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Abstract:
Using a highly stereoselective Evans aldol reaction for the
introduction of the stereogenic center at C-25, we describe
an efficient synthesis of the orthogonally diprotected (25S)-
26-hydroxycholesterol 11. In a few synthetic steps, this crucial
intermediate 11 has been converted into the four (25S)-
cholesten-26-oic acids 1–4, which have been obtained in 12–
15 steps and 19–53% overall yield based on commercially
available 3β-hydroxychol-5-en-24-oic acid (5). Our biological
studies of the compounds 1–4 reveal that (25S)-Δ7-dafach-
Introduction
Reproductive development of nematodes such as Caenorhabditis
elegans and Pristionchus pacificus is controlled by
steroidal ligands, called dafachronic acids (Figure 1).[1,2] In
C. elegans, the biosynthesis of these steroids requires activity
of the cytochrome P450 DAF-9.[3] Dafachronic acids
are ligands which inactivate the nuclear hormone receptor
DAF-12 and thus, lead to reproductive development of
worms. In daf-9 mutant worms, incapable of dafachronic
acid biosynthesis, DAF-12 is active and worms enter the
diapause state generating dauer larvae. Another ligand
known to bind at DAF-12 is (25S)-cholestenoic acid (4).[4]
Mangelsdorf and colleagues prepared (25S)-Δ4-dafachronic
acid (2) and its C-25 epimer from the corresponding
26-hydroxycholesterols.[1a] In 2007, the structure of the
other ligand, (25S)-Δ7-dafachronic acid (1), has been confirmed
by a synthesis from Corey and Giroux.[5] Moreover,
it has been shown that (25S)-Δ7-dafachronic acid (1) represents
the most active ligand known so far.[1a,5] Interestingly,
the synthesis of both C-25 epimers of 2 and 4 was described
previously by Khripach et al.[6] Our investigations on the
synthesis and biological activity of cholesterol derivatives,[7]
led us to an elegant and concise synthesis of the 25R-diastereoisomers
of 1, 2 and 4 starting from commercially
[a] Department Chemie, Technische Universität Dresden,
Bergstraße 66, 01069 Dresden, Germany
Fax: +49-351-463-37030
E-mail: hans-joachim.knoelker@tu-dresden.de
[b] Max-Planck-Institut für Molekulare Zellbiologie und Genetik,
Pfotenhauerstraße 108, 01307 Dresden, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900443.
Eur. J. Org. Chem. 2009, 3703–3714 © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3703
ronic acid (1) represents the most active steroidal ligand for
the hormonal receptor DAF-12 in Caenorhabditis elegans.
Moreover, the saturated (25S)-dafachronic acid (3) represents
a new ligand for this receptor and the (25S)-steroidal acids
are more active as compared to their corresponding (25R)-
counterparts.
