Organic Process Research & Development 2003, 7, 514−520
Chemical Development on the Chiral Auxiliary
(S)-4-(Phenylmethyl)-2-oxazolidinone Utilizing Automated Synthesis and DoE
Lanchi Vo, James Ciula, and Owen W. Gooding*
Chemical DeVelopment Department, Argonaut Technologies, 1101 Chess DriVe, Foster City, California 94404, U.S.A.
Abstract:
controlling the rate of borane-DMS addition to minimize
the build up of high-energy intermediates.3 Throughout the
1990s, many additional syntheses of 2 were reported.4 A
survey of these showed that four of them could be amenable
to scale-up. Following a critical analysis of these procedures,
we centered our study on a sodium borohydride (NaBH4)
reduction of Phe, without the use BF3-etherate, followed
by cyclization of the intermediate amino alcohol 1 with a
phosgene equivalent. Herein, we report the screening,
optimization, and validation of a new one-pot process for
the efficient and scaleable production of 2.
Enantiopure 4-substituted oxazolidinones are well-known chiral
auxiliaries for asymmetric synthesis of carboxylic acid deriva-
tives. The 4-(phenylmethyl)-substituted oxazolidinones derived
from D- or L-phenylalanine are known to be particularly useful.
We have conducted chemical development studies toward an
efficient and scaleable “one-pot” process for production of (S)-
4-(phenylmethyl)-2-oxazolidinone 2. The first step in the process
employed a sodium borohydride reduction of phenylalanine
mediated by an additive. The second step utilized triphosgene
as a phosgene source to effect cyclization of the intermediate
amino alcohol. Both chemical steps and workup procedures
were screened and optimized utilizing statistical design of
experiments (DoE) and parallel synthesis. The procedure was
further characterized in an automated reactor system that
provided heat flow measurements and modeled production at
the plant scale. The efficiency of this process was compared to
those of others previously reported on the basis of raw material
cost, time requirements, safety, and hazardous waste generation.
Results and Discussion
Screening. The synthesis was broken out to the two
individual steps for screening and optimization work (Scheme
1). For the reduction of Phe to amino alcohol 1 in THF (step
1), a series of three additives were examined. The function
of the additive in this sodium borohydride reduction is to
form diborane in situ.5 The diborane, or the BH3-THF
complex, is the active reducing species. The additives studied
included sulfuric acid,5 chlorotrimethylsilane,6 and iodine.7
Reactions were conducted utilizing an Advantage Series 2050
manual chemistry synthesizer8 (AS 2050) and the products
were isolated by an extractive aqueous workup to determine
the yield. The results are shown in Table 1.
The sulfuric acid procedure was repeated 4 times (entries
1-4) in order to assess its reproducibility. Uniformly high
yields (91-95%) were obtained with products isolated as
white waxy solids. The chlorotrimethylsilane (TMS-Cl)
procedure was replicated 3 times and gave none of the
desired product upon extraction of the reaction mixture.
Presumably, the unreacted Phe remained in the aqueous layer.
The iodine procedure was replicated twice and lead to
isolation of product in excellent yield. The products from
Introduction
Enantiopure 4-substituted oxazolidinones are well-known
chiral auxiliaries for asymmetric synthesis of carboxylic acid
derivatives.1 The 4-benzyl substituted oxazolidinones 2
derived from D- or L-phenylalanine have proven to be
particularly useful. In addition to being crystalline solids,
they provide high levels of asymmetric induction, and the
acylation/hydrolysis steps are particularly facile. In connec-
tion with our program of supported reagent development,
we sought an efficient and scaleable process for the produc-
tion of 2.
The initial synthesis of 2 reported by Evans employed
BF3-catalyzed borane-DMS reduction of phenylalanine
(Phe) to afford the amino alcohol 1. Following isolation,
intermediate 1 was then cyclized using diethyl carbonate at
135 °C in the presence of base.2 Although effective, the
reduction step was reported to have dangerous induction
periods resulting in violent eruptions on scale-up to the 0.5
mol level.3 These safety issues were addressed by running
the reaction at a higher temperature in DME and carefully
(4) (a) Correa, A.; Denis, J.-N.; Greene, A. E. Synth. Commun. 1991, 21, 1,
1-9. (b) Ishizuka, T.; Kimura, K.; Ishibuchi, S.; Kunieda, T. Chem. Lett.
1992, 991-994. (c) Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson, R.
W. Synth. Commun. 1995, 25, 4, 561-568. (d) Sudharshan, M.; Hultin, P.
G. Synlett 1997, 171-172. (e) Feroci, M.; Inesi, A.; Mucciante, V.; Rossi,
L. Tetrahedron Lett. 1999, 40, 6059-6060. (f) Wu, Y.; Shen, X. Tetrahedron
Asymmetry 2000, 11, 4359-4363. (g) Chiarotto, I.; Feroci, M. Tetrahedron
Lett. 2001, 42, 3451-3453.
(5) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33 (38), 5717-5718.
(6) Giannis, A.; Sandhoff, K Angew. Chem., Int. Ed. Eng. 1989, 28, 2, 218-
220.
* To whom correspondence should be addressed. E-mail: ogooding@
argotech.com.
(7) (a) Freeguard, G. F.; Long, L. H. Chem. Ind. 1965, 471. (b) Kanth, J. V.
B.; Periasamy, M. J. Org. Chem. 1991, 56, 5964. (c) McKennon, M. J.;
Meyers, A. I. J. Org. Chem. 1993, 58, 3568.
(8) The Advantage Series 2050 manual chemistry synthesizer performs five
reactions at five different temperatures simultaneously. The working volume
is 5-80 mL, and the reactors may be vacuum purged with inert gas.
Reagents are added manually through a top port with a septum cap. Available
(1) (a) Evans, D. A. Aldrichchimica Acta 1982, 15, 23 and references therein.
(b) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construction
of Chiral Molecules Using Amino Acids; Wiley: New York, 1987.
(2) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77.
(3) Pridgen, L. N.; Prol, J., Jr.; Alexander, B.; Gillyard, L. J. Org. Chem. 1989,
54, 3231.
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Vol. 7, No. 4, 2003 / Organic Process Research & Development
10.1021/op034033l CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003