Tetrahedron Letters
A stereoselective synthesis of the allo-bile acids from the 5b-isomers
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Qingjiang Li, Gregory P. Tochtrop
Department of Chemistry, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The allo-bile acids are a subset of the family of steroidal detergents found in most vertebrates. Because
there are no major biological feedstocks for isolation of the allo-bile acids, they must be synthesized from
the abundant 5b-reduced isomers. Here we report a general set of methods for the synthesis of allo-bile
acids from the corresponding 5-b isomers demarcated by a selective C-3 oxidation, IBX unsaturation, and
stereoselective saturation.
Received 13 April 2011
Revised 25 May 2011
Accepted 27 May 2011
Available online 27 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bile acid
Allo bile acid
Selective oxidation
IBX
Lithium–ammonia reduction
Bile acids are ubiquitous small molecules across vertebrates
that facilitate digestion by acting as surfactants in the lumen of
the small intestine. The allo bile acids represent a subfamily of this
class of physiologic molecules that is primarily demarcated by an
Conversely, the approach reported here can be applied across
the bile acid spectrum, and is highly efficient. As shown in Scheme
1, our synthesis begins with a regioselective C-3 oxidation of meth-
ylated 5b-reduced bile acids using Ag2CO3 adsorbed on Celite.9 The
selective nature of this reaction is most likely due to relative steric
accessibility of the C-3 position interacting with the Celite solid
surface. Subsequently, any additional hydroxyl groups are pro-
tected as methoxymethyl ethers.10 2-Iodoxybenzoic acid (IBX)
smoothly and regioselectively performs the dehydrogenation to
give the D4 enone.11
AB-trans ring fusion (also referred to as 5a-reduced see Fig. 1).
They occur widely in lower vertebrates, including various fish,
birds and reptiles, but are also found sporadically in higher verte-
brates and mammals, including humans.1 Since the identification
of the farnesoid X receptor (FXR) as an endogenous nuclear recep-
tor for the bile acids,2 there has been renewed interest in this class
of physiologic molecules, and given the central role of 5
a
-reduced
Stereochemistry of a lithium–ammonia reduction of the D4
moiety proceeds as expected based on the model put forth by Stork
whereby the radical anion intermediate protonates axially.12 From
a technical point of view, achieving correct stoichiometry in the
lithium–ammonia reduction is absolutely crucial for success.
Excess lithium will readily reduce the C-24 ester in addition to
the C-3 carbonyl. In this molecule, the sequence of reactivity
toward the lithium–ammonia reduction proved to be D4 enone,
C-24 ester, C-24 aldehyde (from the C-24 ester), and finally the
C-3 ketone. If the amount of lithium is strictly controlled it is pos-
sible to obtain any of the sequential intermediates, though for this
C24 cholanic acids in gaining access to a major subset of these bile
acids, efficient methods for their synthesis will always represent
important research tools.
No significant biological feedstocks are currently available that
are rich in 5a-reduced bile acids. Consequently, the primary route
for access to these molecules has been via chemical synthesis. To this
point, since the identification of allo-cholic acid by Anderson and
Haslewood in 1962,3 several syntheses have been reported.3–8 Our
laboratory has recently become interested in studying the allo-bile
acids in the context of their ability to modulate cellular signaling
through FXR. After analyzing the literature we came to the conclu-
sion that the available methods are not general across the spectrum
of allo bile acids, and would further preclude access to select mem-
bers of the allo-family. Further, recent reports suffer from iterative
protection–deprotection, and non-selective substitution–elimina-
tion reactions.7
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Corresponding author. Tel.: +1 216 368 2351; fax: +1 216 368 3001.
Figure 1. Numbered and 3-D representation of allo-cholic acid.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.