An efficient, stereocontrolled synthesis of the 25-(R)-diastereomer of dafchronic acid A from β-ergosterol

Article abstract of DOI:10.1021/ol702936f

A direct and stereocontrolled synthesis of the 25-(R)-diastereomer of dafachronic acid A from β-ergosterol has been developed.

Full text of DOI:10.1021/ol702936f

ORGANIC
LETTERS
2008
Vol. 10, No. 5
801-802
An Efficient, Stereocontrolled Synthesis
of the 25-(R)-Diastereomer of
Dafachronic Acid A from
â-Ergosterol
Simon Giroux and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received December 4, 2007
ABSTRACT
A direct and stereocontrolled synthesis of the 25-(R)-diastereomer of dafachronic acid A from
â-ergosterol has been developed.
The lifespan of C. elegans can be increased from 2 weeks
to ca. 12 weeks by loss-of-function mutations in two genes,
daf-2 and daf-9,1 the daf-9 gene codes for a protein (DAF-
9) of the cytochrome P450 class of steroid oxidases. A
product of the DAF-9 pathway serves as a ligand for another
protein, DAF-12, that activates the daf-12 gene and restores
the normal wild-type state of C. elegans. Mangelsdorf,
Antebi, and their colleagues screened a large number of
steroids and compared their activity on C. elegans to the
natural ligand, which was only available in trace amounts.
They found that the most active of the steroids tested
contained a 3-keto group, a ∆7 olefinic linkage, or a 26-
carboxylic function.2 From these observations, they surmised
that the natural regulator might be the steroidal acid 1 (Figure
1), which they named dafachronic acid. We recently syn-
thesized 1 stereoselectively from â-stigmasterol.3 The activity
of synthetic 1 (specifically the 25-(S)-diastereomer, which
we have termed dafachronic acid A) was found to correspond
to that of the natural DAF-12 ligand. At subnanomolar
Figure 1. Chemical structure of dafachronic acid A (1).
concentrations synthetic 1 rescued mutant C. elegans from
the diapausal (i.e., low metabolism, quiescent) state display-
ing a potency equal to that of the natural DAF-12 ligand.
In this paper we report the stereocontrolled and efficient
synthesis of 2, the 25-(R)-diastereomer of 1, starting from
the abundant â-ergosterol by the route summarized in
Scheme 1. We chose â-ergosterol as the starting point not
only because of its abundance but because the ∆7 olefinic
linkage is already in place. In addition, there is some evidence
(1) (a) Motola, D. L.; Cummins, C. L.; Rottiers, V.; Sharma, K. K.; Li,
T.; Li, Y.; Suino-Powell, K.; Xu, H. E.; Auchus, R. J.; Antebi, A.;
Mangelsdorf, D. J. Cell 2006, 124, 1209-1223. (b) Gerisch, B.; Rottiers,
V.; Li, D.; Motola, D. L.; Cummins, C. L.; Lehrach, H.; Mangelsdorf, D.
J.; Antebi, A. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 5014-5019. (c) For
an online resource on C. elegans, see: http://www.wormbook.org.
(2) Rottiers, V.; Motola, D. L.; Gerisch, B.; Cummins, C. L.; Nishiwaki,
K.; Mangelsdorf, D. J.; Antebi, A. DeV. Cell 2006, 10, 473-482.
(3) Giroux, S.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 9866-9867.
10.1021/ol702936f CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/05/2008

Scheme 1. Synthesis of 2 from â-Ergosterol
that the same ∆5,7-diene subunit might be present in a
at -78 °C and trapping of the resulting enolate with tert-
butyldimethylsilyl chloride (TBSCl) led to the Z-silylketene
acetal, which rearranged upon heating to room temperature
to the desired δ,γ-unsaturated acid 6 as a single diastereomer
(25R/25S > 20:1) in 66% yield. The acid 6 was then
converted to 2 by using the following sequence: (1) selective
reduction of the ∆22 olefinic linkage in the presence of the
more hindered ∆7 double bond, using H2-Pd/C in THF; (2)
saponification of the 3-O-benzoate with K2CO3 in MeOH;
and (3) oxidation of the resulting alcohol with 1.5 equiv of
pyridinium chlorochromate (PCC) in CH2Cl2. The synthesis
of 2 described herein is short (10 steps with an overall yield
of 13%) and uses â-ergosterol, a cheap starting material. A
detailed biological comparison of synthetic 1 and 2 is now
underway in the laboratory of Dr. Adam Antebi.
biosynthetic precursor of 1. Specifically, a protein on the
pathway to 1, DAF-36, is homologous to a known oxidase
that produces the ∆5,7-diene system (personal communication
from Dr. Antebi).
A key step in the realization of the synthesis of 2 was our
discovery that â-ergosterol could be selectively reduced at
the ∆5 linkage by a slow addition of a THF solution
containing 3 equiv of tert-amyl alcohol to a solution of 5
equiv of Li in liquid NH3 at -78 °C. Benzoylation of the
reduction product (BzCl, pyridine) afforded the benzoate 3
in nearly quantitative overall yield. Selective oxidation of
the ∆22 double bond was effected by using OsO4(catalytic)
and N-methylmorpholine N-oxide (NMO) in the presence
of 1,4-diazabicyclo[2.2.2]octane (DABCO) (2 equiv) in a
mixture of 1,2-dimethoxyethane and H2O (10:1) at 80 °C
for 48 h, which afforded the 22,23-diol in 55% yield along
with recovered 3 (18%) after flash chromatography on silica
gel. Oxidative cleavage (NaIO4, THF-H2O) of the diol
afforded aldehyde 4 in 86% yield. Addition of vinylmagne-
sium bromide to aldehyde 4 in CH2Cl2 at -78 °C led to the
desired Felkin product in 78% yield, which was acylated by
using propionic anhydride, NEt3, and 4-dimethylaminopy-
ridine (DMAP) in CH2Cl2 to give the propionate 5. This was
then subjected to Claisen rearrangement.4 Deprotonation of
5 with LDA in a mixture of THF-HMPA (4:1) for 45 min
Acknowledgment. S.G. is grateful to NSERC (Canada)
for a postdoctoral fellowship.
Supporting Information Available: Experimental pro-
tocols and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702936F
(4) Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452.
802
Org. Lett., Vol. 10, No. 5, 2008