Organic Process Research & Development 2007, 11, 972–980
Research and Development of an Efficient Synthesis of
Hexahydrofuro[2,3-b]furan-3-ol Moiety—A Key Component of the HIV Protease
Inhibitor Candidates
Richard H. Yu,* Richard P. Polniaszek, Mark W. Becker, Charles M. Cook, and Lok Him L. Yu
Process Research Department, Gilead Sciences, Inc., Foster City, California 94404
Abstract:
involved a radical cyclization13 to the exocyclic alkene. Ozo-
nolysis of the alkene to (()-1 followed by enzymatic resolution
afforded (-)-1. Alternatively, Ghosh directly accessed (-)-1
starting from isopropylidene-D-glyceraldehyde with a key
A highly efficient method for synthesizing racemic hexahydro-
furo[2,3-b]furan-3-ol has been developed utilizing a lanthanide
catalyst, such as Yb(fod) , to promote condensation of 2,3-
3
dihydrofuran and glycolaldehyde dimer. Access to either optically
enriched enantiomer of bisfuran alcohol can be obtained by using
this method employing chiral ligands with the lanthanide catalyst.
In support of Gilead Sciences’ protease inhibitor project, this
method has been demonstrated to be a robust and scalable process
with potential application for the construction of a variety of
furo[2,3-b]furan derivatives.
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12
photochemical step. More recently, an anti-aldol strategy was
reported starting from an ester-derived titanium enolate to afford
highly optically enriched 1. Quaedflieg and co-workers dem-
onstrated two routes to (-)-1, both based on diastereoselective
11
Michael additions of nitromethane. Of the two approaches,
the route that utilized an initial Wittig reaction to the chiral
enoate was proven on a multikiloscale. Other notable approaches
7
included Pezechk’s radical cyclization of bromoacetal and
9
Uchiyama’s asymmetric oxyselenenylation of 2,3-dihydrofuran.
These varied approaches led to the desired optically enriched
bisfuran alcohol; however, in all cases, drawbacks included
multiple synthetic steps, ozonolytic cleavage, and photochemical
transformation, which are not easily amenable to scale-up.
As previously indicated, the bisfuran moiety is a key
component in Gilead Sciences’ protease inhibitor GS-9005. To
support the API needs for the development of the program, we
have developed a direct and highly efficient pathway to
construct the bisfuranyl system leading to the desired alcohol
Introduction
The furo[2,3-b]furan structure, a fused cyclic acetal, exists
in several biologically active natural products. Examples include
aflatoxin, clerodin, asteltoxin, rhyacophiline, and acmimycin,
1–3
among many others. In particular, the (3aR,3aS,6aR)-hexahy-
drofuro[2,3-b]furan-3-ol moiety 1, or “bisfuran alcohol”, plays
a significant role in the effectiveness of HIV protease inhibitor
4
candidates and is a key building block of Gilead Sciences’ HIV
protease inhibitor candidate GS-9005 (Scheme 1). The bisfuran
1
(Scheme 2). With the use of enzymatic assistance, the
alcohol 1 is also an integral component of Tibotec’s PI TMC-
5
6
enantiomerically pure compound can be obtained in good yields
and high chemical and optical purities. The synthetic method
described has been performed at the multikiloscale level in
support of phase I clinical trials. As an extension of the
methodology, results from evaluation in the use of chiral
1
14 and GSK’s brecanavir (GW-0385). Thus, considerable
attention and numerous inquiries into novel synthetic methods
to synthesize 1 have been reported.
efforts by Ghosh, and more recently, Quaedflieg. Ghosh and
co-workers devised several approaches to (-)-1. One approach
5,7–12
Of particular note are
*
Corresponding author. E-mail: richard_yu@gilead.com.
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Vol. 11, No. 6, 2007 / Organic Process Research & Development
10.1021/op700160a CCC: $37.00 2007 American Chemical Society
Published on Web 10/05/2007