demonstrated the enantioselective synthesis of dimethoxy
8
analogue 1b; however, the synthesis provided only small
quantities of material and the nontrivial cleavage of the
methyl ethers was not attempted. Here, we report a brief
and cost-effective total synthesis of (S)-equol that can be
conducted on a large scale to produce over 10 g of the final
product from a single batch.
Retrosynthetic analysis (Figure 2) revealed that the chro-
man skeleton could be formed via intramolecular palladium-
Although we were hesitant to carry through material of
such low purity, this option was still far more appealing than
attempting the five-step synthesis of the benzyl bromide,
provided that we would be able to remove products arising
from the unwanted regioisomers in a subsequent synthetic
step. We first attempted the reaction of benzyl chlorides
2
a-c with chiral N-acyloxazolidinone 4 using LDA as the
base but observed very poor recovery of both the product
and the starting material 4 (Scheme 2). Changing the base
Figure 2. Retrosynthetic analysis of (S)-equol.
catalyzed Buchwald etherification, which is known to pro-
ceed smoothly even when deactivating electron-rich substit-
9
uents are present on the aryl bromide. To obtain the required
10
chiral alcohol precursor, we envisioned an Evans alkylation
using 2-bromo-4-methoxybenzyl halide and a chiral N-acyl-
oxazolidinone derived from 4-methoxyphenylacetic acid.
The synthesis of 2-bromo-4-methoxybenzyl bromide is
11
known but requires five synthetic steps from p-nitrotoluene.
Alternatively, Lythgoe and co-workers reported the synthesis
of 2-bromo-4-methoxybenzyl chloride (2) in one step via
the chloromethylation of 3-bromoanisole.12 Following the
literature procedure, we reacted 3-bromoanisole with form-
aldehyde and hydrogen chloride gas, and the product we
obtained after fractional distillation was characterized by a
narrow boiling point in the gas chromatograph; however, the
1
from LDA to NaHMDS improved the yield slightly, but we
were still lacking a method suitable for large-scale use. In
the previous synthesis of dimethoxy equol, Ferreira and co-
workers reported low (13-30%) yields when using an
oxazolidinone as their chiral auxiliary and hypothesized that
the good leaving group ability of the oxazolidinone results
H NMR spectrum revealed three different products, leading
1
3
us to believe that we had in fact formed three regioisomers.
1
By analogy to the H NMR shifts of similar chemical
structures, we were able to assign the product distribution
1
4
for the three isomers (2a-c) as shown in Scheme 1.
7
(
7) Wang, X. L.; Hur, H. G.; Lee, J. H.; Kim, K. T.; Kim, S. I. Appl.
EnViron. Microbiol. 2005, 71, 214.
8) Versteeg, M.; Bezuidenhoudt, C. B.; Ferreira, D. Tetrahedron 1999,
5, 3365.
in ketene formation in the presence of base. They instead
used an ephedrine-derived imidazolidinone auxiliary, but due
to the higher cost and increased number of synthetic steps
required, we were motivated to find reaction conditions that
would be conducive to use of the oxazolidinone.
We found that increasing the reactivity of the electrophile
by converting the benzyl chlorides 2a-c to benzyl bromides
(
5
1
1
(9) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
23, 12202.
(
10) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
04, 1737.
11) Ghosh, A. K.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Chem. Soc.
Perkin Trans. 1 1997, 18, 2747.
(
(
12) Lythgoe, B.; Trippett, S.; Watkins, J. C. J. Chem. Soc. 1956, 4060.
(
13) The original publication dates back to 1956, prior to the availability
(14) The product distribution was calculated from the integrations of the
benzyl protons of each of the regioisomers in the H NMR spectrum. The
chemical shifts of these protons in CDCl3 are: d 4.84 (2c), 4.68 (2a), and
4.59 (2b).
1
1
of H NMR. Thus, it is unclear whether the initially reported synthesis also
yielded a mixture of three regioisomers that were unknowingly separated
in a later step.
5442
Org. Lett., Vol. 8, No. 24, 2006