A method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition

Abstract

The present invention discloses a method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition, belonging to the field of organic chemistry. Using 2-pyrone and an olefin compound as raw materials, a diastereoselective and enantioselective [4+2] cycloaddition reaction is carried out under the catalysis of a Ni-PyIPI complex to obtain a variety of different bridged bicyclic lactone compounds. In this method, the conjugated diene is a 2-pyrone compound and the dienophile is a styrene / indene compound. The method has the advantages of good yield, high diastereoselectivity, and high enantioselectivity.

Description

Technical Field

[0001] The invention relates to a method for synthesizing chiral bridged bicyclic lactone compounds by catalytic [4+2] cycloaddition, belonging to the technical field of asymmetric synthesis in organic chemistry. Background Art

[0002] Chiral aromatic substituted cyclohexane or cyclohexene motifs are widely present in biologically active natural products, such as (+)-celery, (+)-trans-dihydroarginine, (+)-1-deoxylycorine, lycorine, and (+)-α-lycorine. Although various strategies have been developed to construct these natural products, new synthetic methods are still necessary due to their unique biological properties and stereochemical complexity. Typical synthetic methods in the literature are as follows:

[0003] Cai Quan reported a synthetic method for the [4+2] cycloaddition reaction of 2-pyrone and styrene using Cu(OTf)2-SaBox complex as a catalyst in Angew.Chem.Int.Ed.2021,60,26610-26615 (Supporting Information S36 pages). The reaction equation is as follows:

[0004]

[0005] The substrate diversity of the reaction in this paper is already very wide, and the reaction activity also has excellent results; however, the universality is poor. When conducting asymmetric catalysis research, it is difficult to solve the problem of chiral control using SaBox ligands. For example, the styrene substrate has only 41% ee, the 4,7-dimethyl-substituted indene substrate has 7% ee, and the 4-methoxy-substituted indene substrate has 0% ee.

[0006] Therefore, developing effective synthetic methods to construct different bridged bicyclic lactones and their derivatives is of great research significance. Summary of the Invention

[0007] To address the above-mentioned technical problems, the present invention discloses a method for synthesizing different bridged bicyclic lactone compounds via the [4+2] cycloaddition of styrene catalyzed by a C1-symmetric imidazole-pyridine-imidazolinone tridentate nitrogen ligand. This method utilizes a C1-symmetric tridentate nitrogen ligand to construct different bridged bicyclic lactones via diastereoselective and enantioselective [4+2] cycloaddition. In this method, 2-pyrone is used as a conjugated diene to react with styrene / indene, yielding different bridged bicyclic lactones with excellent yields and enantioselectivities and diastereoselectivities.

[0008] The method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition of the present invention comprises the following steps: using a 2-pyrone compound 1 and an olefin compound 2A-C as raw materials, a [4+2] cycloaddition reaction is carried out in an organic solvent under the catalysis of a metal Lewis acid and a PyIPI ligand to obtain chiral bridged bicyclic lactone compounds 3A-C. The reaction equation is as follows:

[0009]

[0010]

[0011] Among them: R, R 1 、R 2 Each is independently selected from hydrogen, C1-C6 alkyl, benzyl, halogen, C1-C4 alkoxy, phenyl; P is selected from C1-C4 alkyl, Bn, Boc, Cbz.

[0012] Furthermore, in the above technical solution, preferably: R, R 1 、R 2 are H, Me, Et, i-Pr, Cl, Br, tBu, MeO, Ph; P is Cbz.

[0013] Furthermore, in the above technical solution, the PyIPI ligand is selected from the following structures:

[0014]

[0015] Furthermore, in the above technical solution, the PyIPI ligand is preferably L4 or L5.

[0016] Furthermore, in the above technical solution, the metal Lewis acid is selected from Ni(OTf)2, Co(OTf)2 or Zn(OTf)2, etc.; preferably Ni(OTf)2.

[0017] Furthermore, in the above technical solution, the organic solvent is selected from tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile or toluene. The preferred solvent is 1,2-dichloroethane.

[0018] Furthermore, in the above technical solution, the molar ratio of compound 1, compound 2A-C, metal Lewis acid and PyIPI ligand is 1:1-2:0.05-0.1:0.06-0.12.

[0019] Furthermore, in the above technical solution, the reaction temperature is 30-65°C.

[0020] Beneficial effects of the invention:

[0021] 1. Using 2-pyrones and olefins as starting materials, different bridged bicyclic lactones 3 were synthesized via diastereoselective and enantioselective [4+2] cycloaddition reactions catalyzed by a Ni(II)-PyIPI complex. The starting materials were readily available, and the reaction yields and enantioselectivities reached as high as 97% and 99% ee, respectively.

[0022] 2. In the present invention, 2-pyrone compounds are used as conjugated dienes and olefin compounds are used as dienophiles. DETAILED DESCRIPTION

[0023] Example 1 a

[0024] Using 2-pyrone 1a and styrene 2a as raw materials to generate 3aa, we optimized the reaction conditions. A typical procedure involved adding PyIPI, a metal salt, and an organic solvent to a reaction tube. After stirring at 30°C for 1 hour, 2-pyrone 1a and styrene 2a were added. The reaction mixture was stirred at 55°C until 2-pyrone 1a was consumed (as determined by TLC). The reaction mixture was filtered, concentrated, and purified by flash column chromatography (P / E, 20 / 1 to 4 / 1, v / v) to afford product 3. The reaction results are as follows:

[0025]

[0026] The specific reaction results are shown in the following table:

[0027]

[0028]

[0029] a Unless otherwise noted, the reaction conditions were as follows: metal (5 mol%), L (6 mol%), 1a (0.1 mmol), and 2a (0.2 mmol) in DCE (1 mL) at 55°C for 12 h; b NMR yield; c Determined by chiral HPLC analysis; d Ni(OTf)2 / L4 (2 mol%).

[0030] During the reaction condition screening process, the effects of metals on the reaction were first investigated (labeled 1-10). Furthermore, by comparing the effects of different ligands, organic solvents, raw material equivalent ratios, and ligand dosages on the reaction, L4 was ultimately determined to be the optimal ligand, with a 5 mol% addition amount, 1,2-dichloroethane as the optimal reaction solvent, and 55°C as the optimal reaction conditions.

[0031] Example 2

[0032] L4 and Ni(OTf)2 (10 mol%, 1.2:1) were added to a reaction tube, followed by the organic solvent DCE (1.0 mL). The mixture was stirred at 30°C for 1 hour, and then the starting materials 2-pyrone 1a and styrene 2a were added. The reaction mixture was stirred at 55°C for 12 hours until 2-pyrone 1a was consumed (as determined by TLC). The reaction mixture was filtered, concentrated, and purified by flash column chromatography (P / E, 30 / 1 to 4 / 1, v / v) to obtain product 3aa in 92% yield, >95:5 dr, and 98% ee. f =0.40(Pet / EtOAc,2 / 1,v / v); [α] D 25 =+41.40 (c=0.50, CHCl3); reaction time: 12h; HPLC CHIRALPAKAD-H, n-hexane / 2-propanol=90 / 10, flowrate1.0mL / min, λ=210nm, retention time: 11.647min (minor), 13.690min (major). 1 HNMR (400MHz, CDCl3) δ7.24-7.22(m,3H),7.15-7.12(m,2H),6.88-6.86(m,1H),6.78(dd,J=8.0,5.2Hz,1H),5.4 0-5.37(m,1H),3.78(dd,J=9.6,4.4Hz,1H),3.71(s,3H),2.95-2.88(m,1H),1.91(ddd,J=14.0,4.8,1.2Hz,1H). 13 CNMR(100MHz, CDCl3)δ170.0,167.5,139.7,132.4,130.4,130.9,128.6,128.5,127.8,75.0,60.1,52.7,39.7,36.4.HRMS(ESI)exactmasscalcdforC 15 H 14 NaO4 + (M+Na) + requires m / z281.0784,foundm / z281.0789(Δ=+5ppm).IR(neat)2958,1731,1493,1461,1438,1366,1356,1333,129 1,1280,1178,1130,1096,1083,1067,1009,991,972,937,905,866,821,800,768,753,730,705,613,581cm-1 .

[0033] Example 3

[0034] L4 and Ni(OTf)2 (5 mol%, 1.2:1) were added to a reaction tube, followed by the organic solvent DCE (1.0 mL). The mixture was stirred at 30°C for 1 hour. The starting materials 2-pyrone 1a-1d and styrene 2a-2g were then added. The reaction mixture was stirred at 55°C for 12 hours until the 2-pyrone 1a-1d was consumed (as determined by TLC). The reaction mixture was filtered, concentrated, and purified by flash column chromatography (P / E, 30 / 1 to 4 / 1, v / v) to afford products 3ab-3ca. The results are as follows:

[0035]

[0036] Representative NMR characterization data are as follows:

[0037] Methyl(1R,4R,8S)-3-oxo-8-(o-tolyl)-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate(3ab)Whitesolid:24.5mg,>95:5dr,90%yield,98%ee;mp:119.4-121.2℃;R f =0.35(Pet / EtOAc,2 / 1,v / v);[α] D 26 =+21.60 (c=0.25, CHCl3); reaction time: 12h. HPLCCHIRALPAKID, n-hexane / 2-pro panol=90 / 10, flowrate1.0mL / min, λ=210nm, retention time: 23.835min (major), 26.417min (minor). 1 HNMR (400MHz, CDCl3) δ7.14-7.04(m,4H),7.01-6.98(m,1H),6.75(dd,J=8.0,5.2Hz,1H),5.36-5.34 (m,1H),3.97(dd,J=9.6,5.2Hz,1H),3.64(s,3H),3.01-2.94(m,1H),2.40(s,3H),1.63-1.58(m,1H). 13CNMR(100MHz,CDCl3)δ170.3,167.9,139.2,136.6,132.5,130.9,130.4,127.1,126.6,125.4,75.2,59.4,52.8,36.5,35.0,20.1.HRMS(ESI)exactmasscalcdforC 16 H 16 NaO4 + (M+Na) + requiresm / z295.0941,foundm / z295.0944(Δ=+3ppm).IR(neat)3013,2958,1752,1725,1698,1615,1493,1468,1437,1357,1348,1286,1255,1176,1132,1113,1088,1068,1056,1012,973,937,802,765,744,737,720,703,620,605cm -1 .

[0038] Methyl(1R,4R,8S)-3-oxo-8-(p-tolyl)-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate(3ad)Whitesolid:26.7mg,>95:5dr,98%yield,99%ee;m.p.:132.6-135.1℃;R f =0.30(Pet / EtOAc,2 / 1,v / v);[α] D 26 =+41.47(c=0.25,CHCl3);reactiontime:3h.HPLCCHIRALPAKAD-H,n-hexane / 2-pro panol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:10.045min(minor),11.993min(major). 1 HNMR(400MHz,CDCl3)δ7.05-7.00(m,4H),6.87-6.84(m,1H),6.77(dd,J=7.6,4.8Hz,1H),5.39-5.36(m,1H),3.76-3.73(m,1H),3.72(s,3H),2.92-2.85(m,1H),2.29(s,3H),1.88(dd,J=15.2,4.4Hz,1H). 13CNMR(100MHz,CDCl3)δ170.1,167.6,137.5,136.7,132.3,130.5,129.2,128.5,75.1,60.1,52.7,39.4,36.4,21.1.HRMS(ESI)exactmasscalcdforC 16 H 16 NaO4 + (M+Na) + requiresm / z295.0941,foundm / z295.0941(Δ=0ppm).IR(neat)2958,1728,1615,1515,1457,1435,1369,1335,1290,1279,1243,1178,1130,1091,1068,1005,968,943,935,905,868,828,797,744,733,709,611cm -1 .

[0039] Methyl(1R,4R,8S)-8-(4-methoxyphenyl)-3-oxo-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate(3ae)Whitesolid:27.9mg,97%yield,>95:5dr,99%ee;m.p.:102.2-104.6℃;R f =0.25(Pet / EtOAc,2 / 1,v / v);[α] D 26 =+40.93(c=0.25,CHCl3);reactiontime:3h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:15.848min(minor),19.013min(major). 1 HNMR(400MHz,CDCl3)δ7.06-7.04(m,2H),6.85-6.83(m,1H),6.78-6.75(m,3H),5.38-5.36(m,1H),3.76(s,3H),3.74(d,J=4.4Hz,1H),3.72(s,3H),2.92-2.85(m,1H),1.89-1.84(m,1H). 13CNMR(100MHz,CDCl3)δ170.1,167.6,159.2,132.3,131.6,130.5,129.7,113.9,75.0,60.3,55.3,52.7,39.0,36.4.HRMS(ESI)exactmasscalcdforC 16 H 16 NaO5 + (M+Na) + requiresm / z311.0890,foundm / z311.0890(Δ=0ppm).IR(neat)2953,1727,1613,1581,1513,1458,1438,1365,1332,1277,1260,1200,1176,1131,1093,1070,1033,1004,968,946,907,868,834,819,788,744,709,697,612cm -1 .

[0040] Methyl(1R,4R,8S)-8-(4-chlorophenyl)-3-oxo-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate(3af)Whitesolid:26.3mg,90%yield,>95:5dr,98%ee;m.p.:115.9-117.2℃;R f =0.25(Pet / EtOAc,2 / 1,v / v);[α] D 26 =+39.07(c=0.25,CHCl3);reactiontime:15h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:14.762min(minor),17.205min(major). 1 HNMR(400MHz,CDCl3)δ7.22-7.20(m,2H),7.09-7.07(m,2H),6.85-6.83(m,1H),6.79(dd,J=7.6,4.8Hz1H),5.40-5.37(m,1H),3.77-3.73(m,1H),3.72(s,3H),2.94-2.87(m,1H),1.84(ddd,J=14.0,4.4,1.2Hz,1H). 13CNMR(100MHz,CDCl3)δ169.7,167.3,138.3,133.8,132.7,130.3,130.0,128.7,74.9,60.0,52.9,39.0,36.4.HRMS(ESI):exactmasscalcdforC 15 H 13 ClNaO4 + (M+Na) + requiresm / z315.0395,foundm / z315.0395(Δ=0ppm).IR(neat)2956,1730,1615,1495,1484,1455,1437,1414,1369,1331,1288,1277,1240,1178,1131,1090,1067,1006,968,944,935,904,867,834,810,739,729,700,652,610cm -1 .

[0041] Ethyl(1R,4R,8S)-3-oxo-8-phenyl-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate(3ba)Colorlessoil:25.0mg,92%yield,>95:5dr,98%ee;R f =0.30(Pet / EtOAc,2 / 1,v / v);[α] D 26 =+29.60(c=0.50,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=80 / 20,flowrate1.0mL / min,λ=210nm,retentiontime:6.803min(minor),7.583min(major). 1 HNMR(400MHz,CDCl3)δ7.24-7.22(m,3H),7.15-7.12(m,2H),6.88-6.86(m,1H),6.78(dd,J=8.0,5.2Hz,1H),5.40-5.37(m,1H),3.78(dd,J=9.6,4.4Hz,1H),3.71(s,3H),2.95-2.88(m,1H),1.91(ddd,J=14.0,4.8,1.2Hz,1H). 13CNMR(100MHz,CDCl3)δ170.0,167.0,139.9,132.4,130.5,128.7,128.5,127.7,75.0,61.9,59.8,39.6,36.6,14.0.HRMS(ESI)exactmasscalcdforC 16 H 16 NaO4 + (M+Na) + requiresm / z295.0941,foundm / z295.0941(Δ=0ppm).IR(neat)2983,1750,1732,1615,1497,1463,1454,1364,1351,1328,1278,1243,1180,1120,1093,1082,1066,1009,1000,964,939,867,771,750,728,707,617cm -1 .

[0042] Isopropyl(1R,4R,8S)-3-oxo-8-phenyl-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate(3ca)Whitesolid:25.7mg,90%yield,>95:5dr,98%ee;m.p.:91.5-93.6℃;R f =0.35(Pet / EtOAc,2 / 1,v / v);[α] D 26 =+27.07(c=0.25,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=80 / 20,flowrate1.0mL / min,λ=210nm,retentiontime:5.898min(minor),6.700min(major). 1 HNMR(400MHz,CDCl3)δ7.23-7.20(m,3H),7.17-7.15(m,2H),6.92-6.90(m,1H),6.77(dd,J=8.0,5.2Hz,1H),5.37-5.35(m,1H),5.04-4.98(m,1H),3.75(q,J=4.8Hz,1H),2.95-2.88(m,1H),1.88-1.83(m,1H),1.71(d,J=6.0Hz,3H),1.11(d,J=6.4Hz,3H).13 CNMR(150MHz, CDCl3)δ170.1,166.5,140.0,132.4,130.6,128.8,128.4,127.7,74.9,69.8,59.7,39.6,36.8,21.7,21.5.HRMS(ESI)exactmasscalcdforC 17 H 18 NaO4 + (M+Na) + requiresm / z309.1097,foundm / z309.1097(Δ=0ppm).IR(neat)2983,2946,1748,1727,1616,1497,1463,1449,1389,1376, 1355,1324,1277,1244,1180,1146,1120,1082,1065,1010,1001,965,939,921,900,866,836,814,768,749,728,704,617cm -1 .

[0043] Example 4

[0044] L4 and Ni(OTf)2 (5 mol%, 1.2:1) were added to a reaction tube, followed by the organic solvent DCE (1.0 mL). The mixture was stirred at 30°C for 1 hour. The starting materials 2-pyranones 1a-1g and styrenes 4a-4k were then added. The reaction mixture was stirred at 45°C for 12 hours until the 2-pyranones 1a-1d were consumed (as determined by TLC). The reaction mixture was filtered, concentrated, and purified by flash column chromatography (P / E, 30 / 1 to 4 / 1, v / v) to afford products 5aa-5ea. The results are as follows:

[0045]

[0046] R f =0.5(Pet / EtOAc,2 / 1,v / v); [α] D 26=-8.80(c=1.00,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:13.135min(minor),17.500min(major). 1 HNMR(400MHz,CDCl3)δ7.19(t,J=7.6Hz,1H),7.12(dd,J=15.2,7.6Hz,2H),7.01(d,J=8.0Hz,1H),6.53-6.50(m,1H),6.39(dd,J=15.2,4.8Hz,1H),5.29(t,J=4.8Hz,1H),4.36(d,J=8.8Hz,1H),4.03(s,3H),3.46-3.40(m,1H),3.17(dd,J=17.2,10.8Hz,1H),2.55(dd,J=17.2,4.4Hz,1H).IR(neat)2952,2906,2848,1730,1620,1483,1456,1435,1369,1275,1245,1202,1173,1130,1089,1078,1037,1013,982,963,936,897,796,754,718,696,628cm -1 .

[0047] Methyl(1S,4R,4aS,9aS)-5,8-dimethyl-10-oxo-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5ab)Whitesolid:28.0mg,94%yield,>95:5dr,99%ee;R f =0.45(Pet / EtOAc,2 / 1,v / v);[α] D 25 =+14.13(c=0.25,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:9.957min(minor),14.300min(major). 1HNMR(400MHz,CDCl3)δ6.89(dd,J=23.6,7.6Hz,2H),6.69-6.66(m,1H),6.41(dd,J=8.0,5.2Hz,1H),5.25(td,J=4.4,2.0Hz,1H),4.47(d,J=8.4Hz,1H),3.95(s,3H),3.43-3.36(m,1H),2.96(dd,J=17.6,10.8Hz,1H),2.46(dd,J=17.2,3.6Hz,1H),2.19(s,3H),2.12(s,3H).IR(neat)3010,2955,2922,1731,1614,1491,1463,1437,1375,1278,1260,1246,1206,1182,1134,1088,1080,1040,1001,978,959,929,895,811,793,754,721,699,637cm -1 .

[0048] Methyl(1S,4R,4aS,9aS)-5-methoxy-10-oxo-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5ac)Whitesolid:28.2mg,94%yield,>95:5dr,99%ee;R f =0.45(Pet / EtOAc,2 / 1,v / v);[α] D 25 =+23.33(c=0.25,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:17.815min(minor),19.768min(major). 1HNMR(400MHz,CDCl3)δ7.16(t,J=7.6Hz,1H),6.70-6.66(m,2H),6.61(d,J=8.4Hz,1H),6.32(dd,J=8.0,5.2Hz,1H),5.15(br,1H),4.46(d,J=8.0Hz,1H),4.00(s,3H),3.73(s,3H),3.35-3.29(m,1H),3.19(dd,J=17.2,10.4Hz,1H),2.56(dd,J=17.2,3.2Hz,1H).IR(neat)2997,2949,2838,1732,1590,1479,1431,1368,1356,1326,1286,1266,1203,1174,1127,1093,1074,1054,1002,978,931,893,840,791,775,748,698,679,623cm -1 .

[0049] Methyl(1S,4R,4aS,9aS)-8-methyl-10-oxo-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5af)Whitesolid:27.0mg,95%yield,>95:5dr,98%ee;R f =0.5(Pet / EtOAc,2 / 1,v / v);[α] D 26 =-9.60(c=0.25,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:10.860min(minor),14.292min(major). 1HNMR(400MHz,CDCl3)δ7.08-7.00(m,3H),6.84(d,J=7.2Hz,1H),6.55-6.53(m,1H),6.39(dd,J=7.6,4.8Hz,1H),5.30(td,J=4.8,2.0Hz,1H),4.36(d,J=8.8Hz,1H),4.03(s,3H),3.48-3.41(m,1H),3.05(dd,J=17.6,10.8Hz,1H),2.43(dd,J=17.2,4.4Hz,1H),2.17(s,3H).IR(neat)2952,1747,1727,1610,1437,1367,1321,1288,1260,1200,1172,1129,1089,1074,1043,1027,980,951,923,886,838,783,773,707,649cm -1 .

[0050] Methyl(1S,4R,4aS,9aS)-6-(tert-butyl)-10-oxo-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5ai)Whitesolid:31.3mg,96%yield,>95:5dr,99%ee;R f =0.5(Pet / EtOAc,2 / 1,v / v);[α] D 24.5 =+2.93(c=0.25,CHCl3);reactiontime:12h.HPLCCHIRALPAKIB,n-hexane / 2-propanol=90 / 10,flowrate1.0mL / min,λ=210nm,retentiontime:11.130min(minor),11.967min(major). 1HNMR(400MHz,CDCl3)δ7.24(dd,J=8.0,2.0Hz,1H),7.04-7.02(m,2H),6.55-6.53(m,1H),6.38(dd,J=8.0,5.2Hz,1H),5.29(td,J=4.4,2.0Hz,1H),4.34(d,J=8.8Hz,1H),4.05(s,3H),3.48-3.41(m,1H),3.12(dd,J=16.8,10.4Hz,1H),2.51(dd,J=16.8,4.0Hz,1H),1.26(s,9H).IR(neat)2964,1757,1732,1613,1496,1437,1378,1363,1279,1266,1199,1180,1127,1092,1074,1059,1036,1014,979,965,932,915,885,834,794,755,728cm -1 .

[0051] Methyl(1S,4R,4aS,9aS)-6,7-dimethoxy-10-oxo-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5aj)Whitesolid:32.0mg,97%yield,>95:5dr,97%ee;R f =0.35(Pet / EtOAc,2 / 1,v / v);[α] D 25 =-6.45(c=0.15,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=80 / 20,flowrate1.0mL / min,λ=210nm,retentiontime:20.397min(minor),27.282min(major). 1HNMR(400MHz,CDCl3)δ6.57(s,1H),6.55-6.52(m,2H),6.40(dd,J=8.0,4.8Hz,1H),5.28(td,J=4.8,2.0Hz,1H),4.28(d,J=8.4Hz,1H),4.02(s,3H),3.82(s,3H),3.79(s,3H),3.48-3.41(m,1H),3.09(dd,J=16.4,10.4Hz,1H),2.47(dd,J=16.4,3.6Hz,1H).IR(neat)2937,1733,1606,1507,1452,1440,1369,1317,1286,1257,1220,1189,1128,1098,1076,1037,987,979,932,854,782,742,715,629cm -1 .

[0052] Benzyl(1S,4R,4aS,9aS)-10-oxo-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5da)Whitesolid:33.6mg,97%yield,>95:5dr,98%ee;R f =0.5(Pet / EtOAc,2 / 1,v / v);[α] D 25 =-20.53(c=0.25,CHCl3);reactiontime:12h.HPLCCHIRALPAKAD-H,n-hexane / 2-propanol=80 / 20,flowrate1.0mL / min,λ=210nm,retentiontime:13.857min(minor),14.847min(major). 1HNMR(400MHz,CDCl3)δ7.52-7.49(m,2H),7.43-7.37(m,3H),7.16(t,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),6.99(t,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),6.54(d,J=8.0Hz,1H),6.38(dd,J=8.0,4.8Hz,1H),5.49(s,2H),5.28(td,J=4.8,2.0Hz,1H),4.39(d,J=8.8Hz,1H),3.45-3.38(m,1H),3.15(dd,J=17.2,6.4Hz,1H),2.55(dd,J=17.2,4.0Hz,1H).IR(neat)2920,2851,1732,1601,1483,1454,1367,1266,1242,1175,1127,1073,105,1015,979,960,936,790,748,715,694cm -1 Methyl(1R,4S,4aS,9aS)-10-oxo-3-phenyl-1,4a,9,9a-tetrahydro-4H-1,4-(epoxymethano)fluorene-4-carboxylate(5ea)Whitesolid:32.2mg,93%yield,>95:5dr,90%ee;R f =0.35(Pet / EtOAc,2 / 1,v / v);[α] D 24.5 =-100.40(c=0.25,CHCl3);reactiontime:28h.HPLCCHIRALPAKOD-H,n-hexane / 2-propanol=80 / 20,flowrate1.0mL / min,λ=210nm,retentiontime:9.857min(minor),11.490min(major). 1HNMR(400MHz, CDCl3) δ7.79(d,J=7.6Hz,1H),7.25-7.18(m,2H),7.16-7.06(m,4H),6.63(dd,J=8.0,5 .2Hz,2H),6.34(d,J=5.6Hz,1H),5.35(t,J=4.8Hz,1H),4.50(d,J=8.8Hz,1H),3.59(s,3H),3.56-3.49 (m,1H),3.17(dd,J=17.2,10.8Hz,1H),2.62(dd,J=17.2,4.4Hz,1H).IR(neat)2954,1749,1727,1629 ,1495,1483,1446,1363,1283,1265,1240,1162,1089,1077,1023,983,939,856,801,764,,700,662cm -1 .

[0053] Example 5

[0054]

[0055] Anhydrous Ni(OTf)2 (0.05mmol, 1.8mg), ent-L4 (0.06mmol, 4.6mg), and DCE (1.0mL) were added to the reaction tube in sequence. Under a nitrogen atmosphere, the mixture was stirred at 30°C for 1 hour, and then 2-pyrone 1a (0.1mmol, 15.4mg) and 2-pyrroline-1-benzoic acid benzyl ester 9a (0.2mmol, 35.3μL) were added and stirred at 30°C for 3 hours. The reaction was monitored by TLC and column chromatography (P / E=2:1) was used as the eluent to obtain the white product 10aa (yield 95%, 33.9mg). >95:5dr, 95% yield, 98%ee; R f =0.25(Pet / EtOAc,2 / 1,v / v);[α] D 25 =+51.07 (c=0.25, CHCl3); reaction time: 3h. HPLC CHIRALPAKAD-H, n-hexane / 2-propanol=80 / 20, flowrate1.0mL / min, λ=210nm, retention time: 16.738min (minor), 18.545min (major). 1HNMR (400MHz, CDCl3) δ7.39-7.29(m,5H),7.02-6.99(m,1H),6.58(dd,J=8.0,5.2Hz,1H),5.15-5.12(m,2H),5.04-5.01(m ,1H),4.90(d,J=7.6Hz,1H),3.85-3.71(m,4H),3.29-3.23(m,1H),315-3.08(m,1H),2.15-2.04(m,1H),1.66-1.60(m,1H).

[0056] From compound 10aa to (+)-minovincine Reference: Zhang, FQ; Ren, B.-T.; Zhou, YQ; Liu, YB; Feng, XME vincine.Chem.Sci.2022,13,5562-5567.

[0057] The above embodiments illustrate the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and improvements may be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and improvements fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition, characterized in that: The method comprises the following steps: using 2-pyrone compound 1 and olefin compound 2A-C as raw materials, a [4+2] cycloaddition reaction occurs in an organic solvent under the catalysis of a metal Lewis acid and a PyIPI ligand to obtain a chiral bridged bicyclic lactone compound 3A-C; the reaction equation is as follows: Where: R 1 is selected from hydrogen; R 2 is selected from hydrogen, methyl, halogen, methoxy, tert-butyl; R is selected from methyl, ethyl, isopropyl; P is selected from Cbz; the metal Lewis acid is selected from Ni(OTf)2; the PyIPI ligand is selected from:

2. The method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition according to claim 1, characterized in that: The molar ratio of compound 1, compound 2A-C, metal Lewis acid and PyIPI ligand is 1:1-2:0.05-0.1:0.06-0.

12.

3. The method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition according to claim 1, characterized in that: The organic solvent is selected from tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile or toluene.

4. The method for synthesizing chiral bridged bicyclic lactones by catalytic [4+2] cycloaddition according to claim 1, characterized in that: The reaction temperature is 30-65°C.

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