Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity

doi:10.1016/S0040-4020(98)01138-7

Tetrahedron

Volume 55, Issue 11, 12 March 1999, Pages 3255-3264

https://doi.org/10.1016/S0040-4020(98)01138-7 Get rights and content

Abstract

An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3α-hydroxy- and 3α,21-dihydroxy-5α-pregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swern type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6-17-trione, has been efficiently prepared using PCC on montmorillonite K10, under ultrasonic irradiation.

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References (58)

ZeelenF.J.
Medicinal Chemistry of Steroids: Recent Developments
LambertJ.L. et al.
Trends Pharm. Sc.
(1995)
RupprechtR. et al.
J. Steroid Biochem. Mol. Biol.
(1996)
MorenoM.J.S.M. et al.
Tetrahedron Lett.
(1993)
MorenoM.J.S.M. et al.
Synlet
(1994)
VedejsE. et al.
J. Org. Chem
(1978)
CockerJ.D. et al.
J. Chem. Soc.
(1965)
RubottomG.M. et al.
Org. Synthesis
(1986)
MarshD.A. et al.
J. Med. Chem.
(1985)
FieserL.F.
Miranda MorenoM.J.S. et al.
Tetrahedron Lett.
(1991)

ParishE.J. et al.

Chem. Phys. Lipids

(1995)

LiSheng-Hui et al.

Steroids

(1998)

MasonT.J.

Chem. Soc. Rev.

(1997)

ClarkJ.H. et al.

Chem. Soc. Rev.

(1996)

ZweifelG. et al.

Hydration of Olefins, Dienes and Acetylenes via Hydroboration

ZeelenF.J.

BlickenstaffR.T.

LewisD.F.V.

JohannessenD.C. et al.

Drugs & Aging

(1992)

YuefeiH. et al.

J. Med. Chem.

(1993)

FinnD.A. et al.

J. Pharmacol. Exp. Ther.

(1993)

GeeK.W. et al.

Crit. Rev. Neurobiol.

(1995)

PurdyP.H. et al.

J. Med. Chem.

(1990)

HaddadY.M.Y. et al.

BrowneP.A. et al.

J. Chem. Soc. C

(1969)

HenbestH.B. et al.

J. Chem. Soc. C

(1970)

Pereira Costa, S. et al.; unpublished...

Pouchert, C. J.; Behnke, J. The Aldrich Library of 13C and 1H FT NMR Spectra, Aldrich Chemical Company Ed.; Vol. I.,...

WaringA.J.

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Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity

Abstract

Graphical abstract

Trends Pharm. Sc.

J. Steroid Biochem. Mol. Biol.

Tetrahedron Lett.

Synlet

J. Org. Chem

J. Chem. Soc.

Org. Synthesis

J. Med. Chem.

Tetrahedron Lett.

Chem. Phys. Lipids

Steroids

Chem. Soc. Rev.

Chem. Soc. Rev.

Drugs & Aging

J. Med. Chem.

J. Pharmacol. Exp. Ther.

Crit. Rev. Neurobiol.

J. Med. Chem.

J. Chem. Soc. C

J. Chem. Soc. C