TY - JOUR
T1 - A chiral pool approach for asymmetric syntheses of both antipodes of equol and sativan
AU - Yalamanchili, Chinni
AU - Chittiboyina, Amar G.
AU - Chandra Kumar Rotte, Sateesh
AU - Katzenellenbogen, John A.
AU - Helferich, William G.
AU - Khan, Ikhlas A.
N1 - This study was made possible by NIH Grant Number P50AT006268 from the National Center for Complementary and Integrative Health (NCCIH), the Office of Dietary Supplements (ODS) and the National Cancer Institute (NCI). This study was supported in part by 1R01CA173499-01A1 , National Institute of Health ( NIH ) and United States Department of Agriculture , Agricultural Research Service, Specific Cooperative Agreement 58-6060-6-015 . We are thankful to Professor Jon Parcher for valuable suggestions while editing our manuscript and Drs. Bharathi Avula and Sathyanarayana Raju Sagi for help with obtaining HRMS data. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NCCIH, ODS, NCI, the NIH, or the USDA.
This study was made possible by NIH Grant Number P50AT006268 from the National Center for Complementary and Integrative Health (NCCIH), the Office of Dietary Supplements (ODS) and the National Cancer Institute (NCI). This study was supported in part by 1R01CA173499-01A1, National Institute of Health (NIH) and United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement 58-6060-6-015. We are thankful to Professor Jon Parcher for valuable suggestions while editing our manuscript and Drs. Bharathi Avula and Sathyanarayana Raju Sagi for help with obtaining HRMS data. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NCCIH, ODS, NCI, the NIH, or the USDA.
PY - 2018/4/19
Y1 - 2018/4/19
N2 - For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98% ee with good overall yields starting from readily available starting materials. The chiral isoflavan, (−)-equol is produced from soy isoflavones, formonentin and daidzein by the action of intestinal bacteria in certain groups of population and other chiral isoflavans are reported from various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans’ enantioselective aldol condensation was used as a chiral-inducing step to introduce the required chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity. Functional group transformations followed by intramolecular Mitsunobu reaction and deprotection steps resulted the target compounds, S-(−)-equol and S-(+)-sativan, with high degree of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and following the same synthetic sequence the antipodes, R-(+)-equol and R-(−)-sativan were achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. This flexible synthetic process lends itself quite readily to the enantioselective syntheses of other biologically active C-3 chiral isoflavans.
AB - For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98% ee with good overall yields starting from readily available starting materials. The chiral isoflavan, (−)-equol is produced from soy isoflavones, formonentin and daidzein by the action of intestinal bacteria in certain groups of population and other chiral isoflavans are reported from various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans’ enantioselective aldol condensation was used as a chiral-inducing step to introduce the required chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity. Functional group transformations followed by intramolecular Mitsunobu reaction and deprotection steps resulted the target compounds, S-(−)-equol and S-(+)-sativan, with high degree of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and following the same synthetic sequence the antipodes, R-(+)-equol and R-(−)-sativan were achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. This flexible synthetic process lends itself quite readily to the enantioselective syntheses of other biologically active C-3 chiral isoflavans.
KW - Asymmetric synthesis
KW - Chirality
KW - Evans aldol
KW - Isoflavans
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U2 - 10.1016/j.tet.2018.03.004
DO - 10.1016/j.tet.2018.03.004
M3 - Article
AN - SCOPUS:85043757507
SN - 0040-4020
VL - 74
SP - 2020
EP - 2029
JO - Tetrahedron
JF - Tetrahedron
IS - 16
ER -