Synthesis method of polysubstituted conjugated diene and conjugated triene

Abstract

The invention belongs to the technical field of polysubstituted olefin synthesis methods, and particularly relates to a synthesis method of polysubstituted conjugated diene and conjugated triene, which is characterized in that under relatively mild conditions, simple transition metal salt is adopted as a catalyst, and polysubstituted conjugated diene and conjugated triene compounds are prepared from a simple raw material alkyl amide; the product obtained by the invention is brand new and is not reported; the two-step alkenylation reaction can be realized through a'one-pot method '; the synthesis method is simple to operate, mild in reaction condition, high in reaction yield, wide in application range and very good in economic value, the polysubstituted conjugated polyene compound is synthesized by adopting multiple C-H functionalization reactions in the synthesis method, the operation is simple and effective, the synthesis raw materials are economical and easy to obtain, and the synthesis method is suitable for industrial production. The method is suitable for high-selectivity preparation of polysubstituted olefins, has a wide application prospect, and is an effective supplement of the existing method in the aspect of preparation methods.

Description

Technical Field

[0001] This invention relates to the field of polysubstituted olefin synthesis methods, and more particularly to a method for synthesizing polysubstituted conjugated dienes and conjugated trienes. Background Technology

[0002] Polysubstituted alkenes are among the most useful and important structures in natural products, pharmaceuticals, materials, and agrochemicals (J. Org. Chem., 2010, 75, 3151-3182), and alkenes with different configurations possess unique pharmacological activities (J. Am. Chem. Soc., 2016, 138, 2532-2535). Therefore, the efficient and convenient synthesis of polysubstituted alkenes is a challenge in organic synthesis. Among these methods, alkenyl CH functionalization reactions involving cyclometallic intermediates under the influence of a directing group are an efficient way to construct highly selective polysubstituted alkenes. However, previous reports have focused on simple CH functionalization reactions of alkenes, with few reports on alkenyl CH functionalization reactions involving two or more reactions under the influence of a single directing group. Therefore, developing a novel and efficient method for constructing polysubstituted alkenes is essential.

[0003] Currently, transition metal-catalyzed bidentate-directed programmed CH functionalization reactions of E-configured aryl alkenes have been reported (Angew. Chem. Int. Ed., 2024, 63, e202315273.). This method involves a high-energy exo-type metal heterocyclic intermediate to achieve multi-step CH alkenylation of E-configured aryl alkenes under the action of a single directing group, exhibiting excellent Z / E selectivity. However, due to the reactivity and selectivity issues of E-configured aliphatic alkenes, methods for achieving multiple CH functionalization reactions under the action of a single directing group have not yet been reported.

[0004] Building upon this, this invention reports a method for preparing polysubstituted conjugated alkenes by the multiple CH functionalization of pyrazine-2-carboxamide (PC) catalyzed with electron-deficient alkenes via palladium(II) catalysis. Using palladium(II) acetate as a catalyst and pentanoic acid, manganese dioxide, and benzoquinone as additives, this invention achieves α- / β-position selective CH alkenylation of E-configured alkyl alkenes under suitable solvents and mild reaction conditions, selectively constructing polysubstituted conjugated alkenes. This is very rare in previous reports and has high value. This invention can obtain polysubstituted deconjugated dienes and conjugated trienes in high yields and with an E / Z selectivity of up to 99:1. Experiments show that this invention has good compatibility with functional groups such as trifluoromethyl, methoxy, and fluorine atoms. This invention is also applicable to one-pot processes. Furthermore, this invention has been successfully applied to the late-stage modification of natural product molecules.

[0005] This invention develops a palladium(II)-catalyzed 2-pyrazinecarboxamide (PC)-guided CH alkenylation reaction of E-configured alkylolefins to obtain trisubstituted and tetrasubstituted conjugated dienes and tetrasubstituted and pentasubstituted conjugated trienes with excellent E / Z selectivity. Summary of the Invention

[0006] To address the aforementioned problems, this invention proposes a method for synthesizing polysubstituted conjugated dienes and conjugated trienes, thereby more accurately resolving the issues raised in the background section.

[0007] This invention is achieved through the following technical solution: This invention proposes a method for synthesizing polysubstituted conjugated dienes and conjugated trienes.

[0008]

[0009] To achieve the above objective, this invention, under relatively mild conditions, uses a simple transition metal salt as a catalyst to prepare polysubstituted conjugated dienes and conjugated trienes from simple alkylamides. The following technical solution is employed: a CH alkenylation reaction occurs at the alfa position of an E-configuration alkyl olefin to synthesize the trisubstituted 1,3-conjugated diene shown in formula (1), as follows:

[0010] In formula (1), R1, R2, and R3 are alkyl groups; R4 is an electron-withdrawing group.

[0011] Furthermore, in formula (1), R1, R2, and R3 are more preferably C1-6 alkyl groups; R4 is an ester group, amide group, sulfonyl group, or carbonyl group.

[0012] Furthermore, in formula (1), R1 is more preferably methyl, propyl, isopropyl, isobutyl, pentyl, hexyl, cyclohexyl, or phenethyl; R2 and R3 are more preferably methyl, ethyl, or phenyl; and R4 is more preferably 2-methoxyethyl ester, n-butyl ester, tert-butyl ester, N,N-dimethylamide, diethyl phosphonate, N-benzylamide, benzylsulfonyl, phenyl ester, tetrahydrofuran ester, geraniol, isomenthyl ester, or β-sitosterol.

[0013] Furthermore, in the reaction, the molar ratio of the amide derivative, alkenylating agent, transition metal salt catalyst 1, additive 2, additive 3, and additive 4 described in this invention is 1: 2.5: 0.1: 1.5: 3.0: 0.1.

[0014] Furthermore, the organic solvent is dimethyl sulfoxide.

[0015] Furthermore, the transition metal salt catalyst described in this invention is a palladium salt.

[0016] Furthermore, the transition metal salt catalyst described in this invention is preferably palladium acetate.

[0017] Typically, the volumetric amount of the organic solvent used in this invention, expressed as the molar amount of the amide derivative, is 0.15 mmol / mL.

[0018] Furthermore, the heating reaction temperature in the first step of the present invention is 80-120°C; the reaction time is 36-48 hours.

[0019] Furthermore, this invention also investigated alfa-position alkenylation products of E-configuration alkyl olefins, and synthesized tetrasubstituted 1,3,5-conjugated trienes as shown in formula (2) by CH alkenylation at the beta position.

[0020]

[0021] In formula (2), R1, R2, and R3 are alkyl groups; R4 and R5 are electron-withdrawing groups.

[0022] Furthermore, in formula (2), R1, R2, and R3 are more preferably C1-6 alkyl groups; R4 and R5 are ester groups and amide groups.

[0023] Furthermore, in formula (2), R1 is more preferably methyl, propyl, isobutyl, pentyl, hexyl, or phenethyl; R2 and R3 are more preferably methyl or ethyl; and R4 and R5 are more preferably 2-methoxyethyl ester, tert-butyl ester, ethyl ester, N,N-dimethylamide, or tetrahydrofuran ester.

[0024] Furthermore, the molar ratio of the amide derivative: alkenylating agent: metal salt catalyst 1: additive 5: additive 3: additive 4 is 1: 2.5: 0.1: 2.0: 3.0: 0.1; the transition metal salt catalyst is preferably palladium acetate; the organic solvent is acetonitrile; the volume of the organic solvent used is 0.15 mmol / mL based on the molar amount of the amide derivative; the heating reaction temperature is 100℃; and the reaction time is 36 hours.

[0025] Furthermore, this invention also investigated the alfa- / beta-iso-alkenylation reaction to prepare the tetrasubstituted 1,3,5-conjugated triene shown in formula (3).

[0026]

[0027] In formula (3), R1 and R2 are alkyl groups; R3 is an electron-withdrawing group.

[0028] Furthermore, in formula (3), R1 and R2 are more preferably C1~5 alkyl groups; R3 is an ester group.

[0029] Furthermore, in formula (3), R1 is more preferably methyl, pentyl, or phenethyl; R2 is more preferably methyl; and R3 is more preferably 2-methoxyethyl ester or tert-butyl ester.

[0030] Furthermore, the molar ratio of the amide derivative: alkenylating agent: metal salt catalyst 1: additive 5: additive 3: additive 4 is 1: 5.0: 0.1: 2.0: 3.0: 0.1; the transition metal salt catalyst is preferably palladium acetate; the organic solvent is acetonitrile; the volume of the organic solvent used is 0.15 mmol / mL based on the molar amount of the amide derivative; the heating reaction temperature is 100℃; and the reaction time is 72 hours.

[0031] Furthermore, this invention also investigated alkyne-involved alkenylation reactions at the alfa- / beta- positions of E-configured alkyl olefins to prepare tetrasubstituted conjugated dienes and pentasubstituted conjugated trienes as shown in formula (4).

[0032]

[0033] In formula (4), R1 is an alkyl group and Ar1 is an aryl group.

[0034] Furthermore, in formula (4), R1 is more preferably a C3 alkyl group; Ar1 ​​is a substituted phenyl group.

[0035] Furthermore, in formula (4), R1 is more preferably propyl; Ar1 ​​is more preferably 4-methoxyphenyl or 4-fluorophenyl.

[0036] Furthermore, the molar ratio of the amide derivative, alkenylating agent, metal salt catalyst 1, and additive 6 is 1:5.0:0.1:1.5; the transition metal salt catalyst is preferably palladium acetate; the organic solvent is acetonitrile:1,4-dioxane; the volume of the organic solvent used is 0.05 mmol / mL based on the molar amount of the amide derivative; the heating reaction temperature is 100℃; and the reaction time is 72 hours.

[0037] Furthermore, this invention also studied the alfa-position alkenylation of E-configuration alkyl olefins involving alkynes, followed by CH alkenylation reaction to prepare the pentasubstituted conjugated trienes shown in formula (5).

[0038]

[0039] In formula (5), R1 is an alkyl group; R2 is an electron-withdrawing group; and Ar1 is an aryl group.

[0040] Furthermore, in formula (5), R1 is more preferably a C3 alkyl group; R2 is an ester group; and Ar1 is a substituted phenyl group.

[0041] Furthermore, in formula (5), R1 is more preferably propyl; R2 is more preferably 2-methoxyethyl ester; and Ar1 is more preferably 4-methoxyphenyl or 4-fluorophenyl.

[0042] Furthermore, the molar ratio of the amide derivative: alkenylating agent: metal salt catalyst 1: additive 5: additive 3: additive 4 is 1: 2.5: 0.1: 2.0: 3.0: 0.1; the transition metal salt catalyst is preferably palladium acetate; the organic solvent is acetonitrile; the volume of the organic solvent used is 0.15 mmol / mL based on the molar amount of the amide derivative; the heating reaction temperature is 100℃; and the reaction time is 36 hours.

[0043] Furthermore, the related applications of the compounds obtained in this invention include: a) epoxidation reactions; b) Michael addition reactions; c) hydrogenation reduction reactions; d) removal of directing groups; and e) synthesis of macrolides.

[0044]

[0045] Furthermore, the post-processing described in this invention is as follows: the reaction solution is packed into a column, the remaining reaction solution is dissolved and transferred with a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 30:1, and separated by column chromatography using 300-mesh silica gel. The eluent is a mixture of petroleum ether and ethyl acetate. The eluent containing the target compound is collected, concentrated, and dried to obtain the corresponding target product.

[0046] More specifically, the trisubstituted and tetrasubstituted conjugated dienes, tetrasubstituted and pentasubstituted conjugated trienes, and related compounds for application expansion are one of the following.

[0047] Compared with the prior art, the present invention provides a method for synthesizing polysubstituted conjugated dienes and conjugated trienes, which has the following beneficial effects: (1) This invention provides an efficient method for synthesizing trisubstituted and tetrasubstituted conjugated dienes and tetrasubstituted and pentasubstituted conjugated trienes. The products obtained are all novel and have not been reported before. The two-step alkenylation reaction can be achieved by a one-pot synthesis. (2) The synthesis method of the present invention is simple to operate, has mild reaction conditions, high reaction yield, wide range of applications, and has very good economic value.

[0048] (3) The synthesis method of the present invention uses multiple CH functionalization reaction to synthesize multisubstituted conjugated polyene compounds, which is simple and effective.

[0049] (4) The raw materials for the synthesis of the present invention are economical and readily available, suitable for the highly selective preparation of polysubstituted olefins, and have broad application prospects. In terms of preparation methods, it is an effective supplement to existing methods.

[0050] (5) The compounds synthesized in this invention can be used as luminescent materials. Attached Figure Description

[0051] Figure 1 This is a schematic diagram of the structure of a method for synthesizing polysubstituted conjugated dienes and conjugated trienes proposed in this invention. Figure 2 The image shows the luminescence performance test results of a method for synthesizing polysubstituted conjugated dienes and conjugated trienes proposed in this invention. Figure 3 The emission spectra of compounds 8a, 8b, and 8c are those of compounds from the synthetic method for polysubstituted conjugated dienes and conjugated trienes proposed in this invention. Detailed Implementation

[0052] To more clearly and completely illustrate the technical solution of the present invention, the present invention will be further described below with reference to the accompanying drawings.

[0053] like Figure 1 As shown, one embodiment of the present invention provides a method for the efficient synthesis of trisubstituted and tetrasubstituted conjugated dienes and tetrasubstituted and pentasubstituted conjugated trienes. Example 1: (2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid tert-butyl ester

[0054] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3a (43.7 mg, yield 81%, Z / E = 93 / 7). 1H NMR (500 MHz, Chloroform-d) δ 9.41 (m, 1H), 8.75 (d, J = 2.4Hz, 1H), 8.54 – 8.50 (m, 1H), 7.86 (s, 1H), 7.62 (d, J = 15.1 Hz, 1H), 5.84(d, J = 15.9 Hz, 1H), 5.77 (t, J = 7.7 Hz, 1H), 3.50 (q, J = 7.0 Hz, 2H), 2.32 (t, J = 7.6 Hz, 2H), 2.26 (q, J = 7.5 Hz, 2H), 1.86 – 1.78 (m, 2H), 1.50 (s, 9H), 1.43 (q, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (126MHz, Chloroform-d) δ 166.92, 162.91, 147.19, 144.49, 144.37, 142.48, 139.24,139.18, 133.94, 119.43, 80.31, 39.13, 31.03, 29.92, 28.44, 28.18, 22.84,13.75. HRMS (ESI) for C20H29N3O3Na[M+Na]+: 382.2101, found: 382.2105. FTIR(KBr, cm-1) 3467.29, 2947.92, 2836.45, 2711.08, 1602.80, 1358.88, 1064.49,772.90. Example 2: (2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid butyl ester

[0055] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2b (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3b (34.5 mg, yield 64%, Z / E = 93 / 7).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.54 – 8.51 (m, 1H), 7.85 (s, 1H), 7.69 (d, J =15.9 Hz, 1H), 5.91 (d, J = 15.8 Hz, 1H), 5.80 (t, J = 7.6 Hz, 1H), 4.16 (t, J= 6.7 Hz, 2H), 3.50 (q, J = 6.8 Hz, 2H), 2.33 (t, J = 7.7 Hz, 2H), 2.26 (q, J= 7.5 Hz, 2H), 1.85 – 1.78 (m, 2H), 1.70 – 1.61 (m, 2H), 1.47 – 1.38 (m, 4H), 0.99 – 0.89 (m, 6H). 13C NMR (126 MHz, Chloroform-d) δ 167.59, 162.91,147.21, 144.47, 144.38, 142.46, 140.10, 139.77, 133.96, 117.70, 64.28, 39.10,30.95, 30.76, 29.95, 28.43, 22.81, 19.18, 13.73. HRMS (ESI) for C20H29N3O3Na[M+Na]+: 382.2101, found: 382.2111. FTIR (KBr, cm-1) 3445.17, 2960.52,2830.37, 2716.27, 1606.90, 1362.37, 1195.44, 1072.90, 773.98. Example 3: (2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid ethyl ester

[0056] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2c (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3c (42.9 mg, yield 86%, Z / E = 94 / 6).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.3 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.53 – 8.51 (m, 1H), 7.86 (s, 1H), 7.69 (d, J =15.9 Hz, 1H), 5.90 (d, J = 15.9 Hz, 1H), 5.80 (t, J = 7.7 Hz, 1H), 4.21 (q, J= 7.1 Hz, 2H), 3.50 (q, J = 6.9 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 2.27 (q, J= 7.5 Hz, 2H), 1.85 – 1.78 (m, 2H), 1.43 (q, J = 7.4 Hz, 2H), 1.30 (t, J =7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ167.49, 162.92, 147.21, 144.46, 144.37, 142.47, 140.10, 139.82, 133.94,117.71, 60.34, 39.10, 30.97, 29.95, 28.43, 22.80, 14.31, 13.73. HRMS (ESI)for C18H25N3O3Na[M+Na]+: 354.1788, found: 354.1792. FTIR (KBr, cm-1) 3456.27,2957.89, 2829.30, 2711.08, 2357.06, 1606.14, 1361.18, 1205.26, 1070.64,773.93. Example 4: Phenyl(2E, 4Z)-4-(3-(pyrazin-2-carboxamide)propyl)octyl-2,4-dienoic acid ester

[0057] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2d (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 48 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3d (22.8 mg, yield 40%, Z / E = 87 / 13).1H NMR (500 MHz, Chloroform-d) δ 9.43 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.52 (dd, J = 2.4, 1.5 Hz, 1H), 7.88 (d, J = 15.8Hz, 1H), 7.88 (s, 1H), 7.40 (t, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.14 (d, J =7.3 Hz, 1H), 6.11 (d, J = 15.9 Hz, 1H), 5.89 (t, J = 7.7 Hz, 1H), 3.54 (q, J= 6.8 Hz, 2H), 2.40 (t, 13C NMR (126MHz, Chloroform-d) δ 165.88, 162.98, 150.82, 147.26, 144.45, 144.41, 142.50,142.01, 141.14, 134.01, 129.39, 125.70, 121.62, 116.80, 39.11, 30.93, 30.09,28.52, 22.80, 13.75. HRMS (ESI) for C22H25N3O3Na[M+Na]+: 402.1788, found:402.1791. FTIR (KBr, cm-1) 3453.29, 2957.89, 2827.88, 2703.60, 2354.95,1612.58, 1359.83, 1212.74, 1068.86, 773.81. Example 5: 2-Methoxyethyl(2E, 4Z)-4-(3-(pyrazin-2-carboxamide)propyl)octyl-2,4-dienoic acid ester

[0058] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and alkene 2e (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 48 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3e (43.6 mg, yield 80%, Z / E = 95 / 5).1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.54 – 8.52 (m, 1H), 7.86 (s, 1H), 7.72 (d, J = 15.9 Hz,1H), 5.97 (d, J = 15.9 Hz, 1H), 5.81 (t, J = 7.6 Hz, 1H), 4.33 – 4.28 (m,2H), 3.66 – 3.62 (m, 2H), 3.49 (q, J = 6.8 Hz, 2H), 3.41 (s, 3H), 2.32 (t, J= 7.5 Hz, 2H), 2.26 (q, J = 7.5 Hz, 2H), 1.84 – 1.76 (m, 2H), 1.43 (q, J =7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ167.46, 162.91, 147.20, 144.45, 144.36, 142.49, 140.68, 140.15, 133.94,117.24, 70.56, 63.42, 58.99, 39.08, 30.94, 29.98, 28.41, 22.79, 13.72. HRMS(ESI) for C19H27N3O4Na[M+Na]+: 384.1894, found: 384.1905. FTIR (KBr, cm-1)3453.36, 2965.51, 2829.07, 2716.20, 2355.36, 1606.28, 1361.43, 1210.40,1068.69, 773.87. Example 6: (tetrahydrofuran-2-yl)methyl(2E, 4Z)-4-(3-(pyrazin-2-carboxamide)propyl)oct-2,4-dienoic acid ester

[0059] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2f (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 48 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3f (25.6 mg, yield 44%, Z / E = 92 / 8).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 2.5, 1.5 Hz, 1H), 7.84 (s, 1H), 7.72(d, J = 15.9 Hz, 1H), 5.97 (d, J = 15.9 Hz, 1H), 5.81 (t, J = 7.7 Hz, 1H), 4.26 (dd, J = 11.4, 3.4 Hz, 1H), 4.17 (dd, J = 7.0, 3.4 Hz, 1H), 4.09 (dd, J= 11.4, 7.0 Hz, 1H), 3.94 – 3.89 (m, 1H), 3.86 – 3.78 (m, 1H), 3.49 (q, 2H), 2.32 (t, J = 7.7 Hz, 2H), 2.27 (q, J = 7.5 Hz, 2H), 2.06 – 1.99 (m, 1H), 1.99– 1.89 (m, 2H), 1.86 – 1.76 (m, 2H), 1.70 – 1.58 (m, 1H), 1.49 – 1.38 (m,2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.45,162.92, 147.20, 144.47, 144.36, 142.50, 140.65, 140.12, 133.96, 117.29,76.62, 68.45, 66.48, 39.09, 30.95, 29.99, 28.41, 28.01, 25.67, 22.80, 13.74.HRMS (ESI) for C21H29N3O4Na[M+Na]+: 410.2050, found: 410.2040. FTIR (KBr, cm-1) 3444.89, 2957.53, 2829.48, 2716.56, 1606.29, 1362.04, 1210.40, 1070.09,773.72. Example 7: N-((4Z, 5E)-4-butadiene-7-oxonon-5-en-1-yl)pyrazine-2-carboxamide

[0060] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2 g (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give 3 g of a yellow oily liquid (18.0 mg, yield 38%, Z / E = 88 / 12).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.1 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.52 (dd, J = 2.4, 1.5 Hz, 1H), 7.85 (s, 1H), 7.58 (d, J= 16.0 Hz, 1H), 6.22 (d, J = 16.1 Hz, 1H), 5.85 (t, J = 7.7 Hz, 1H), 3.50 (q,J = 6.9 Hz, 2H), 2.61 (q, J = 7.3 Hz, 2H), 2.34 (t, J = 7.6 Hz, 2H), 2.28 (q,J = 7.5 Hz, 2H), 1.85 – 1.78 (m, 2H), 1.45 (q, J = 7.4 Hz, 2H), 1.13 (t, J =7.3 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ201.45, 162.94, 147.26, 144.45, 144.40, 142.48, 140.61, 137.61, 134.28,125.56, 39.11, 34.09, 30.94, 30.04, 28.53, 22.81, 13.76, 8.26. HRMS (ESI) forC18H25N3O2Na[M+Na]+: 338.1839, found: 338.1840. FTIR (KBr, cm-1) 3445.08,2957.46, 2829.42, 2716.53, 2358.96, 1605.49, 1360.52, 1200.28, 1070.24,773.63.. Example 8: N-((Z)-4-((E)-3(dimethylamine)-3-oxopropyl-1-en-1-yl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0061] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2h (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to obtain a yellow oily liquid (42.1 mg, yield 85%, Z / E = 90 / 10).1H NMR (500 MHz, Chloroform-d) δ 9.33 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.49 – 8.39 (m, 1H), 7.79 (s, 1H), 7.58 (d, J = 15.4 Hz,1H), 6.27 (d, J = 15.4 Hz, 1H), 5.66 (t, J = 7.6 Hz, 1H), 3.43 (q, J = 6.8Hz, 2H), 3.01 (s, 3H), 2.96 (s, 3H), 2.27 (t, J = 7.5 Hz, 2H), 2.20 (q, J =7.5 Hz, 2H), 1.80 – 1.72 (m, 2H), 1.35 (q, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.31, 162.94, 147.25, HRMS (ESI) for C18H26N4O2Na[M+Na]+: 353.1948,found: 353.1955. FTIR (KBr, cm-1) 3444.70, 2975.35, 2829.77, 2716.29,1605.38, 1361.29, 1200.28, 1068.90, 773.83. Example 9: Diethyl((1E, 3Z)-3-(3-(pyrazin-2-carboxamide)propyl)hept-1,3-dien-1-yl)phosphate

[0062] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2i (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic phase was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3i (16.0 mg, yield 27%, Z / E = 88 / 12).1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.5 Hz, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.46 (dd, J = 2.4, 1.5 Hz, 1H), 7.78 (s, 1H), 7.41 (dd,J = 23.2, 17.1 Hz, 1H), 5.73 – 5.68 (m, 1H), 5.63 (t, J = 18.1 Hz, 1H), 4.07– 3.97 (m, 4H), 3.43 (q, J = 6.8 Hz, 2H), 2.24 (t, J = 7.7 Hz, 2H), 2.18 (q,J = 7.5 Hz, 2H), 1.76 – 1.70 (m, 2H), 1.41 – 1.30 (m, 2H), 1.26 (t, J = 7.0Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 161.92,146.23, 143.43, 143.37, 143.11 (d, J = 6.5 Hz), 141.48, 137.87, 133.16 (d, J= 22.7 Hz), 112.18 (d, J = 191.5 Hz), 60.73, 60.69, 38.12, 29.51, 28.80,27.32, 21.78, 15.41, 15.36, 12.71. HRMS (ESI) for C19H30N3O4PNa[M+Na]+:418.1866, found: 418.1869. FTIR (KBr, cm-1) 3444.22, 2957.11, 2829.78,2716.20, 2359.14, 2340.85, 1604.39, 1360.32, 1202.77, 1068.76, 773.72. Example 10: N-((Z)-4((E)-2-(benzenesulfonyl)vinyl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0063] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2j (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3j (35.0 mg, yield 58%, Z / E = 80 / 20).1H NMR (500 MHz, Chloroform-d) δ 9.30 (d, J = 5.4 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.46 – 8.42 (m, 1H), 7.84 – 7.79 (m, 2H), 7.61 (d, J =15.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 3H), 6.28 (d, J = 15.3 Hz, 1H), 5.84 (t, J= 7.4 Hz, 1H), 3.39 (q, J = 6.6 Hz, 2H), 2.22 (q, J = 7.5 Hz, 2H), 2.17 (t, J= 7.6 Hz, 2H), 1.72 – 1.65 (m, 2H), 1.42 – 1.34 (m, 2H), 0.86 (t, J = 7.5 Hz,3H). 13C NMR (126 MHz, Chloroform-d) δ 161.95, 146.28, 143.34, 141.53,141.49, 141.23, 139.87, 136.99, 132.23, 131.26, 128.27, 126.48, 125.70,37.94, 29.66, 29.13, 27.09, 21.67, 12.69. HRMS (ESI) for C21H25N3O3SNa[M+Na]+: 422.1509, found: 422.1508. FTIR (KBr, cm-1) 3451.23, 2957.89, 2829.23,2716.07, 1606.67, 1360.53, 1197.78, 1068.75, 773.83. Example 11: N-((Z)-4((E)-3-(benzylamine)-3-oxopropyl-1-en-1-yl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0064] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2k (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3k (18.4 mg, yield 31%, Z / E = 88 / 12).1H NMR (500 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.64 (d, J= 2.5 Hz, 1H), 8.39 – 8.36 (m, 1H), 7.77 (s, 1H), 7.60 (d, J = 15.5 Hz, 1H),7.26 – 7.16 (m, 4H), 5.98 (t, J = 5.8 Hz, 1H), 5.84 (d, J = 15.5 Hz, 1H), 5.66 (t, J = 7.6 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.41 (q, J = 6.7 Hz, 2H),2.25 – 2.16 (m, 4H), 1.76 – 1.68 (m, 2H), 1.38 – 1.30 (m, 2H), 0.84 (t, J =7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.28, 162.99, 147.27,144.41, 144.36, 142.46, 138.67, 138.30, 136.92, 133.83, 128.72, 128.00,127.54, 119.94, 43.86, 39.24, 31.19, 29.92, 28.65, 22.89, 13.77. HRMS (ESI)for C23H28N4O2Na[M+Na]+: 415.2104, found: 415.2110. FTIR (KBr, cm-1) 3445.09,2960.52, 2829.43, 2716.10, 2358.13, 2339.75, 1612.46, 1360.26, 1215.38,1068.59, 773.86. Example 12: N-((Z)-4((E)-styryl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0065] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2l (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give 3l of a yellow solid (34.7 mg, yield 69%, Z / E = 90 / 10) (melting point 84.5 °C).1H NMR (500 MHz, Chloroform-d) δ 9.34 (s, 1H), 8.66(s, 1H), 8.43 (s, 1H), 7.80 (s, 1H), 7.34 (d, J = 7.5 Hz, 2H), 7.24 (t, J =7.5 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 16.3 Hz, 1H), 6.50 (d, J = 16.3 Hz, 1H), 5.44 (t, J = 7.3 Hz, 1H), 3.46 (q, J = 6.7 Hz, 2H), 2.35 (t,J = 7.4 Hz, 2H), 2.18 (q, 13C NMR (126 MHz, Chloroform-d) δ161.84, 146.12, 143.56, 143.37, 141.42, 136.80, 134.15, 131.37, 127.56,126.89, 126.28, 125.28, 123.89, 38.22, 30.35, 28.68, 27.62, 22.04, 12.85.HRMS (ESI) for C21H25N3ONa[M+Na]+: 358.1890, found: 358.1890. FTIR (KBr, cm-1) 3466.48, 2950.42, 2829.52, 2713.57, 1612.33, 1362.34, 1210.25, 1068.85,773.97. Example 13: N-((Z)-4((E)-4-chlorostyryl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0066] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2m (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow solid 3m (21.4 mg, yield 39%, Z / E = 88 / 12) (melting point 82.7 °C).1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.6Hz, 1H), 8.67 (d, J = 2.5 Hz, 1H), 8.46 – 8.42 (m, 1H), 7.79 (s, 1H), 7.26(d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 16.3 Hz, 1H), 6.44 (d, J = 16.3 Hz, 1H), 5.47 (s, 1H), 3.46 (q, J = 6.8 Hz, 2H), 2.34 (t, J= 7.5 Hz, 2H), 2.18 (q, J = 7.4 Hz, 2H), 1.84 – 1.76 (m, 2H), 1.38 (q, J =7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ161.86, 146.16, 143.52, 143.39, 141.41, 135.33, 133.95, 131.95, 131.79,127.71, 126.43, 125.58, 124.47, 38.22, 30.27, 28.71, 27.63, 22.01, 12.84.HRMS (ESI) for C21H24ClN3ONa[M+Na]+: 392.1500, found: 392.1501. FTIR (KBr,cm-1) 3470.55, 2945.43, 2830.27, 2711.08, 2357.27, 2334.63, 1612.42, 1359.20, 1222.71, 1068.06, 773.73. Example 14: N-((Z)-4((E)-4-fluorostyryl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0067] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and alkene 2n (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a white solid 3n (24.8 mg, yield 47%, Z / E = 88 / 12) (melting point 82.7 °C).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.4Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.51 (dd, J = 2.4, 1.5 Hz, 1H), 7.87 (s,1H), 7.38 (dd, J = 8.7, 5.4 Hz, 2H), 7.03 – 6.98 (m, 3H), 6.53 (d, J = 16.3Hz, 1H), 5.52 (t, J = 7.5 Hz, 1H), 3.54 (q, J = 6.9 Hz, 2H), 2.42 (t, J = 7.6Hz, 2H), 2.25 (q, J = 7.4 Hz, 2H), 1.91 – 1.85 (m, 2H), 1.51 – 1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 162.89, 147.18,144.57, 144.41, 142.45, 135.01, 134.01 (d, J = 3.4 Hz), 132.41, 127.74 (d, J= 7.9 Hz), 126.70, 124.74, 124.72, 115.52 (d, J = 21.6 Hz), 39.27, 31.35,29.71, 28.65, 23.06, 13.88. 19F NMR (471 MHz, Chloroform-d) δ -114.77. HRMS(ESI) for C21H24FN3ONa[M+Na]+: 376.1796, found: 376.1791. FTIR (KBr, cm-1)3431.58, 2950.42, 2830.84, 2718.69, 1605.61, 1356.07, 1210.25, 1070.09,781.31. Example 15: N-((Z)-4((E)-4-methoxystyryl)oct-4-en-1-yl)pyrazin-2-carboxamide

[0068] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2o (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 3o (16.9 mg, yield 31%, Z / E = 88 / 12) (melting point 89.7 °C).1H NMR (500 MHz, Chloroform-d) δ 9.42 (d, J = 1.5Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.53 – 8.49 (m, 1H), 7.87 (s, 1H), 7.36(d, J = 8.6 Hz, 2H), 6.97 (d, J = 16.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 16.3 Hz, 1H), 5.47 (s, 1H), 3.82 (s, 3H), 3.54 (q, 2H), 2.42 (t,J = 7.5 Hz, 2H), 2.25 (q, J = 7.4 Hz, 2H), 1.93 – 1.85 (m, 2H), 1.45 (q, J =7.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ162.86, 159.08, 147.15, 144.60, 144.41, 142.44, 135.26, 131.36, 130.63,127.47, 127.41, 122.99, 114.07, 55.32, 39.27, 31.43, 29.69, 28.66, 23.11,13.90. HRMS (ESI) for C22H27N3O2Na[M+Na]+: 388.1995, found: 388.2000. FTIR(KBr, cm-1) 3463.99, 2960.39, 2830.58, 2706.09, 1607.51, 1362.20, 1207.76,1060.66, 774.38. Example 16: (E)-3,7-dimethyloctyl-2,6-dien-1-yl(2E, 4Z)-4-(3-(pyrazin-2-carboxamide)propyl)octyl-2,4-dienoate

[0069] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2p (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3p (49.5 mg, yield 75%, Z / E = 95 / 5).1H NMR (500 MHz, Chloroform-d) δ 9.42 (d, J = 1.5 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.53 – 8.49 (m, 1H), 7.87 (s, 1H), 7.36 (d, J = 8.6Hz, 2H), 6.97 (d, J = 16.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.53 (d, J =16.3 Hz, 1H), 5.47 (s, 1H), 3.82 (s, 3H), 3.54 (q, 2H), 2.42 (t, J = 7.5 Hz,2H), 2.25 (q, J = 7.4 Hz, 2H), 1.93 – 1.85 (m, 2H), 1.45 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 162.86, 159.08,147.15, 144.60, 144.41, 142.44, 135.26, 131.36, 130.63, 127.47, 127.41,122.99, 114.07, 55.32, 39.27, 31.43, 29.69, 28.66, 23.11, 13.90. HRMS (ESI)for C22H27N3O2Na[M+Na]+: 388.1995, found: 388.2000. FTIR (KBr, cm-1) 3463.99,2960.39, 2830.58, 2706.09, 1607.51, 1362.20, 1207.76, 1060.66, 774.38. Example 17: (1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl(2E,4Z)-4-(3-(pyrazin-2-carboxamido)propyl)octyl-2,4-dienoic acid ester

[0070] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2q (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic phase was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3q (25.4 mg, yield 40%, Z / E = 93 / 7).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.2 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.52 (dd, J = 2.3, 1.5 Hz, 1H), 7.85 (s, 1H), 7.67 (d, J= 15.9 Hz, 1H), 5.86 (d, J = 15.9 Hz, 1H), 5.80 (t, J = 7.8 Hz, 1H), 4.76(dd, J = 7.7, 3.8 Hz, 1H), 3.50 (q, J = 6.9 Hz, 2H), 2.33 (t, J = 7.5 Hz,2H), 2.24 (q, J = 7.5 Hz, 2H), 1.85 – 1.78 (m, 4H), 1.78 – 1.74 (m, 1H), 1.73– 1.67 (m, 1H), 1.60 – 1.53 (m, 1H), 1.43 (q, J = 7.4 Hz, 2H), 1.22 – 1.16(m, 1H), 1.13 – 1.07 (m, 1H), 1.03 (s, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.87(s, 3H), 0.86 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.95, 162.93,147.22, 144.47, 144.39, 142.48, 139.75, 139.47, 134.07, 118.18, 80.90, 48.86,46.96, 45.06, 39.11, 38.85, 33.72, 30.79, 29.97, 28.40, 27.06, 22.85, 20.14,19.97, 13.75, 11.51. HRMS (ESI) for C26H37N3O3Na[M+Na]+: 462.2727, found:462.2732. FTIR (KBr, cm-1) 3444.72, 2958.03, 2830.22, 2716.02, 1606.22, 1362.32, 1205.41, 1068.86, 774.05. Example 18: (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl(2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid ester

[0071] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2r (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3r (25.4 mg, yield 80%, Z / E = 94 / 6).1H NMR (500 MHz, Chloroform-d) δ 9.42 (d, J = 1.5 Hz, 1H),8.76 (d, J = 2.3 Hz, 1H), 8.56 – 8.51 (m, 1H), 7.88 (s, 1H), 7.69 (d, J =15.8 Hz, 1H), 5.90 (d, J = 15.9 Hz, 1H), 5.80 (t, J = 7.7 Hz, 1H), 4.78 (td,J = 10.9, 4.3 Hz, 1H), 3.51 (q, J = 6.8 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H),2.27 (q, J = 7.5 Hz, 2H), 2.07 – 2.00 (m, 1H), 1.93 – 1.86 (m, 1H), 1.86 –1.79 (m, 2H), 1.73 – 1.66 (m, 2H), 1.56 – 1.49 (m, 1H), 1.47 – 1.40 (m, 3H),1.14 – 0.97 (m, 2H), 0.95 – 0.87 (m, 10H), 0.78 (d, J = 6.9 Hz, 3H). 13C NMR(126 MHz, Chloroform-d) δ 167.14, 162.93, 147.18, 144.48, 144.35, 142.49,140.00, 139.66, 133.97, 118.03, 74.11, 47.16, 41.03, 39.14, 34.28, 31.39,30.92, 29.95, 28.41, 26.33, 23.56, 22.82, 22.03, 20.73, 16.47, 13.74. HRMS(ESI) for C26H39N3O3Na[M+Na]+: 464.2884, found: 464.2884. FTIR (KBr, cm-1)3454.72, 2972.85, 2830.04, 2716.07, 1611.92, 1362.10, 1202.77, 1068.97,774.15.。 Example 19: (2R,8S,9S,10R,13R,14S,17R)-17-((2R,5R)-5-ethyl-6-methylheptane-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-2-yl(2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid ester Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1a (1.0 equivalent, 0.15 mmol), and olefin 2s (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3s (30.5 mg, yield 50%, Z / E = 86 / 14). 1H NMR (500 MHz, Chloroform-d) δ 9.41 (s, 1H), 8.75 (d, J = 2.5 Hz,1H), 8.54 – 8.51 (m, 1H), 7.84 (s, 1H), 7.68 (d, J = 15.8 Hz, 1H), 5.89 (d, J= 15.8 Hz, 1H), 5.79 (t, J = 7.7 Hz, 1H), 5.39 (d, J = 5.0 Hz, 1H), 4.76 –4.64 (m, 1H), 3.54 – 3.42 (m, 2H), 2.39 – 2.31 (m, 5H), 2.27 (q, J = 7.5 Hz,2H), 2.05 – 1.95 (m, 2H), 1.93 – 1.78 (m, 6H), 1.72 – 1.49 (m, 8H), 1.48 –1.41 (m, 4H), 1.30 – 1.23 (m, 4H), 1.21 – 1.13 (m, 5H), 1.07 – 1.00 (m, 4H), 0.93 (t, J = 7.4 Hz, 4H), 0.88 – 0.76 (m, 11H), 0.69 (s, 3H). 13C NMR (126MHz, Chloroform-d) δ 166.93, 162.91, 147.21, 144.48, 144.40, 142.47, 140.01, 139.76, 139.71, 133.97, 122.66, 118.10, 73.99, 56.70, 56.03, 50.04, 45.83, 42.32, 39.73, 39.13, 38.23, 37.02, 36.63, 36.15, 33.94, 31.92, 31.87, 31.02,29.97, 29.15, 28.46, 27.87, 26.07, 24.30, 23.07, 22.83, 21.95, 21.04, 19.82,19.35, 19.04, 18.78, 13.76, 11.99, 11.86. HRMS (ESI) for C45H69N3O3Na[M+Na]+:722.5231, found: 722.5226. FTIR (KBr, cm-1) 3455.15, 2940.58, 2829.91, 2706.23, 2357.00, 1612.57, 1359.78, 1190.45, 1068.61, 774.04. Example 20: (2E,4Z)-7-methyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid tert-butyl ester

[0072] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1t (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give 3t of a pale yellow oily liquid (35.3 mg, yield 63%, Z / E > 99 / 1), melting point 79.0 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.5Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.54 – 8.51 (m, 1H), 7.80 (s, 1H), 7.62(d, J = 16.0 Hz, 1H), 5.87 (d, J = 16.0 Hz, 1H), 5.78 (t, J = 7.6 Hz, 1H), 3.53 – 3.35 (m, 2H), 2.64 – 2.52 (m, 1H), 2.27 (q, J = 7.5 Hz, 2H), 1.88 –1.79 (m, 1H), 1.79 – 1.71 (m, 1H), 1.50 (s, 9H), 1.44 (q, J = 7.4 Hz, 2H), 1.15 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.94, 162.84, 147.16, 144.51, 144.35, 142.45, 139.61,139.14, 136.43, 119.03, 80.26, 37.80, 35.83, 33.12, 29.95, 28.19, 22.93,20.75, 13.75. HRMS (ESI) for C21H31N3O3Na[M+Na]+: 396.2258, found: 396.2260.FTIR (KBr, cm-1) 3444.86, 2959.81, 2830.84, 2715.89, 1605.61, 1361.68,1070.09, 775.70. Example 21: (2E,4Z)-4-(2-methyl-3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid tert-butyl ester

[0073] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1u (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic phase was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3u (55.5 mg, yield 99%, Z / E = 96 / 4).1H NMR (500 MHz, Chloroform-d) δ 9.34 (m, 1H), 8.68 (d, J = 2.4Hz, 1H), 8.49 – 8.39 (m, 1H), 7.81 (s, 1H), 7.54 (d, J = 15.8 Hz, 1H), 5.73(d, J = 15.9 Hz, 1H), 5.68 (t, J = 7.6 Hz, 1H), 3.38 – 3.24 (m, 2H), 2.27(dd, J = 13.7, 6.3 Hz, 1H), 2.20 (q, J = 7.4 Hz, 2H), 2.05 – 1.99 (m, 1H),1.97 – 1.89 (m, 1H), 1.42 (s, 9H), 1.37 (q, 2H), 0.89 (d, J = 6.5 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 165.86, 161.97,146.18, 143.47, 143.41, 141.45, 139.56, 138.35, 131.92, 118.61, 79.28, 44.06,38.29, 31.31, 28.98, 27.16, 21.85, 16.92, 12.77. HRMS (ESI) for C21H31N3O3Na[M+Na]+: 396.2258, found: 396.2259. FTIR (KBr, cm-1) 3450.47, 2959.81,2828.04, 2718.69, 1605.61, 1361.68, 1064.49, 770.09. Example 22: (2E,4Z)-4-(2-(pyrazin-2-carbamoyl)methyl)butyl)octyl-2,4-dienoate tert-butyl ester

[0074] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1v (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3v (50.0 mg, yield 86%, Z / E = 93 / 7).1H NMR (500 MHz, Chloroform-d) δ 9.33 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 2.3, 1.6 Hz, 1H), 7.75 (s, 1H), 7.54 (d, J= 15.8 Hz, 1H), 5.76 – 5.66 (m, 2H), 3.45 – 3.38 (m, 1H), 3.35 – 3.27 (m,1H), 2.27 – 2.17 (m, 3H), 2.14 – 2.07 (m, 1H), 1.78 – 1.72 (m, 1H), 1.42 (s,9H), 1.40 – 1.31 (m, 4H), 0.91 (t, J = 7.5 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, Chloroform-d) δ 166.86, 162.95, 147.17, 144.49, HRMS (ESI) for C22H33N3O3Na[M+Na]+:410.2414, found: 410.2414. FTIR (KBr, cm-1) 3442.06, 2954.21, 2828.04,2724.30, 1602.80, 1358.88, 1067.29, 775.70. Example 23: (2E,4Z)-4-(2-phenyl-3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid tert-butyl ester

[0075] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1w (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3w (28.1 mg, yield 43%, Z / E = 90 / 10).1H NMR (500 MHz, Chloroform-d) δ 9.36 (m, 1H), 8.70 (d, J = 2.3Hz, 1H), 8.45 – 8.41 (m, 1H), 7.71 (s, 1H), 7.57 (d, J = 15.9 Hz, 1H), 7.35 –7.29 (m, 2H), 7.26 – 7.16 (m, 3H), 5.84 (d, J = 15.9 Hz, 1H), 5.52 (t, J =7.7 Hz, 1H), 3.94 – 3.83 (m, 1H), 3.66 – 3.57 (m, 1H), 3.15 – 3.07 (m, 1H),2.68 (dd, J = 14.0, 6.4 Hz, 1H), 2.50 (dd, J = 14.0, 8.4 Hz, 1H), 2.21 – 2.08(m, 2H), 1.50 (s, 9H), 1.26 – 1.19 (m, 4H), 1.15 – 1.08 (m, 2H), 0.84 (t, J =7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.90, 162.85, 147.14,144.36, 144.33, 142.48, 141.80, 141.69, 139.24, 131.68, 128.66, 127.76,126.95, 119.36, 80.31, 44.27, 44.24, 38.64, 31.18, 29.07, 28.20, 27.84,22.44, 13.96. HRMS (ESI) for C28H37N3O3Na[M+Na]+: 486.2727, found: 486.2728.FTIR (KBr, cm-1) 3444.86, 2962.62, 2833.64, 2710.28, 2359.81, 1614.02,1370.09, 1070.09, 778.50. Example 24: (2E,4E)-4-(3-methyl-4-(pyrazin-2-carboxamido)but-2-yl)oct-2,4-dienoic acid tert-butyl ester

[0076] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1x (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic phase was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3x (34.3 mg, yield 59%, Z / E = 68 / 32).1H NMR (500 MHz, Chloroform-d) δ 9.41 (s, 1H), 8.76 – 8.72 (m,1H), 8.55 – 8.51 (m, 1H), 7.80 (s, 1H), 7.63 (d, J = 16.0 Hz, 1H), 5.85 (d, J= 16.0 Hz, 1H), 5.75 (t, J = 7.6 Hz, 1H), 3.55 – 3.49 (m, 1H), 3.38 – 3.32(m, 1H), 2.43 (q, J = 7.1 Hz, 1H), 2.28 (q, J = 7.6 Hz, 2H), 1.96 – 1.89 (m,1H), 1.50 (s, 9H), 1.47 – 1.40 (m, 2H), 1.16 (d, J = 7.0 Hz, 3H), 0.97 (d, J= 6.8 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ166.97, 162.95, 147.18, 144.51, 144.41, 142.44, 140.07, 138.70, 137.38,119.19, 80.32, 42.54, 39.20, 37.34, 30.04, 28.20, 22.96, 22.94, 16.83, 13.79.HRMS (ESI) for C22H33N3O3Na[M+Na]+: 410.2414, found: 410.2414. FTIR (KBr, cm-1) 3447.66, 2965.42, 2830.84, 2715.89, 1600.00, 1361.68, 1070.09, 770.09. Example 25: (2E,4Z)-4-ethylidene-7-(pyrazin-2-carbamoyl)hept-2-enoic acid tert-butyl ester

[0077] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1y (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3y (39.8 mg, yield 80%, Z / E = 89 / 11). 1H NMR (500 MHz, Chloroform-d) δ 9.41 (m, 1H), 8.75 (d, J= 2.4 Hz, 1H), 8.52 (dd, J = 2.4, 1.5 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J =15.8 Hz, 1H), 5.88 – 5.81 (m, 2H), 3.49 (q, J = 6.9 Hz, 2H), 2.31 (t, J = 7.5Hz, 2H), 1.86 (d, J = 7.1 Hz, 3H), 1.85 – 1.78 (m, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 166.90, 162.91, 147.20, 144.48, 144.37, 142.48,138.77, 134.71, 133.30, 119.40, 80.33, 39.14, 31.01, 28.34, 28.18, 13.77.HRMS (ESI) for C18H25N3O3Na[M+Na]+: 354.1788, found: 354.1788. FTIR (KBr, cm-1) 3428.17, 2943.07, 2833.78, 2716.02, 1605.75, 1367.44, 1068.14, 775.85. Example 26: (2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)dec-2,4-dienoic acid tert-butyl ester

[0078] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1z (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 48 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 3z (57.0 mg, 98% yield, Z / E = 95 / 5), melting point 80.0 °C.1H NMR (500 MHz, Chloroform-d) δ 9.33 (d, J = 1.2 Hz,1H), 8.67 (d, J = 2.4 Hz, 1H), 8.45 (dd, 1H), 7.80 (s, 1H), 7.54 (d, J = 15.8Hz, 1H), 5.76 (d, J = 15.9 Hz, 1H), 5.69 (t, J = 7.7 Hz, 1H), 3.42 (q, J =6.9 Hz, 2H), 2.23 (t, J = 7.6 Hz, 2H), 2.19 (q, J = 7.6 Hz, 2H), 1.78 – 1.70(m, 2H), 1.42(s, 9H), 1.35 – 1.29 (m, 2H), 1.25 – 1.19 (m, 4H), 0.80 (t, J =6.9 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.88, 162.89, 147.17,144.47, 144.34, 142.46, 139.44, 139.13, 133.73, 119.39, 80.24, 39.12, 31.39, 31.00, 29.29, 28.41, 28.15, 27.87, 22.44, 13.98. HRMS (ESI) for C22H33N3O3Na[M+Na]+: 410.2414, found: 410.2418. FTIR (KBr, cm-1) 3486.92, 2943.07,2830.84, 2715.89, 1600.00, 1361.68, 1075.70, 778.50. Example 27: (2E,4Z)-7-methyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4-dienoic acid tert-butyl ester

[0079] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1aa (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 48 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3aa (52.1 mg, yield 93%, Z / E = 97 / 3).1H NMR (500 MHz, Chloroform-d) δ 9.42 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 2.4, 1.5 Hz, 1H), 7.88 (s, 1H), 7.62 (d, J= 15.8 Hz, 1H), 5.84 (d, J = 15.9 Hz, 1H), 5.79 (t, J = 7.8 Hz, 1H), 3.51 (q,J = 6.9 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 2.17 (t, J = 7.3 Hz, 2H), 1.87 –1.79 (m, 2H), 1.72 – 1.65 (m, 1H), 1.51 (s, 9H), 0.91 (d, J = 6.7 Hz, 6H).13C NMR (126 MHz, Chloroform-d) δ 166.94, 162.91, 147.21, 144.49, HRMS (ESI) for C21H31N3O3Na[M+Na]+: 396.2258, found:396.2258. FTIR (KBr, cm-1) 3450.47, 2962.62, 2828.04, 2713.08, 1602.80,1364.49, 1067.29, 781.31. Example 28: (2E,4Z)-6-methyl-4-(3-(pyrazin-2-carbamoyl)propyl)hept-2,4-dienoic acid tert-butyl ester

[0080] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1ab (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a white solid 3ab (43.7 mg, yield 81%, Z / E > 99 / 1), melting point 64.9 °C. 1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.3 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.52 (dd, 1H), 7.86 (s, 1H), 7.62 (d, J = 15.8 Hz, 1H), 5.83 (d, J = 15.8 Hz, 1H), 5.55 (d, J = 9.8 Hz, 1H), 3.49 (q, J = 6.9Hz, 2H), 2.95 – 2.86 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 1.84 – 1.77 (m, 2H),1.50 (s, 9H), 0.99 (d, J = 6.6 Hz, 6H). 13C NMR (126 MHz, Chloroform-d) δ166.89, 162.90, 147.20, 146.42, 144.48, 144.37, 142.46, 139.24, 131.47,119.56, 80.30, 39.10, 30.90, 28.40, 28.18, 27.05, 23.07. HRMS (ESI) forC20H29N3O3Na[M+Na]+: 382.2101, found: 382.2104. FTIR (KBr, cm-1) 3428.04,2959.81, 2828.04, 2721.50, 1597.20, 1367.29, 1070.09, 772.90. Example 29: (2E,4Z)-7-phenyl-4-(3-(pyrazin-2-carbamoyl)propyl)hept-2,4-dienoic acid tert-butyl ester

[0081] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1ac (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 100 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic phase was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3ac (40.5 mg, yield 64%, Z / E = 93 / 7).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.52 (dd, J = 2.4, 1.5 Hz, 1H), 7.81 (s, 1H), 7.55(d, J = 15.8 Hz, 1H), 7.29 – 7.25 (m, 2H), 7.20 – 7.15 (m, 3H), 5.81 (d, J =15.9 Hz, 1H), 5.77 (t, J = 7.5 Hz, 1H), 3.45 (q, J = 6.8 Hz, 2H), 2.72 (t, J= 7.6 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.82 –1.75 (m, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 166.75, 162.91,147.22, 144.49, 144.40, 142.48, 141.08, 138.79, 137.66, 134.51, 128.45,128.40, 126.01, 119.90, 80.37, 39.05, 35.76, 31.00, 29.63, 28.37, 28.19. HRMS(ESI) for C25H31N3O3Na[M+Na]+: 444.2258, found: 444.2258. FTIR (KBr, cm-1)3436.45, 2955.40, 2830.84, 2715.89, 1591.59, 1364.49, 1067.29, 775.70. Example 30: (2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)-7-(o-tolyl)hept-2,4-dienoic acid tert-butyl ester

[0082] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1ad (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3ad (40.5 mg, yield 62%, Z / E = 97 / 3).1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.2 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.52 (dd, J = 2.3, 1.5 Hz, 1H), 7.83 (s, 1H), 7.55 (d, J= 15.9 Hz, 1H), 7.14 – 7.06 (m, 4H), 5.84 – 5.78 (m, 2H), 3.47 (q, J = 6.8Hz, 2H), 2.70 (t, 2H), 2.56 (q, J = 7.6 Hz, 2H), 2.38 – 2.27 (m, 5H), 1.85 –1.76 (m, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 166.69, 162.93,147.22, 144.49, 144.38, 142.49, 139.24, 138.66, 137.65, HRMS (ESI) for C26H33N3O3Na[M+Na]+: 458.2414, found:458.2416. FTIR (KBr, cm-1) 3447.66, 2951.40, 2839.25, 2715.89, 1597.20,1364.49, 1081.31, 778.50. Example 31: (2E,4Z)-7-(4-chlorophenyl)-4-(3-(pyrazin-2-carbamoyl)propyl)hept-2,4-dienoic acid tert-butyl ester

[0083] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1ae (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 100 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3ae (41.7 mg, yield 61%, Z / E = 97 / 3).1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.47 – 8.43 (m, 1H), 7.74 (s, 1H), 7.43 (d, J =15.8 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 5.74 (d, J= 15.8 Hz, 1H), 5.65 (t, J = 7.6 Hz, 1H), 3.37 (q, J = 6.8 Hz, 2H), 2.61 (t,J = 7.5 Hz, 2H), 2.50 (q, J = 7.5 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.74 –1.66 (m, 2H), 1.42 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 166.69, 162.93,147.23, 144.45, 144.37, 142.48, 139.46, 138.60, 137.00, 134.81, 131.73,129.82, 128.46, 120.04, 80.42, 39.02, 35.05, 30.96, 29.44, 28.36, 28.17. HRMS(ESI) for C25H30ClN3O3Na[M+Na]+: 478.1868, found: 478.1871. FTIR (KBr, cm-1)3475.70, 2962.62, 2836.45, 2721.50, 1600.00, 1364.49, 1070.09, 781.21. Example 32: (2E,4Z)-4-(3-(pyrazin-2-carbamoyl)propyl)-7-(3-(trifluoromethyl)phenyl)hept-2,4-dienoic acid tert-butyl ester

[0084] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1af (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3af (44.8 mg, yield 61%, Z / E = 95 / 5).1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.44 (dd, J = 2.5, 1.5 Hz, 1H), 7.75 (s, 1H), 7.42 (d, J= 15.8 Hz, 1H), 7.38 – 7.27 (m, 4H), 5.74 (d, J = 15.8 Hz, 1H), 5.66 (t, J =7.6 Hz, 1H), 3.38 (q, J = 6.9 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 2.54 (q, J =7.6 Hz, 2H), 2.22 (t, J = 7.5 Hz, 2H), 1.75 – 1.65 (m, 2H), 1.42 (s, 9H). 13CNMR (126 MHz, Chloroform-d) δ 166.62, 162.93, 147.23, 144.45, 144.37, 142.48,141.91, 138.44, 136.57, 135.07, 131.88, 130.61 (q, J = 32.0 Hz), 128.84,125.17 (q, J = 3.8 Hz), 124.17 (q, J = 272.4 Hz), 122.92 (q, J = 3.8 Hz),120.21, 80.43, 39.02, 35.48, 30.95, 29.31, 28.43, 28.14. 19F NMR (471 MHz,Chloroform-d) δ -62.56. HRMS (ESI) for C26H30F3N3O3Na[M+Na]+: 512.2131,found: 512.2134. FTIR (KBr, cm-1) 3447.66, 2962.88, 2833.64, 2715.89,1594.39, 1364.49, 1070.09, 772.90. Example 33: (2E,4Z)-4-(cyclohexylmethylene)-5-methyl-7-(pyrazin-2-carbamoyl)hept-2-enoic acid tert-butyl ester

[0085] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1 ag (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give 3 ag of white solid (50.9 mg, yield 82%, Z / E = 98 / 2), melting point 129.8 °C.1H NMR (500 MHz, Chloroform-d) δ 9.32 (d, J = 1.5 Hz,1H), 8.67 (d, J = 2.5 Hz, 1H), 8.44 (dd, J = 2.4, 1.5 Hz, 1H), 7.73 (s, 1H),7.57 (d, J = 15.9 Hz, 1H), 5.79 (d, J = 15.9 Hz, 1H), 5.51 (d, J = 9.6 Hz,1H), 3.45 – 3.28 (m, 2H), 2.54 – 2.45 (m, 2H), 1.79 – 1.52 (m, 7H), 1.42 (s,9H), 1.30 – 1.17 (m, 3H), 1.06 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.05, 162.82, 147.14, 144.50, 144.33, 142.46, 142.44,139.91, 137.05, 118.73,80.25,37.74,36.72,35.81,33.28,33.17,32.71,28.19,25.82,25.62,25.60,20.78. C24H35N3O3Na[M+Na]+:436.2571, found: 436.2573. FTIR (KBr, cm-1) 3444.86, 2957.01, 2828.04, 2715.89, 1608.41, 1358.88, 1067.29, 778.50. Example 34: (2E, 4Z)-4-(4-(pyrazin-2-carbamoyl)butyl)octyl-2,4-dienoic acid tert-butyl ester

[0086] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1ah (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3ah (12.9 mg, yield 23%, Z / E > 99 / 1).1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.1 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.49 – 8.35 (m, 1H), 7.74 (s, 1H), 7.54 (d, J = 15.8 Hz,1H), 5.75 (d, J = 15.8 Hz, 1H), 5.64 (t, J = 7.6 Hz, 1H), 3.43 (d, J = 6.5Hz, 2H), 2.17 (q, J = 7.7 Hz, 4H), 1.64 – 1.54 (m, 2H), 1.49 (q, J = 8.6, 8.2Hz, 2H), 1.43 (s, 9H), 1.35 (q, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, Chloroform-d) δ 167.07, 162.83, 147.17, 144.55, HRMS (ESI) for C21H31N3O3Na[M+Na]+: 396.2258,found: 396.2262. FTIR (KBr, cm-1) 3456.07, 2962.62, 2828.04, 2715.89,1608.41, 1358.88, 1070.09, 772.90. Example 35: (2E,4Z)-4-(2-(pyrazin-2-carbamoyl)ethyl)octyl-2,4-dienoic acid tert-butyl ester

[0087] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1ai (1.0 equivalent, 0.15 mmol), and olefin 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 3ai (29.0 mg, yield 56%, Z / E = 79 / 21). 1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.3 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.49 (dd, J = 2.4, 1.5 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J= 15.9 Hz, 1H), 5.94 (d, J = 15.9 Hz, 1H), 5.80 (t, J = 7.7 Hz, 1H), 3.60 (q,J = 6.9 Hz, 2H), 2.55 (t, J = 6.9 Hz, 2H), 2.28 (q, J = 7.5 Hz, 2H), 1.50 (s,9H), 1.42 (q, J = 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.78, 162.82, 147.22, 144.44, 144.31, 142.46, 140.88,138.70, 131.69, 119.86, 80.45, 38.22, 33.53, 29.96, 28.17, 22.73, 13.67. HRMS(ESI) for C19H27N3O3Na[M+Na]+: 368.1945, found: 368.1946. FTIR (KBr, cm-1)3464.49, 2951.40, 2833.64, 2721.50, 1611.21, 1367.29, 1081.31, 775.70. Example 36: (2E,4Z)-6-methyl-4-(2-(pyrazin-2-carbamoyl)ethyl)hept-2,4-dienoic acid tert-butyl ester

[0088] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, tervaponic acid (1.5 equivalent, 0.23 mmol), amide 1aj (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 3aj (32.6 mg, yield 63%, Z / E = 91 / 9). 1H NMR (500 MHz, Chloroform-d) δ 9.40 (m, 1H), 8.75 (d, J =2.4 Hz, 1H), 8.51 – 8.47 (m, 1H), 7.84 (s, 1H), 7.64 (d, J = 15.9 Hz, 1H), 5.94 (d, 0.99 (d, J= 6.6 Hz, 6H). 13C NMR (126 MHz, Chloroform-d) δ 166.76, 162.75, 148.27,147.22, 144.46, 144.29, 142.47, 138.67, 129.07, 120.01, 80.49, 38.01, 33.43,28.18, 27.16, 22.96. HRMS (ESI) for C19H27N3O3Na[M+Na]+: 368.1945, found:368.1947. FTIR (KBr, cm-1) 3454.00, 2950.42, 2829.97, 2716.95, 1598.65, 1363.39, 1210.28, 1070.09, 774.71. Example 37: (2E,4Z)-4-(2-(pyrazin-2-carbamoyl)ethyl)undec-2,4-dienoic acid tert-butyl ester

[0089] Alfa-CH-alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1ak (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a yellow solid 3ak (24.4 mg, yield 42%, Z / E = 97 / 3), melting point 80.4 °C.1H NMR (500 MHz, Chloroform-d) δ 9.33 (d, J = 1.3 Hz,1H), 8.68 (d, J = 2.4 Hz, 1H), 8.42 (dd, J = 2.3, 1.5 Hz, 1H), 7.76 (s, 1H),7.57 (d, J = 15.8 Hz, 1H), 5.86 (d, J = 15.9 Hz, 1H), 5.73 (t, J = 7.7 Hz,1H), 3.52 (q, J = 6.8 Hz, 2H), 2.48 (t, J = 6.9 Hz, 2H), 2.22 (q, J = 7.5 Hz,2H), 1.43 (s, 9H), 1.32 – 1.27 (m, 2H), 1.24 – 1.15 (m, 6H), 0.80 (t, J = 6.8Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.79, 162.82, 147.22, 144.47,144.35, HRMS (ESI) for C22H33N3O3Na[M+Na]+:410.2414, found: 410.2412. FTIR (KBr, cm-1) 3453.90, 2962.62, 2830.13,2716.30, 1599.14, 1362.70, 1072.90, 774.94. Example 38: (2E, 4Z)-4-(1-(pyrazin-2-carboxamido)but-2-yl)oct-2,4-dienoic acid tert-butyl ester

[0090] Alfa-CH alkenylation: Palladium acetate (10 mol%, 0.015 mmol), manganese dioxide (3.0 equivalent, 0.45 mmol), benzoquinone (10 mol%, 0.015 mmol), and dimethyl sulfoxide (1.0 mL) were placed in a screw-cap vial. Then, terpentine (1.5 equivalent, 0.23 mmol), amide 1al (1.0 equivalent, 0.15 mmol), and alkene 2a (2.5 equivalent, 0.38 mmol) were added sequentially to the solution. The vial was sealed under argon atmosphere, heated to 80 °C, and stirred for 36 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was directly subjected to rapid column chromatography (PE / EA mixture) to give a white solid 3al (18.5 mg, yield 33%, Z / E = 90 / 10), melting point 75.0 °C.1H NMR (500 MHz, Chloroform-d) δ 9.39 (m, 1H), 8.73 (d,J = 2.4 Hz, 1H), 8.51 – 8.45 (m, 1H), 7.75 (s, 1H), 7.66 (d, J = 16.0 Hz,1H), 5.93 (d, J = 16.0 Hz, 1H), 5.79 (t, J = 7.7 Hz, 1H), 3.68 – 3.61 (m,1H), 3.51 – 3.43 (m, 1H), 2.67 – 2.60 (m, 1H), 2.32 (q, J = 7.5 Hz, 2H), 1.65– 1.59 (m, 1H), 1.58 – 1.52 (m, 2H), 1.49 (s, 7H), 1.48 – 1.42 (m, 2H), 0.95– 0.88 (m, 7H). 13C NMR (126 MHz, Chloroform-d) δ 166.85, 162.84, 147.17,144.45, HRMS (ESI) for C21H31N3O3Na[M+Na]+:396.2258, found: 396.2258. FTIR (KBr, cm-1) 3451.78, 2957.01, 2830.31,2716.70, 1598.28, 1362.59, 1213.08, 1075.70, 774.78. Example 39: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-propyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0091] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3a (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 4a (29.3 mg, yield 60%, E / Z > 99 / 1), melting point 99.2 °C.1H NMR (500 MHz, Chloroform-d) δ 9.33 – 9.32 (m, 1H), 8.68 (d, J = 2.4Hz, 1H), 8.46 (dd, J = 2.5, 1.5 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J = 15.6 Hz,1H), 7.67 (d, J = 15.7 Hz, 1H), 6.09 (d, J = 15.6 Hz, 1H), 5.96 (d, J = 15.7Hz, 1H), 4.26 – 4.20 (m, 2H), 3.60 – 3.54 (m, 2H), 3.45 (q, J = 6.9 Hz, 2H),3.34 (s, 3H), 2.58 – 2.51 (m, 2H), 2.43 – 2.36 (m, 2H), 1.76 – 1.67 (m, 2H), 1.42 (s, 9H), 1.40 – 1.35 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (126MHz, Chloroform-d) δ 167.09, 166.33, 163.03, 147.16, 144.43, 144.33, 142.52,141.58, 141.19, 140.19, 140.19, 122.44, 120.23, 80.68, 70.47, 63.57, 58.99,39.10, 30.24, 29.95, 28.13, 25.46, 23.39, 14.17. HRMS (ESI) for C26H37N3O6Na[M+Na]+: 510.2575, found: 510.2571. FTIR (KBr, cm-1) 3454.08, 2965.37, 2829.72, 2716.59, 1598.29, 1362.23, 1204.71, 1075.76, 774.69. Example 40: 1-(tert-butyl)8-ethyl(2E,4E,6E)-5-propyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0092] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3a (1.0 equivalent, 0.10 mmol), and olefin 2c (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 4b (20.1 mg, yield 44%, E / Z = 85 / 15), melting point 87.7 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.2 Hz, 1H), 8.75 (d,J = 2.4 Hz, 1H), 8.56 – 8.50 (m, 1H), 7.89 (s, 1H), 7.83 – 7.67 (m, 2H), 6.10(d, J = 15.6 Hz, 1H), 6.03 (d, J = 15.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.53 (q, J = 6.8 Hz, 2H), 2.68 – 2.57 (m, 2H), 2.55 – 2.44 (m, 2H), 1.86 –1.74 (m, 2H), 1.50 (s, 9H), 1.49 – 1.42 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.12, 166.40,163.04, 147.21, 144.44, 144.40, 142.49, 141.29, 141.05, 140.27, 139.89,122.34, 120.77, 80.70, 60.57, 39.12, 30.26, 29.95, 28.17, 25.47, 23.43,14.29, 14.19. HRMS (ESI) for C25H35N3O5Na[M+Na]+: 480.2469, found: 480.2465.FTIR (KBr, cm-1) 3455.32, 2957.31, 2830.02, 2716.63, 1598.57, 1362.88,1070.09, 774.77. Example 41: 1-(tert-butyl)8-methyl(2E,4E,6E)-5-propyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0093] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3a (1.0 equivalent, 0.10 mmol), and olefin 2t (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 4c (15.1 mg, yield 34%, E / Z > 99 / 1).1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.2 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 2.5, 1.5 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J = 15.8 Hz, 1H), 7.74(d, J = 15.8 Hz, 1H), 6.11 (d, J = 15.7 Hz, 1H), 6.03 (d, J = 15.7 Hz, 1H), 3.74 (s, 3H), 3.53 (q, J = 6.9 Hz, 2H), 2.65 – 2.60 (m, 2H), 2.52 – 2.41 (m,2H), 1.86 – 1.75 (m, 2H), 1.50 (s, 9H), 1.48 – 1.43 (m, 2H), 0.95 (t, J = 7.3Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.51, 166.37, 163.05, 147.22,144.43, 144.40, 142.50, 141.24, 141.22, 140.22, 140.03, 122.44, 120.33,80.73, 51.73, 39.09, 30.24, 29.93, 28.16, 25.46, 23.41, 14.18. HRMS (ESI) forC24H33N3O5Na[M+Na]+: 466.2312, found: 466.2311. FTIR (KBr, cm-1) 3443.95,2965.37, 2830.30, 2716.65, 1598.38, 1362.76, 1072.90, 774.81. Example 42: (2E,4E,6E)-8-(dimethylamino)-8-oxo-5-propyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid tert-butyl ester

[0094] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3a (1.0 equivalent, 0.10 mmol), and olefin 2h (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 4d (18.3 mg, yield 41%, E / Z > 99 / 1), melting point 105.0 °C. 1H NMR (500 MHz, Chloroform-d) δ 9.39 (d, J = 1.2 Hz, 1H), 8.74 (d,J = 2.4 Hz, 1H), 8.55 – 8.51 (m, 1H), 7.93 (s, 1H), 7.76 (d, J = 15.4 Hz,2H), 6.55 (d, J = 15.1 Hz, 1H), 6.00 (d, J = 15.7 Hz, 1H), 3.51 (q, J = 6.9Hz, 2H), 3.12 (s, 3H), 3.02 (s, 3H), 2.67 – 2.58 (m, 2H), 2.55 – 2.47 (m,2H), 1.84 – 1.74 (m, 2H), 1.56 – 1.42 (m, 11H), 0.96 (t, J = 7.4 Hz, 3H). 13CNMR (126 MHz, Chloroform-d) δ 166.83, 166.60, 163.02, 147.12, 144.52, 144.34,142.54, 141.72, 140.56, 139.10, 138.72, 121.60, 119.92, 80.56, 39.16, 37.37,35.89, 30.43, 29.80, 28.18, 25.39, 23.47, 14.26. HRMS (ESI) for C25H36N4O4Na[M+Na]+: 479.2629, found: 479.2631. FTIR (KBr, cm-1) 3453.17, 2940.44,2829.62, 2716.64, 1598.38, 1362.37, 1073.13, 774.71. Example 43: (2E,4E,6E)-8-oxo-5-propyl-4-(3-(pyrazin-2-carbamoyl)propyl)-9-(tetrahydrofuran-2-yl)non-2,4,6-trienoic acid tert-butyl ester

[0095] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3a (1.0 equivalent, 0.10 mmol), and olefin 2f (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 4e (17.0 mg, yield 33%, E / Z > 99 / 1).1HNMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 2.4 Hz,1H), 8.53 (dd, J = 2.4, 1.5 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J = 15.6 Hz, 1H),7.74 (d, J = 15.7 Hz, 1H), 6.17 (d, J = 15.6 Hz, 1H), 6.03 (d, J = 15.7 Hz,1H), 4.24 (dd, J = 11.4, 3.4 Hz, 1H), 4.20 – 4.12 (m, 1H), 4.07 (dd, J =11.4, 7.1 Hz, 1H), 3.95 – 3.88 (m, 1H), 3.85 – 3.78 (m, 1H), 3.52 (q, J = 6.9Hz, 2H), 2.65 – 2.59 (m, 2H), 2.50 – 2.43 (m, 2H), 2.07 – 2.00 (m, 1H), 1.98– 1.89 (m, 2H), 1.83 – 1.75 (m, 2H), 1.67 – 1.59 (m, 1H), 1.50 (s, 9H), 1.49– 1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ167.10, 166.37, 163.04, 147.18, 144.44, 144.37, 142.51, 141.59, 141.24,140.23, 140.18, 122.44, 120.29, 80.71, 76.57, 68.46, 66.66, 39.13, 30.26,29.97, 28.15, 28.02, 25.67, 25.49, 23.41, 14.18. HRMS (ESI) for C28H39N3O5Na[M+Na]+: 552.3044, found: 552.3041. FTIR (KBr, cm-1) 3452.64, 2957.15,2830.29, 2716.47, 1598.71, 1363.22, 1072.90, 774.99.。 Example 44: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-methyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0096] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3y (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 4f (24.3 mg, yield 53%, E / Z = 95 / 5).1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.55 – 8.53 (m, 1H), 7.91 (s, 1H), 7.88 (d, J = 15.5 Hz, 1H), 7.78 (d, J =15.7 Hz, 1H), 6.17 (d, J = 15.5 Hz, 1H), 6.03 (d, J = 15.7 Hz, 1H), 4.32 –4.27 (m, 2H), 3.66 – 3.62 (m, 2H), 3.53 (q, J = 6.9 Hz, 2H), 3.41 (s, 3H), 2.66 – 2.60 (m, 2H), 2.05 (s, 3H), 1.85 – 1.75 (m, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 166.97, 166.36, 163.03, 147.17, 144.43, 144.34,142.53, 142.25, 140.36, 140.26, 136.13, 122.48, 120.80, 80.75, 70.46, 63.56,59.00, 39.11, 29.88, 28.12, 25.58, 14.43. HRMS (ESI) for C24H33N3O6Na[M+Na]+:482.2262, found: 482.2257. FTIR (KBr, cm-1) 3454.34, 2940.44, 2828.22,2718.69, 1597.59, 1355.37, 1210.28, 1072.90, 772.58. Example 45: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-pentyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0097] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3z (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give 4 g of a yellow solid (22.2 mg, yield 43%, E / Z > 99 / 1), melting point 100.3 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.4 Hz, 1H), 8.75 (d, J =2.4 Hz, 1H), 8.54 (dd, J = 2.4, 1.5 Hz, 1H), 7.91 (s, 1H), 7.81 (d, J = 15.6Hz, 1H), 7.73 (d, J = 15.7 Hz, 1H), 6.16 (d, J = 15.6 Hz, 1H), 6.03 (d, J =15.7 Hz, 1H), 4.34 – 4.27 (m, 2H), 3.67 – 3.62 (m, 2H), 3.53 (q, J = 6.9 Hz, 2H), 3.42 (s, 3H), 2.66 – 2.58 (m, 2H), 2.51 – 2.41 (m, 2H), 1.85 – 1.75 (m,2H), 1.50 (s, 9H), 1.44 – 1.37 (m, 2H), 1.35 – 1.30 (m, 4H), 0.89 (t, J = 6.4Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.13, 166.31, 163.04, 147.18,144.44, 144.36, 142.51, 141.60, 141.41, 140.13, 140.02, HRMS (ESI) for C28H41N3O6Na[M+Na]+: 538.2888, found: 538.2889.FTIR (KBr, cm-1) 3446.34, 2955.40, 2828.11, 2716.07, 1612.18, 1358.21,1070.15, 773.45. Example 46: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-pentyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0098] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3aa (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow solid (15.0 mg, 30% yield, E / Z > 99 / 1) with a melting point of 83.9 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.5 Hz, 1H), 8.75 (d,J = 2.5 Hz, 1H), 8.53 (dd, J = 2.5, 1.5 Hz, 1H), 7.91 (s, 1H), 7.84 (d, J =15.6 Hz, 1H), 7.77 (d, J = 15.7 Hz, 1H), 6.14 (d, J = 15.6 Hz, 1H), 6.02 (d,J = 15.7 Hz, 1H), 4.35 – 4.27 (m, 2H), 3.67 – 3.62 (m, 2H), 3.54 (q, J = 6.8Hz, 2H), 13C NMR (126) MHz,Chloroform-d) δ 167.12, 166.33, 163.06, 147.19, 144.44, 144.39, 142.51,142.11, 141.02, 140.65, 140.39, 122.25, 120.67, 80.67, 70.50, 63.61, 59.02,39.16, 36.65, 30.07, 29.69, 29.23, 28.16, 25.64, 22.55. HRMS (ESI) forC27H39N3O6Na[M+Na]+: 524.2731, found: 524.2732. FTIR (KBr, cm-1) 3450.86,2962.62, 2830.68, 2716.40, 1598.43, 1362.64, 1072.90, 774.94. Example 47: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-phenethyl-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0099] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3ac (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow solid 4i (27.5 mg, 50% yield, E / Z > 99 / 1), melting point 102.3 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.4 Hz, 1H), 8.75 (d,J = 2.5 Hz, 1H), 8.54 (dd, J = 2.4, 1.5 Hz, 1H), 7.90 (s, 1H), 7.83 (d, J =15.6 Hz, 1H), 7.58 (d, J = 15.7 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.20 – 7.14 (m,3H), 6.23 (d, J = 15.7 Hz, 1H), 5.94 (d, J = 15.7 Hz, 1H), 4.37 – 4.26 (m,2H), 3.68 – 3.62 (m, 2H), 3.52 (q, J = 6.8 Hz, 2H), 3.42 (s, 3H), 2.83 – 2.76(m, 2H), 2.74 – 2.69 (m, 2H), 2.63 – 2.58 (m, 2H), 1.81 – 1.70 (m, 2H), 1.51(s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 167.05, 166.03, 163.02, 147.13,144.51, 144.31, 142.62, 141.27, 141.05, 140.68, 139.67, 139.38, HRMS (ESI) for C31H39N3O6Na[M+Na]+: 572.2731,found: 572.2727. FTIR (KBr, cm-1) 3451.70, 2955.40, 2830.29, 2713.08,1597.56, 1361.53, 1070.09, 774.80. Example 48: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-(2-methylphenylethyl)-4-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienedioate

[0100] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3ad (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 4j (20.8 mg, yield 37%, E / Z > 99 / 1), melting point 113.8 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.4 Hz, 1H), 8.75 (d,J = 2.4 Hz, 1H), 8.54 (dd, J = 2.4, 1.5 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J =15.6 Hz, 1H), 7.52 (d, J = 15.7 Hz, 1H), 7.12 – 7.08 (m, 3H), 7.07 – 7.04 (m,1H), 6.23 (d, J = 15.7 Hz, 1H), 5.91 (d, J = 15.7 Hz, 1H), 4.34 – 4.29 (m,2H), 3.67 – 3.63 (m, 2H), 3.52 (q, J = 6.9 Hz, 2H), 3.42 (s, 3H), 2.78 – 2.68(m, 4H), 2.62 – 2.57 (m, 2H), 2.35 (s, 3H), 1.81 – 1.73 (m, 2H), 1.50 (s,9H). 13C NMR (126 MHz, Chloroform-d) δ 167.04, 165.98, 163.06, 147.22,144.43, 144.40, 142.52, 141.37, 141.17, 139.48, 139.40, 138.84, 135.80,130.29, 129.19, 126.35, 126.06, 122.72, 120.06, 80.62, 70.50, 63.68, 59.05,39.13, 33.17, 29.94, 28.74, 28.16, 25.68, 19.52. HRMS (ESI) for C32H41N3O6Na[M+Na]+: 586.2888, found: 586.2885. FTIR (KBr, cm-1) 3453.66, 2955.40,2829.78, 2716.89, 1598.33, 1363.72, 1069.14, 774.80. Example 49: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-(4-chlorophenylethyl)-4-(3-(pyrazin-2-carboxamido)propyl)octyl-2,4,6-trienedioate

[0101] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3ae (1.0 equivalent, 0.10 mmol), and alkene 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 4K (27.4 mg, yield 47%, E / Z > 99 / 1), melting point 138.2 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.3 Hz, 1H), 8.76 (d,J = 2.4 Hz, 1H), 8.54 (dd, J = 2.3, 1.5 Hz, 1H), 7.90 (s, 1H), 7.81 (d, J =15.7 Hz, 1H), 7.50 (d, J = 15.7 Hz, 1H), 7.26 – 7.19 (m, 2H), 7.11 – 7.04 (m,2H), 6.19 (d, J = 15.7 Hz, 1H), 5.93 (d, J = 15.7 Hz, 1H), 4.36 – 4.30 (m,2H), 3.69 – 3.64 (m, 2H), 3.52 (q, J = 6.8 Hz, 2H), 3.42 (s, 3H), 2.81 – 2.74(m, 2H), 2.72 – 2.65 (m, 2H), 2.62 – 2.56 (m, 2H), 1.82 – 1.72 (m, 2H), 1.51(s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 166.92, 165.97, 163.05, 147.19,144.44, 144.36, 142.55, 141.28, 141.11, 139.53, 139.04, 138.85, HRMS (ESI) for C31H38ClN3O6Na[M+Na]+: 606.2341,found: 606.2335. FTIR (KBr, cm-1) 3452.80, 2957.86, 2830.14, 2716.69,1598.82, 1363.27, 1058.88, 774.95. Example 50: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-4-(3-(pyrazin-2-carbamoyl)propyl)-5-(3-(trifluoromethyl)phenethyl)oct-2,4,6-trienedioate

[0102] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3af (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give 4 μL of a pale yellow oily liquid (32.7 mg, yield 53%, E / Z > 99 / 1).1H NMR (500 MHz, Chloroform-d) δ 9.33 (d, J = 1.2 Hz, 1H), 8.68 (d, J = 2.4Hz, 1H), 8.48 – 8.46 (m, 1H), 7.82 (s, 1H), 7.74 (d, J = 15.7 Hz, 1H), 7.43(d, J = 15.7 Hz, 1H), 7.38 – 7.35 (m, 1H), 7.32 – 7.30 (m, 2H), 7.26 (s, 1H),6.12 (d, J = 15.7 Hz, 1H), 5.86 (d, J = 15.7 Hz, 1H), 4.26 – 4.22 (m, 2H),3.62 – 3.55 (m, 2H), 3.45 (q, J = 6.8 Hz, 2H), 3.35 (s, 3H), 2.78 – 2.68 (m,4H), 2.55 – 2.48 (m, 2H), 1.73 – 1.64 (m, 2H), 1.42 (s, 9H). 13C NMR (126MHz, Chloroform-d) δ 166.87, 165.89, 163.06, 147.22, 144.41, 144.38, 142.52,141.44, 141.41, 141.04, 139.35, 138.64, 132.02, 132.01, 130.68 (d, J = 31.8Hz), 128.96, 125.20 (q, J = 3.7 Hz), 123.19 – 123.05 (q, J = 3.6 Hz), 122.97,120.30, 80.77, 70.46, 63.70, 59.03, 39.08, 35.51, 29.95, 29.74, 28.11, 25.60.19F NMR (471 MHz, Chloroform-d) δ -62.50. HRMS (ESI) for C32H38F3N3O6Na[M+Na]+: 640.2605, found: 640.2605. FTIR (KBr, cm-1) 3443.82, 2954.21, 2830.37,2716.37, 1599.67, 1363.19, 1072.90, 775.16.。 Example 51: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-5-propyl-4-(4-(pyrazin-2-carbamoyl)but-2-yl)oct-2,4,6-trienoic acid ester

[0103] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3t (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid, 4 mL (15.0 mg, yield 30%, E / Z > 99 / 1).1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 1.3 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.52 – 8.50 (m, 1H), 7.85 (d, J = 15.6 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J =16.3 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 5.99 (d, J = 16.3 Hz, 1H), 4.32 –4.24 (m, 2H), 3.67 – 3.58 (m, 2H), 3.44 – 3.35 (m, 5H), 3.25 (q, J = 6.9 Hz,1H), 2.43 – 2.36 (m, 2H), 1.90 (q, J = 7.4 Hz, 2H), 1.51 (s, 9H), 1.48 – 1.40(m, 2H), 1.24 (d, J = 7.1 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (126MHz, Chloroform-d) δ 167.18, 165.89, 162.86, 147.14, 144.77, 144.41, 144.31,142.49, 141.45, 140.41, 138.82, 124.39, 120.04, 80.80, 70.51, 63.56, 59.04,38.01, 35.15, 32.51, 31.81, 28.18, 23.20, 20.26, 14.18. HRMS (ESI) forC27H39N3O6Na[M+Na]+: 524.2731, found: 524.2732. FTIR (KBr, cm-1) 3444.06, 2959.81, 2830.76, 2716.29, 1598.16, 1362.61, 1067.29, 774.93. Example 52: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-4-(2-methyl-3-(pyrazin-2-carbamoyl)propyl)-5-propyloctyl-2,4,6-trienoic acid ester

[0104] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3u (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow oily liquid 4n (22.6 mg, yield 45%, E / Z > 99 / 1).1HNMR (500 MHz, Chloroform-d) δ 9.42 – 9.33 (m, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.54 – 8.47 (m, 1H), 7.91 (s, 1H), 7.82 (d, J = 15.6 Hz, 1H), 7.76 (d, J =15.7 Hz, 1H), 6.15 (d, J = 15.6 Hz, 1H), 5.99 (d, J = 15.7 Hz, 1H), 4.33 –4.22 (m, 2H), 3.65 – 3.58 (m, 2H), 3.46 – 3.31 (m, 5H), 2.61 (dd, J = 14.2, 6.3 Hz, 1H), 2.50 – 2.45 (m, 2H), 2.01 – 1.93 (m, 1H), 1.88 – 1.70 (m, 1H), 1.51 – 1.39 (m, 9H), 0.94 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, Chloroform-d) δ 167.12, 166.33, 163.09, 147.20, 144.43, 144.40, 142.49, 142.13, 142.04,140.77, 139.32, 122.87, 120.08, 80.70, 70.50, 63.59, 59.02, 45.07, 34.76,32.56, 30.47, 28.15, 23.49, 17.82, 14.23. HRMS (ESI) for C27H39N3O6Na[M+Na]+:524.2731, found: 524.2735. FTIR (KBr, cm-1) 3452.77, 2945.43, 2830.07, 2716.69, 1598.19, 1362.80, 1075.70, 774.77. Example 53: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-4-(2-methyl-3-(pyrazin-2-carbamoyl)propyl)-5-propyloctyl-2,4,6-trienoic acid ester

[0105] Beta-C-Alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3v (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 4O (23.2 mg, yield 45%, E / Z > 99 / 1), melting point 101.8 °C.1H NMR (500 MHz, Chloroform-d) δ 9.38 (d, J = 1.4 Hz, 1H), 8.75 (d, J =2.4 Hz, 1H), 8.53 (dd, J = 2.4, 1.5 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.78 (d, J= 15.7 Hz, 1H), 6.16 (d, J = 15.6 Hz, 1H), 6.01 (d, J = 15.7 Hz, 1H), 4.34 –4.24 (m, 2H), 3.70 – 3.60 (m, 2H), 3.49 (dd, J = 13.3, 6.7 Hz, 1H), 3.41 (s, 3H), 3.38 – 3.30 (m, 1H), 2.63 (dd, J = 14.4, 6.9 Hz, 1H), 2.57 – 2.52 (m,1H), 2.52 – 2.46 (m, 2H), 1.80 (dt, J = 12.9, 6.5 Hz, 1H), 1.49 (s, 9H), 1.47– 1.39 (m, 4H), 1.03 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.06, 166.27, 163.06, 147.16, 144.42, 144.38,142.47, 142.11, 141.92, 140.85, 139.51, 122.84, 120.16, 80.68, 70.48, 63.58,59.01, 41.99, 40.99, 30.62, 30.51, 28.14, 24.92, 23.46, 14.24, 11.22. HRMS(ESI) for C28H41N3O6Na[M+Na]+: 538.2888, found: 538.2887. FTIR (KBr, cm-1)3442.91, 2960.39, 2829.90, 2716.44, 1598.40, 1363.32, 1067.35, 774.96. Example 54: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-4-(2-methyl-3-(pyrazin-2-carbamoyl)propyl)-5-propyloctyl-2,4,6-trienoic acid ester

[0106] Beta-CH alkenylation: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 3ai (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 4p (26.0 mg, yield 55%, E / Z > 99 / 1), melting point 86.9 °C.1H NMR (500 MHz, Chloroform-d) δ 9.38 (d, J = 1.3 Hz, 1H), 8.71 (d,J = 2.4 Hz, 1H), 8.47 – 8.45 (m, 1H), 7.89 (s, 1H), 7.83 (d, J = 15.6 Hz,1H), 7.76 (d, J = 15.7 Hz, 1H), 6.20 (d, J = 15.7 Hz, 1H), 6.11 (d, J = 15.6Hz, 1H), 4.28 – 4.23 (m, 2H), 3.65 – 3.60 (m, 2H), 3.55 (q, J = 6.9 Hz, 2H),3.40 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 2.52 – 2.43 (m, 2H), 1.49 (s, 9H), 1.46 – 1.38 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 166.95, 166.35, 163.05, 147.19, 144.38, 144.27, 142.72, 142.44, 141.61,140.07, 137.38, 122.90, 120.53, 80.78, 70.46, 63.65, 59.01, 39.15, 30.43,29.69, 28.15, 23.42, 14.22. HRMS (ESI) for C25H35F3N3O6Na[M+Na]+: 496.2418, found: 496.2416. FTIR (KBr, cm-1) 3453.19, 2959.81, 2830.30, 2716.59, 1598.89, 1362.80, 1070.09, 774.97. Example 55: Bis(2-methoxyethyl)(2E,4E,6E)-4-propyl-5-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0107] One-pot bisCH alkenylation reaction: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 1a (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow solid 5a (28.4 mg, yield 58%, E / Z > 99 / 1), melting point 90.6 °C.1H NMR (500 MHz, Chloroform-d) δ 9.32 (d, J = 1.2 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.48 – 8.46 (m, 1H), 7.83 (s, 1H), 7.77 (d, J = 15.7 Hz,1H), 7.73 (d, J = 15.6 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H), 6.09 (d, J = 8.5Hz, 1H), 4.27 – 4.24 (m, 2H), 4.24 – 4.22 (m, 2H), 3.58 – 3.55 (m, 4H), 3.45(q, J = 6.8 Hz, 2H), 3.34 (s, 6H), 2.58 – 2.53 (m, 2H), 2.43 – 2.38 (m, 2H), 1.75 – 1.68 (m, 2H), 1.42 – 1.33 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.04, 167.01, 163.06, 147.19, 144.41, 144.37,142.54, 142.02, 141.69, 141.44, 139.97, 120.69, 120.09, 70.48, 63.69, 63.63,59.02, 39.08, 30.30, 29.91, 25.49, 23.48, 14.14. HRMS (ESI) for C25H35N3O7Na[M+Na]+: 512.2367, found: 512.2367. FTIR (KBr, cm-1) 3439.26, 2955.40,2829.40, 2708.59, 1612.17, 1359.51, 1068.42, 774.13.. Example 56: Bis(2-methoxyethyl)(2E,4E,6E)-4-pentyl-5-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0108] One-pot bisCH alkenylation reaction: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Then, acetic acid (2.0 equivalent, 0.20 mmol), amide 1t (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 5b (31.8 mg, yield 61%, E / Z > 99 / 1), melting point 91.4 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.3 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.54 (dd, J = 2.3, 1.5 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J= 15.7 Hz, 1H), 7.80 (d, J = 15.6 Hz, 1H), 6.19 (d, J = 8.1 Hz, 1H), 6.16 (d,J = 8.2 Hz, 1H), 4.34 – 4.32 (m, 2H), 4.32 – 4.29 (m, 2H), 3.66 – 3.63 (m,4H), 3.52 (q, J = 6.9 Hz, 2H), 3.41 (s, 3H), 3.41 (s, 3H), 2.64 – 2.58 (m,2H), 2.52 – 2.45 (m, 2H), 1.83 – 1.75 (m, 2H), 1.44 – 1.37 (m, 2H), 1.34 –1.29 (m, 4H), 0.90 (t, J = 6.2 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ167.02, 163.05, 147.19, 144.42, 144.37, 142.54, 142.26, 141.64, 141.43,139.76, 120.62, 120.09, 70.48, 63.69, 63.64, 59.03, 59.01, 39.08, 31.90,29.99, 29.90, 28.41, 25.47, 22.42, 14.00. HRMS (ESI) for C27H39N3O7Na[M+Na]+:540.2680, found: 540.2677. FTIR (KBr, cm-1) 3434.07, 2950.42, 2830.85,2713.10, 1605.63, 1364.51, 1070.12, 775.73. Example 57: Bis(2-methoxyethyl)(2E,4E,6E)-4-phenylethyl-5-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester.

[0109] One-pot bisCH alkenylation reaction: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 1ac (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 5c (33.2 mg, yield 60%, E / Z > 99 / 1), melting point 92.6 °C.1H NMR (500 MHz, Chloroform-d) δ 9.33 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.47 (dd, J = 2.4, 1.5 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J= 15.7 Hz, 1H), 7.62 (d, J = 15.7 Hz, 1H), 7.21 – 7.16 (m, 2H), 7.12 – 7.07(m, 3H), 6.17 (d, J = 15.7 Hz, 1H), 6.00 (d, J = 15.7 Hz, 1H), 4.26 – 4.23(m, 4H), 3.59 – 3.56 (m, 4H), 3.44 (q, J = 6.8 Hz, 2H), 3.35 (s, 3H), 3.34(s, 3H), 2.75 – 2.70 (m, 2H), 2.67 – 2.61 (m, 2H), 2.56 – 2.51 (m, 2H), 1.74– 1.65 (m, 2H). 13C NMR (126 MHz, Chloroform-d) δ 166.92, 166.77, 163.08,147.22, 144.41, 144.38, 142.55, 141.24, 141.09, 140.77, 140.59, 140.22,128.52, 128.48, 126.24, 120.59, 120.21, 70.49, 70.48, 63.69, 63.66, 59.03,59.01, 39.07, 36.01, 30.42, 29.91, 25.57. HRMS (ESI) for C30H37N3O7Na[M+Na]+:574.2524, found: 574.2527. FTIR (KBr, cm-1) 3456.51, 2975.35, 2830.84,2718.69, 1608.41, 1367.29, 1070.09, 772.90. Example 58: Bis(2-methoxyethyl)(2E,4E,6E)-4-(4-chlorophenylethyl)-5-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid ester

[0110] One-pot bisCH alkenylation reaction: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 1ae (1.0 equivalent, 0.10 mmol), and alkene 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a pale yellow solid 5d (28.9 mg, yield 49%, E / Z > 99 / 1), melting point 95.4 °C.1H NMR (500 MHz, Chloroform-d) δ 9.35 – 9.29 (m, 1H), 8.68 (d, J= 2.4 Hz, 1H), 8.49 – 8.46 (m, 1H), 7.82 (s, 1H), 7.73 (d, J = 15.7 Hz, 1H),7.54 (d, J = 15.7 Hz, 1H), 7.17 – 7.12 (m, 2H), 7.04 – 6.97 (m, 2H), 6.13 (d,J = 15.7 Hz, 1H), 5.99 (d, J = 15.7 Hz, 1H), 4.25 (q, J = 4.6 Hz, 4H), 3.61 –3.54 1.72 – 1.64 (m, 2H).13C NMR (126 MHz, Chloroform-d) δ 165.81, 165.70, 162.07, 146.21, 143.36,141.53, 140.04, 139.98, 139.96, 138.69, 137.98, 131.03, HRMS (ESI) for C30H36ClN3O7Na[M+Na]+: 608.2134, found:608.2138. FTIR (KBr, cm-1) 3411.63, 2970.36, 2828.04, 2718.69, 1608.41,1364.49, 1072.90, 775.70. Example 59: (2E,4E,6E)-4-propyl-5-(3-(pyrazin-2-carbamoyl)propyl)octyl-2,4,6-trienoic acid diethyl ester

[0111] One-pot bisCH alkenylation reaction: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 1a (1.0 equivalent, 0.10 mmol), and olefin 2c (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a white solid 5e (14.2 mg, yield 33%, E / Z > 99 / 1), melting point 115.6 °C.1H NMR (500 MHz, Chloroform-d) δ 9.40 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 2.4, 1.5 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J= 15.7 Hz, 1H), 7.78 (d, J = 15.6 Hz, 1H), 6.12 (d, J = 8.9 Hz, 1H), 6.09 (d,J = 8.9 Hz, 1H), 4.21 (dq, J = 10.1, 7.1 Hz, 4H), 3.53 (q, J = 6.9 Hz, 2H),2.68 – 2.58 (m, 2H), 2.54 – 2.41 (m, 2H), 1.84 – 1.76 (m, 2H), 1.51 – 1.40(m, 2H), 1.30 (td, J = 7.1, 2.3 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR(126 MHz, Chloroform-d) δ 167.08, 167.07, 163.06, 147.21, 144.42, 144.40,142.49, 141.80, 141.20, 140.94, 139.75, 121.06, 120.46, 60.61, 39.10, 30.26,29.90, 25.48, 23.45, 14.28, 14.14. HRMS (ESI) for C23H31N3O5Na[M+Na]+:452.2156, found: 452.2156. FTIR (KBr, cm-1) 3471.47, 2965.37, 2828.04, 2715.89, 1602.80, 1361.68, 1067.29, 770.09. Example 60: Bis(2-methoxyethyl)(2E,4E,6E)-4-(2-methyl-3-(pyrazin-2-carbamoyl)propyl)-5-propyl-2,4,6-trienoic acid ester

[0112] One-pot bisCH alkenylation reaction: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Then, acetic acid (2.0 equivalent, 0.20 mmol), amide 1u (1.0 equivalent, 0.10 mmol), and olefin 2e (2.5 equivalent, 0.25 mmol) were added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 5f (25.6 mg, yield 41%, E / Z > 99 / 1).1H NMR (500 MHz, Chloroform-d) δ 9.40 – 9.39 (m, 1H), 8.76 (d, J = 2.4 Hz,1H), 8.55 (dd, J = 2.5, 1.5 Hz, 1H), 7.93 (s, 1H), 7.89 (d, J = 15.7 Hz, 1H),7.84 (d, J = 15.6 Hz, 1H), 6.19 (d, J = 15.6 Hz, 1H), 6.15 (d, J = 15.7 Hz,1H), 4.35 – 4.29 (m, 4H), 3.65 (m, 4H), 3.43 – 3.39 (m, 8H), 2.67 – 2.61 (m,1H), 2.54 – 2.47 (m, 3H), 2.03 – 1.96 (m, 1H), 1.52 – 1.44 (m, 2H), 0.99 –0.94 (m, 6H). 13C NMR (126 MHz, Chloroform-d) δ 167.02, 163.10, 147.20,144.42, 144.41, 142.91, 142.52, 142.26, 141.87, 139.10, 120.51, 120.49,70.48, 63.70, 63.62, 59.02, 59.01, 45.04, 34.74, 32.56, 30.50, 23.55, 17.80,14.19. HRMS (ESI) for C26H37N3O7Na[M+Na]+: 526.2524, found: 526.2522. FTIR(KBr, cm-1) 3429.09, 2965.42, 2828.04, 2715.89, 1614.02, 1361.68, 1072.90,775.70. Example 61: Bis(2-methoxyethyl)(2E,4E,6E)-4-(2-methyl-3-(pyrazin-2-carboxamido)propyl)-5-propyl-2,4,6-trienoic acid ester (7a); N-(E)-4,5-bis(E)-1,2-bis(4-methoxyphenyl)vinyl)oct-4-en-1-yl)pyrazin-2-carboxamide (8a)

[0113] One-pot bisCH alkenylation reaction involving alkynes: Palladium acetate (10 mol%, 0.01 mmol), 2,4,6-trimethylbenzoic acid (1.5 equivalent, 0.15 mmol), alkyne 6a (2.5 equivalent, 0.25 mmol), amide 1a (1.0 equivalent, 0.10 mmol), acetonitrile (1.0 mL), and dioxane (1.0 mL) were separately placed into screw-cap vials. The vials were then sealed under argon atmosphere, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to obtain a yellow oily liquid 7a (21.2 mg, yield 45%, Z / E = 86 / 14).1H NMR (500 MHz,Chloroform-d) δ 9.40 (d, J = 1.5 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.49 (dd,J = 2.4, 1.5 Hz, 1H), 7.80 (s, 1H), 7.04 – 7.01 (m, 2H), 6.83 – 6.80 (m, 4H),6.64 – 6.60 (m, 2H), 6.54 (s, 2H), 5.44 (t, J = 7.4 Hz, 1H), 3.80 (s, 3H),3.73 (s, 3H), 3.50 (q, J = 6.8 Hz, 2H), 2.36 – 2.30 (m, 2H), 2.11 (q, J = 7.4Hz, 2H), 1.82 – 1.71 (m, 2H), 1.42 – 1.36 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, Chloroform-d) δ 162.84, 158.54, 157.94, 147.14, 144.56,144.38, 142.42, 142.37, 141.92, 132.12, 131.72, 131.06, 130.62, 130.38,125.02, 113.91, 113.28, 55.15, 55.13, 39.27, 30.70, 28.56, 25.41, 22.96,13.94. HRMS (ESI) for C29H33N3O3Na[M+Na]+: 494.2414, found: 494.2411. FTIR(KBr, cm-1) 3444.86, 2951.40, 2828.04, 2718.69, 2354.21, 1608.41, 1361.68,1067.29, 778.50.。 The mixture was passed through a column to give a yellow solid 8a (18.5 mg, yield 26%, E / Z > 99 / 1), melting point 124.3 °C. 1HNMR (400 MHz, Chloroform-d) δ 9.40 – 9.35 (m, 1H), 8.73 (d, J = 2.3 Hz, 1H), 8.51 – 8.45 (m, 1H), 7.57 (s, 1H), 7.06 (d, J = 8.7 Hz, 4H), 6.80 (d, J = 8.6Hz, 4H), 6.69 – 6.59 (m, 10H), 3.72 (s, 6H), 3.71 (s, 6H), 3.35 (q, J = 6.5Hz, 2H), 2.08 – 2.03 (m, 2H), 1.94 – 1.88 (m, 2H), 1.56 – 1.51 (m, 2H), 1.30– 1.25 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ162.78, 157.88, 157.83, 147.03, 146.22, 144.50 , 144.30 , 142.98 ,142.42 , 131.37 , 130.81 , 129.00 , 128.59 , 113.04 , 112.97 , 64.70 , 55.01, 54.98 , 39.51 , 28.22 , 25.99 , 23.54 , 13.88 . HRMS (ESI) for C45H47N3O5Na[M+Na]+: 732.3408, found: 732.3418. FTIR (KBr, cm-1) 3447.66, 2961.74,2842.06, 2715.89, 2351.40, 1608.41, 1358.88, 1072.90, 772.90. Example 62: N-(Z)-3-(Z)-1,2-bis(4-methoxyphenyl)vinyl)hept-3-en-1-yl)pyrazin-2-carboxamide (7b); N-((E)-3,4-bis((E)-1,2-bis(4-methoxyphenyl)vinyl)hept-3-en-1-yl)pyrazin-2-carboxamide (8b)

[0114] One-pot bisCH alkenylation reaction involving alkynes: Palladium acetate (10 mol%, 0.01 mmol), 2,4,6-trimethylbenzoic acid (1.5 equivalent, 0.15 mmol), alkyne 6a (2.5 equivalent, 0.25 mmol), amide 1ai (1.0 equivalent, 0.10 mmol), acetonitrile (1.0 mL), and dioxane (1.0 mL) were separately placed into screw-cap vials. The vials were then sealed under argon atmosphere, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 7b (28.8 mg, yield 63%, Z / E = 82 / 18).1H NMR (500 MHz,Chloroform-d) δ 9.42 (d, J = 1.5 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.46 (dd,J = 2.5, 1.5 Hz, 1H), 7.93 (s, 1H), 7.07 – 7.04 (m, 2H), 6.86 – 6.82 (m, 4H),6.64 (d, J = 2.3 Hz, 2H), 6.62 (s, 1H), 5.55 (t, J = 7.4 Hz, 1H), 3.82 (s,3H), 3.73 (s, 3H), 3.57 (q, J = 6.9 Hz, 2H), 2.59 (t, J = 7.1 Hz, 2H), 2.15(q, J = 7.4 Hz, 2H), 1.39 (q, J = 7.3 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13CNMR (126 MHz, Chloroform-d) δ 162.86, 158.67, 158.03, 147.13, 144.61, 144.35,142.46, 142.18, 139.56, 133.51, 131.87, 131.08, 130.70, 130.22, 125.50,114.03, 113.29, 55.18, 55.13, 38.60, 30.65, 27.78, 22.91, 13.85. HRMS (ESI)for C28H31N3O3Na[M+Na]+: 480.2258, found: 480.2260. FTIR (KBr, cm-1) 3449.57,2956.52, 2828.70, 2724.35, 1594.78, 1357.39, 1065.22, 773.04.。 The mixture was passed through a column to give a yellow solid 8b (22.3 mg, yield 32%, E / Z > 99 / 1), with a melting point of 117.7 °C. 1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.5 Hz, 1H), 8.72 (d, J = 2.5Hz, 1H), 8.43 (dd, J = 2.5, 1.5 Hz, 1H), 7.87 (s, 1H), 7.17 (d, J = 8.7 Hz,2H), 7.15 – 7.10 (m, 2H), 7.04 – 7.00 (m, 2H), 6.98 – 6.94 (m, 2H), 6.84 –6.81 (m, 2H), 6.79 – 6.77 (m, 2H), 6.71 – 6.69 (m, 2H), 6.68 – 6.66 (m, 2H),6.48 (s, 1H), 6.42 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.75(s, 3H), 3.58 (q, J = 6.5 Hz, 2H), 2.65 – 2.58 (m, 2H), 2.31 – 2.19 (m, 2H), 1.52 – 1.42 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 162.50, 158.86, 158.77, 158.29, 158.24, 147.02, 144.81, 144.68, 144.40,142.36, 139.20, 138.86, 137.80, 131.61, 131.34, 130.59, 130.46, 130.44,130.29, 129.74, HRMS (ESI) for C44H45N3O5Na[M+Na]+:718.3251, found: 718.3256. FTIR (KBr, cm-1) 3472.90, 2957.01, 2828.04,2715.89, 2351.40, 1594.39, 1364.49, 1067.29, 770.09. Example 63: N-(Z)-3-(Z)-1,2-bis(4-fluorophenyl)vinyl)hept-3-en-1-yl)pyrazin-2-carboxamide (7c); N-((E)-3,4-bis((E)-1,2-bis(4-fluorophenyl)vinyl)hept-3-en-1-yl)pyrazin-2-carboxamide (8c)

[0115] One-pot bisCH alkenylation reaction involving alkynes: Palladium acetate (10 mol%, 0.01 mmol), 2,4,6-trimethylbenzoic acid (1.5 equivalent, 0.15 mmol), alkyne 6b (2.5 equivalent, 0.25 mmol), amide 1ai (1.0 equivalent, 0.10 mmol), acetonitrile (1.0 mL), and dioxane (1.0 mL) were separately placed into screw-cap vials. The vials were then sealed under argon atmosphere, heated to 100 °C, and stirred for 72 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 7c (27.3 mg, yield 63%, Z / E > 99 / 1).1H NMR (500 MHz,Chloroform-d) δ 9.42 (d, J = 1.5 Hz, 1H), 8.74 (d, J = 2.6 Hz, 1H), 8.47 (dd,J = 2.5, 1.5 Hz, 1H), 7.93 (s, 1H), 7.10 – 7.06 (m, 2H), 7.03 – 6.98 (m, 2H),6.85 – 6.81 (m, 2H), 6.80 – 6.75 (m, 2H), 6.72 (s, 1H), 5.52 (t, J = 7.4 Hz,1H), 3.59 (q, J = 6.9 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.16 (q, J = 7.4 Hz,2H), 1.42 – 1.35 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz,Chloroform-d) δ162.92, 162.07 (d, J = 246.6 Hz), 161.32 (d, J = 247.1 Hz),147.23, 144.49, 144.38, 142.45, 138.86, 134.70, 131.61 (d, J = 7.8 Hz),131.00 (d, J = 7.7 Hz), 125.39, 115.69 (d, J = 21.3 Hz), 114.83 (d, J = 21.4Hz), 38.55, 30.68, 22.81, 13.83. 19F NMR (471 MHz, Chloroform-d) δ -114.63, -115.10. HRMS (ESI) for C26H25F2N3ONa[M+Na]+: 456.1858, found: 456.1859. FTIR(KBr, cm-1) 3397.20, 2973.83, 2833.64, 2718.69, 1594.39, 1364.49, 1070.09,775.70.。 The mixture was passed through a column to give a yellow solid 8c (15.5 mg, yield 24%, E / Z > 99 / 1), melting point 128.7 °C. 1HNMR (500 MHz, Chloroform-d) δ 9.27 (d, J = 1.5 Hz, 1H), 8.67 (d, J = 2.5 Hz,1H), 8.36 (dd, J = 2.5, 1.5 Hz, 1H), 7.73 (s, 1H), 7.13 – 7.08 (m, 2H), 7.07– 7.03 (m, 2H), 6.98 – 6.86 (m, 8H), 6.82 – 6.74 (m, 4H), 6.49 (s, 1H), 6.42(s, 1H), 3.52 (q, J = 6.6 Hz, 2H), 2.53 (t, J = 6.7 Hz, 2H), 2.22 – 2.11 (m,2H), 1.46 – 1.33 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ162.56, 162.24 (d, J = 247.6 Hz), 162.17 (d, J = 247.6 Hz),161.70 (d, J = 247.3 Hz), 161.64 (d, J = 247.4 Hz), 147.25, 144.50, 144.46,144.43, 142.33, 139.94, 139.53, 137.73, 134.63, 134.43, 132.55, 132.53,130.97 (d, J = 7.9 Hz), 130.88 (d, J = 7.9 Hz), 130.82 (d, J = 7.9 Hz), 130.67 (d, J = 7.9 Hz), 129.07, 128.55, 115.82 19F NMR (471 MHz, Chloroform-d) δ -113.62, -113.77, -114.37, -114.40. HRMS (ESI) for C40H33FN3ONa[M+Na]+: 670.2452, found:670.2450. FTIR (KBr, cm-1) 3439.25, 2940.19, 2836.45, 2713.08, 1616.82,1378.50, 1070.09, 778.50. Example 64: 2-Methoxyethyl(2E,4Z,6Z)-4,5-bis(4-methoxyphenyl)-6-(2-(pyrazin-2-carbamoyl)ethyl)deca-2,4,6-trienoic acid ester

[0116] CH-alkenylation of compound 7: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 7b (1.0 equivalent, 0.10 mmol), and alkene 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 9b (26.4 mg, yield 45%, Z / E > 99 / 1).1H NMR (500 MHz, Chloroform-d) δ 9.38 – 9.35 (m, 1H), 8.73 (d, J = 2.4Hz, 1H), 8.54 – 8.52 (m, 1H), 8.05 (d, J = 15.5 Hz, 1H), 7.82 (s, 1H), 6.94 –6.86 (m, 4H), 6.72 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 5.73 (t, J= 7.4 Hz, 1H), 5.59 (d, J = 15.5 Hz, 1H), 4.23 – 4.17 (m, 2H), 3.77 (s, 3H),3.71 (s, 3H), 3.58 – 3.53 (m, 2H), 3.47 – 3.41 (m, 2H), 3.36 (s, 3H), 2.40(t, J = 7.0 Hz, 2H), 2.33 (q, J = 7.4 Hz, 2H), 1.57 (q, J = 7.3 Hz, 2H), 1.02(t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.47, 162.80,158.66, 158.33, 151.50, 147.13, 147.09, 144.50, 144.24, 142.55, 138.56,136.45, 136.39, 132.20, 131.55, 131.44, 131.42, 119.65, 113.56, 113.20,70.55, 63.05, 58.96, 55.17, 55.07, 38.00, 30.62, 29.48, 22.91, 14.05. HRMS(ESI) for C34H39N3O6Na[M+Na]+: 608.2731, found: 608.2735. FTIR (KBr, cm-1)3453.7, 2965.42, 2836.45, 2718.69, 1608.41, 1358.88, 1065.22, 775.65. Example 65: 2-Methoxyethyl(2E,4Z,6Z)-4,5-bis(4-fluorophenyl)-6-(2-(pyrazin-2-carbamoyl)ethyl)deca-2,4,6-trienoic acid ester

[0117] CH-alkenylation of compound 7: Palladium acetate (10 mol%, 0.01 mmol), manganese dioxide (3.0 equivalent, 0.30 mmol), benzoquinone (10 mol%, 0.01 mmol), and acetonitrile (1.0 mL) were placed in a screw-cap vial. Acetic acid (2.0 equivalent, 0.20 mmol), amide 7c (1.0 equivalent, 0.10 mmol), and alkene 2e (2.5 equivalent, 0.25 mmol) were then added sequentially to the solution. The vial was sealed in air, heated to 100 °C, and stirred for 36 hours. After cooling, the mixture was directly applied to rapid column chromatography (PE / EA mixture) to give a yellow oily liquid 9c (21.9 mg, yield 39%, Z / E > 99 / 1). 1H NMR (500 MHz, Chloroform-d) δ 9.36 (d, J = 1.4 Hz, 1H), 8.74 (d, J =2.4 Hz, 1H), 8.53 (dd, J = 2.4, 1.5 Hz, 1H), 8.02 (d, J = 15.6 Hz, 1H), 7.81(s, 1H), 6.99 – 6.92 (m, 4H), 6.90 – 6.85 (m, 2H), 6.82 – 6.76 (m, 2H), 5.76(t, J = 7.4 Hz, 1H), 5.54 (d, J = 15.6 Hz, 1H), 4.22 – 4.16 (m, 2H), 3.58 –3.53 (m, 2H), 3.48 – 3.42 (m, 2H), 3.36 (s, 3H), 2.38 (t, J = 6.9 Hz, 2H), 2.33 (q, J = 7.4 Hz, 2H), 1.58 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, Chloroform-d) δ 167.10, 162.84, 161.74 (d, J = 246.9 Hz),160.88, 151.20, 147.19, 146.13, 144.37, 144.26, 142.56, 139.13, 136.76,135.94, 134.91 (d, J = 3.4 Hz), 134.64 (d, J = 3.5 Hz), 132.63 (d, J = 8.0Hz), 131.79 (d, J = 8.1 Hz), 120.65, 115.20 (d, J = twenty one.4 Hz), 114.99 (d, J =21.5 Hz), 70.48, 63.21, 58.97, 37.82, 30.63, 29.31, 22.87, 14.03. 19F NMR (471 MHz, Chloroform-d) δ -113.57, -114.70. HRMS (ESI) for C32H33F2N3O4Na[M+Na]+: 584.2331, found: 584.2334. FTIR (KBr, cm-1) 3450.47, 2948.60, 2822.43,2721.50, 1594.39, 1356.07, 1072.90, 778.50. Example 66: (E)-3-(3-propyl-2-(3-(pyrazin-2-carbamoyl)propyl)ethylene oxide-2-yl)tert-butyl acrylate (10)

[0118] At 0 °C, m-chloroperoxybenzoic acid (1.2 equivalents) and sodium hydrogen phosphate dihydrate (2.4 equivalents) were added to a 0.03 M solution of dichloromethane (1.0 equivalent). The mixture was heated to room temperature and reacted for 24 hours. After the reaction was complete, the dichloromethane layer was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give the corresponding epoxidized product 10 as a yellow solid (69.5 mg, yield 80%, E / Z > 99 / 1) with a melting point of 80.1 °C. 1H NMR (500 MHz, Chloroform-d) δ 9.41 –9.38 (m, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.55 – 8.50 (m, 1H), 7.92 (s, 1H),6.81 (d, J = 15.6 Hz, 1H), 5.92 (d, J = 15.6 Hz, 1H), 3.57 – 3.46 (m, 2H), 2.99 (t, J = 5.7 Hz, 1H), 2.05 – 1.96 (m, 1H), 1.82 – 1.73 (m, 2H), 1.64 –1.56 (m, 2H), 1.49 (s, 9H), 1.47 – 1.38 (m, 3H), 0.93 (t, J = 6.8 Hz, 3H).13C NMR (126 MHz, Chloroform-d) δ 165.15, 162.99, 147.20, 144.47, 144.40,142.50, 142.48, 125.83, 80.77, 65.86, 62.58, 39.03, 33.03, 29.70, 28.11,25.21, 19.56, 13.83. HRMS (ESI) for C20H29N3O4Na[M+Na]+: 398.2050, found:398.2052. FTIR (KBr, cm-1) 3453.28, 2962.88, 2825.25, 2715.90, 1602.83, 1358.91, 1067.32, 772.93. Example 67: (Z)-3-(nitromethyl)-4-(3-(pyrazin-2-carbamoyl)propyl)oct-4-enoic acid tert-butyl ester (11)

[0119] DBU (2.0 equivalent) was added to acetonitrile (0.1 M) solution 3a (1.0 equivalent), and the mixture was heated to 100 °C until the reaction was complete. After cooling to room temperature, the mixture was diluted with dichloromethane, washed with 2 N hydrochloric acid solution, and the organic phases were combined and dried with anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography to obtain the corresponding product 11, which was a yellow oily liquid (23.9 mg, yield 57%, Z / E>99 / 1). 1H NMR (500 MHz, Chloroform-d) δ 9.44 – 9.38(m, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.55 – 8.50 (m, 1H), 7.92 (s, 1H), 5.48(t, J = 7.3 Hz, 1H), 4.42 (dd, J = 12.1, 8.4 Hz, 1H), 4.35 (dd, J = 12.1, 6.9Hz, 1H), 3.53 – 3.46 (m, 2H), 2.98 (d, J = 7.3 Hz, 2H), 2.95 – 2.86 (m, 1H),2.17 – 2.06 (m, 2H), 1.79 – 1.70 (m, 2H), 1.50 – 1.39 (m, 11H), 1.37 – 1.27(m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 170.60,163.07, 147.27, 144.42, 144.40, 142.52, 139.41, 120.98, 80.92, 79.20, 44.51,39.37, 34.93, 33.71, 28.68, 28.00, 27.40, 20.02, 13.92. HRMS (ESI) forC21H32N4O5Na[M+Na]+: 443.2265, found: 443.2263. FTIR (KBr, cm-1) 3436.45,2954.21, 2830.84, 2715.89, 1614.02, 1358.88, 1070.09, 772.90. Example 68: 4-(3-(pyrazin-2-carbamoyl)propyl)tert-butyl octanoate (12)

[0120] 10% Pd / C (30 mol%), ethyl acetate (0.1 M), and amide 3a (1.0 equivalent) were sequentially charged into a dry 10 mL pressure vessel. The reaction was carried out at room temperature for 48 hours under a hydrogen atmosphere at 3.5 MPa. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to give the corresponding product 12 as a pale yellow oily liquid (18.6 mg, yield 51%). 1H NMR (500 MHz, Chloroform-d) δ 9.34 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.50 – 8.43 (m, 1H), 7.76 (s, 1H), 3.40 (q, J = 6.9 Hz,2H), 2.16 – 2.08 (m, 2H), 1.64 – 1.60 (m, 1H), 1.60 – 1.53 (m, 2H), 1.52 –1.46 (m, 2H), 1.37 (s, 9H), 1.30 – 1.26 (m, 2H), 1.19 (qd, J = 7.6, 5.2 Hz, 6H), 0.81 (t, J = 6.8 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 172.37,161.84, 146.14, 143.56, 143.39, 141.44, 79.03, 38.77, 35.69, 31.94, 31.84,29.55, 27.74, 27.66, 27.10, 25.72, 22.01, 13.07. HRMS (ESI) for C20H33N3O3Na[M+Na]+: 386.2414, found: 386.2414. FTIR (KBr, cm-1) 3467.29, 2962.62,2829.03, 2716.79, 1594.39, 1358.88, 1070.09, 775.70. Example 69: 1-(tert-butyl)8-(2-methoxyethyl)(2E,4E,6E)-4-(3-((tert-butoxycarbonyl)amino)propyl)-5-propyl-2,4,6-trienoic acid octaester (13)

[0121] Boc anhydride (10.0 equivalents) was added to a solution of 4a (1.0 equivalents) and DMAP (2.0 equivalents) in acetonitrile (0.1 M), and the reaction mixture was reacted at room temperature for 5 hours. After the reaction was complete, it was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the mixture was purified by silica gel column chromatography to give the corresponding product (98%, E / Z = 95:5). Then, lithium aluminum hydride (2.0 equiv, 2.5 M diethyl ether solution) was slowly added dropwise to a solution of N-Boc protected amide in tetrahydrofuran / ethanol (0.02 M, v:v = 1:1) at 0 °C, and the mixture was heated to room temperature for 7 hours. After the reaction was complete, it was quenched with 2 N sodium hydroxide solution and extracted with diethyl ether.After combining the organic phases, anhydrous sodium sulfate was added and the mixture was dried. The solvent was removed under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give the corresponding product 13 (83.3 mg, 95% yield for two steps, E / Z>99:1). ¹H NMR (500 MHz, Chloroform-d) δ 7.81 (d, J = 15.6 Hz, 1H), 7.73 (d, J = 15.7 Hz, 1H), 6.16 (d, J = 15.6 Hz, 1H), 6.03 (d, J = 15.7 Hz, 1H), 4.70 (s, 1H), 4.36 – 4.33 (m, 2H), 3.68 – 3.65 (m, 2H), 3.42 (s, 3H), 3.21 – 3.10 (m, 2H), 2.56 – 2.50 (m, 2H), 2.49 – 2.43 (m, 2H),1.66 – 1.57 (m, 2H), 1.52 (s, 9H), 1.49 – 1.41 (m, 11H), 0.95 (t, J = 7.3 Hz,3H). 13C NMR (126 MHz, Chloroform-d) δ 167.17, 166.45, 141.79, 140.91,140.68, 140.28, 122.40, 119.97, 80.66, 70.50, 63.56, 58.98, 30.52, 30.18,28.39, 28.16, 25.42, 23.39, 14.17. HRMS (ESI) for C26H43NO7Na[M+Na]+:504.2932, found: 504.2933. FTIR (KBr, cm-1) 3454.02, 2955.40, 2833.64,2718.69, 1608.41, 1364.49, 1072.90, 770.09. Example 70: N-(3-((3E,5Z)-2-oxooxoheterocyclic tetradecyl-3,5-dien-5-yl)propyl)pyrazine-2-carboxamide (14)

[0122] Palladium acetate (10 mol%), manganese dioxide (3.0 equivalents), 1,4-benzoquinone (10 mol%), amide 24 (1.0 equivalent), sulfoxide (0.01 M), and tertivalic acid (1.5 equivalent) were sequentially loaded into a dry 48 mL pressure-resistant sealed tube. The reaction was carried out at 80 °C for 36 hours under an argon atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, the organic phase was washed three times with water, the organic phases were combined, and anhydrous sodium sulfate was added for drying. The solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to give the corresponding alkenylated product 14 as a white solid (15.2 mg, yield 41%, E / Z > 99 / 1) with a melting point of 122.5 °C. 1H NMR (500 MHz, Chloroform-d) δ 9.41 (d, J = 1.2 Hz, 1H), 8.75 (d, J =2.4 Hz, 1H), 8.57 – 8.43 (m, 1H), 7.84 (s, 1H), 7.66 (d, J = 15.9 Hz, 1H), 5.88 (d, J = 15.9 Hz, 1H), 5.81 (t, J = 8.0 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.49 (q, J = 6.8 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.25 (q, J = 7.7 Hz,2H), 1.86 – 1.76 (m, 2H), 1.72 – 1.63 (m, 2H), 1.44 – 1.36 (m, 4H), 1.35 –1.28 (m, 6H). 13C NMR (126 MHz, Chloroform-d) δ 167.30, 162.94, 147.23,144.46, 144.40, 142.48, 139.77, 139.54, 134.13, 118.00, 64.36, 39.08, 30.82,29.52, 29.09, 28.91, 28.87, 28.63, 28.42, 27.77, 25.89. HRMS (ESI) forC21H29N3O3H[M+H]+: 372.2282, found: 372.2285. FTIR (KBr, cm-1) 3478.50,2833.64, 2713.08, 1602.80, 1361.68, 1078.50, 784.11, 542.99.

[0125] Finally, it should be noted that the basic concepts have been described above. Obviously, for those skilled in the art, the detailed disclosure above is merely illustrative and does not constitute a limitation of this specification. Although not explicitly stated herein, those skilled in the art may make various modifications, improvements, and corrections to this specification. Such modifications, improvements, and corrections are suggested in this specification, and therefore remain within the spirit and scope of the exemplary embodiments of this specification. Furthermore, this specification uses specific terms to describe embodiments of this specification. For example, "an embodiment," "one embodiment," and / or "some embodiments" refer to a feature, structure, or characteristic associated with at least one embodiment of this specification. Therefore, it should be emphasized and noted that "an embodiment," "one embodiment," or "an alternative embodiment" mentioned twice or more in different locations in this specification do not necessarily refer to the same embodiment. In addition, certain features, structures, or characteristics in one or more embodiments of this specification can be appropriately combined. Moreover, unless expressly stated in the claims, the order of processing elements and sequences, the use of numbers and letters, or other names described in this specification are not intended to limit the order of the processes and methods of this specification.

[0126] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing polysubstituted conjugated dienes and conjugated trienes, characterized in that, This method involves the preparation of multisubstituted conjugated alkenes by a multiple C-H functionalization reaction of E-configured alkyl alkenes and electron-deficient alkenes under palladium(II) catalysis and pyrazine-2-carboxamide (PC) catalysis. The specific steps are as follows: Under relatively mild conditions, using a simple transition metal salt as a catalyst, polysubstituted conjugated dienes and conjugated trienes are prepared from simple alkylamide raw materials; using palladium(II) acetate as a catalyst, and tervaponic acid, manganese dioxide, and benzoquinone as additives, in a suitable organic solvent, at a reaction temperature of 80-120°C, C-H alkenylation of E-configured alkyl olefins with electron-deficient olefins is carried out; wherein, the E-configured alkyl olefins have the structure shown; R1, R2, and R3 are alkyl groups; and R4 is an electron-withdrawing group. 。 2. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, R1, R2, and R3 are more preferably C1-6 alkyl groups; R4 is an ester group, amide group, sulfonyl group, or carbonyl group. R1 is more preferably methyl, propyl, isopropyl, isobutyl, pentyl, hexyl, cyclohexyl, or phenethyl; R2 and R3 are more preferably methyl, ethyl, or phenyl; R4 is more preferably 2-methoxyethyl ester, n-butyl ester, tert-butyl ester, N,N-dimethylamide, diethyl phosphonate, N-benzylamide, benzylsulfonyl, phenyl ester, tetrahydrofuran ester, geraniol, isomenthyl ester, or β-sitosterol. In the reaction, the molar ratio of the amide derivative, alkenylating agent, transition metal salt catalyst 1, additive 2, additive 3, and additive 4 is 1: 2.5: 0.1: 1.5: 3.0: 0.1, in the reaction, the molar ratio of the amide derivative, alkenylating agent, transition metal salt catalyst 1, additive 2, additive 3, and additive 4 is 1: 2.5: 0.1: 1.5: 3.0: 0.1, the organic solvent is dimethyl sulfoxide, the transition metal salt catalyst is palladium salt, preferably palladium acetate, the volume of the organic solvent is 0.15 mmol / mL based on the molar amount of the amide derivative, the heating temperature in the first step is 80-120℃, and the reaction time is 36-48 hours.

3. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, =, the alfa-position alkenylation product of the E-configuration alkyl olefin undergoes a CH alkenylation reaction at the beta position to synthesize a tetrasubstituted 1,3,5-conjugated triene, where R1, R2, and R3 are alkyl groups; and R4 and R5 are electron-withdrawing groups. .

4. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, R1, R2, and R3 are more preferably C1-6 alkyl groups; R4 and R5 are ester groups and amide groups, with R1 more preferably methyl, propyl, isobutyl, pentyl, hexyl, or phenethyl; R2 and R3 are more preferably methyl or ethyl; R4 and R5 are more preferably 2-methoxyethyl ester, tert-butyl ester, ethyl ester, N,N-dimethylamide, or tetrahydrofuran ester. The molar ratio of the amide derivative, alkenylating agent, metal salt catalyst 1, additive 5, additive 3, and additive 4 is 1:2.5:0.1:2.0:3.0:0.

1. The transition metal salt catalyst is preferably palladium acetate. The organic solvent is acetonitrile. The volumetric amount of the organic solvent, based on the molar amount of the amide derivative, is 0.15 mmol / mL. The heating reaction temperature is 100°C, and the reaction time is 36 hours.

5. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, The tetrasubstituted 1,3,5-conjugated trienes with iso-alfa- / beta- positions in the alfa- / beta-alkenylation reaction are as follows: R1 and R2 are alkyl groups; R3 is an electron-withdrawing group. 。 6. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 5, characterized in that, R1 and R2 are more preferably C1-5 alkyl groups; R3 is an ester group, with R1 more preferably methyl, pentyl, or phenethyl; R2 more preferably methyl; and R3 more preferably 2-methoxyethyl ester or tert-butyl ester. The molar ratio of the amide derivative, alkenylating agent, metal salt catalyst 1, additive 5, additive 3, and additive 4 is 1: 5.0: 0.1: 2.0: 3.0: 0.

1. The transition metal salt catalyst is preferably palladium acetate. The organic solvent is acetonitrile. The volumetric amount of the organic solvent, based on the molar amount of the amide derivative, is 0.15 mmol / mL. The heating reaction temperature is 100°C, and the reaction time is 72 hours.

7. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, The alfa- / beta- positions of the E-configuration alkyl olefins undergo alkyne-involved alkenylation reactions, as shown below, where R1 is an alkyl group and Ar1 is an aryl group in the tetrasubstituted conjugated diene and pentasubstituted conjugated triene. .

8. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 7, characterized in that, R1 is more preferably C3 alkyl; Ar1 ​​is a substituted phenyl; the molar ratio of the amide derivative: alkenylating agent: metal salt catalyst 1: additive 6 is 1: 5.0: 0.1: 1.5; the transition metal salt catalyst is preferably palladium acetate; the organic solvent is acetonitrile: 1,4-dioxane; the volume of the organic solvent used is 0.05 mmol / mL based on the molar amount of the amide derivative; the heating reaction temperature is 100℃; the reaction time is 72 hours.

9. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, Alkynes involved in the E-configuration alkyl olefin alfa-position alkenylation reaction undergo further CH alkenylation, as shown in the pentasubstituted conjugated trienes below: R1 is an alkyl group; R2 is an electron-withdrawing group; Ar1 ​​is an aryl group. .

10. The method for synthesizing polysubstituted conjugated dienes and conjugated trienes according to claim 1, characterized in that, R1 is more preferably C3 alkyl; R2 is ester group; Ar1 ​​is substituted phenyl; the molar ratio of the amide derivative: alkenylating agent: metal salt catalyst 1: additive 5: additive 3: additive 4 is 1: 2.5: 0.1: 2.0: 3.0: 0.1; the transition metal salt catalyst is preferably palladium acetate; the organic solvent is acetonitrile; the volume of organic solvent used is 0.15 mmol / mL based on the molar amount of the amide derivative; the heating reaction temperature is 100℃; the reaction time is 36 hours.

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