The synthesis of functionalized 13,14-seco-steroids via Grob fragmentation

Asymmetric Total Synthesis of the Indole Diterpene Alkaloid Paspaline

“…N-Methylmorpholine (3.60 mL, 35.7 mmol, 1.10 equiv) and ethyl propiolate (3.92 mL, 35.7 mmol, 1.10 equiv) were added sequentially, and the mixture was allowed to stir until complete conversion of the starting material was observed by TLC analysis, typically 4 h. The reaction mixture was concentrated on a rotary evaporator, and the crude product was purified via flash chromatography (80:20 to 70:30 hexanes/EtOAc) to give the vinyl ether 16 (11.4 g, 97% yield) as a clear oil. Analytical data: 1 H NMR (600 MHz, CDCl 3 ) δ 7.77 (d,J = 8.4 Hz,2H),7.34 (d,J = 8.4 Hz,2H),7.28 (d,J = 12.6 Hz,1H),5.14 (d,J = 12.6 Hz,1H),4.97 (s,1H),4.93 (s,1H),4.31 (dd,J = 4.8,4.2 Hz,1H),4H), 2.43 (s, 3H), 1.97 (m, 2H), 1.61 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 167.6, 160. 5, 145.0, 141.5, 132.6, 129.9, 127.9, 115.4, 98.6, 81.5, 66.2, 59.8, 32.7, 21.6, 16.7, 14.3; HRMS (ESI + ) calcd for C 18 H 24 O 6 S+Na, 391.1191; found 391.1181; IR (thin film, cm −1 ) 2980, 2916, 2849, 1706, 1644, 1488, 1362, 1189, 1097TLC (80:20…”

“…The product was purified via flash chromatography (90:10 to 80:20 hexanes/EtOAc) to afford the alkyl iodide 13 (8.67 g, 87% yield) as a pale yellow oil. Analytical data: 1 H NMR (600 MHz, CDCl 3 ) δ 7.46 (d,J = 12.6 Hz,1H),5.27 (d,J = 12.6 Hz,1H), 5.05 (s, 1H), 5.04 (s, 1H), 4.39 (dd, J = 4.8, 3.0 Hz, 1H), 4.14 (m, 2H), 3.17 (m, 2H), 2.21 (m, 1H), 2.07 (m, 1H), 1.67 (s, 3H), 1.25 (t, J = 7.2 Hz, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 167. 7, 160.8, 141.5, 115.3, 98.6, 85.5, 59.8, 36.7, 17.0, 14.3, 0.9; HRMS (ESI + ) calcd for C 11 H 17 IO 3 +Na, 347.0120; found 347.0111; IR (thin film, cm −1 ) 3078, 2978, 2916, 1707, 1644, 1456, 1322, 1171, 1006TLC (80:20 (17).…”

“…The diastereomeric ratio was determined via 1 H NMR spectroscopic analysis of this crude material, which revealed a single compound. Analytical data: 1 H NMR (600 MHz, C 6 D 6 ) δ 10.56 (br s, 1H), 5.02 (s, 1H), 4.90 (s, 1H), 4.84 (s, 1H), 4.80 (s, 1H), 3.84 (dd, J = 7.2, 1.8 Hz, 1H), 3.58 (d,J = 11.4 Hz,1H),3.31 (s,3H), 2.56 (d, J = 13.2 Hz, 1H), 2.33 (m, 2H), 2.17 (m, 2H), 2.08 (m, 1H), 1.71 (s, 3H), 1.68− 1.67 (m, 4H), 1.34 (d, J = 1.8 Hz, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 177. 1, 169.6, 145.3, 145.0, 110.8, 110.4, 81.1, 80.3, 56.6, 52.2, 34.8, 32.2, 30.1, 26.1, 22.2, 19.2; HRMS (ESI + ) calcd for C 16 H 24 O 5 +Na, 319.1521; found 319.1513; IR (thin film, cm −1 ) 3566, 3074, 2952, 2857, 2633, 1650, 1438, 1268, 1080TLC (75:25 (20).…”

Steroids: partial synthesis in medicinal chemistry

“…20, towards organometallic reagents 46 and the radical decomposition of oxalate esters 47 have been examined in the context of preparing 11-substituted derivatives. Further work has been reported on the preparation of 13,14seco-steroids by the Grob fragmentation of 14a-hydroxy-17btosyloxy steroids, 21 → 22, 48 and by the lead tetra-acetate and iodine oxidation of 14a-hydroxy-17-keto steroids. 49 The reaction of (13S)-13-iodo-16b-methoxy-3a,5a-cyclo-13,14-secoandrostan-14,17-dione with hydroxylamine has been examined.…”

Diastereo- and enantioselective bioreduction of ethyl 2-(4-chlorophenoxy)-3-oxobutanoate clofibrate analogues by Kluyveromyces marxianus and other whole cell biocatalysts

“…[1][2][3][4][5] One of the easiest and widely used synthetic routes to prepare this crucial class of compounds is the chemical and chemo-enzymatic asymmetric reduction of prochiral ketones. Various chiral reducing agents [6][7][8][9] or chirally modified boron-and aluminium-hydrides for hydride transfer, 10,11 catalytic reduction with chiral transition metal complexes [12][13][14][15][16][17][18] are the most used chemical methods to enantioselectively reduce the carbonyl. Chemo-enzymatic hydride transfer represents a valuable alternative to chemical methodologies.…”