10.1002/ejoc.202000465
European Journal of Organic Chemistry
FULL PAPER
(4a-C), 136.1 (3-C), 127.2 (1-C), 121.7 (2-C), 121.1 (8a-C), 118.0 (4-C), 78.3
(5a-C), 75.0 (10-C), 47.1 (16-C), 44.4 (5-C), 40.9 (11-C), 40.8 (7a-C), 34.3
(14-C), 31.6 (12-C), 26.2 (17-C), 23.4 (15-C), 22.1 (13-C), 20.9 (19-C), 16.2
(18-C), 12.4 (9-C) ppm. HRMS: (ESI+): m/z calc. for C22H30O4Na [M+Na]+:
381.2036, found 381.2048. IR: (ATR) = 3007 (w), 2994 (w), 2979 (m), 2922
(125 MHz, CDCl3) δ = 191.2 (d, J = 1.8 Hz, 8-C), 172.4 (6-C), 157.5 (d, J =
242.2 Hz, 2-C), 157.6 (d, J = 1.7 Hz, 4a-C), 123.6 (d, J = 24.6 Hz, 3-C), 121.5
(d, J = 6.5 Hz, 8a-C), 119.6 (d, J = 7.4 Hz, 4-C), 112.2 (d, J = 23.3 Hz, 1-C),
78.6 (5a-C), 75.1 (10-C), 47.1 (16-C), 44.3 (5-C), 40.9 (11-C), 40.5 (7a-C),
34.3 (14-C), 31.6 (12-C), 26.2 (17-C), 23.3 (15-C), 22.1 (13-C), 20.9 (19-C),
16.2 (18-C), 12.4 (9-C) ppm. HRMS: (ESI+): m/z calc. for C22H29O4FNa
[M+Na]+: 399.1948, found 399.1952. IR: (ATR) = 3004 (m), 2919 (w), 2895
(w), 1747 (m), 1725 (s), 1633 (m), 1606 (w), 1488 (s), 1392 (m), 1380 (w),
1358 (w), 1343 (w), 1332 (w), 1318 (m), 1280 (w), 1249 (m), 1218 (w), 1193
(s), 1169 (w), 1153 (w), 1131 (w), 1113 (w), 1097 (w), 1086 (w), 1061 (m),
1024 (w), 1010 (w), 999 (w), 977 (w), 953 (m), 930 (w), 920 (w), 898 (w), 883
(w), 860 (w), 782 (s), 755 (w), 719 (w), 615 (w), 601 (m), 577 (w), 537 (w), 520
(w) cm-1. m.p.: 85 °C (diethyl ether). [α]: +9.86 (c 1.0, CHCl3).
(w), 1756 (m), 1727 (s), 1647 (w), 1504 (s), 1479 (w), 1460 (m), 1425 (w),
1410 (w), 1383 (w), 1355 (w), 1339 (m), 1293 (m), 1277 (w), 1255 (w), 1234
(s), 1219 (w), 1200 (w), 1190 (w), 1150 (w), 1136 (m), 1114 (w), 1100 (w),
1069 (w), 1049 (w), 1025 (w), 997 (m), 980 (w), 954 (w), 928 (m), 912 (w), 903
(w), 890 (m), 860 (w), 840 (s), 830 (w), 790 (w), 775 (w), 741 (w), 715 (m), 687
(w), 663 (w) cm-1. m.p.: 103 °C (diethyl ether). [α]: +2.48 (c 1.0, CHCl3).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl
chroman-2-yl)propanoate (23c):
(S)-2-((R)-5-methoxy-4-oxo-
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-2-((R)-6-chloro-4-oxochro-
man-2-yl)propanoate (23f):
Prepared according to general procedure I; Colourless solid (192 mg, 0.494
mmol, 99%). 1H-NMR: (500 MHz, CDCl3) δ = 7.35 (t, 1H, J = 8.4 Hz, 3-H),
6.54 (d, 1H, J = 8.7 Hz, 4-H), 6.51 (d, 1H, J = 8.7 Hz, 2-H), 4.58-4.80 (m, 2H,
5a-H, 9-H), 3.90 (s, 3H, 8-H3), 2.55-2.90 (m, 3H, 7a-H2, 5-H), 1.94-2.05 (m, 1H,
13-H), 1.78-1.93 (m, 1H, 16-H), 1.59-1.75 (m, 2H, 14-H2), 1.38-1.58 (m, 2H,
11-H2), 1.33 (d, 3H, J = 7.1 Hz, 7-H3), 0.94-1.11 (m, 2H, 12-H2), 0.90 (d, 3H, J
= 6.5 Hz, 17-H3a), 0.86-0.93 (m, 1H, 10-H), 0.82 (d, 3H, J = 7.0 Hz, 17-H3b),
0.72 (d, 3H, J = 0.7 Hz, 15-H3) ppm. 13C NMR: (125 MHz, CDCl3) δ = 190.7 (8-
C), 172.5 (6-C), 163.1 (1-C), 160.9 (8a-C), 135.9 (3-C), 111.5 (4a-C), 110.1 (4-
C), 104.2 (2-C), 77.8 (9-C), 75.0 (5a-C), 56.3 (8-C), 47.1 (10-C), 44.3 (7a-C),
42.2 (5-C), 40.9 (14-C), 34.4 (12-C), 31.6 (13-C), 26.1 (16-C), 23.3 (11-C),
22.1 (17-Ca), 20.9 (17-Cb), 16.1 (15-C), 12.3 (7-C) ppm. HRMS: (ESI+): m/z
calc. for C23H32O5Na [M+Na]+: 411.2147, found 411.2145. IR: (ATR) = 3003
Prepared according to general procedure I; Colourless solid (183 mg, 0.466
mmol, 93%). 1H-NMR: (500 MHz, CDCl3) δ = 7.84 (d, 1H, J = 2.7 Hz, 1-H),
7.41 (dd, 1H, J = 8.8 Hz, 2.7 Hz, 3-H), 6.91 (d, 1H, J = 8.9 Hz, 4-H), 4.74 (td,
1H, J = 10.9 Hz, 4.4 Hz, 1H, 10-H), 4.70 (ddd, 1H, J = 13.2 Hz, 6.2 Hz, 2.9 Hz,
5a-H), 2.86 – 2.78 (m, 2H, 7a-Hα, 5-H), 2.69 (dd, 1H, J = 16.8 Hz, 2.9 Hz, 5-
Hβ), 2.02 – 1.96 (m, 1H, 11-Hα), 1.85 (heptd, 1H, J = 6.9 Hz, 2.7 Hz, 17-H),
1.72 – 1.63 (m, 2H, 14-Hα, 15-Hα), 1.55 – 1.44 (m, 1H, 12-H), 1.41 – 1.37 (m,
1H, 16-H), 1.35 (d, 3-H, J = 7.1 Hz, 9-H3), 1.05 (ddd, 1H, J = 16.2 Hz, 13.4 Hz,
4.1 Hz, 15-Hβ), 0.98 (q, 1H, J = 11.4 Hz, 11-Hβ), 0.91 (d, 3H, J = 6.6 Hz, 13-
H3), 0.91 – 0.85 (m, 1H, 14-Hβ), 0.84 (d, 3H, J = 7.0 Hz, 19-H3), 0.74 (d, 3H, J
= 7.0 Hz, 18-H3) ppm. 13C NMR: (125 MHz, CDCl3) δ = 190.8 (8-C), 172.3 (6-
C), 159.8 (4a-C), 135.9 (3-C), 127.3 (2-C), 126.5 (1-C), 121.8 (8a-C), 119.7 (4-
C), 78.6 (5a-C), 75.2 (10-C), 47.1 (16-C), 44.3 (5-C), 40.9 (11-C), 40.5 (7a-C),
34.3 (14-C), 31.6 (12-C), 26.2 (17-C), 23.4 (15-C), 22.1 (13-C), 20.9 (19-C),
16.2 (18-C), 12.4 (9-C) ppm. HRMS: (ESI+): m/z calc. for C22H29ClO4Na
[M+Na]+: 415.1652, found 415.1653. IR: (ATR) = 2999 (w), 2952 (w), 2921
(m), 2975 (w), 2920 (w), 1749 (m), 1718 (s), 1628 (s), 1605 (m), 1498 (m),
1470 (m), 1396 (m), 1353 (m), 1327 (m), 1304 (m), 1277 (w), 1254 (s), 1222
(s), 1209 (w), 1190 (w), 1171 (m), 1123 (m), 1106 (s), 1074 (m), 1054 (m),
1026 (m), 998 (m), 980 (m), 957 (w), 931 (w), 918 (m), 811 (s), 803 (m), 754
(m), 590 (m) cm-1. m.p.: 124 °C (ethyl acetate). [α]: +9.27 (c 1.0, CHCl3).
(w), 1742 (w), 1731 (s), 1631 (m), 1600 (w), 1493 (m), 1445 (w), 1407 (m),
1362 (w), 1345 (w), 1296 (s), 1244 (w), 1218 (w), 1193 (s), 1146 (w), 1127
(w), 1112 (w), 1099 (w), 1077 (w), 1053 (m), 1009 (w), 999 (w), 979 (w), 955
(w), 928 (w), 917 (w), 876 (w), 859 (w), 837 (m), 781 (w), 751 (w), 722 (w),
688 (w), 658 (w), 599 (m), 541 (m), 522 (w), 468 (w) cm-1. m.p.: 91 °C (diethyl
ether). [α]: -1.12 (c 1.0, CHCl3).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-2-((R)-6-methyl-4-oxochro-
man-2-yl)propanoate (23d):
Prepared according to general procedure I; Colourless solid (184 mg, 0.494
mmol, 99%). 1H-NMR: (500 MHz, CDCl3) δ = 7.67 (d, 1H, J = 1.7 Hz, 1-H),
7.28 (dd, 1H, J = 8.5 Hz, 2.3 Hz, 3-H), 6.84 (d, 1H, J = 8.4 Hz, 4-H), 4.74 (td,
1H, J = 10.9 Hz, 4.4 Hz, 1H, 10-H), 4.67 (ddd, 1H, J = 13.1 Hz, 6.2 Hz, 2.8 Hz,
5a-H), 2.84 – 2.76 (m, 2H, 7a-Hα, 5-H), 2.66 (dd, 1H, J = 16.7 Hz, 2.8 Hz, 5-
Hβ), 2.30 (s, 3H, -CH3), 2.03 – 1.97 (m, 1H, 11-Hα), 1.88 (heptd, 1H, J = 7.0 Hz,
2.9 Hz, 17-H), 1.72 – 1.64 (m, 2H, 14-Hα, 15-Hα), 1.55 – 1.44 (m, 1H, 12-H),
1.41 – 1.36 (m, 1H, 16-H), 1.35 (d, 3-H, J = 7.1 Hz, 9-H3), 1.05 (ddd, 1H, J =
16.2 Hz, 13.4 Hz, 4.4 Hz, 15-Hβ), 0.98 (q, 1H, J = 11.9 Hz, 11-Hβ), 0.91 (d, 3H,
J = 6.6 Hz, 13-H3), 0.90 – 0.84 (m, 1H, 14-Hβ), 0.83 (d, 3H, J = 7.0 Hz, 19-H3),
0.74 (d, 3H, J = 7.0 Hz, 18-H3) ppm. 13C NMR: (125 MHz, CDCl3) δ = 192.3 (8-
C), 172.6 (6-C), 159.5 (4a-C), 137.2 (3-C), 131.1 (2-C), 126.7 (1-C), 120.7 (8a-
C), 117.8 (4-C), 78.3 (5a-C), 75.0 (10-C), 47.1 (16-C), 44.4 (5-C), 40.9 (7a-C),
40.9 (11-C), 34.4 (14-C), 31.6 (12-C), 26.2 (17-C), 23.4 (15-C), 22.1 (13-C),
20.9 (19-C), 20.5 (-CH3), 16.2 (18-C), 12.4 (9-C) ppm. HR-MS: (ESI+): m/z
calc. for C23H32O4Na [M+Na]+: 395.2193, found 395.2204. IR: (ATR) = 3005
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-2-((R)-6-bromo-4-oxochro-
man-2-yl)propanoate (23g):
Prepared according to general procedure I; Colourless solid (207 mg, 0.473
mmol, 95%). 1H-NMR: (500 MHz, CDCl3) δ = 7.99 (d, 1H, J = 2.5 Hz, 1-H),
7.54 (dd, 1H, J = 8.8 Hz, 2.6 Hz, 3-H), 6.85 (d, 1H, J = 8.8 Hz, 4-H), 4.74 (td,
1H, J = 11.0 Hz, 4.5 Hz, 1H, 10-H), 4.70 (ddd, 1H, J = 13.2 Hz, 6.2 Hz, 2.9 Hz,
5a-H), 2.86 – 2.78 (m, 2H, 7a-Hα, 5-H), 2.69 (dd, 1H, J = 16.8 Hz, 2.9 Hz, 5-
Hβ), 2.02 – 1.96 (m, 1H, 11-Hα), 1.85 (heptd, 1H, J = 7.0 Hz, 2.8 Hz, 17-H),
1.73 – 1.63 (m, 2H, 14-Hα, 15-Hα), 1.55 – 1.44 (m, 1H, 12-H), 1.42 – 1.36 (m,
1H, 16-H), 1.35 (d, 3-H, J = 7.1 Hz, 9-H3), 1.05 (ddd, 1H, J = 16.2 Hz, 13.4 Hz,
4.1 Hz, 15-Hβ), 0.98 (q, 1H, J = 11.4 Hz, 11-Hβ), 0.91 (d, 3H, J = 6.6 Hz, 13-
H3), 0.90 – 0.85 (m, 1H, 14-Hβ), 0.84 (d, 3H, J = 7.0 Hz, 19-H3), 0.74 (d, 3H, J
= 7.0 Hz, 18-H3) ppm. 13C NMR: (125 MHz, CDCl3) δ = 190.7 (8-C), 172.3 (6-
C), 160.3 (4a-C), 138.7 (3-C), 129.7 (1-C), 122.3 (2-C), 120.0 (4-C), 114.4 (8a-
C), 78.6 (5a-C), 75.2 (10-C), 47.1 (16-C), 44.2 (5-C), 40.9 (11-C), 40.4 (7a-C),
34.3 (14-C), 31.6 (12-C), 26.2 (17-C), 23.4 (15-C), 22.1 (13-C), 20.9 (19-C),
16.2 (18-C), 12.4 (9-C) ppm. HRMS: (ESI+): m/z calc. for C22H29BrO4Na
[M+Na]+: 459.1141, found 459.1153. IR: (ATR) = 3006 (w), 2970 (w), 2951
(m), 2981 (w), 2953 (w), 2921 (w), 1743 (w), 1721 (s), 1645 (m), 1605 (w),
1513 (m), 1483 (w), 1444 (w), 1431 (w), 1395 (m), 1363 (w), 1344 (w), 1311
(s), 1283 (w), 1247 (m), 1232 (w), 1212 (w), 1189 (s), 1157 (w), 1126 (w),
1100 (w), 1055 (m), 1022 (w), 999 (w), 977 (w), 954 (w), 927 (w), 884 (w), 859
(w), 835 (m), 810 (w), 787 (w), 727 (w), 602 (m), 548 (w), 521 (w), 470 (w)
cm-1. m.p.: 114 °C (diethyl ether). [α]: -4.57 (c 1.0, CHCl3).
(w), 2921 (w), 1731 (s), 1626 (m), 1489 (m), 1441 (w), 1402 (m), 1362 (w),
1345 (w), 1294 (s), 1244 (m), 1219 (m), 1192 (s), 1172 (w), 1148 (w), 1125
(w), 1099 (w), 1053 (m), 1009 (w), 999 (w), 978 (w), 954 (w), 928 (w), 917 (w),
836 (m), 773 (w), 721 (w), 644 (w), 599 (m), 536 (m), 522 (w) cm-1. m.p.:
100 °C (diethyl ether). [α]: +3.81 (c 1.0, CHCl3).
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-2-((R)-6-fluoro-4-oxochro-
man-2-yl)propanoate (23e):
Prepared according to general procedure I; Colourless solid (186 mg, 0.494
mmol, 99%). 1H-NMR: (500 MHz, CDCl3) δ = 7.53 (dd, 1H, J = 8.2 Hz, 3.2 Hz
1-H), 7.19 (ddd, 1H, J = 9.0 Hz, 7.7 Hz, 3.2 Hz, 3-H), 6.93 (dd, 1H, J = 9.1 Hz,
4.2 Hz, 4-H), 4.73 (td, 1H, J = 10.9 Hz, 4.4 Hz, 1H, 10-H), 4.70 (ddd, 1H, J =
13.2 Hz, 6.2 Hz, 2.9 Hz, 5a-H), 2.88 – 2.76 (m, 2H, 7a-Hα, 5-H), 2.69 (dd, 1H,
J = 16.8 Hz, 3.1 Hz, 5-Hβ), 2.05 – 1.95 (m, 1H, 11-Hα), 1.86 (heptd, 1H, J = 7.0
Hz, 2.8 Hz, 17-H), 1.74 – 1.62 (m, 2H, 14-Hα, 15-Hα), 1.58 – 1.44 (m, 1H, 12-
H), 1.43 – 1.37 (m, 1H, 16-H), 1.35 (d, 3-H, J = 7.1 Hz, 9-H3), 1.14 – 0.95 (m,
2H, 11-Hβ, 15-Hβ), 0.91 (d, 3H, J = 6.5 Hz, 13-H3), 0.92 – 0.86 (m, 1H, 14-Hβ),
0.83 (d, 3H, J = 7.0 Hz, 19-H3), 0.74 (d, 3H, J = 7.0 Hz, 18-H3) ppm. 13C-NMR:
(S)-5-(Difluoromethoxy)-2-((S)-1-hydroxypropan-2-yl)chroman-4-one (15):
tert-Butyldimethylsilyl trifluoromethanesulfonate (3.90 ml, 17.0 mmol, 1.50
equiv.) was added to a solution of 5-(difluoromethoxy)-4H-chromen-4-one
(2.00 g, 11.4 mmol, 1.00 equiv.) 14 in dichloromethane (100 ml) and stirred for
1.5 h. The orange solution was cooled to -78 °C and a solution of silyl ketene
acetal (4.47 g, 13.7 mmol, 1.20 equiv.) ent-22 in dichloromethane (20 ml) was
8
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