Total synthesis of (8S,11R,12R)- and (8R,11R,12R)-topsentolide B2 diastereomers and assignment of the absolute configuration

An improved total synthesis of (8S,11R,12R)- and (8R,11R,12R)-topsentolide B2 diastereomers has been completed in eight steps with overall yields of 10.2% and 10.4%, respectively. The key steps involve a regioselective asymmetric dihydroxylation, diastereoselective Roush allylation, and ring closing metathesis. The stereochemistry of natural topsentolide B2 has been determined to be (8S,11R,12R) by comparison of the specific rotation.

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(4R,5R,2E,7Z)-Ethyl 4,5-dihydroxytrideca-2,7-dienoateC15H26O4[α]D25=+23.4 (c 1.0, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (4R,5R,2E,7Z)

(4R,5R,2E,7Z)-Ethyl 4,5-isopropylidenedioxytridec-2,7-dieneoteC18H30O4[α]D25=+26.6 (c 0.5, CHCl3)Source of chirality: asymmetric dihydroxylationAbsolute configuration: (4R,5R,2E,7Z)

(4S,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,10-trien-4-olC19H32O3[α]D25=+7.9 (c 1.2, CHCl3)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (4S,7R,8R,5E,10Z)

(4R,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,10-trien-4-olC19H32O3[α]D25=-4.2 (c 1.0, CHCl3)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (4R,7R,8R,5E,10Z)

(4S,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,10-trien-4-yl hex-5-enoateC25H40O4[α]D25=+4.9 (c 1.0, CHCl3)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (4S,7R,8R,5E,10Z)

(4R,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,10-trien-4-yl hex-5-enoateC25H40O4[α]D25=+24.7 (c 0.8, CHCl3)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (4R,7R,8R,5E,10Z)

(9S,6Z)-9-[(3R,4R,1E,6Z)-3,4-Isopropylidenedioxydodec-1,6-dienyl]-4,5,8,9-tetrahydro-(3H)-oxonin-2-oneC23H36O4[α]D25=+9.5 (c 0.28, CHCl3)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (9S,6Z,3R,4R,1E,6Z)

(9R,6Z)-9-[(3R,4R,1E,6Z)-3,4-Isopropylidenedioxydodec-1,6-dienyl]-4,5,8,9-tetrahydro-(3H)-oxonin-2-oneC23H36O4[α]D25=+18.7 (c 0.34, CHCl3)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (9R,6Z,3R,4R,1E,6Z)

(8S,11R,12R)-Topsentolide B2C20H32O4[α]D25=+8.9 (c 0.27, MeOH)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (8S,11R,12R)

(8R,11R,12R)-Topsentolide B2C20H32O4[α]D25=+49.4 (c 0.27, MeOH)Source of chirality: asymmetric dihydroxylation and Roush allylationAbsolute configuration: (8R,11R,12R)