,6aR*)-3-oxo-2-tosyloctahydrocyclopenta[c]pyrrol-1-yl)acetate 20a

[0209] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.30). Isolated yield 22% over 2 steps (7.8 mg, 0.022 mmol, white solid).1H 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, 3.2 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S+[M+H]+: 352.1219, Found: 352.1219.TSRI 2214.1PCBenzyl 2-((3R*,4aS*,7aS*)-1-oxo-2-tosyloctahydro-1H-cyclopenta[c]pyridin-3-yl)acetate 21b

[0210] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by benzyl ester formation, the compound was purified as the benzyl ester by pTLC (40% EA / hexanes, Rf = 0.50). Isolated yield 60% over 2 steps (26.5 mg, 0.060 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C24H28NO5S+[M+H]+: 442.1688, Found: 442.1689.Benzyl 2-((3R*,4aS*,8aS*-1-oxo-2-tosyldecahydroisoquinolin-3-yl)acetate 22b

[0211] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by benzyl ester formation, the compound was purified as the benzyl ester by pTLC (40% EA / hexanes, Rf= 0.50). Isolated yield 60% over 2 steps (27.2 mg, 0.060 mmol, white solid).TSRI 2214.1PC1H 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, 5.7 Hz, 1H), 1.39 – 1.33 (m, 3H), 1.34 – 1.29 (m, 1H), 1.29 – 1.20 (m, 1H).3C 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. HRMS (ESI-TOF) Calculated for C25H30NO5S+[M+H]+: 456.1845, Found: 456.1853.Methyl 2-(3-oxo-2-tosylisoindolin-1-yl)acetate 23a

[0212] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.30). Isolated yield 60% over 2 steps (21.6 mg, 0.060 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H18NO5S+[M+H]+: 360.0906, Found: 360.0897.TSRI 2214.1PC Methyl 2-(1-oxo-2-tosyl-1,2,3,4-tetrahydroisoquinolin-3-yl)acetate 24b

[0213] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by benzyl ester formation, the compound was purified as the benzyl ester by pTLC (30% EA / hexanes, Rf = 0.30). Isolated yield 65% over 2 steps (24.2 mg, 0.065 mmol, white solid).1H 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, 1.4 Hz, 1H), 2.61 (dd, J = 16.1, 10.6 Hz, 1H), 2.42 (s, 3H).13C 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. HRMS (ESI-TOF) Calculated for C19H20NO5S+[M+H]+: 374.1062, Found: 374.1070.Benzyl 2-(1-methoxy-5-oxopyrrolidin-2-yl)acetate 25a

[0214] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by benzyl ester formation, the compound was purified as the benzyl ester by pTLC (75% EA / hexanes, Rf = 0.30). Isolated yield 61% over 2 steps (16.0 mg, 0.061 mmol, colorless oil).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H18NO4 [M+H]+: 264.1236, Found: 264.1239. Characterization data of products obtained from the cycloamination reactionTSRI 2214.1PCMethyl 2-(1-tosylpyrrolidin-2-yl)acetate 26a

[0215] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (50% EA / hexanes, Rf= 0.30). Isolated yield 65% over 2 steps (19.3 mg, 0.065 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H20NO4S+[M+H]+: 298.1114, Found: 298.1110.2-((2S*,5R*)-5-(tert-Butyl)-1-tosylpyrrolidin-2-yl)acetic acid 27a

[0216] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14, the compound was purified as the acid by pTLC (EA + 1% AcOH, Rf= 0.40). Isolated yield 55% (18.6 mg, 0.055 mmol, white solid).1H 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).13C 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.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C17H26NO4S+[M+H]+: 340.1583, Found: 340.1597.2-((2S*,5R*)-5-Phenyl-1-tosylpyrrolidin-2-yl)acetic acid 28a

[0217] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14, the compound was purified as the acid by pTLC (EA + 1% AcOH, Rf = 0.40). Isolated yield 67% (24.1 mg, 0.067 mmol, pale brown solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H22NO4S+[M+H]+: 360.1270, Found: 360.1285.Methyl 2-(5,5-dimethyl-1-tosylpyrrolidin-2-yl)acetate 29a

[0218] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (50% EA / hexanes, Rf= 0.50). Isolated yield 60% over 2 steps (19.5 mg, 0.06 mmol, white solid).1H 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C16H24NO4S+[M+H]+: 326.1426, Found: 326.1436.Methyl 2-(5-tosyl-5-azaspiro[3.4]octan-6-yl)acetate 30a

[0219] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (50% EA / hexanes, Rf = 0.57). Isolated yield 67% over 2 steps (22.5 mg, 0.067 mmol, white solid).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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S+[M+H]+: 338.1426, Found: 338.1424.Methyl 2-(1-tosyl-1-azaspiro[4.4]nonan-2-yl)acetate 31a

[0220] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.40). Isolated yield 50% over 2 steps (17.5 mg, 0.05 mmol, white solid).TSRI 2214.1PC1H 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, 3.5 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO4S+[M+H]+: 352.1583, Found: 352.1584.Methyl 2-(1-tosyl-8-oxa-1-azaspiro[4.5]decan-2-yl)acetate 32a

[0221] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (50% EA / hexanes, Rf = 0.27). Isolated yield 51% over 2 steps (18.7 mg, 0.051 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO5S+[M+H]+: 368.1532, Found: 368.1534.Methyl 2-(4,4-dimethyl-1-tosylpyrrolidin-2-yl)acetate 33aTSRI 2214.1PC

[0222] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.41). Isolated yield 50% over 2 steps (16.3 mg, 0.05 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H24NO4S+[M+H]+: 326.1426, Found: 326.1437.Methyl 2-(6-tosyl-6-azaspiro[3.4]octan-7-yl)acetate 34a

[0223] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.33). Isolated yield 50% over 2 steps (16.8 mg, 0.05 mmol, white solid).1H 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 = 10.3 Hz, 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, 7.7 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S+[M+H]+: 338.1426, Found: 338.1427.TSRI 2214.1PC Methyl 2-(2-tosyl-2-azaspiro[4.4]nonan-3-yl)acetate 35a

[0224] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2 and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.42). Isolated yield 40% over 2 steps (14.0 mg, 0.04 mmol, white solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO4S+[M+H]+: 352.1583, Found: 352.1591.Methyl 2-((2R*,3S*)-3-methyl-1-tosylpyrrolidin-2-yl)acetate 36a

[0225] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.30). Isolated yield 82% over 2 steps (25.5 mg, 0.082 mmol, white solid).1H 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, JTSRI 2214.1PC = 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).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. HRMS (ESI-TOF) Calculated for C15H22NO4S+[M+H]+: 312.1270, Found: 312.1277.Methyl 2-((2R*,3R*)-3-(tert-butyl)-1-tosylpyrrolidin-2-yl)acetate 37a

[0226] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.45). Isolated yield 70% over 2 steps (24.7 mg, 0.07 mmol, white solid).1H 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).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. HRMS (ESI-TOF) Calculated for C18H28NO4S+[M+H]+: 354.1739, Found: 354.1730.TSRI 2214.1PCMethyl 2-((2R*,3R*)-3-phenyl-1-tosylpyrrolidin-2-yl)acetate 38a

[0227] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.30). Isolated yield 70% over 2 steps (26.1 mg, 0.07 mmol, white solid).1H 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, 4.0 Hz, 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).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. HRMS (ESI-TOF) Calculated for C20H24NO4S+[M+H]+: 374.1426, Found: 374.1439.Methyl 2-(6-tosyl-6-azaspiro[3.4]octan-5-yl)acetate 39a

[0228] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.35). Isolated yield 35% over 2 steps (12.0 mg, 0.035 mmol, white solid).TSRI 2214.1PC1H 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).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. HRMS (ESI-TOF) Calculated for C17H24NO4S+[M+H]+: 338.1426, Found: 338.1436.Methyl 2-(2-tosyl-2-azaspiro[4.4]nonan-1-yl)acetate 40a

[0229] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L18 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.42). Isolated yield 27% over 2 steps (9.5 mg, 0.027 mmol, white solid).1H 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, 8.2 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO4S+[M+H]+: 352.1583, Found: 352.1595.Methyl 2-((1S*,3aS*,6aR*)-2-tosyloctahydrocyclopenta[c]pyrrol-1-yl)acetate 41aTSRI 2214.1PC

[0230] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.35). Isolated yield 30% over 2 steps (10.0 mg, 0.03 mmol, white solid).1H 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, 8.2 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S+[M+H]+: 338.1426, Found: 338.1437.Methyl 2-((2S*,3aS*,7aS*)-1-tosyloctahydro-1H-indol-2-yl)acetate 42a

[0231] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2 and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf= 0.41). Isolated yield 60% over 2 steps (21.0 mg, 0.06 mmol, white solid).1H 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, 6.4 Hz, 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C18H26NO4S+[M+H]+: 352.1583, Found: 352.1577.Methyl 2-(1-tosyl-1,2,3,4-tetrahydroquinolin-2-yl)acetate 43b

[0232] Following the general procedure for its synthesis using 15 mol% Pd(OAc)2and 17 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (20% EA / hexanes, Rf = 0.25). Isolated yield 53% over 2 steps (19.0 mg, 0.053 mmol, pale yellow solid).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H22NO4S+[M+H]+: 360.1270, Found: 360.1288.Methyl 2-(1-((2-nitrophenyl)sulfonyl)pyrrolidin-2-yl)acetate 44a

[0233] Following the general procedure for its synthesis using 10 mol% Pd(OAc)2and 12 mol% L14 followed by methyl ester formation, the compound was purified as the methyl ester by pTLC (30% EA / hexanes, Rf = 0.20). Isolated yield 40% over 2 steps (13.1 mg, 0.04 mmol, yellow solid).1H 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, 3.9TSRI 2214.1PC 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). 13C 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. HRMS (ESI-TOF) Calculated for C13H27N2O6S+[M+H]+: 329.0808, Found: 329.0811. Synthesis and characterization of substrates for the lactamization reaction General procedure A for the preparation of α-substituted amido acids (unless stated otherwise):Figure S17. General procedure for the preparation of α-substituted amido acids.

[0234] Step 1: A solution of nBuLi (2.5M in hexanes, 2.1 eq.) was added to a solution of DIPA (2.0 eq.) in THF (0.1M) at 0 °C. The resultant solution was stirred at 0 °C for 30 minutes. Generic carboxylic acid S8 (10.0 mmol, 1.0 eq.) was dissolved in THF (5.0 mL) and added dropwise to the LDA solution at 0 °C, in which the solution was warmed to r.t and stirred for 2 hours. The reaction mixture was then cooled to 0 °C and a solution of haloalkene (10.0 mmol, 1.0 eq.) in THF (5.0 mL) was added. The reaction was warmed to room temperature and stirred overnight. The completion of the reaction was confirmed by TLC analysis of the reaction mixture. The reaction was then quenched with aq. HCl (1.0 M) and extracted three times with EtOAc. The combined organic layer was dried with anhydrous MgSO4, filtered, and concentrated under vacuum. The crude obtained was filtered through a short plug of silica gel to remove polar impurities (usually orange in color), concentrated to give a pale yellow oil, and used subsequently in the next step without further purification.

[0235] Step 2: The generic crude carboxylic acids S9 or S10 obtained in the previous step was dissolved in anhydrous THF (0.1 M) at room temperature, followed by addition of Et3N (1.1 eq.) and then TsNCO (1.1 eq.). The reaction mixture was then stirred at room temperature overnight with a needle outlet (Gas evolution was observed as reaction proceeds). The completion of the reaction was confirmed by TLC analysis of the reactionTSRI 2214.1PC mixture. The reaction mixture was then quenched with sat. NaHCO3(aq) and extracted with EtOAc three times. The combined organic layer was dried with anhydrous MgSO4, filtered, and concentrated under vacuum. The desired generic amido alkenes S11 or S12 were obtained after purification by flash column chromatography on silica gel (Range of eluent polarity: 20% EA / hexanes to 50% EA / hexanes). The average yield for this 2-steps sequence is around 60%.

[0236] Step 3: The generic amido alkenes S11 or S12 were dissolved in DMF (0.1 M) and OsO4 (1 mol %, 2.5 wt % in tert-butanol) was added to the reaction mixture, in which the reaction mixture was observed to turn from colorless to pale brown in color. The reaction mixture was stirred for 5 minutes and then Oxone ® (4.0 eq.) was added. The reaction mixture was then stirred vigorously overnight. The completion of the reaction was confirmed by TLC analysis. The reaction was diluted with deionized water and extracted with EtOAc three times. The organic layers were combined, dried with anhydrous MgSO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel to give the desired generic amido acids S13 and S14 (Range of eluent polarity: 50% EA / hexanes + 1% AcOH to EA + 1% AcOH). The average yield for this oxidative cleavage step is around 80%. General procedure B for the preparation of α,β-disubstituted and β-substituted amido acids (unless stated otherwise):Figure S18. General procedure for the preparation of α,β-disubstituted and β-substituted amido acids.

[0237] Step 1: The generic α,β-unsaturated compound S15 (10.0 mmol) was dissolved in anhydrous THF (0.1 M), CuI (10 mol%) was added subsequently, and the reaction mixture was cooled to -15 °C with vigorous stirring. TMSCl (2.0 eq.) was added to the reaction mixture and then the Grignard reagent was added dropwise to the reaction mixture. The color of the reaction mixture was observed to turn from pale yellow to dark blue upon completion addition of the Grignard reagent. The reaction mixture was allowed to stir and warm up to room temperature overnight. The completion of the reaction was confirmed by TLC analysis.TSRI 2214.1PC The reaction mixture was quenched with sat. NH4Cl(aq) and extract 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 plug of silica gel to remove polar impurities.

[0238] Step 2: The generic crude addition product S16 and S17 was suspended in 15% aq. NaOH, heated to reflux, and stirred at this temperature overnight. The reaction mixture was cooled to room temperature and extracted three times with Et2O. The aqueous layer was collected and acidified by the addition of aq. HCl (6.0 M) to pH ~ 2. The aqueous layer was then extracted with EtOAc three times. The combined EtOAc layers were dried with anhydrous MgSO4, concentrated under reduced pressure, and filtered through a short plug of silica gel to remove polar impurities to give the crude generic carboxylic acids S18 and S19 which were used in the next step without further purification.

[0239] Step 3: The generic crude carboxylic acids S18 or S19 obtained in the previous step was dissolved in anhydrous THF (0.1 M) at room temperature, followed by addition of Et3N (1.1 eq.) and then TsNCO (1.1 eq.). The reaction mixture was then stirred at room temperature overnight with a needle outlet (Gas evolution was observed as reaction proceeds). The completion of the reaction was confirmed by TLC analysis of the reaction mixture. The reaction mixture was then quenched with sat. NaHCO3(aq) and extracted with EtOAc three times. The combined organic layer was dried with anhydrous MgSO4, filtered, and concentrated under vacuum. The desired generic amido alkenes S20 or S21 were obtained after purification by flash column chromatography on silica gel (Range of eluent polarity: 20% EA / hexanes to 50% EA / hexanes). The average yield for this 3-steps sequence is around 42%.

[0240] Step 4: The generic amido alkenes S20 or S21 were dissolved in DMF (0.1 M) and OsO4 (1 mol %, 2.5 wt % in tert-butanol) was added to the reaction mixture, in which the reaction mixture was observed to turn from colorless to pale brown in color. The reaction mixture was stirred for 5 minutes and then Oxone ® (4.0 eq.) was added. The reaction mixture was then stirred vigorously overnight. The completion of the reaction was confirmed by TLC analysis. The reaction was diluted with deionized water and extracted with EtOAc three times. The organic layers were combined, dried with anhydrous MgSO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel to give the desired amido acids S22 and S23 (Range of eluent polarity: 50% EA / hexanes + 1% AcOH to EA + 1% AcOH). The average yield for this oxidative cleavage step is around 80%.TSRI 2214.1PCN-Tosylhept-6-enamide SS1

[0241] This compound was prepared according to step 2 of the general procedure A from commercially available hept-6-enoic acid.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H20NO3S+[M+H]+: 282.1164, Found: 282.1157.6-((4-Methylphenyl)sulfonamido)-6-oxohexanoic acid 1

[0242] This compound was prepared according to step 3 of the general procedure A from SS1.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C13H16NO5S- [M-H]-: 298.0749, Found: 298.0757.2,2-Dimethyl-N-tosylhept-6-enamide SS7TSRI 2214.1PC

[0243] This compound was prepared according to general procedure A from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H24NO3S+[M+H]+: 310.1477, Found: 310.1477.5,5-Dimethyl-6-((4-methylphenyl)sulfonamido)-6-oxohexanoic acid 7

[0244] This compound was prepared according to general procedure A from SS7.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C15H20NO5S- [M-H]-: 326.1062, Found: 326.1064.1-(Pent-4-en-1-yl)-N-tosylcyclobutane-1-carboxamide SS8

[0245] This compound was prepared according to general procedure A from O commercially available.1H 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, 1.6TSRI 2214.1PC 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO3S+[M+H]+: 322.1477, Found: 322.1479.4-(1-(Tosylcarbamoyl)cyclobutyl)butanoic acid 8

[0246] This compound was prepared according to general procedure A from SS8.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H20NO5S- [M-H]-: 338.1062, Found: 338.1065.1-(Pent-4-en-1-yl)-N-tosylcyclopentane-1-carboxamide SS9

[0247] This compound was prepared according to general procedure A from O commercially available.1H 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).13C 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.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C18H26NO3S+[M+H]+: 322.1477, Found: 322.1477.4-(1-(Tosylcarbamoyl)cyclopentyl)butanoic acid 9

[0248] This compound was prepared according to general procedure A from SS9.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S- [M-H]-: 352.1219, Found: 352.1219.4-(Pent-4-en-1-yl)-N-tosyltetrahydro-2H-pyran-4-carboxamide SS10

[0249] This compound was prepared according to general procedure A from commercially available.1H 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, 1.4 Hz, 2H), 1.55 – 1.46 (m, 2H), 1.46 – 1.41 (m, 2H), 1.15 – 0.80 (m, 2H).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO4S+[M+H]+: 352.1583, Found: 352.1590.TSRI 2214.1PC4-(4-(Tosylcarbamoyl)tetrahydro-2H-pyran-4-yl)butanoic acid 10

[0250] This compound was prepared according to general procedure A from SS10.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO6S- [M-H]-: 368.1168, Found: 368.1178.3-Methyl-N-tosylhept-6-enamide SS11

[0251] This compound was prepared according to general procedure B from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C15H22NO3S+[M+H]+: 296.1321, Found: 296.1314.TSRI 2214.1PC 4-Methyl-6-((4-methylphenyl)sulfonamido)-6-oxohexanoic acid 11

[0252] This compound was prepared according to general procedure B from SS11.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H18NO5S- [M-H]-: 312.0906, Found: 312.0912. 6-enamide SS12 was prepared according to general procedure B from known.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H28NO3S+[M+H]+: 338.1790, Found: 338.1802.4-(tert-Butyl)-6-((4-methylphenyl)sulfonamido)-6-oxohexanoic acid 12

[0254] This compound was prepared according to general procedure B from SS12.TSRI 2214.1PC1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO5S- [M-H]-: 354.1375, Found: 354.1375.3-Phenyl-N-tosylhept-6-enamide SS13

[0255] This compound was prepared according to general procedure B from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C20H24NO3S+[M+H]+: 358.1477, Found: 358.1475.6-((4-Methylphenyl)sulfonamido)-6-oxo-4-phenylhexanoic acid 13

[0256] This compound was prepared according to general procedure B from SS13.1H 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C19H20NO5S- [M-H]-: 374.1062, Found: 374.1067. -N-tosylacetamide SS14 was prepared according to general procedure B from known.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO3S+[M+H]+: 322.1477, Found: 322.1480.3-(1-(2-((4-Methylphenyl)sulfonamido)-2-oxoethyl)cyclobutyl)propanoic acid 14

[0258] This compound was prepared according to general procedure B from SS14.1H 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).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. HRMS (ESI-TOF) Calculated for C16H20NO5S- [M-H]-: 338.1062, Found: 338.1070.2-(1-(But-3-en-1-yl)cyclopentyl)-N-tosylacetamide SS15TSRI 2214.1PC

[0259] This compound was prepared according to general procedure B from known.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO3S+[M+H]+: 336.1634, Found: 336.1630.3-(1-(2-((4-Methylphenyl)sulfonamido)-2-oxoethyl)cyclopentyl)propanoic acid 15

[0260] This compound was prepared according to general procedure B from SS15.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S- [M-H]-: 352.1219, Found: 352.1225.N-Tosyloct-7-enamide SS2

[0261] This compound was prepared according to step 2 of the general procedure A from commercially available oct-7-enoic acid.1H 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C15H22NO3S+[M+H]+: 296.1322, Found: 296.1321.7-((4-Methylphenyl)sulfonamido)-7-oxoheptanoic acid 2

[0262] This compound was prepared according to general procedure A from SS2.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H18NO5S- [M-H]-: 312.0906, Found: 312.0902.2,2-Dimethyl-N-tosyloct-7-enamide SS16

[0263] This compound was prepared according to general procedure A from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H26NO3S+[M+H]+: 324.1635, Found: 324.1637.TSRI 2214.1PC6,6-Dimethyl-7-((4-methylphenyl)sulfonamido)-7-oxoheptanoic acid 16

[0264] This compound was prepared according to general procedure A from SS16.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H22NO5S- [M-H]-: 340.1219, Found: 340.1222.1-(Hex-5-en-1-yl)-N-tosylcyclobutane-1-carboxamide SS17

[0265] This compound was prepared according to general procedure A from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO3S+[M+H]+: 336.1625, Found: 336.1629.5-(1-(Tosylcarbamoyl)cyclobutyl)pentanoic acid 17TSRI 2214.1PC

[0266] This compound was prepared according to general procedure A from SS17.1H 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).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. HRMS (ESI-TOF) Calculated for C17H22NO5S- [M-H]-: 352.1219, Found: 352.1223.1-(Hex-5-en-1-yl)-N-tosylcyclopentane-1-carboxamide SS6

[0267] This compound was prepared according to general procedure A from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H28NO3S+[M+H]+: 350.1791, Found: 350.1780.5-(1-(Tosylcarbamoyl)cyclopentyl)pentanoic acid 6

[0268] This compound was prepared according to general procedure A from SS6.TSRI 2214.1PC1H 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, 1.4 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO5S- [M-H]-: 366.1375, Found: 366.1373.4-(Hex-5-en-1-yl)-N-tosyltetrahydro-2H-pyran-4-carboxamide SS18

[0269] This compound was prepared according to general procedure A from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H28NO4S+[M+H]+: 366.1741, Found: 366.1741.5-(4-(Tosylcarbamoyl)tetrahydro-2H-pyran-4-yl)pentanoic acid 18

[0270] This compound was prepared according to general procedure A from SS18.TSRI 2214.1PC1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO6S- [M-H]-: 382.1336, Found: 382.1333.2-(1-(Pent-4-en-1-yl)cyclopentyl)-N-tosylacetamide SS19

[0271] This compound was prepared according to general procedure B from known.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H28NO3S+[M+H]+: 350.1791, Found: 350.1795.4-(1-(2-((4-Methylphenyl)sulfonamido)-2-oxoethyl)cyclopentyl)butanoic acid 19

[0272] This compound was prepared according to general procedure B from SS19.1H 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, 1.7 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO5S- [M+H]+: 368.1532, Found: 368.1537.TSRI 2214.1PC2-(But-3-en-1-yl)-N-tosylcyclopentane-1-carboxamide SS20

[0273] This compound was prepared according to general procedure B from commercially available.1H 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).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. HRMS (ESI-TOF) Calculated for C17H24NO3S- [M+H]+: 322.1478, Found: 322.1473.3-(2-(Tosylcarbamoyl)cyclopentyl)propanoic acid 20

[0274] This compound was prepared according to general procedure B from SS20.1H NMR (600 MHz, MeOD) δ 8.04 – 7.66 (m, 4H), 7.38 (dd, J = 8.1, 6.1 Hz, 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C16H20NO5S- [M-H]-: 338.1062, Found: 338.1064.2-(Pent-4-en-1-yl)-N-tosylcyclopentane-1-carboxamide SS21

[0275] This compound was prepared according to general procedure B from commercially available.1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 2H), 7.95 (dd, J = 8.4, 4.7 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO3S- [M+H]+: 336.1634, Found: 336.1628.Racemization might have occurred under oxidative cleavage conditions. 4-(2-(Tosylcarbamoyl)cyclopentyl)butanoic acid 21

[0276] This compound was prepared according to general procedure B from SS21.1H 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),TSRI 2214.1PC 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).13C 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. HRMS (ESI-TOF) Calculated for C17H22NO5S- [M-H]-: 352.1219, Found: 352.1220.Apparent single diastereomer(1R*,2R*)-2-(pent-4-en-1-yl)-N-tosylcyclohexane-1-carboxamide SS22

[0277] This compound was prepared according to general procedure B from commercially available.1H 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, 1.4 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C19H28NO3S- [M+H]+: 350.1790, Found: 350.1792.d.r. ~ 4:1. Racemization might have occurred under oxidative cleavage conditions. 4-(2-(Tosylcarbamoyl)cyclohexyl)butanoic acid 22

[0278] This compound was prepared according to general procedure B from SS22.TSRI 2214.1PC1H 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, 4.0 Hz, 1H).13C 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. HRMS (ESI-TOF) Calculated for C18H24NO5S- [M-H]-: 366.1375, Found: 366.1380.3-(2-(Tosylcarbamoyl)phenyl)propanoic acid 23

[0279] This compound was prepared according to general procedure A from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H16NO5S- [M-H]-: 346.0749, Found: 346.0757.4-(2-(Tosylcarbamoyl)phenyl)butanoic acid 24TSRI 2214.1PC

[0280] This compound was prepared according to general procedure A from commercially available. The reaction of the dianion of the benzoic acid starting material with 4-bromobut-1-ene was found to be rather low-yielding (~20% yield). Presumably, competitive E2 elimination of 4-bromobut-1-ene to give butadiene was facile relative to the desired alkylation reaction.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H18NO5S- [M-H]-: 360.0906, Found: 360.0906.6-(Methoxyamino)-6-oxohexanoic acid 25 Note: this compound was found to possess considerable water solubility. Hence, the following synthetic sequence was designed for its synthesis.Figure S19. Procedure for the preparation of 25.

[0281] According to the procedure reported by Robert and co-workers7, the 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. The crude anhydride S25 was obtained after evaporation of the volatiles under reduced pressure, and immediately redissolved inTSRI 2214.1PC anhydrous DCM (0.1 M), followed by addition of benzyl alcohol (11 mmol), Et3N (11 mmol), and DMAP (1 mmol) and stirred overnight. The reaction mixture was quenched with 1M HCl(aq)and washed three times with 1M HCl(aq). The organic layer was collected, dried with anhydrous MgSO4, filtered, and concentrated to provide the crude monobenzylated ester S26. The crude ester S26 was purified by flash column chromatography (20% EA / hexane to 50% EA / hexane) to give the known pure ester S26 in 61% yield over 2 steps (1.4 g, 6.1 mmol).8The ester S26 (5.0 mmol) was then dissolved in DCM (0.1 M), followed by successive addition of MeONH2·HCl (5.5 mmol), Et3N (5.5 mmol), and EDCI (5.5 mmol) and stirred at room temperature for 2 hours. The reaction mixture was then quenched with 1M HCl(aq)and washed three times with 1M HCl(aq). The organic layer was collected, dried with anhydrous MgSO4, filtered, and concentrated to provide the crude amido ester S27. The crude S27 was purified by flash column chromatography (50% EA / hexane to 70% EA / hexane) to give S27 in 96% yield (1.3 g, 4.8 mmol). The compound S27 then underwent hydrogenolysis with Pd / C and H2 (balloon pressure) in EtOH to give 25 in quantitative yield after removal of volatiles.Benzyl 6-(methoxyamino)-6-oxohexanoate S271H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H20NO4+[M+H]+: 266.1394, Found: 266.1399.6-(Methoxyamino)-6-oxohexanoic acid 251H 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).13C NMR (151 MHz, MeOD) δ 177.2, 172.4, 64.3, 34.5, 33.4, 26.0, 25.4.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C7H12NO4- [M-H]-: 174.0766, Found: 174.0773. Synthesis and characterization of substrates for the cycloamination reaction General procedure C for the preparation of α-substituted amino acids (unless stated otherwise):aq. HCl (6M) then 1,4-dioxane TsCl, Et3N, r.t. O.N. DCM, r.t., O.N.Figure S20. General procedure for the preparation of α-substituted amino acids.

[0282] Step 1: The intermediate S10 was prepared according to general procedure A as described above.

[0283] Step 2: The intermediate S10 was dissolved in toluene (0.1 M) and Et3N (1.1 eq.) was added followed by DPPA (1.1 eq.). The reaction mixture was stirred at room temperature for 30 minutes before heating to reflux and stirred at reflux for 2 hours (Caution: copious gas evolution). The reaction mixture was cooled to room temperature and quenched by addition of deionized water. The organic layer was washed three times with deionized water, and then dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the crude isocyanate S28.

[0284] Steps 3 and 4: The crude isocyanate S28 was then dissolved in 1,4-dioxane (0.1 M) and stirred at room temperature. An aqueous solution of HCl (6M) was added dropwise until pH of the reaction mixture was around 1. The reaction mixture was left to stir overnight and then basified with aq. NaOH (3.75M) to pH ~ 12. The reaction mixture was then diluted with deionized water and extracted with Et2O three times. The organic layers were collected, dried with anhydrous MgSO4, filtered, and concentrated to give the crude amine. The crude amine was dissolved in DCM at room temperature, followed by addition of Et3N (1.1 eq.) and TsCl (1.1 eq.) and stirred overnight. The reaction mixture was then quenched with sat. NaHCO3and extracted three times with DCM. The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the crude tosylTSRI 2214.1PC protected amine S29. The crude tosyl protected amine S29 was purified with flash column chromatography (Range of eluent polarities: 20% EA / hexane to 50% EA / hexane). Average yield of S29 for this 4-steps sequence is around 35%.

[0285] Step 5: The oxidative cleavage was carried out as described according to general procedure A. General procedure D for the preparation of β-substituted amino acids (unless stated otherwise):Figure S21. General procedure for the preparation of β-substituted amino acids.

[0286] Step 1: The intermediate S11 was prepared according to general procedure A as described above.

[0287] Step 2: The intermediate S11 was dissolved in dry THF (0.1 M) and cooled to 0 °C. A solution of LiAlH4(2.0 M in Et2O, 4 eq.) was added dropwise to the reaction mixture (Caution: copious gas evolution). After addition, the reaction was gradually warmed to room temperature and stirred overnight. The reaction was then worked-up using the Fieser workup procedures (Dilute reaction mixture with Et2O and cool to 0 °C. For x g of LiAlH4used, add x mL of water, followed by x mL of 15% aq. NaOH, and then 3x mL of water. After addition, warm the reaction mixture to r.t. and stir 15 minutes, and then add anhydrous MgSO4, stir for another 15 minutes and filter.). The crude S31 was purified with flash column chromatography (Range of eluent polarities: 20% EA / hexane to 50% EA / hexane). The average yield of S31 for this reduction is around 60%.

[0288] Step 3: The oxidative cleavage was carried out as described according to general procedure A. General procedure E for the preparation of γ-substituted amido acids (unless stated otherwise):TSRI 2214.1PCFigure S22. General procedure for the preparation of γ-substituted amido acids.

[0289] Step 1: The intermediate S20 was prepared according to general procedure B as described above.

[0290] Step 2: The intermediate S33 was prepared according to general procedure D as described above.

[0291] Step 3: The oxidative cleavage was carried out as described according to general procedure B.6-((4-Methylphenyl)sulfonamido)hexanoic acid 26

[0292] This known compound was prepared according to the method reported by Pavlidis and co-workers from commercially available 6-aminohexanoic acid.9N-(2,2-Dimethylnon-8-en-3-yl)-4-methylbenzenesulfonamide SS27

[0293] This compound was prepared according to the general procedure C from O tBu commercially availableHO. 1H 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C18H30NO2S+[M+H]+: 324.1999, Found: 324.2002.7,7-Dimethyl-6-((4-methylphenyl)sulfonamido)octanoic acid 27

[0294] This compound was prepared according to the general procedure C from SS27.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H26NO4S- [M-H]-: 340.1583, Found: 340.1581.4-Methyl-N-(1-phenylhept-6-en-1-yl)benzenesulfonamide SS28

[0295] This compound was prepared according to the general procedure C from O Ph commercially availableHO.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C20H26NO2S+[M+H]+: 344.1686, Found: 344.1679.TSRI 2214.1PC6-((4-Methylphenyl)sulfonamido)-6-phenylhexanoic acid 28

[0296] This compound was prepared according to the general procedure C from SS28.1H 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).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. HRMS (ESI-TOF) Calculated for C19H22NO4S- [M-H]-: 360.1270, Found: 360.1281.4-Methyl-N-(2-methyloct-7-en-2-yl)benzenesulfonamide SS29

[0297] This compound was prepared according to the general procedure C from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H26NO2S+[M+H]+: 296.1686, Found: 296.1688.6-Methyl-6-((4-methylphenyl)sulfonamido)heptanoic acid 29TSRI 2214.1PC

[0298] This compound was prepared according to the general procedure C from SS29.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C15H22NO4S- [M-H]-: 312.1270, Found: 312.1275.N-(1-(Hex-5-en-1-yl)cyclobutyl)-4-methylbenzenesulfonamide SS30

[0299] This compound was prepared according to the general procedure C from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H26NO2S+[M+H]+: 308.1686, Found: 308.1686.5-(1-((4-Methylphenyl)sulfonamido)cyclobutyl)pentanoic acid 30

[0300] This compound was prepared according to the general procedure C from SS30.1H 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).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C16H22NO4S- [M-H]-: 324.1270, Found: 324.1270.N-(1-(Hex-5-en-1-yl)cyclopentyl)-4-methylbenzenesulfonamide SS31

[0301] This compound was prepared according to the general procedure C from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H28NO2S+[M+H]+: 322.1842, Found: 322.1840.5-(1-((4-Methylphenyl)sulfonamido)cyclopentyl)pentanoic acid 31

[0302] This compound was prepared according to the general procedure C from SS31.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S- [M-H]-: 338.1426, Found: 338.1428.TSRI 2214.1PCN-(4-(Hex-5-en-1-yl)tetrahydro-2H-pyran-4-yl)-4-methylbenzenesulfonamide SS32

[0303] This compound was prepared according to the general procedure C from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H28NO3S+[M+H]+: 338.1790, Found: 338.1799.5-(4-((4-Methylphenyl)sulfonamido)tetrahydro-2H-pyran-4-yl)pentanoic acid 32

[0304] This compound was prepared according to the general procedure C from SS32.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO5S- [M-H]-: 354.1375, Found: 354.1374.N-(2,2-Dimethylhept-6-en-1-yl)-4-methylbenzenesulfonamide SS33TSRI 2214.1PC

[0305] This compound was prepared according to the general procedure D from O commercially available.1H 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).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. HRMS (ESI-TOF) Calculated for C16H26NO2S+[M+H]+: 296.1685, Found: 296.1682.5,5-Dimethyl-6-((4-methylphenyl)sulfonamido)hexanoic acid 33

[0306] This compound was prepared according to the general procedure D from SS33.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C15H22NO4S- [M-H]-: 312.1270, Found: 312.1273.4-Methyl-N-((1-(pent-4-en-1-yl)cyclobutyl)methyl)benzenesulfonamide SS34

[0307] This compound was prepared according to the general procedure D from O commercially available.1H 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,TSRI 2214.1PC 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).13C 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. HRMS (ESI-TOF) Calculated for C17H26NO2S+[M+H]+: 308.1686, Found: 308.1680.4-(1-(((4-Methylphenyl)sulfonamido)methyl)cyclobutyl)butanoic acid 34

[0308] This compound was prepared according to the general procedure D from SS34.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H22NO4S- [M-H]-: 324.1270, Found: 324.1272.4-Methyl-N-((1-(pent-4-en-1-yl)cyclopentyl)methyl)benzenesulfonamide SS35

[0309] This compound was prepared according to the general procedure D from O commercially available.1H 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).13C 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.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C18H28NO2S+[M+H]+: 322.1842, Found: 322.1841.4-(1-(((4-Methylphenyl)sulfonamido)methyl)cyclopentyl)butanoic acid 35

[0310] This compound was prepared according to the general procedure D from SS35.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S- [M-H]-: 338.1426, Found: 338.1430.4-Methyl-N-(3-methylhept-6-en-1-yl)benzenesulfonamide SS36

[0311] This compound was prepared according to the general procedure E from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C15H24NO2S+[M+H]+: 282.1528, Found: 282.1528.4-Methyl-6-((4-methylphenyl)sulfonamido)hexanoic acid 36TSRI 2214.1PC

[0312] This compound was prepared according to the general procedure E from SS36.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H20NO4S- [M-H]-: 298.1113, Found: 298.1112. en-1-yl)-4-methylbenzenesulfonamide SS37 was prepared according to the general procedure E from known.1H 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, 6.5 Hz, 1H), 2.42 (s, 3H), 1.98 (dq, J = 14.9, 6.6 Hz, 1H), 1.89 (dq, J = 14.6, 7.2 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C18H30NO2S+[M+H]+: 324.1998, Found: 324.1993.5,5-Dimethyl-4-(2-((4-methylphenyl)sulfonamido)ethyl)hexanoic acid 37

[0314] This compound was prepared according to the general procedure E from SS37.1H 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,TSRI 2214.1PC 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).13C 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. HRMS (ESI-TOF) Calculated for C17H26NO4S- [M-H]-: 340.1583, Found: 340.1586.4-Methyl-N-(3-phenylhept-6-en-1-yl)benzenesulfonamide SS38

[0315] This compound was prepared according to the general procedure E from O commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C20H26NO2S+[M+H]+: 344.1685, Found: 344.1688.6-((4-Methylphenyl)sulfonamido)-4-phenylhexanoic acid 38

[0316] This compound was prepared according to the general procedure E from SS38.1H 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).13C 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.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C19H22NO4S- [M-H]-: 360.1270, Found: 360.1270. cyclobutyl)ethyl)-4-methylbenzenesulfonamide SS39 was prepared according to the general procedure E from known.1H 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). 13C 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. HRMS (ESI-TOF) Calculated for C17H26NO2S+[M+H]+: 308.1685, Found: 308.1677.3-(1-(2-((4-Methylphenyl)sulfonamido)ethyl)cyclobutyl)propanoic acid 39

[0318] This compound was prepared according to the general procedure E from SS39.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C16H22NO4S- [M-H]-: 324.1269, Found: 324.1275.N-(2-(1-(But-3-en-1-yl)cyclopentyl)ethyl)-4-methylbenzenesulfonamide SS40TSRI 2214.1PC

[0319] This compound was prepared according to the general procedure E from known.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H28NO2S+[M+H]+: 322.1841, Found: 322.1840.3-(1-(2-((4-Methylphenyl)sulfonamido)ethyl)cyclopentyl)propanoic acid 40

[0320] This compound was prepared according to the general procedure E from SS40.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S- [M-H]-: 338.1426, Found: 338.1426.N-((2-(But-3-en-1-yl)cyclopentyl)methyl)-4-methylbenzenesulfonamide SS41

[0321] This compound was prepared according to the general procedure E from commerciallyTSRI 2214.1PC1H 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).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. HRMS (ESI-TOF) Calculated for C17H26NO2S+[M+H]+: 308.1685, Found: 308.1689.3-(2-(((4-Methylphenyl)sulfonamido)methyl)cyclopentyl)propanoic acid 41

[0322] This compound was prepared according to the general procedure E from SS41.1H 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).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. HRMS (ESI-TOF) Calculated for C16H22NO4S- [M-H]-: 324.1270, Found: 324.1272.Relative configuration deduced from 42a4-Methyl-N-((1R*,2R*)-2-(pent-4-en-1-yl)cyclohexyl)benzenesulfonamide SS42TSRI 2214.1PC

[0323] This compound was prepared according to steps 1 and 2 of general procedure B, followed by steps 2-4 of general procedure C, from commercially available.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H28NO2S+[M+H]+: 322.1841, Found: 322.1845.Relative configuration deduced from 42a. 4-((1R*,2R*)-2-((4-Methylphenyl)sulfonamido)cyclohexyl)butanoic acid 42

[0324] This compound was prepared according to the general procedure C from SS42.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C17H24NO4S- [M-H]-: 338.1426, Found: 338.1442.N-(2-(Hex-5-en-1-yl)phenyl)-4-methylbenzenesulfonamide SS43TSRI 2214.1PC

[0325] This compound was prepared according to general procedure C from commercially available.1H NMR (600 MHz, CDCl3) δ 7.79 – 7.48 (m, 2H), 7.34 (dd, J = 7.7, 1.4 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C19H24NO2S+[M+H]+: 330.1528, Found: 330.1528.5-(2-((4-Methylphenyl)sulfonamido)phenyl)pentanoic acid 43

[0326] This compound was prepared according to general procedure C from SS43.1H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H20NO4S- [M-H]-: 346.1113, Found: 346.1116.6-((2-Nitrophenyl)sulfonamido)hexanoic acid 44

[0327] This known compound was prepared according to the method reported by Pavlidis and co-workers from commercially available 6-aminohexanoic acid.9TSRI 2214.1PC1H 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).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. HRMS (ESI-TOF) Calculated for C12H15N2O6S- [M-H]-: 315.0651, Found: 315.0653. Preliminary investigations of reaction behavior Role of carboxylic acid:

[0328] Protection of carboxylic acid obliterates lactamization reactivity, suggesting the presence of carboxylic acid is crucial to the lactamization reaction.Figure S23. Reactivity of 3 and 4.

[0329] Compounds 3 and 4 were synthesized according to the general procedure of methyl ester formation as described above from compounds 1 and 2, respectively. Tosylcarboxamides do not undergo methylation under the mentioned reaction conditions.Methyl 6-((4-methylphenyl)sulfonamido)-6-oxohexanoate 31H 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).13C 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. HRMS (ESI-TOF) Calculated for C14H20NO5S+[M+H]+: 314.1063, Found: 314.1064.TSRI 2214.1PCMethyl 7-((4-methylphenyl)sulfonamido)-7-oxoheptanoate 41H 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).13C 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. HRMS (ESI-TOF) Calculated for C15H22NO5S+[M+H]+: 328.1219, Found: 328.1223. Effect of α-quaternization of carboxylic acid:

[0330] Quaternization of the α-position of carboxylic acid obliterates lactamization reactivity. Performing the same experiment in HFIP-OD resulted in no deuterium incorporation at the β-methylene position (Figure S15). β-Methyl positions were around 30% deuterated. This suggests that quaternization of the α-position of carboxylic acid may suppress C–H activation at the β-methylene position, which as a result obliterates lactamization reactivity. The alternative rationalization for the lack of lactamization reactivity in which β-methylene C–H activation was operative but the lactamization reaction fails to proceed is less likely given the results obtained. This experiment suggests that α- quaternization of a substrate may not be a good approach to rule out α,β-desaturation pathways in related cyclization reactions.Figure S24. Reactivity of α-quaternized compound S38.TSRI 2214.1PCFigure S25.1H NMR of compound S38, crude1H NMR of compound S38-d and crude 2H NMR of compound S38-d in MeOH-d4.Figure S26. Procedure for the synthesis of compound S38. Compound S38 was synthesized according to the general procedures as described above.2,2-Dimethyl-6-((4-methylphenyl)sulfonamido)-6-oxohexanoic acid S38TSRI 2214.1PC 1H NMR (400 MHz, MeOH-d4) 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). 13C NMR (100 MHz, MeOH-d4) 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. HRMS (ESI-TOF) Calculated for C15H20NO5S- [M-H]-: 326.1062, Found: 326.1060. Ligand controlled C–H lactamization versus C–H lactonization:The compound 5 was prepared according to the procedure as described below:Figure S27. Preparation of substrate 5.

[0331] The preparation of intermediate S26 follows the procedure exactly as described above (Figure S9). Compound S26 was dissolved in DCM (0.1 M) and oxalyl chloride (1.1 eq.) was added followed by a drop of DMF (Caution: Copious gas evolution). The reaction mixture was allowed to stir at room temperature overnight and was concentrated the next day under reduced pressure. The crude acyl chloride was then dissolved in toluene (1.0 M) and ArFNH2 (1.1 eq.) was added followed by heating to reflux and stirred overnight. TLC analysis at this stage confirmed the disappearance of starting material. All volatiles were removed under reduced pressure and the crude S39 was purified by flash columnTSRI 2214.1PC chromatography (50% EA / hexanes) to give pure S39 as a white solid (80% over 2 steps). Compound S39 then underwent hydrogenolysis in EtOH (0.1M) with Pd / C and H2 (balloon pressure) to give compound 5 quantitatively.6-Oxo-6-((2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)amino)hexanoic acid 51H 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).13C 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, 25.5.19F{1H} NMR (376 MHz, MeOD) δ -57.5 (t, J = 21.9 Hz), -142.1 – -144.6 (m), -144.6 – -146.1 (m). HRMS (ESI-TOF) Calculated for C13H9F7NO3- [M-H]-: 360.0470, expected m / z not found.

[0332] Compound 5a was isolated as its methyl ester in 57% isolated yield.Methyl 2-(5-oxo-1-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)pyrrolidin-2-yl)acetate 5a1H 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).13C NMR (151 MHz, CDCl3) δ 174.2, 170.1, 56.6, 52.1, 38.8, 29.4, 26.0. (13C resonances of the ArF moiety are not visible).19F{1H} NMR (376 MHz, CDCl3) δ -56.2 (t, J = 21.9 Hz), -138.4 – -139.8 (m), -140.0, -143.0.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C14H11F7NO3+[M+H]+: 374.0628, found: 374.0635.2-(5-Oxotetrahydrofuran-2-yl)-N-(2,3,5,6-tetrafluoro-4- (trifluoromethyl)phenyl)acetamide 5c1H 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).13C NMR (151 MHz, CDCl3) δ 176.0, 166.7, 76.4, 42.1, 28.6, 27.8. (13C resonances of the ArF moiety are not visible).19F{1H} NMR (376 MHz, CDCl3) δ -56.0 (t, J = 21.7 Hz), -138.0 – -141.2 (m), -141.6 – -145.5 HRMS (ESI-TOF) Calculated for C13H9F7NO3+[M+H]+: 360.0471, found: 360.0470. Lactamization of α-monosubstituted substrates= = = = isolated as methyl ester isolated as methyl ester isolated as methyl esterisolated as methyl esterMethyl 2-(5-oxo-4-phenyl-1-tosylpyrrolidin-2-yl)acetate S391H 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,TSRI 2214.1PC 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).13C 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. HRMS (ESI-TOF) Calculated for C20H22NO5S+[M+H]+: 388.1219, found: 388.1219.Methyl 2-(4-(tert-butyl)-5-oxo-1-tosylpyrrolidin-2-yl)acetate S401H 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).13C 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. HRMS (ESI-TOF) Calculated for C18H26NO5S+[M+H]+: 368.1532, found: 368.1535.Methyl 2-(6-oxo-5-phenyl-1-tosylpiperidin-2-yl)acetate S411H 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 = 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 = 9.9, 6.4, 3.3 Hz, 1H), 3.7 (d, J = 14.7 Hz, 7H), 3.5 (t, J = 9.1 Hz, 1H), 3.3 – 3.2 (m, 1H), 3.1 (ddd, J = 16.1, 3.3, 1.0 Hz, 1H), 2.9 (td, J = 16.2, 10.5 Hz, 2H), 2.4 (s, 3H), 2.4 (s, 3H), 2.3 (ddd, J = 17.0, 9.7, 4.8 Hz, 1H), 2.2 – 2.1 (m, 1H), 2.1 (dt, J = 10.4, 5.0 Hz, 1H), 2.1 – 2.1 (m, 3H), 1.9 – 1.8 (m, 2H).TSRI 2214.1PC13C 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. HRMS (ESI-TOF) Calculated for C21H24NO5S+[M+H]+: 402.1376, found: 402.1371.Methyl 2-(5-(tert-butyl)-6-oxo-1-tosylpiperidin-2-yl)acetate S421H 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).13C 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. HRMS (ESI-TOF) Calculated for C19H27NO5S+[M+H]+: 382.1689, found: 382.1690. Synthetic applications of the lactamization reactionTSRI 2214.1PC Figure S28. Synthesis of bicyclic lactam scaffolds.

[0333] Gram scale synthesis of 1a from 1 was carried out in an analogous fashion as reported in our previous dicarboxylic acid lactonization paper.6Compound 1a was purified by column chromatography (50%EA / hexanes + 1% AcOH to 75%EA / hexanes + 1% AcOH) to give the desired product as a pale brown solid (566 mg, 1.90 mmol, 57% yield).Allyl 2-(1-allyl-5-oxopyrrolidin-2-yl)acetate 47

[0334] The compound 1a (566 mg, 1.90 mmol) was dissolved in anhydrous dimethoxyethane (19 mL) and cooled to -40 °C. A solution of sodium naphthalenide (prepared by sonicating chopped Na(s) (19.0 mmol) and naphthalene (19.0 mmol) in 20 mL of anhydrous dimethoxyethane for 30 minutes. Observation: Solution turned from colorless to dark green.) was titrated dropwise against the solution of compound 1a until a pale green color persists for more than 5 minutes after addition of the dark green sodium naphthalenide solution. The solution was then warmed to room temperature, and a solution of allyl bromide (1.65 mL, 19.0 mmol) in dry DMF (10 mL) was added to the reaction mixture. The reaction mixture was then heated to 40 °C and stirred overnight at this temperature. Completion of reaction was confirmed by TLC analysis. The reaction mixture was concentrated under reduced pressure, rinsed and sonicated three times with hexanes to remove most of the naphthalene, the residue was then suspended in water and washed three times with EtOAc. The EtOAc layers were collected, dried with anhydrous MgSO4, and concentrated under reduced pressure to afford crude 47. The compound 47 was purified by flash column chromatography (50% EA / hexane to 100%EA) to give the desired compound 47 as a yellow oil (216 mg, 0.97 mmol, 51%, Rf= 0.32 (100% EA)).1H 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,TSRI 2214.1PC 7.3 Hz, 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).13C 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. HRMS (ESI-TOF) Calculated for C12H18NO3+[M+H]+: 224.1287, Found: 224.1282.

[0335] Note 1: Using DMF as a co-solvent is crucial for alkylation to proceed with allyl bromide. Do not use lithium naphthalenide for the deprotection / alkylation sequence as lithium alkoxides / amides were found to be inefficient at achieving the desired alkylation with allyl bromide.

[0336] Note 2: One could also quench the reaction with formic acid, followed by evaporation of the volatiles, and rinse / sonicate with hexanes to obtain the compound(Note: water soluble) that could be sequentially alkylated at oxygen and nitrogen using different electrophiles. Conditions for oxygen alkylation: Alkyl bromide / iodide (10.0 eq.), K2CO3 (10.0 eq.), MeCN (0.5 M), 50 °C, overnight. Conditions for nitrogen alkylation: Alkyl bromide / iodide (2.0 eq.), NaH (1.1 eq.), DMF (0.5 M), 0 °C to r.t., progress monitored by TLC.major diastereomer as shown, relative configuration deduced from 49. (S*)-2-((S*)-1-Allyl-5-oxopyrrolidin-2-yl)pent-4-enoic acid 48

[0337] The compound 47 (50.0 mg, 0.22 mmol) was dissolved in dry 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 eq.) was quickly added followed by LHMDS (0.51 mL, 3.0 eq. ~1.3 M solution in THF). The reaction mixture was stirred for 10 minutes at -78 °C and then warmed to room temperature. The reaction mixture was then heated to 85 °C and stirred at this temperature for 1 hour. TLC analysis at this stage confirmed the complete disappearance of starting material.TSRI 2214.1PC The reaction was quenched with sat. NH4Cl(aq) and extracted three times with EtOAc. The organic layers were collected, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude was redissolved in THF and a solution of TBAF (1M in THF) was added followed by AcOH to desilylate any adventitiously silylated material. The desilylation was allowed to proceed for 1 hour with stirring, quenched with 1M HCl and extracted with EtOAc three times. The EtOAc layers were collected, dried with MgSO4, filtered, and concentrated under reduced pressure to give crude 48, which was purified by flash column chromatography (70% EA / hexanes to 100% EA to EA + 1% AcOH) to give pure 48 as a colorless oil that solidified upon standing (36.0 mg, 0.16 mmol, 73%, d.r. ~ 5:1, Rf= 0.30 (EA + 1% AcOH)).1H NMR (600 MHz, MeOD) δ 5.97 – 5.66 (m, 2.4H), 5.26 (dq, J = 17.2, 1.5 Hz, 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).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. HRMS (ESI-TOF) Calculated for C12H16NO3- [M-H]-: 222.1130, Found: 222.1135.major diastereomer as shown. (9S*,9aS*)-3-Oxooctahydro-1H-pyrrolo[1,2-a]azepine-9-carboxylic acid 49

[0338] The compound 48 (36.0 mg, 0.16 mmol) was dissolved in dry DCM (3.2 mL, 0.05M) in a 20 mL reaction vial and Grubbs’ 2ndgeneration catalyst was added (14.0 mg,TSRI 2214.1PC 0.016 mmol). The reaction mixture was then degassed through bubbling with Argon and the reaction 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 starting material. The reaction mixture was then cooled to room temperature and extracted three times with sat. NaHCO3(aq), the aqueous layers were collected and acidified by addition of 6M HCl to pH ~ 2, then extracted with EtOAc three times. The EtOAc layers were combined, dried with anhydrous MgSO4, filtered, and concentrated to give crude 52 (characterization listed below). The crude 52 was then dissolved in EtOH (5.0 mL) and underwent hydrogenation with Pd / C (50 mg) and a H2(balloon pressure). The reaction mixture was left to stir overnight at room temperature and was filtered through a plug of Celite® the next day to obtain crude 49. Crude 49 was purified by flash column chromatography (EA + 1% AcOH to 95% EA + 5% MeOH + 1% AcOH) and gave pure 49 as a white solid (27.1 mg, 0.14 mmol, 85% over 2 steps, d.r. ~ 5:1, Rf= 0.4 (95% EA + 5% MeOH + 1% AcOH)).1H 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).13C 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. HRMS (ESI-TOF) Calculated for C10H14NO3- [M-H]-: 196.0973, Found: 196.0980.(9S*,9aS*)-3-Oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-9-carboxylic acid 52

[0339] Compound 52 could be obtained from compound 48 (12.0 mg 0.053 mmol), following the procedure for cross-metathesis using Grubb’s 2ndgeneration catalyst as described above. Compound 52 was isolated as a pale brown solid (9.6 mg, 0.049 mmol, 92%, d.r. ~ 5:1, Rf = 0.4 (95% EA + 5% MeOH + 1% AcOH)).TSRI 2214.1PC1H 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).13C 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. HRMS (ESI-TOF) Calculated for C10H12NO3- [M-H]-: 194.0817, Found: 194.0822.Hexahydro-3H-pyrrolo[1,2-a]azepine-3,9(2H)-dione 50

[0340] According to a modified procedure reported by Faraggi and co-workers10: Compound 49 (5.0 mg, 0.025 mmol), Na2CO3 (5.4 mg, 0.05 mmol), 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 a 2 dram vial. DMSO (1.25 mL) was added followed by bubbling of the reaction mixture and flushing the headspace with O2. The vial was sealed with a Teflon cap and the reaction mixture was stirred for 10 minutes. Afterwards, the reaction mixture was stirred vigorously (1250 rpm) and irradiated with a 34W blue LED with fan cooling at ~30 °C for 24 hours. TLC analysis at this stage confirmed the complete disappearance of starting material. The reaction mixture was diluted with ethyl acetate, washed three times with brine, and the organic layer dried with anhydrous MgSO4. All volatiles were evaporated and the crude 50 was purified by flash column chromatography (DCM + 1% MeOH to DCM + 2.5% MeOH). The compound 50 was isolated as a pale yellow oil (2.5 mg, 0.015 mmol, 60% yield, Rf = 0.30 (DCM + 2.5% MeOH)). Note: Attempted scale-up of this reaction to 100 mg scale was not successful. The reported 60% yield herein could only be replicated at a 5.0 mg scale.1H 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).13C NMR (151 MHz, CDCl3) δ 212.6, 175.0, 68.4, 44.0, 40.9, 30.1, 29.0, 24.5, 22.4.TSRI 2214.1PC HRMS (ESI-TOF) Calculated for C9H14NO2+[M+H]+: 168.1025, Found: 168.1025.Bromohexahydro-4H-1,4-methanopyrrolo[2,1-d][1,5]oxazocine- 2,8-dione 53

[0341] 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 complete disappearance of the starting material. The reaction was quenched with sat. NaHCO3(aq)and washed three times with DCM. The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated to give crude 53. The crude 53 was purified by flash column chromatography (70% EA / hexane to 100% EA) to give the product 53 as a white solid (9.3 mg, 0.034 mmol, 70% yield, d.r. ~ 5:1, Rf= 0.30 (100% EA)).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).13C 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. HRMS (ESI-TOF) Calculated for C10H1379BrNO3+[M+H]+: 274.0079, Found: 274.0085.

[0342] The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof.

[0343] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practicedTSRI 2214.1PC within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

[0344] All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

TSRI 2214.1PC WHAT IS CLAIMED IS:

1. A method of Palladium-catalyzed methylene C–H lactamization, or cycloamination comprising treating a carboxylic acid substrate with a pyridine-pyridone ligand in the presence of a Pd source; and ii) addition of p-xyloquinone, an Ag salt, and K2HPO4 in a reaction vessel.

2. The method of claim 1, wherein the pyridine-pyridone ligand is a chlorinated pyridine-pyridone ligand selected from the group consisting of:.

3. The method of either Claim 1 or Claim 2, wherein the carboxylic acid is a N- protected ω-amino acid.

4. The method of any one of Claims 1-3, wherein the Pd source is Pd(OAc)2.

5. The method of any one of Claims 1-4, wherein the Ag salt is Ag2CO3.

6. The method of any one of Claims 1-5, wherein the chlorinated pyridine-pyridone ligand is L1, L14, or L18.

7. The method of Claim 1, according to the following schemeTSRI 2214.1PCR1and R2are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6-C10) aryl; R is an N-protecting group; and n is 1 or 2.

8. The method of Claim 7, comprising the following scheme 10 mol%wherein: Z is -C(=O)- or -C(R1)(R2)-; R1and R2are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1-C6) alkyl (C6- C10) aryl; R is an N-protecting group; and n is 1 or 2.

9. The method of Claim 1, comprising the following schemewherein: R3, R4, R5, and R6are independently H, (C1-C6) alkyl, (C6-C10) aryl, orTSRI 2214.1PC (C1-C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1.

10. The C–H cycloamination reaction of Claim 1, comprising the following reaction schemewherein: R3, R4, R5, R6, R7, and R8are independently H, (C1-C6) alkyl, (C6-C10) aryl, or (C1- C6) alkyl (C6-C10) aryl; or any two of R3, R4, R5, and R6together form a (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl or (C6-C10) aryl; R is an N-protecting group; and n is 0 or 1.

11. A method of synthesis of Stemoamide, comprising the lactamiztion reaction of Claim 1.

12. A method of synthesis of Stemoamide, comprising the lactamiztion reaction of Claim 9.

13. The method of any one of Claims 1-12, wherein L is L1.

14. The method of any one of Claims 1-12, wherein L is L14.

15. The method of any one of Claims 1-12, wherein L is L18.

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