Ligand for β-C–H functionalization enables β-C(sp3)–H lactonization

Abstract

The present invention provides a method for forming a β-lactone from a carboxylic acid having a β-carbon with a hydrogen atom thereon. The method comprises contacting a carboxylic acid of formula (1) as described herein with an effective amount of a palladium (II) catalyst, an effective amount of an N-protected amino acid ligand, and tert-butyl hydroperoxide in a solvent comprising hexafluoroisopropanol (HFIP) at about 60 °C to provide a β-lactone of formula (2) as described herein.

Description

[0001] Priority Claim

[0002] This application claims the priority benefit of U.S. Provisional Application No. 62 / 854,807, filed on May 30, 2019, which is incorporated herein by reference in its entirety.

[0003] Statement of Government Support

[0004] This invention was made with government support under Grant No. GM084019 awarded by the National Institutes of Health. The government has certain rights in the invention. Background of the Invention

[0005] The past two decades have witnessed the rapid development of palladation-based carbon-carbon (C-C) and carbon-heteroatom (C-Y) bond-forming reactions based on C(sp 3 )-H bonds (1-3). Alkyl carboxylic acids are ubiquitous and inexpensive reagents in organic chemistry and can be used in various substitution patterns; thus, they are highly desirable substrates for C-H activation reactions (4-5). To access a wide range of β-substituted aliphatic acids, diverse transformations must be developed to install different carbon fragments or functional groups. Challenges in developing C-H activation reactions include extensive catalyst design and directing group optimization for various transformations, as well as the generally limited scope of transformations due to incompatibilities of certain reaction partners. For example, for C-C bond formation, alkylation reactions are limited to primary alkyl iodides or alkyl boron coupling partners (6-8), alkenylation reactions are limited to electron-deficient alkenes (9,10), and despite the design of various directing groups, the scope of heteroarylation reactions remains highly limited (11-14). Moreover, in the absence of an exogenous directing group, most of these reactions are incompatible with free aliphatic acids. Summary of the Invention

[0006] In one embodiment, the present disclosure provides a method for forming a β-lactone of formula (2) from a carboxylic acid having a β-carbon with a hydrogen atom disposed thereon: The method includes contacting a carboxylic acid of formula (1):

[0007]

[0008] R 1 and R 2 are each independently H or alkyl, provided that R 1 and R 2At least one of them is an alkyl group. In some embodiments, the alkyl group is unsubstituted, or in other embodiments, the alkyl group is substituted with: halogen, oxy, dialkylphosphonyl, cycloalkyl, alkoxy, aryloxy, benzyloxy, heterocyclic group, aryl, or heteroaryl.

[0009] The contacting occurs at about 60 °C in a solvent containing hexafluoroisopropanol (HFIP) in the presence of an effective amount of a palladium(II) catalyst, an effective amount of an N-protected amino acid ligand, and tert-butyl hydroperoxide to provide the β-lactone of formula (2).

[0010] In another embodiment, the method further comprises subjecting the β-lactone of formula (2):

[0011]

[0012] to contact with a nucleophile (Nu - ) to provide the β-functionalized carboxylic acid of formula (3):

[0013]

[0014] Nu is selected from C(sp 3 ), C(sp 2 ), CN, N3, 2-nitrobenzenesulfonylamino, OH, F, Br, and SPh.

[0015] In various embodiments, optionally in combination with any other embodiments described herein, the palladium(II) catalyst comprises at least one palladium-chlorine bond. In other embodiments, the palladium(II) catalyst is Pd(CH3CN)2Cl2 or Pd(OAc)2.

[0016] The present disclosure also provides in other embodiments the method described herein, wherein the N-protected amino acid ligand is selected from L1 to L6:

[0017]

[0018] In one embodiment, the N-protected amino acid ligand is L5:

[0019] In various embodiments, optionally in combination with any other embodiments described herein, the β-lactone of formula (2) is selected from one of the following table:

[0020]

[0021]

[0022] Description of the Drawings

[0023] Figure 1 A in Figure 1 B in Figure 1 and C in 3 : Challenges in β-C(sp

[0024] Figure 2 )–H Functionalization (1A); A Stepping-Stone Strategy (1B); Ligand-Activated β-C-H Lactonization (1C). 3 : Range of Aliphatic Acids for β-C(sp

[0025] Figure 3 A in Figure 3 and B in

[0026] Figure 4 : Structure of Ligands of N-Monoprotected β-Alanine Derivatives Detailed Description

[0027] Definitions

[0028] "Alkyl" means a straight-chain or branched-chain hydrocarbon group containing from 1 to about 20 carbon atoms. For example, an alkyl group can have 1 to 10 carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl groups include straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc., and also include branched isomers of straight-chain alkyl groups such as, but not limited to, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, etc. Thus, alkyl groups include primary, secondary, and tertiary alkyl groups. An alkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0029] The term "alkoxy" means -O-alkyl having a specified number of carbon atoms. For example, (C1-C6)-alkoxy includes -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl, and -O-neohexyl.

[0030] The term "cycloalkyl" means a saturated monocyclic, bicyclic, tricyclic or polycyclic 3- to 14-membered ring system, such as C3-C8-cycloalkyl. The cycloalkyl can be attached by any atom. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0031] When used alone or as part of another term, "aryl" means a carbocyclic aromatic group having a specified number of carbon atoms or, if no number is specified, up to 14 carbon atoms, whether or not fused, such as C6-C 10 aryl or C6-C 14 aryl. Examples of aryl include phenyl, naphthyl, biphenyl, phenanthryl, tetracenyl, etc. (see, for example, Lang’s Handbook of Chemistry (edited by Dean, J.A.), 13th edition, Table 7-2

[1985] ). An exemplary aryl is phenyl. The aryl can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0032] The term "heteroatom" means N, O and S. Compounds of the present disclosure containing N or S atoms can optionally be oxidized to the corresponding N-oxides, sulfoxides or sulfone compounds.

[0033] "Heteroaryl", alone or in combination with any other part described herein, is a monocyclic aromatic ring structure containing one or more (e.g., 1 to 4, 1 to 3 or 1 to 2) heteroatoms independently selected from O, S and N, having 5 to 10, such as 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxides of tertiary ring nitrogen. A carbon or heteroatom is a point of attachment of the heteroaryl ring structure such that stable compounds are produced. Examples of heteroaryl include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, quinoxalinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, azolyl, thiazolyl, thienyl, iso azolyl, thiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furyl, benzofuryl, and indolyl.

[0034] "Heterocycloalkyl" is a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system having 3 to 14 (e.g., 3 to 6) atoms in which 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N. The heterocycloalkyl is optionally fused to an aryl or heteroaryl of 5 to 6 ring members and contains oxidized S or N, such as sulfinyl, sulfonyl and N-oxides of tertiary ring nitrogen. The point of attachment of the heterocycloalkyl ring is at a carbon or heteroatom such that a stable ring is maintained. Examples of heterocycloalkyl include, but are not limited to, morpholinyl, tetrahydrofuranyl, dihydropyridyl, piperidyl, pyrrolidinyl, piperazinyl, dihydrobenzofuranyl and dihydroindolyl.

[0035] The compounds described herein can exist in various isomeric forms including configurational isomers, geometric isomers and conformational isomers (including, for example, cis or trans conformations). The compounds can also exist in one or more tautomeric forms (including both single tautomers and mixtures of tautomers). The term "isomers" is intended to cover all isomeric forms of the compounds of the present disclosure (including the tautomeric forms of the compounds). The compounds of the present disclosure can also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms can be produced by loss of water. The specific composition of the open-chain and cyclized forms can depend on how the compound is isolated, stored or administered. For example, a compound may exist predominantly in an open-chain form under acidic conditions and may cyclize under neutral conditions. All forms are included in the present disclosure.

[0036] Some of the compounds described herein can have asymmetric centers and thus exist in different enantiomeric and diastereomeric forms. The compounds as described herein can be in the form of optical isomers or diastereoisomers. Accordingly, the present disclosure encompasses compounds as described herein in their optical isomers, diastereoisomers and mixtures thereof (including racemic mixtures) and their uses. The optical isomers of the compounds of the present disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or via chemical separation of stereoisomers by using an optically active resolving agent.

[0037] Unless otherwise indicated, the term "stereoisomer" means a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, such as greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of other stereoisomers of the compound. A stereoisomer as described above can be regarded as a composition comprising two stereoisomers present in their respective weight percentages as described herein.

[0038] If there is a discrepancy between the structure shown and the name given to that structure, the structure shown shall prevail. Further, if the stereochemistry of a structure or a part of a structure is not indicated, for example, by thick or dashed lines, the structure or the part of the structure shall be interpreted to cover all of its stereoisomers. However, in some cases, in the presence of more than one chiral center, the structure and the name may be represented as a single enantiomer to aid in the description of relative stereochemistry. One of ordinary skill in the art of organic synthesis will know whether a compound is prepared as a single enantiomer by the method used to prepare it.

[0039] The present disclosure addresses the need for methods for carbon-heteroatom bond-forming reactions (fluorination, hydroxylation, amination, etc.) based on free aliphatic acid β-C–H activation that have not been met heretofore ( Figure 1 A) in ). Disclosed herein is a method for the β-lactonization of ubiquitous aliphatic acids activated by a Pd(II) catalyst having a mono-protected β-amino acid ligand. The highly practical advantages of the method include the use of inexpensive TBHP as the sole oxidant and purification by simple aqueous workup without chromatography. In addition, the diverse reactivity of the resulting β-lactones opens up new avenues for diverse para-β-C–H functionalization with exclusive single selectivity and an unparalleled scope.

[0040] In this context, β-lactones are strained heterocycles (15) that have received significant attention as valuable synthetic intermediates in the synthesis of natural and non-natural products. Due to their inherent ring strain, β-lactones readily react with a wide range of nucleophiles via acyl C–O or alkyl C–O bond cleavage, enabling various transformations. Thus, according to various embodiments of the present disclosure, β-lactonization of free carboxylic acids is a useful method for achieving these diverse transformations. Furthermore, the formation of β-lactones from aliphatic acids ensures exclusive mono-selectivity and thus provides an effective solution to a long-standing problem in β-C–H functionalization.

[0041] In a pioneering example reported by Sen, a mixture of K2PtCl4 (17 mol%) and K2PtCl6 (33 mol%) could promote the formation of γ-lactones from aliphatic acids in 16% yield, along with 5% of β-lactones (16, 17). The γ-lactonization of benzylic C–H bonds using Pd and Pt catalysts has also been reported (18, 19). Based on previous work using co-oxidants to facilitate C–H activation / cyclization reactions (20, 21), we have discovered catalysts and conditions for achieving unprecedented β-C–H lactonization reactions. Compared to β-lactam formation (22) in which a nucleophilic directing group can be used to form a strong C–N bond, β-C–H lactonization is extremely challenging due to the low nucleophilicity of carboxylic acids and the strain generated by the four-membered ring.

[0042] In one embodiment of the present disclosure, 2,2-dimethylbutyric acid (1a) was selected as an exemplary substrate to be used in combination with a wide range of oxidants and catalysts. Through extensive experimentation, we found that a combination of Pd(CH3CN)2Cl2, CsHCO3, and hexafluoroisopropanol (HFIP) solvent formed the desired β-lactone 2a in 15% NMR yield. According to the method exemplified by this embodiment, neither γ-lactones nor β-hydroxylated products or γ-hydroxylated products were observed during the reaction. Testing reactions with other Pd(II) catalysts highlighted the Pd–Cl bond as being favorable for selective C–O reductive elimination to form lactones. In various embodiments, an easily accessible, inexpensive, and effective oxidant is tert-butyl hydroperoxide (TBHP) (4).

[0043] According to various embodiments, the lactonization of formula (1) is catalyzed by a Pd(II) catalyst. Many simple Pd(II) salts are suitable for use as catalysts or as precursors for in situ formation of the catalyst. Examples include chloride salts such as Pd(CH3CN)2Cl2. Another example is Pd(OAc)2. The catalyst is present in an effective amount (expressed as a mole percentage of substrate of formula (1)) as a minimum catalyst loading to effect the conversion of the compound of formula (1) to the compound of formula (2). Exemplary catalyst loadings are in the range of about 0.1 mol% to about 15 mol%, about 0.5 mol% to about 10 mol%, and about 0.8 mol% to about 3 mol%. In various embodiments, the catalyst is present at about 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, or about 10 mol%.

[0044] In various embodiments, the methods described herein are suitable for use with amino acid ligands such as N-protected amino acid ligands (see, for example Figure 4 ). Based on recent advances in ligand-promoted Pd(II)-catalyzed C–H activation (23), we identified ligands that significantly improve the reaction in embodiments. Using the mono-N-protected α-amino acid (MPAA) ligand N-acetylglycine L1 as an exemplary embodiment, the yield was improved to 36%. However, extensive modification of the backbone of the α-amino acid ligand gave only marginal improvement (yield of 40% in the case of L2). Changing the ligand binding mode from five-membered chelation to six-membered chelation with a commercially available N-acetyl-β-alanine L3, for example, under the same conditions, improved the yield to 48%. Based on this promising finding, we then investigated the effect of substituents on the ligand side chain. Some substituents at the β-position slightly decreased the reactivity (L4), while substitution at the α-position proved beneficial (L5 to L6), giving a yield of 65% in the case of the methyl-substituted L5. When using TBHP in decane, the isolated yield of the desired β-lactone can be further improved to 73%.

[0045] The amount of the N-protected amino acid ligand can be varied and is typically adjusted to provide suitable conversion, yield, and observed reaction rate. In various embodiments, the amount of the ligand, expressed as a mole percentage of substrate of formula (1), is in the range of about 0.5 mol% to about 30 mol%, about 1 mol% to about 25 mol%, or about 2 mol% to about 20 mol%. Exemplary amounts of the ligand include about 1 mol%, about 2 mol%, about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, and about 30 mol%.

[0046] In multiple embodiments, the methods described herein are applicable for use with aliphatic carboxylic acids of formula (1) as defined herein. Exemplary carboxylic acids of formula (1) are represented as β-lactone products of formula (2) in Figure 2 . For example, aliphatic acids containing an α-gem-dimethyl are all compatible with various aliphatic chains (2f) containing cyclobutane, resulting in high yields of β-lactones (2a to 2f). Many functionalities such as fluorine (2g), chlorine (2h), trifluoromethyl (2i), ketone (2j), and phosphate (2k) are acceptable, where the halogen (2h), ketone (2j), and phosphate (2k) moieties serve as synthetic handles useful for subsequent derivatization. Lactone products containing piperidine (2l) or tetrahydropyran (2m) moieties are useful embodiments. Different protecting groups on the hydroxyl include simple methyl (Me) (2n), benzyl (Bn) (2o), and methoxymethyl (MOM) (2p) and are all readily acceptable.

[0047] Aryl groups such as phenyl (2q to 2r) and phenyl ether (2s to 2v) groups can also be used in the methods described herein, and although potentially reactive aryl or benzylic C–H bonds, they remain intact. In multiple embodiments, the aryl is optionally substituted with from 1 to 3 electron-donating groups (Me and O-alkyl) to electron-withdrawing groups (chlorine, bromine, and nitro) that are all well-accepted. The oral drug gemfibrozil (1v) (24) for reducing lipid levels is converted to the corresponding β-lactone 2v in high yield. This lactone can be used as a general intermediate for library construction in medicinal chemistry. In these and other embodiments, the remaining α-methyl can undergo further C–H functionalization to provide greater structural diversity. In addition to those substrates containing an α-hydrogen (2ac to 2ag), tertiary aliphatic acids containing a single α-methyl (2w to 2ab) also consistently provide useful yields.

[0048] In an embodiment demonstrating the scalability and utility of the methods described herein, we conducted a gram-scale β-lactonization of gemfibrozil (1v) ( Figure 3A) in [reference]. The pure product (2v) was obtained by simple aqueous washing without chromatography. Thus, in this embodiment, 1.0 g of gemfibrozil (1v), Pd(OAc)2 (1.0 mmol%), commercially available MPAA ligand L3 (2.0 mmol%), and NaOAc (1.0 equiv) in HFIP were added to a reaction tube, and then TBHP (70% in water) (2.0 equiv) was added. After stirring at 60 °C for 24 h, the HFIP solvent was removed by evaporation, then dissolved in ethyl acetate, and washed with saturated NaHCO3 solution to remove unreacted acid, ligand, and metal complex. Evaporation of the ethyl acetate gave the lactone product (2v) in 92% yield. From a practical perspective, this reaction has several key advantages over other C-H activation protocols: (1) use of the inexpensive oxidant TBHP; (2) the reaction is tolerant to air and moisture; (3) the reaction can be reliably scaled up; (4) simple aqueous washing gives the final product without chromatography.

[0049] As Figure 3 shown in B in [reference], the β-lactone product 2v is a stepping stone for the site-selective installation of many alkyl, alkenyl, aryl, halogen, amino, hydroxy, and thiophenyl groups (25 - 27). Various alkyl (3a to 3e), alkenyl (3f to 3g), and aryl (3h to 3i) Grignard reagents are able to successfully open the β-lactone in the presence of catalytic copper to construct new C-C bonds at the β-position of the parent aliphatic acid (25, 26). In several embodiments, secondary alkyl structural motifs such as isopropyl (3c), cyclopropyl (3d), and cyclopentyl (3e) were installed efficiently, in contrast to which similar secondary alkyl iodides are generally incompatible in Pd-catalyzed C-H alkylation reactions.

[0050] In additional embodiments, β-vinyl aliphatic acids (3f to 3g) can be obtained directly by reaction with their corresponding vinyl (3f) and isopropenyl (3g) Grignard reagents. These embodiments provide, for example, a strategy complementary to Pd-catalyzed β-C-H olefination of free acids and their derivatives where only electron-deficient olefins are effective.

[0051] In another embodiment, β-lactone 2v is converted to the corresponding β-arylated aliphatic acids (3h to 3i). For example, this method is useful in the case of 3i because aryl iodide is generally not a viable coupling partner due to its steric hindrance.

[0052] In another embodiment, the nucleophile cyanide opens the lactone to form a new C-C bond, resulting in the corresponding β-cyano aliphatic acid (3j). In other embodiments, the electrophilicity of the β-lactone carbonyl is further demonstrated by adding a weak fluoride nucleophile (3k) to introduce the bioisosteric CH2F moiety that is highly sought after in medicinal chemistry. Through a similar β-lactone ring-opening, MgBr2 releases the formal β-bromo aliphatic acid (3l) in high yield; the product 3l is a versatile compound for further processing.

[0053] In other embodiments, the manipulation of the β-lactone in the presence of the hard nucleophiles NaN3 and sodium 2-nitrophenylsulfonamide (NaNHNs) correspondingly affords the valuable β-amino acid scaffolds 3m and 3n in consistent high yields. By using the β-lactone as a masked aldol adduct, mild hydrolysis gives the β-hydroxy acid 3o in high yield. In addition, sodium benzenethiolate as a nucleophile can be used to obtain the β-chalcogenated product 3p in near-quantitative yield.

[0054] The list of cited references in this disclosure is as follows:

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[0082] Examples

[0083] Some other embodiments of the present disclosure include the following examples.

[0084] General Information: HFIP was obtained from Oakwood, and other solvents were obtained from Sigma-Aldrich, Alfa-Aesar, and Acros and used directly without further purification. Pd(CH3CN)2Cl2 and Pd(OAc)2 were obtained from Strem. Ag2CO3 was purchased from Sigma-Aldrich. Carboxylic acids were obtained from commercial sources or synthesized according to literature methods. Unless otherwise noted, other reagents were purchased at the highest commercial quality and used without further purification. Analytical thin-layer chromatography was performed on 0.25 mm silica gel 60 - F254. Visualization was carried out using short-wave UV light or KMnO4 and heat as developers. 1H NMR spectra were recorded on Bruker DRX-600, DRX-500, and AMX-400 instruments. With reference to 0.0 ppm for TMS, chemical shifts are cited in parts per million (ppm). The following abbreviations (or combinations thereof) are used to indicate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. Coupling constants J are reported in hertz (Hz). Recorded on Bruker DRX-600 and DRX-500 1 1H NMR spectra. With reference to 0.0 ppm for TMS, chemical shifts are cited in parts per million (ppm). The following abbreviations (or combinations thereof) are used to indicate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. Coupling constants J are reported in hertz (Hz). 1313C NMR spectra were recorded with broadband proton decoupling. Chemical shifts were reported in ppm by referencing to the center line of the triplet at 77.0 ppm for CDCl3. Column chromatography was carried out using E. Merck silica (60, particle size 0.043 mm to 0.063 mm), and pTLC was performed on Merck silica plates (60F-254). High-resolution mass spectra (HRMS) were recorded on an Agilent mass spectrometer using ESI-TOF (electrospray ionization - time of flight).

[0085] General method for β-C(sp 3 )–H lactonization

[0086]

[0087] General method A: In a culture tube, Pd(CH3CN)2Cl2 (10 mol%, 2.6 mg), ligand L5 (20 mol%, 2.9 mg), CsHCO3 (0.5 equiv, 9.7 mg), and carboxylic acid 1 (0.1 mmol) were successively weighed in air and a magnetic stir bar was added. Then HFIP (1.0 mL) and TBHP (ca. 5.5 M in decane) (2.0 equiv, 36 μL) were added. The reaction mixture was stirred at room temperature for 3 minutes and then heated to 60 °C for 12 h (600 rpm). After cooling to room temperature, the mixture was concentrated in vacuo and the resulting mixture was purified by pTLC as the eluent or by dissolving in EA and washing with saturated aqueous NaHCO3 solution.

[0088]

[0089] General method B: In a culture tube, Pd(OAc)2 (10 mol%, 2.2 mg), ligand L5 (20 mol%, 2.9 mg), NaOAc (1.0 equiv, 8.2 mg), and carboxylic acid 1 (0.1 mmol) were successively weighed in air and a magnetic stir bar was added. Then HFIP (1.0 mL) and TBHP (ca. 5.5 M in decane) (2.0 equiv, 36 μL) were added. The reaction mixture was stirred at room temperature for 3 minutes and then heated to 60 °C for 12 h (600 rpm). After cooling to room temperature, the mixture was concentrated in vacuo and the resulting mixture was purified by pTLC as the eluent or by dissolving in EA and washing with saturated aqueous NaHCO3 solution.

[0090] Substrate scope for β-C(sp 3 )–H lactonization

[0091]

[0092] On a 0.1 mmol scale according to General Method A. Due to the volatility of the product, CH2Br2 (0.1 mmol, 7 μL) was used as an internal standard to determine the yield (50% yield) by 1H NMR analysis of the crude product. 1 H NMR analysis to determine the yield (50% yield).

[0093]

[0094] On a 0.1 mmol scale according to General Method A. It was purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to obtain the title compound (colorless oil, 8.3 mg, 73% yield).

[0095] 1 1H NMR (600 MHz, CDCl3) δ 4.16 (d, J = 5.0 Hz, 1H), 4.03 (d, J = 5.0 Hz, 1H), 1.81 - 1.68 (m, 2H), 1.42 (s, 3H), 1.03 (t, J = 7.5 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 175.04, 71.02, 58.00, 27.38, 18.97, 8.98.

[0096]

[0097] On a 0.1 mmol scale according to the general method. It was purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to obtain the title compound (colorless oil, 9.1 mg, 71% yield).

[0098] 1 1H NMR (600 MHz, CDCl3) δ 4.16 (d, J = 5.0 Hz, 1H), 4.02 (d, J = 5.0 Hz, 1H), 1.71 - 1.65 (m, 2H), 1.59 - 1.48 (m, 2H), 1.42 (s, 3H), 0.97 (t, J = 7.3 Hz, 4H); 13 13C NMR (150 MHz, CDCl3) δ 175.15, 71.55, 57.48, 36.57, 19.33, 18.05, 14.31.

[0099]

[0100] On a 0.1 mmol scale according to the general method. It was purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to obtain the title compound (colorless oil, 10.5 mg, 74% yield).

[0101] 1 1H NMR (600 MHz, CDCl3) δ 4.16 (d, J = 5.0 Hz, 1H), 4.02 (d, J = 5.0 Hz, 1H), 1.76 - 1.64 (m, 2H), 1.51 - 1.44 (m, 1H), 1.42 (s, 3H), 1.39 - 1.27 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 175.20, 71.53, 57.44, 34.16, 26.80, 22.94, 19.35, 13.99.

[0102]

[0103] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 10.4 mg, 73% yield).

[0104] 1 1H NMR (600 MHz, CDCl3) δ 4.21 (d, J = 5.0 Hz, 1H), 4.06 (dd, J = 5.0, 0.8 Hz, 1H), 1.87 - 1.78 (m, 1H), 1.78 - 1.71 (m, 1H), 1.61 - 1.55 (m, 1H), 1.42 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 175.54, 72.80, 56.75, 42.64, 24.80, 23.97, 22.35, 18.92.

[0105]

[0106] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 7.0 mg, 4&5% yield).

[0107] 1 1H NMR (600 MHz, CDCl3) δ 4.16 (d, J = 5.0 Hz, 1H), 3.98 (d, J = 5.0 Hz, 1H), 2.52 - 2.41 (m, 1H), 2.16 - 2.01 (m, 2H), 1.95 - 187 (m, 1H), 1.87 - 1.75 (m, 3H), 1.75 - 1.66 (m, 2H), 1.38 (s, 3H); 1313C NMR (150 MHz, CDCl3) δ 175.14, 71.48, 57.19, 41.37, 32.64, 30.00, 29.41, 19.72, 19.15.

[0108]

[0109] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 11.5 mg, 72% yield).

[0110] 1 1H NMR (600 MHz, CDCl3) δ 4.48 (dt, J = 47.2, 5.9 Hz, 2H), 4.18 (d, J = 5.1 Hz, 1H), 4.06 (d, J = 5.1 Hz, 1H), 1.82 - 1.70 (m, 4H), 1.70 - 1.60 (m, 1H), 1.55 - 1.47 (m, 1H), 1.45 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 174.91, 83.67 (d, J = 165.0 Hz), 71.45, 57.31, 34.04, 30.50 (d, J = 19.9 Hz), 20.69 (d, J = 4.9 Hz), 19.25;

[0111] C8H 14 FO3 [M + H] + HRMS (ESI - TOF) calcd for C8HFO3 [M + H]: 161.0978; found: 161.0975.

[0112]

[0113] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 9.0 mg, 47% yield).

[0114] 1 1H NMR (600 MHz, CDCl3) δ 4.15 (d, J = 5.0 Hz, 1H), 4.04 (d, J = 5.0 Hz, 1H), 3.54 (t, J = 6.6 Hz, 2H), 1.86 - 1.75 (m, 2H), 1.75 - 1.66 (m, 2H), 1.55 - 1.46 (m, 2H), 1.43 (s, 3H), 1.40 - 1.29 (m, 2H), 1313C NMR (150 MHz, CDCl3) δ 174.90, 71.48, 57.36, 44.93, 34.34, 32.39, 27.05, 24.04, 19.38;

[0115] C9H 16 ClO2 [M+H] + HRMS (ESI-TOF) calcd for C9H ClO2 [M+H]: 191.0839; found: 191.0827.

[0116]

[0117] On a 0.1 mmol scale according to the general method. Purified by dissolution in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 14.0 mg, 67% yield).

[0118] 1 1H NMR (600 MHz, CDCl3) δ 4.15 (d, J = 5.1 Hz, 1H), 4.05 (d, J = 5.1 Hz, 1H), 2.18 - 2.00 (m, 2H), 1.77 - 1.68 (m, 2H), 1.67 - 1.50 (m, 4H), 1.43 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 174.70, 127.10 (q, J = 276.4 Hz), 71.45, 57.20, 34.14, 33.60 (q, J = 28.6 Hz), 23.84, 22.18 (q, J = 2.9 Hz), 19.31;

[0119] C9H 14 F3O2 [M+H] + HRMS (ESI-TOF) calcd for C9H F3O2 [M+H]: 211.0946; found: 211.0949.

[0120]

[0121] On a 0.1 mmol scale according to the general method. Purified by dissolution in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 11.6 mg, 74% yield).

[0122] 11H NMR (600 MHz, CDCl3) δ 3.84 (d, J = 8.7 Hz, 1H), 3.80 (dd, J = 8.7, 2.9 Hz, 1H), 2.19 - 2.08 (m, 1H), 2.08 - 1.99 (m, 1H), 1.88 - 1.79 (m, 2H), 1.56 (s, 3H), 1.16 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 208.49, 175.48, 72.09, 38.26, 31.38, 28.95, 24.30, 16.40;

[0123] C8H 13 O3 [M + H] + HRMS (ESI - TOF) calcd for C8H O3 [M + H]: 157.0865; found: 157.0863.

[0124]

[0125] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3, the title compound (colorless oil, 10.0 mg, 38% yield) was obtained.

[0126] 1 1H NMR (600 MHz, CDCl3) δ 4.17 (d, J = 5.2 Hz, 1H), 4.15 - 4.05 (m, 4H), 4.04 (d, J = 5.2 Hz, 1H), 1.87 - 1.68 (m, 6H), 1.44 (s, 3H), 1.33 (t, J = 7.1 Hz, 6H); 13 13C NMR (150 MHz, CDCl3) δ 174.53, 71.37, 61.94 (d, J = 6.7 Hz), 61.93 (d, J = 6.8 Hz), 57.17 (d, J = 1.7 Hz), 35.09 (d, J = 16.0 Hz), 25.70 (d, J = 142.3 Hz), 19.16, 18.03 (d, J = 4.9 Hz), 16.57 (d, J = 5.9 Hz);

[0127] C 11 H 22 O5P [M + H] + HRMS (ESI - TOF) calcd for C H O5P [M + H]: 265.1205; found: 265.1208.

[0128]

[0129] On a 0.1 mmol scale according to the general method. Purified by dissolution in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 14.5 mg, 51% yield).

[0130] 1 1H NMR (600 MHz, CDCl3) δ 4.16 (d, J = 5.1 Hz, 1H), 4.11 (br s, 2H), 4.06 (d, J = 5.0 Hz, 1H), 2.68 (br s, 2H), 1.79 - 1.57 (m, 7H), 1.45 (s, 9H), 1.21 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 175.00, 154.90, 79.69, 56.31, 40.73, 33.24, 33.06, 32.66, 28.59, 28.57.

[0131]

[0132] On a 0.1 mmol scale according to the general method. Purified by dissolution in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 13.0 mg, 71% yield).

[0133] 1 1H NMR (600 MHz, CDCl3) δ 4.18 (d, J = 5.1 Hz, 1H), 4.06 (d, J = 5.1 Hz, 1H), 4.00 - 3.91 (m, 2H), 3.45 - 3.33 (m, 2H), 1.79 - 1.70 (m, 2H), 1.70 - 1.62 (m, 2H), 1.54 - 1.47 (m, 1H), 1.44 (s, 3H), 1.42 - 1.34 (m, 2H); 13 13C NMR (150 MHz, CDCl3) δ 175.03, 72.48, 67.96, 67.72, 56.28, 41.11, 33.86, 33.21, 31.68, 19.32;

[0134] C 10 H 17 O3 [M + H] + The HRMS (ESI - TOF) calculated value for C9H11O3 [M + H]: 185.1178; found: 185.1172.

[0135]

[0136] On a 0.1 mmol scale according to the general method. Purification was carried out by dissolving in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 12.8 mg, 81% yield).

[0137] 1 1H NMR (600 MHz, CDCl3) δ 4.17 (d, J = 5.0 Hz, 1H), 4.04 (d, J = 5.0 Hz, 1H), 3.41 (t, J = 5.8 Hz, 2H), 3.33 (s, 3H), 1.83 - 1.70 (m, 3H), 1.67 - 1.57 (m, 1H), 1.43 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 175.08, 72.21, 71.62, 58.70, 57.08, 31.16, 24.82, 19.20;

[0138] C8H 15 O3 [M + H] + The HRMS (ESI - TOF) calculated value for C8H13O3 [M + H]: 159.1021; found: 159.1022.

[0139]

[0140] On a 0.1 mmol scale according to the general method. Purification was carried out by pTLC to give the title compound (colorless oil, 11.5 mg, 46% yield).

[0141] 1 1H NMR (600 MHz, CDCl3) δ 7.41 - 7.31 (m, 3H), 7.31 - 7.26 (m, 2H), 4.50 (s, 2H), 4.15 (d, J = 5.0 Hz, 1H), 4.01 (d, J = 5.0 Hz, 1H), 3.48 (t, J = 6.2 Hz, 2H), 1.78 - 1.56 (m, 6H), 1.41 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 175.02, 138.56, 128.55, 127.84, 127.76, 73.17, 71.49, 69.87, 57.42, 34.23, 29.92, 21.52, 19.30.

[0142]

[0143] On a 0.1 mmol scale according to the general method. Purification was carried out by dissolving in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 9.0 mg, 56% yield).

[0144] 1 1H NMR (600 MHz, CDCl3) δ 5.42 - 5.33 (m, 2H), 4.16 (d, J = 11.3 Hz, 1H), 3.77 - 3.72 (m, 2H), 3.35 (s, 3H), 3.23 (d, J = 9.2 Hz, 1H), 1.31 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 171.68, 95.10, 75.53, 72.35, 59.53, 45.96, 20.89;

[0145] C7H 13 O4[M + H] + The HRMS (ESI-TOF) calculated value for C7H9O4[M + H]+: 161.0814; found: 161.0821.

[0146]

[0147] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 12.3 mg, 60% yield).

[0148] 1 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.23 (m, 2H), 7.23 - 7.14 (m, 3H), 4.12 (d, J = 5.0 Hz, 1H), 4.01 (d, J = 5.0 Hz, 1H), 2.66 (t, J = 7.2 Hz, 2H), 1.88 - 1.77 (m, 1H), 1.77 - 1.61 (m, 3H), 1.41 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 174.92, 141.46, 128.60, 128.50, 126.21, 71.45, 57.33, 35.89, 33.93, 26.41, 19.36.

[0149]

[0150] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 11.0 mg, 46% yield).

[0151] 11H NMR (600 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 4.11 (d, J = 5.0 Hz, 1H), 4.01 (d, J = 5.0 Hz, 1H), 2.67 - 2.58 (m, 2H), 1.84 - 1.75 (m, 1H), 1.75 - 1.66 (m, 2H), 1.68 - 1.59 (m, 1H), 1.41 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 174.77, 139.86, 131.97, 129.84, 128.71, 71.42, 57.27, 35.21, 33.85, 26.30, 19.38.

[0152]

[0153] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 9.7 mg, 41% yield).

[0154] 1 1H NMR (600 MHz, CDCl3) δ 7.90 (dd, J = 8.1, 1.7 Hz, 1H), 7.56 (ddd, J = 8.6, 7.5, 1.7 Hz, 1H), 7.17 - 7.07 (m, 2H), 4.69 (d, J = 5.1 Hz, 1H), 4.36 (d, J = 9.5 Hz, 1H), 4.19 (d, J = 5.1 Hz, 1H), 4.11 (d, J = 9.5 Hz, 1H), 1.58 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 185.74, 172.18, 151.43, 134.50, 126.11, 122.01, 115.63, 69.93, 69.49, 57.76, 16.45;

[0155] C 11 H 12 NO5[M + H] + HRMS (ESI-TOF) calcd for: 238.0715; found: 238.0716.

[0156]

[0157] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 17.8 mg, 86% yield).

[0158] 11H NMR (600 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.01 - 6.94 (m, 1H), 6.90 - 6.85 (m, 2H), 4.47 (d, J = 5.1 Hz, 1H), 4.20 - 4.13 (m, 1H), 4.14 - 4.08 (m, 2H), 2.39 - 2.30 (m, 1H), 2.16 - 2.08 (m, 1H), 1.50 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 174.77, 158.38, 129.73, 121.40, 114.49, 72.45, 63.66, 55.63, 33.25, 19.03;

[0159] C 12 H 15 O3[M + H] + HRMS (ESI - TOF) calcd for C11H13O3[M + H]+: 207.1021; found: 207.1029.

[0160]

[0161] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 20.7 mg, 94% yield).

[0162] 1 1H NMR (600 MHz, CDCl3) δ 7.31 - 7.26 (m, 2H), 6.98 - 6.92 (m, 1H), 6.90 - 6.86 (m, 2H), 4.18 (d, J = 5.1 Hz, 1H), 4.06 (d, J = 5.1 Hz, 1H), 3.99 (t, J = 5.8 Hz, 2H), 2.04 - 1.94 (m, 1H), 1.94 - 1.89 (m, 2H), 1.88 - 1.77 (m, 1H), 1.47 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 174.81, 158.80, 129.63, 120.99, 114.52, 71.65, 67.24, 57.08, 31.23, 24.65, 19.23;

[0163] C 13 H 17 O3[M + H] + HRMS (ESI - TOF) calcd for C12H15O3[M + H]+: 221.1178; found: 221.1181.

[0164]

[0165] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 23.0 mg, 93% yield).

[0166] 1 H NMR (600 MHz, CDCl3) δ 7.01 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.19 (d, J = 5.1 Hz, 1H), 4.07 (d, J = 5.1 Hz, 1H), 4.03 - 3.92 (m, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 2.04 - 1.98 (m, 1H), 1.98 - 1.90 (m, 2H), 1.90 - 1.78 (m, 1H), 1.48 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 174.82, 156.78, 136.72, 130.55, 123.62, 121.13, 112.03, 71.66, 67.24, 57.14, 31.33, 24.86, 21.54, 19.26, 15.94;

[0167] C 15 H 21 O3[M + H] + HRMS (ESI - TOF) calcd for C9H15O3[M + H]: 249.1491; found: 249.1492.

[0168]

[0169] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3 to give the title compound (colorless oil, 9.7 mg, 62% yield).

[0170] 1 H NMR (600 MHz, CDCl3) δ 4.16 (d, J = 5.2 Hz, 1H), 4.11 (d, J = 5.2 Hz, 1H), 1.84 - 1.74 (m, 4H), 1.62 - 1.55 (m, 1H), 1.04 (t, J = 7.5 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 174.86, 70.11, 61.45, 40.97, 25.20, 24.68, 24.13, 22.54, 8.88;

[0171] C9H 17 O2[M + H]+ HRMS (ESI-TOF) calculated value: 157.1229; found: 157.1226.

[0172]

[0173] On a 0.1 mmol scale according to the general method. Purified by dissolution in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 9.0 mg, 52% yield).

[0174] 1 H NMR (600 MHz, CDCl3) δ 4.47 (dt, J = 46.9, 5.6 Hz, 2H), 4.12 (d, J = 5.7 Hz, 1H), 4.11 (d, J = 5.7 Hz, 1H), 1.85 - 1.67 (m, 5H), 1.67 - 1.59 (m, 1H), 1.53 - 1.39 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 174.28, 83.69 (d, J = 165.1 Hz), 68.72, 62.13, 31.93, 30.61 (d, J = 19.9 Hz), 25.43, 20.55 (d, J = 4.8 Hz), 8.85;

[0175] C9H 16 FO2[M + H] + HRMS (ESI-TOF) calculated value: 175.1134; found: 175.1135.

[0176]

[0177] On a 0.1 mmol scale according to the general method. Purified by dissolution in EA and washing with saturated aqueous NaHCO3 solution to give the title compound (colorless oil, 10.7 mg, 62% yield).

[0178] 1 H NMR (600 MHz, CDCl3) δ 4.11 (s, 2H), 3.44 - 3.39 (m, 2H), 3.33 (s, 3H), 1.86 - 1.71 (m, 5H), 1.66 - 1.54 (m, 1H), 1.03 (t, J = 7.5 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 173.85, 71.68, 68.28, 61.29, 58.13, 28.44, 24.81, 24.09, 8.23;

[0179] C9H17 O3[M+H] + HRMS (ESI-TOF) calculated value for: 173.1178; found: 173.1189.

[0180]

[0181] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 12.8 mg, 59% yield).

[0182] 1 H NMR (600 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.23 - 7.18 (m, 1H), 7.18 - 7.13 (m, 2H), 4.08 (d, J = 5.2 Hz, 1H), 4.06 (d, J = 5.2 Hz, 1H), 2.72 - 2.62 (m, 2H), 1.86 - 1.69 (m, 5H), 1.69 - 1.61 (m, 1H), 0.99 (t, J = 7.5 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 174.37, 141.49, 128.59, 128.49, 126.20, 68.76, 62.11, 35.97, 31.80, 26.24, 25.47, 8.84;

[0183] C 14 H 19 O2[M+H] + HRMS (ESI-TOF) calculated value for: 219.1385; found: 219.1387.

[0184]

[0185] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 15.0 mg, 68% yield).

[0186] 1 H NMR (500 MHz, CDCl3) δ 7.36 - 7.29 (m, 2H), 7.03 - 6.96 (m, 1H), 6.93 - 6.85 (m, 2H), 4.45 (d, J = 5.3 Hz, 1H), 4.20 (d, J = 5.3 Hz, 1H), 4.19 - 4.16 (m, 1H), 4.16 - 4.08 (m, 1H), 2.42 - 2.32 (m, 1H), 2.26 - 2.16 (m, 1H), 1.91 - 1.82 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H); 1313C NMR (125 MHz, CDCl3) δ 174.10, 158.39, 129.71, 121.36, 114.49, 69.72, 63.74, 60.35, 31.49, 25.37, 8.87.

[0187]

[0188] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 21.0 mg, 90% yield).

[0189] 1 1H NMR (500 MHz, CDCl3) δ 7.32 - 7.24 (m, 2H), 6.98 - 6.91 (m, 1H), 6.91 - 6.84 (m, 2H), 4.13 (s, 2H), 4.02 - 3.96 (m, 2H), 2.05 - 1.89 (m, 3H), 1.89 - 1.75 (m, 3H), 1.05 (t, J = 7.5 Hz, 3H); 13 13C NMR (125 MHz, CDCl3) δ 174.25, 158.82, 129.63, 120.98, 114.54, 68.92, 67.31, 61.86, 29.08, 25.38, 24.50, 8.83;

[0190] C 14 H 19 HRMS (ESI - TOF) calcd for [M + H]+ of O3: 235.1334; found: 235.1336.

[0191]

[0192] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3 to give the title compound (colorless oil, 8.0 mg, 51%).

[0193] 1 1H NMR (600 MHz, CDCl3) δ 4.33 (dd, J = 6.4, 5.4 Hz, 1H), 4.11 (dd, J = 5.4, 4.6 Hz, 1H), 4.04 - 3.98 (m, 2H), 3.62 (ddd, J = 8.5, 6.4, 4.6 Hz, 1H), 3.46 - 3.38 (m, 2H), 2.12 - 2.00 (m, 1H), 1.93 - 1.85 (m, 1H), 1.55 - 1.46 (m, 2H); 1313C NMR (150 MHz, CDCl3) δ 170.40, 67.47, 67.42, 62.77, 57.36, 34.55, 30.29, 30.22;

[0194] C8H 13 O3 [M+H] + The HRMS (ESI-TOF) calculated value for C8H O3 [M+H]: 157.0865; found: 157.0852.

[0195]

[0196] On a 0.1 mmol scale according to the general method. Purified by dissolving in EA and washing with saturated aqueous NaHCO3, the title compound (colorless oil, 13.0 mg, 82%) was obtained.

[0197] 1 1H NMR (600 MHz, CDCl3) δ 4.37 (dd, J = 6.3, 5.2 Hz, 1H), 4.05 - 4.00 (m, 1H), 3.75 - 3.68 (m, 1H), 3.39 (t, J = 6.1 Hz, 2H), 3.33 (s, 3H), 1.95 - 1.85 (m, 1H), 1.83 - 1.76 (m, 1H), 1.65 - 1.52 (m, 3H), 1.51 - 1.43 (m, 1H); 13 13C NMR (150 MHz, CDCl3) δ 171.85, 72.36, 65.11, 58.75, 52.17, 29.36, 28.09, 23.76.

[0198]

[0199] On a 0.1 mmol scale according to the general method. Purified by pTLC, the title compound (colorless oil, 14.5 mg, 69%) was obtained.

[0200] 1 1H NMR (600 MHz, CDCl3) δ 7.32 - 7.27 (m, 2H), 6.99 - 6.92 (m, 1H), 6.91 - 6.85 (m, 2H), 4.40 (dd, J = 6.3, 5.3 Hz, 1H), 4.05 (dd, J = 5.3, 4.5 Hz, 1H), 4.03 - 3.98 (m, 2H), 3.84 - 3.77 (m, 1H), 2.35 (t, J = 7.5 Hz, 1H), 2.14 - 1.95 (m, 4H), 1.95 - 1.85 (m, 1H), 1.68 - 1.60 (m, 1H); 13CNMR(150MHz, CDCl3) δ 171.64, 158.78, 129.68, 121.06, 114.52, 66.92, 65.28, 51.96, 26.77, 25.38;

[0201] C 12 H 15 O3[M + H] + The HRMS (ESI-TOF) calculated value for [O3[M + H]]: 207.1021; found: 207.1023.

[0202]

[0203] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 7.0 mg, 32%).

[0204] 1 H NMR (600 MHz, CDCl3) δ 7.30 - 7.26 (m, 2H), 6.97 - 6.91 (m, 1H), 6.91 - 6.86 (m, 2H), 4.38 (dd, J = 6.3, 5.2 Hz, 1H), 4.06 - 4.01 (m, 1H), 3.98 (t, J = 6.2 Hz, 2H), 3.78 - 3.70 (m, 1H), 1.99 - 1.89 (m, 1H), 1.89 - 1.80 (m, 2H), 1.74 - 1.65 (m, 1H), 1.65 - 1.55 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 171.69, 158.99, 129.62, 120.87, 114.58, 67.32, 65.07, 52.18, 29.06, 28.06, 23.76;

[0205] C 13 H 17 O3[M + H] + The HRMS (ESI-TOF) calculated value for [O3[M + H]]: 221.1178; found: 221.1183.

[0206]

[0207] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 12.0 mg, 40%).

[0208] 11H NMR (600 MHz, CDCl3) δ 7.40 - 7.34 (m, 2H), 6.80 - 6.73 (m, 2H), 4.38 (dd, J = 6.3, 5.2 Hz, 1H), 4.03 (dd, J = 5.2, 4.5 Hz, 1H), 3.94 (t, J = 6.2 Hz, 2H), 3.78 - 3.70 (m, 1H), 2.00 - 1.90 (m, 1H), 1.90 - 1.76 (m, 3H), 1.73 - 1.63 (m, 1H), 1.63 - 1.57 (m, 1H), 13 13C NMR (150 MHz, CDCl3) δ 171.63, 158.12, 132.42, 116.38, 113.01, 67.71, 65.02, 52.14, 28.96, 28.04, 23.67;

[0209] C 13 H 16 BrO3[M + H] + The HRMS (ESI - TOF) calculated value for: 299.0283; found: 299.0284.

[0210]

[0211] In a sealed tube, Pd(OAc)2 (1.0 mol%, 2.6 mg), ligand L3 (2.0 mol%, 2.9 mg), NaOAc (1.0 equiv, mg), and carboxylic acid 1 (4.0 mmol, 1.0 g) were successively weighed in air and a magnetic stir bar was placed in. Then HFIP (40.0 mL) and TBHP (70% in water) (2.0 equiv, 36 μL) were added. The reaction mixture was stirred at room temperature for 3 minutes and then heated to 60 °C for 24 h (600 rpm). After cooling it to room temperature, the mixture was concentrated in vacuo and the resulting mixture was purified by pTLC as the eluent or dissolved in EA and washed with saturated aqueous NaHCO3 solution for purification.

[0212] General method for β - C(sp 3 ) - H functionalization

[0213]

[0214] General Method A: In a culture tube, CuBr2·Me2S (20 mol%, 4.1 mg), β-lactone 2v (0.1 mmol, 24.8 mg), and Me2S (1.0 equivalent, 7 μL) were successively added in air and a magnetic stir bar was placed. Then THF (1.0 mL) was added. The reaction mixture was stirred at room temperature for 3 minutes and then a Grignard reagent (3.0 equivalents) was added dropwise at 0 °C. After stirring it at 0 °C for 1 hour, the mixture was quenched with saturated NH4Cl. The resulting mixture was diluted with EA, washed with saturated NH4Cl, and dried over MgSO4. After concentrating it in vacuo, the resulting mixture was purified by pTLC using hexane / EA and AcOH (1%) (if necessary) as the eluent.

[0215]

[0216] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 26.0 mg, 93%).

[0217] 1 1H NMR (600 MHz, CDCl3) δ 6.99 (d, J = 7.5 Hz, 1H), 6.65 (dd, J = 7.5, 1.5 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H), 3.97 - 3.86 (m, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.87 - 1.78 (m, 2H), 1.78 - 1.69 (m, 1H), 1.69 - 1.61 (m, 2H), 1.49 (ddd, J = 13.4, 12.3, 4.6 Hz, 1H), 1.40 - 1.26 (m, 2H), 1.20 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 184.00, 157.07, 136.59, 130.43, 123.72, 120.82, 112.06, 68.06, 45.72, 41.45, 35.39, 24.88, 21.55, 21.38, 17.88, 15.90, 14.71;

[0218] C 17 H 26 NaO3 [M + Na] + HRMS (ESI-TOF) calculated for: 301.1780; found: 301.1771.

[0219]

[0220] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 28.0 mg, 82%).

[0221] 1 H NMR (600 MHz, CDCl3) δ 7.32 - 7.21 (m, 2H), 7.22 - 7.14 (m, 3H), 6.99 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.00 - 3.87 (m, 2H), 2.71 - 2.54 (m, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 2.07 - 1.97 (m, 1H), 1.95 - 1.70 (m, 5H), 13 C NMR (150 MHz, CDCl3) δ 183.85, 157.02, 142.15, 136.59, 130.46, 128.54, 128.49, 126.04, 123.71, 120.87, 112.04, 67.92, 45.74, 40.99, 35.42, 31.19, 24.85, 21.55, 15.94

[0222] (One carbon signal was not assigned due to overlap);

[0223]

[0224] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 23.0 mg, 79%).

[0225] 1 H NMR (600 MHz, CDCl3) δ 6.99 (d, J = 7.5 Hz, 1H), 6.65 (dd, J = 7.5, 1.5 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H), 4.00 - 3.85 (m, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.90 - 1.79 (m, 2H), 1.79 - 1.58 (m, 4H), 1.46 (dd, J = 13.9, 5.4 Hz, 1H), 1.20 (s, 3H), 0.91 (d, J = 6.6 Hz, 3H); 0.88 (d, J = 6.6 Hz, 3H); 1313C NMR (150 MHz, CDCl3) δ 184.66, 157.08, 136.58, 130.43, 123.73, 120.82, 112.05, 68.04, 48.29, 45.25, 36.65, 24.98, 24.72, 24.55, 23.34, 21.54, 21.15, 15.90;

[0226] C 18 H 29 O3[M + H] + HRMS (ESI-TOF) calcd for C15H23O3[M + H]: 293.2117; found: 293.2115.

[0227]

[0228] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 22.0 mg, 76%).

[0229] 1 1H NMR (600 MHz, CDCl3) δ 6.99 (d, J = 7.5 Hz, 1H), 6.70 - 6.64 (m, 1H), 6.61 (d, J = 1.5 Hz, 1H), 4.00 - 3.87 (m, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.96 - 1.87 (m, 1H), 1.88 - 1.79 (m, 1H), 1.79 - 1.70 (m, 1H), 1.72 - 1.64 (m, 1H), 1.62 (dd, J = 14.0, 6.9 Hz, 1H), 1.53 - 1.45 (m, 1H), 1.28 (s, 3H), 0.75 - 0.67 (m, 1H), 0.53 - 0.39 (m, 2H), 0.14 - 0.04 (m, 2H); 13 13C NMR (150 MHz, CDCl3) δ 184.13, 157.08, 136.58, 130.42, 123.73, 120.82, 112.08, 68.09, 46.52, 44.22, 35.51, 24.97, 21.55, 21.42, 15.90, 6.77, 4.78, 4.36;

[0230] C 18 H 27 O3[M + H] + HRMS (ESI-TOF) calcd for C15H21O3[M + H]: 291.1960; found: 291.1953.

[0231]

[0232] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 21.0 mg, 66%).

[0233] 1 H NMR (600 MHz, CDCl3) δ 6.99 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 6.60 (s, 1H), 3.99 - 3.86 (m, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.91 - 1.68 (m, 7H), 1.68 - 1.53 (m, 4H), 1.52 - 1.40 (m, 2H), 1.22 (s, 3H), 1.14 - 1.02 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 184.53, 157.08, 136.58, 130.42, 123.72, 120.81, 112.05, 68.07, 45.86, 45.76, 36.99, 36.23, 34.37, 33.65, 25.19, 24.98, 24.87, 21.55, 21.47, 15.91.

[0234]

[0235] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 25.0 mg, 91%).

[0236] 1 H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.60 (s, 1H), 5.83 - 5.72 (m, 1H), 5.15 - 5.10 (m, 1H), 5.09 (s, 1H), 3.96 - 3.88 (m, 2H), 2.44 (dd, J = 13.8, 7.1 Hz, 1H), 2.34 - 2.25 (m, 4H), 2.17 (s, 3H), 1.88 - 1.71 (m, 3H), 1.71 - 1.63 (m, 1H), 1.21 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 183.29, 157.05, 136.59, 133.65, 130.44, 123.73, 120.85, 118.59, 112.04, 67.94, 43.03, 35.05, 24.88, 21.55, 21.49, 15.91

[0237] (One carbon signal was not assigned due to overlap); C 17 H 24 NaO3 [M+Na] + HRMS (ESI-TOF) calcd for C: 299.1623; found: 299.1613.

[0238]

[0239] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 23.5 mg, 81%).

[0240] 1 H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.60 (s, 1H), 4.85 (s, 1H), 4.72 (s, 1H), 3.98 - 3.87 (m, 2H), 2.54 (d, J = 13.7 Hz, 1H), 2.30 (s, 3H), 2.23 (d, J = 13.7 Hz, 1H), 2.17 (s, 3H), 1.96 - 1.81 (m, 2H), 1.77 - 1.74 (m, 1H), 1.72 (s, 3H), 1.67 - 1.58 (m, 1H), 1.20 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 183.81, 157.05, 141.99, 136.59, 130.44, 123.73, 120.85, 114.97, 112.05, 67.96, 47.58, 45.58, 36.40, 24.90, 23.83, 21.55, 21.01, 15.91;

[0241] C 18 H 27 O3 [M+H] + HRMS (ESI-TOF) calcd for C: 291.1960; found: 291.1961.

[0242]

[0243] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 25.5 mg, 70%).

[0244] 11H NMR (600 MHz, CDCl3) δ 7.41 - 7.35 (m, 2H), 7.30 - 7.25 (m, 3H), 6.99 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.65 - 6.61 (m, 1H), 4.04 (d, J = 8.7 Hz, 1H), 3.95 (d, J = 8.7 Hz, 1H), 3.70 (s, 3H), 2.42 (t, J = 7.0 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.95 (td, J = 12.8, 4.9 Hz, 1H), 1.80 (td, J = 12.8, 4.6 Hz, 1H), 1.67 - 1.55 (m, 2H), 1.37 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 176.04, 156.79, 136.71, 131.69, 130.44, 128.33, 127.73, 124.01, 123.84, 121.12, 112.03, 89.67, 81.18, 72.60, 52.09, 47.13, 35.25, 24.04, 21.51, 20.40, 20.01, 15.82.

[0245]

[0246] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 20.0 mg, 61%).

[0247] 1 1H NMR (600 MHz, CDCl3) δ 7.31 - 7.26 (m, 2H), 7.26 - 7.19 (m, 2H), 7.20 - 7.14 (m, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.03 - 3.83 (m, 2H), 3.06 (d, J = 13.4 Hz, 1H), 2.82 (d, J = 13.4 Hz, 1H), 2.31 (s, 3H), 2.17 (s, 3H), 1.99 - 1.76 (m, 3H), 1.65 (td, J = 12.3, 4.1 Hz, 1H), 1.17 (s, 3H); 1313C NMR (150 MHz, CDCl3) δ 182.32, 157.04, 137.31, 136.62, 130.46, 130.40, 128.25, 126.78, 123.75, 120.88, 112.06, 67.94, 45.18, 35.49, 25.13, 21.56, 21.01, 15.94 (one carbon signal was not assigned due to overlap);

[0248]

[0249] On a 0.1 mmol scale according to General Method A. Purified by pTLC to give the title compound (colorless oil, 25.0 mg, 68%).

[0250] 1 1H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.5 Hz, 1H), 6.82 (s, 2H), 6.66 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.02 - 3.85 (m, 2H), 3.20 (d, J = 14.8 Hz, 1H), 2.99 (d, J = 14.8 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 6H), 2.23 (s, 3H), 2.17 (s, 3H), 2.15 - 2.06 (m, 1H), 1.91 - 1.81 (m, 1H), 1.78 - 1.61 (m, 2H), 1.11 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 183.67, 157.07, 137.86, 136.62, 135.75, 131.87, 130.46, 129.37, 123.75, 120.87, 112.10, 68.02, 47.32, 38.50, 37.07, 25.49, 21.55, 21.38, 20.90, 20.26, 15.91;

[0251] C 24 H 32 NaO3 [M + Na] + HRMS (ESI-TOF) calcd for 391.2249; found 391.2247.

[0252]

[0253] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 27.0 mg, 98%).

[0254] 11H NMR (600 MHz, CDCl3) δ 7.04 - 6.97 (m, 1H), 6.67 (dd, J = 7.5, 1.5 Hz, 1H), 6.59 (d, J = 1.5 Hz, 1H), 3.95 (t, J = 6.0 Hz, 2H), 2.72 (d, J = 16.8 Hz, 1H), 2.64 (d, J = 16.8 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 3H), 2.04 - 1.86 (m, 2H), 1.86 - 1.72 (m, 2H), 1.45 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 180.16, 156.75, 136.66, 130.54, 123.69, 121.12, 117.31, 112.01, 67.18, 34.90, 25.86, 24.91, 23.17, 21.53, 15.89

[0255] (One carbon signal was not assigned due to overlap); C 16 H 22 NO3 [M + H] + HRMS (ESI - TOF) calcd for 276.1600; found 276.1603.

[0256]

[0257] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 13.5 mg, 50%).

[0258] 1 1H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 6.60 (s, 1H), 4.55 (dd, J = 47.1, 9.0 Hz, 1H), 4.44 (dd, J = 47.1, 9.0 Hz, 1H), 3.93 (t, J = 5.5 Hz, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.91 - 1.71 (m, 4H), 1.32 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 180.72, 156.93, 136.63, 130.49, 123.73, 120.99, 112.07, 87.11 (d, J = 175.0 Hz), 67.66, 47.04 (d, J = 18.3 Hz), 31.42 (d, J = 4.8 Hz), 24.54, 21.53, 21.52, 19.11 (d, J = 4.8 Hz), 15.87;

[0259] C 15 H 21 FNaO3[M+Na] + HRMS(ESI-TOF) calculated value for: 291.1372; measured value: 291.1363.

[0260]

[0261] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 30.0 mg, 92%).

[0262] 1 H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.4 Hz, 1H), 6.72 - 6.64 (m, 1H), 6.60 (d, J = 1.6 Hz, 1H), 3.94 (t, J = 5.8 Hz, 2H), 3.65 (d, J = 10.2 Hz, 1H), 3.53 (d, J = 10.2 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 3H), 2.02 - 1.90 (m, 1H), 1.90 - 1.72 (m, 3H), 1.39 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 179.34, 156.31, 136.03, 129.89, 123.11, 120.38, 111.43, 66.91, 38.82, 33.46, 24.27, 20.96, 20.94, 15.30

[0263] (One carbon signal was not assigned due to overlap); C 15 H 21 BrNaO3[M+Na] + HRMS(ESI-TOF) calculated value for: 351.0572; measured value: 351.0565.

[0264]

[0265] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 25.0 mg, 86%).

[0266] 11H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.63 - 6.53 (m, 1H), 3.93 (t, J = 5.5 Hz, 2H), 3.60 (d, J = 12.1 Hz, 1H), 3.43 (d, J = 12.1 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 3H), 1.88 - 1.72 (m, 4H), 1.29 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 181.17, 156.90, 136.63, 130.49, 129.68, 123.72, 121.00, 112.06, 67.59, 57.85, 46.89, 33.16, 24.63, 21.54, 20.50, 15.88;

[0267] C 15 H 21 N3NaO3 [M+Na] + HRMS (ESI-TOF) calcd for: 314.1481; found: 314.1477.

[0268]

[0269] 1 1H NMR (600 MHz, CDCl3) δ 8.16 - 8.04 (m, 1H), 7.90 - 7.79 (m, 1H), 7.79 - 7.66 (m, 2H), 6.99 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.57 (s, 1H), 5.98 (t, J = 6.7 Hz, 1H), 3.95 - 3.82 (m, 2H), 3.70 (s, 3H), 3.27 (dd, J = 12.6, 6.5 Hz, 1H), 3.10 (dd, J = 12.6, 7.1 Hz, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 1.85 - 1.69 (m, 4H), 1.28 (s, 3H), 13 13C NMR (150 MHz, CDCl3) δ 176.34, 156.82, 148.26, 136.61, 133.70, 132.89, 131.02, 130.43, 125.53, 123.58, 120.94, 111.99, 67.47, 52.44, 49.66, 46.34, 33.45, 24.40, 21.50, 20.99, 15.86

[0270] (One carbon signal was not assigned due to overlap); C22 H 29 N2O7S[M+H] + HRMS(ESI-TOF) calculated value for: 465.1695; measured value: 465.1695.

[0271]

[0272] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 25.5 mg, 95%).

[0273] 1 H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 7.5 Hz, 1H), 6.66 (dd, J = 7.5, 1.4 Hz, 1H), 6.60 (d, J = 1.4 Hz, 1H). 3.99 - 3.87 (m, 2H), 3.78 (d, J = 11.3 Hz, 1H), 3.61 (d, J = 11.3 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 3H), 1.89 - 1.71 (m, 4H), 1.26 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 182.50, 156.96, 136.63, 130.48, 123.72, 120.98, 112.14, 68.04, 67.89, 32.30, 24.55, 21.54, 19.60, 15.90

[0274] (One carbon signal was not assigned due to overlap); C 15 H 23 O4[M+H] + HRMS(ESI-TOF) calculated value for: 267.1596; measured value: 267.1596.

[0275]

[0276] On a 0.1 mmol scale according to the general method. Purified by pTLC to give the title compound (colorless oil, 33.0 mg, 92%).

[0277] 11H NMR (600 MHz, CDCl3) δ 7.42 - 7.37 (m, 2H), 7.26 - 7.22 (m, 2H), 7.17 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.58 (s, 1H), 3.94 - 3.84 (m, 2H), 3.30 (d, J = 12.7 Hz, 1H), 3.19 (d, J = 12.7 Hz, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 1.93 (dt, J = 11.4, 6.6 Hz, 1H), 1.88 - 1.70 (m, 3H), 1.33 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 182.00, 156.97, 136.89, 136.58, 130.45, 130.36, 129.05, 126.57, 123.72, 120.90, 112.05, 67.71, 47.21, 43.06, 34.75, 24.88, 21.82, 21.54, 15.93;

[0278] C 21 H 26 NaO3S [M + Na] + HRMS (ESI - TOF) calcd for 381.1500; found 381.1494.

[0279] The following references cited in the above Examples section are as follows:

[0280] 1. Katritzky, A.R.; Xu, Y.J.; He, H.Y.; Mehta, S. J. Org. Chem. 2001, 66, 5590.

[0281] 2. Adams, H.; Anderson, J.C.; Cubbon, R.; James; D.S.; Mathias, J.P. J. Org. Chem. 1999, 64, 8256.

[0282] 3. M. Kawashima, T. Sato, T. Fujisawa, A facile method for synthesis of three carbon-homologated carboxylic acid by regioselective ring-opening of β-propiolactones with organocopper reagents. Tetrahedron 45, 403-412 (1989).

[0283] 4. N. D. Smith, A. M. Wohlrab, M. Goodman, Enantiocontrolled synthesis of α-methyl amino acids via Bn2N-α-methylserine-β-lactone. Org. Lett. 7, 255-258 (2005).

[0284] 5. L. D. Arnold, T. H. Kalantar, J. C. Vederas, Conversion of serine to stereochemically pure β-substituted α-amino acids via β-Lactones. J. Am. Chem. Soc. 107, 7105-7109 (1985).

[0285] 6. M. Shinoda, K. Iseki, T. Oguri, Y. Hayasi, S. Yamada, M. Shibasaki, A convenient synthesis of β-alkynylpropionic acids from β-propiolactones. Synthesis of 4, 4, 5, 5-tetradehydro-9(O)-methano-Δ 6(9α) -PGI1. Tetrahedron Lett. 27, 87-90 (1986).

[0286] All patent documents and publications cited in this disclosure are hereby incorporated by reference as if fully set forth.

Claims

1. A method for forming a β-lactone of formula (2) from a carboxylic acid having a β-carbon with a hydrogen atom thereon: comprising contacting a carboxylic acid of formula (1) with an effective amount of a palladium(II) catalyst in the presence of an effective amount of an N-protected amino acid ligand and tert-butyl hydroperoxide in a solvent comprising hexafluoroisopropanol (HFIP) in the presence of CsHCO3 or NaOAc at 60 °C to provide the β-lactone of formula (2): wherein R 1 and R 2 each independently is H or an alkyl group having 1 to 20 carbon atoms, provided that at least one of R 1 and R 2 is an alkyl group having 1 to 20 carbon atoms, wherein the alkyl group having 1 to 20 carbon atoms is unsubstituted or substituted with: halogen, oxy, bis(C1-C6)alkylphosphonyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C6-C 14 )aryloxy, benzyloxy, a heterocycloalkyl group having 3 to 14 carbon atoms in which 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O or S, or (C6-C 14 )aryl, the palladium(II) catalyst is Pd(OAc)2 or Pd(CH3CN)2Cl2, the N-protected amino acid ligand is L5:

2. The method according to claim 1, further comprising the β-lactone of formula (2): Contact with a nucleophile (Nu - ) to provide a β-functionalized carboxylic acid of formula (3): wherein Nu is selected from C(sp 3 ), C(sp 2 ), CN, N3, 2-nitrobenzenesulfonylamino, OH, F, Br, and SPh.

3. The method according to claim 1, wherein the β-lactone of formula (2) is one selected from the following table:

4. A method for forming a β-lactone from a carboxylic acid having a β-carbon with a hydrogen atom thereon, comprising contacting a carboxylic acid having a β-carbon with a hydrogen atom thereon with an effective amount of a palladium(II) catalyst in the presence of an effective amount of an N-protected amino acid ligand and tert-butyl hydroperoxide in a solvent comprising hexafluoroisopropanol (HFIP) in the presence of CsHCO3 or NaOAc at 60 °C to provide the β-lactone: the palladium(II) catalyst is Pd(OAc)2 or Pd(CH3CN)2Cl2, the N-protected amino acid ligand is L5: Among them, The carboxylic acid having a β-carbon with a hydrogen atom thereon is and the β-lactone is or The carboxylic acid having a β-carbon with a hydrogen atom thereon is and the β-lactone is or The carboxylic acid having a β-carbon with a hydrogen atom thereon is and the β-lactone is or The carboxylic acid having a β-carbon with a hydrogen atom thereon is and the β-lactone is or The carboxylic acid having a β-carbon with a hydrogen atom thereon is and the β-lactone is or The carboxylic acid having a β-carbon with a hydrogen atom thereon is and the β-lactone is

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