5H-Oxazol-4-ones as Building Blocks for Asymmetric Synthesis of α-Hydroxycarboxylic Acid Derivatives

Article abstract of DOI:10.1021/ja031539a

5H-Alkyl-2-phenyl-oxazol-4-ones, a little-known heterocyclic ring system, are readily available via a microwave-assisted, sodium fluoride catalyst cyclization of mono-α-haloimides, which in turn are accessed by N-acylation of benzamides with α-bromo acid

Full text of DOI:10.1021/ja031539a

Published on Web 01/28/2004
5H-Oxazol-4-ones as Building Blocks for Asymmetric Synthesis of
r-Hydroxycarboxylic Acid Derivatives
Barry M. Trost,* Kalindi Dogra, and Maurizio Franzini
Department of Chemistry, Stanford UniVeristy, Stanford, California 94305-5080
Received December 5, 2003; E-mail: bmtrost@stanford.edu
Table 1. Optimization of Mo-AAA Using Methyl Oxalactim
5H-Alkyl-2-phenyl-oxazol-4-ones 3, though differing from 4H-
4-alkyl-2-phenyl-oxazol-5-ones (commonly known as azlactones)
only in the relative position of oxygen and nitrogen atoms, are a
greatly overlooked and underutilized class of heterocycles.1 We saw
in them a potential class of nucleophiles that would provide easy
access to R-hydroxy acids.2 Our recent success in Mo-catalyzed
AAA to control diastereo- and enantioselectivity at the nucleophile
using azlactones3 led us to expect similar results with “oxalactims”.4
Due to the dearth of information in the literature with regards to a
general synthesis of oxalactims, we decided to implement a simple
two-step process to make them, as shown in Scheme 1.5 R-Bromo
acid halides are condensed with benzamide in the presence of pyri-
dine at 60 °C to form diamide 2. Oxalactims can then be obtained
from cyclization of 2 in DMA containing sodium fluoride with
microwave irradiation at 180 °C in under 10 min in 44-82% yields.
entry
X
base
yield
b/l
dr
ee
1
2
3
4
OCO2CH3
OCO2CH3
OCO2CH3
KHMDS
NaHMDS 80%
LiHMDS
88%
6.7:1
24:1
1.4:1
2.7:1
80%
98%
91%
90%
99:1 11.5:1 >99%
7:1 8.1:1 96%
OP(O)(C2H5)2 LiHMDS
Table 2. Mo-AAA of Oxalactims
Scheme 1. Synthesis of 5H-Alkyl-2-phenyl-oxazol-4-one
(Oxalactims)
Initial studies examined the reaction shown in eq 1 with Ar )
Ph and R ) CH3. Due to its past history of clean generation of
enolates, we relied on hexamethyldisilamide (HMDS) as the base.
Lithium turned out to be the counterion of choice, giving higher
yield, regio-, diastereo-, and enantioselectivity over both sodium
and potassium, as shown in Table 1.
a In all cases X ) OCO2CH3. b Yield in parentheses based on recovered
starting material. cAll reactions were worked up after 16 h. db/l ) branched
to linear regioisomeric ratio. e Substrate was
f b/l > 95/5.
Carbonate served as a better leaving group than phosphate. Thus,
reaction of the lithium enolate of methyl oxalactim with methyl
cinnamyl carbonate gave 91% yield of the desired adduct with a
branched-to-linear ratio of 99:1. The diastereomeric ratio of the
branched product was 11.5:1, and the major diastereomer had an
enantiomeric excess of greater than 99%. The branched-to-linear
ratio as well diastereomeric ratio were determined using 1H NMR,
whereas chiral HPLC was used to determine the enantiomeric
excess.
Conditions shown in entry 3 of Table 1 were adopted as the
standard for further exploration of the reaction. Variation of Ar
and R substituents, as in eq 1, with carbonate as the leaving group
gave us results summarized in Table 2. In all cases except entry 4,
enantiomeric excesses of 98% or higher were observed. Even the
racemic substrate (entry 2), which is usually prone to give lower
ee values than its linear counterpart, worked well. The nonaromatic
substrates (entries 3, 4) also functioned well under these reaction
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10.1021/ja031539a CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Figure 1. Stereochemistry at the electrophile.
Figure 2. Stereochemistry at the nucleophile.
conditions, though showing a slight loss in diastereoselectivity. The
lower ee observed in entry 4 appears to be a characteristic of this
particular substrate.6 There appears to be some steric effect on the
regioselectivity with some loss as the size of the R group increases
(entries 5-9). Curiously, the benzyl group (entry 10) gives virtually
a single regioisomer in contrast to the isobutyl substituent (entry
7). We believe this may be due to the fact that it can rotate edgewise
in a fashion so as to present very little steric bulk.
Table 3. Hydrolysis of Oxalactims to R-Hydroxy Amides
Even though the relative and absolute stereochemistry of these
compounds is yet to be determined, a rationale consistent with our
results in the Mo-catalyzed reaction of azlactones as well as Pd-
catalyzed reactions of these oxalactims provides a reasonable basis
for its assignment. The structure of the metal bound π-allyl is as
shown in Figure 1, 7.7-9 With the approach of the nucleophile, the
weakly bound amide carbonyl group of the ligand is dissociated
and the nucleophile takes its place as in 8. The nucleophile is then
internally delivered, to result in the stereochemistry at the electro-
phile as observed in 9. The nucleophile itself can approach the
electrophile from either of its two faces as shown in Figure 2. Path
A is clearly favored as the least sterically demanding in the
transition state, hence resulting in the stereochemistry at the
nucleophile as depicted. This hypothesis is supported in the case
of azlactones (X ) O, Y ) N) by the X-ray structure, and the
stereochemical outcome is as shown.3
to the nucleophile as well as the electrophile. A useful feature of
the AAA is the presence of a double bond in the product, which
allows for further structural elaboration. For example, combining
an AAA with a ring-closing metathesis provides access to chiral
cyclic products (eq 3). The product of Table 2, entry 6, can undergo
ring-closing metathesis, yielding cyclic hydroxy carboxamides after
hydrolysis. This represents the first example of using 5-alkyl-2-
phenyl-oxazol-4-ones (oxalactims) as nucleophiles, leading to facile
asymmetric synthesis of tertiary R-hydroxy acids.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Institute (GM-13598), for their generous support of our programs.
Mass spectra were provided by the Mass Spectrometry Facility of
the University of California-San Francisco, supported by the NIH
Division of Research Resources.
Products from the Mo-AAA reaction could be easily opened
to the corresponding R-hydroxy amides (eq 2) by treatment with 1
N NaOH in ethanol at 60 °C. Some examples are shown in Table
3.
Supporting Information Available: Full experimental procedures,
synthesis of oxalactims, and characterization data for all unknown
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Palmer, D. C., Ed. Oxazoles: Synthesis, Reactions, and Spectroscopy,
Part A; John Wiley & Sons: Hoboken, NJ, 2003. Hartner, F. W., Jr. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; p 282; Rao, Y. S.;
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1986; pp 644-659.
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(3) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256.
(4) A name we coined for easy reference to 5H-alkyl-2-phenyl-oxazol-4-ones
analogons to the common term azlactone.
The corresponding carboxylic acids can, in turn, be uneventfully
obtained by diazotization of the primary amides by treatment at
room temperature with isoamyl nitrite in anhydrous 1,4-dioxane
and 2 M HCl in diethyl ether.10
(5) Rodehorsh, R. M.; Koch, T. H. J. Am. Chem. Soc. 1975, 97, 7298.
(6) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256.
(7) Trost, B. M.; Dogra, K.; Hachiya, I.; Emura, T.; Hughes, D. L.; Krska,
S.; Reamer, R. A.; Palucki, M.; Yasuda, N.; Reider, P. J. Angew. Chem.,
Int. Ed. 2002, 41, 1929;
(8) Lloyd-Jones, G. C.; Krska, S. W.; Hughes, D. L.; Gouriou, L.; Bonnet,
V. D.; Jack, K.; Sun, Y.; Reamer, R. A. Manuscript submitted for
publication. We thank Dr. Hughes for permission to quote this work.
(9) As given by the X-ray structure: Krska, S. W.; Hughes, D. L.; Reamer,
R. A.; Mahre, D. J.; Sun, Y. J. Am. Chem. Soc. 2002, 124, 12656.
(10) Sperber, N.; Papa, D.; Scwhwenk, E. J. Am. Chem. Soc. 1948, 70, 3091.
The high levels of regio-, diastereo-, and enantioselectivity
demonstrated in the Mo-catalyzed AAA reactions of oxalactims as
the nucleophile gives easy access to unusual R-hydroxy acids. It
should be noted that excellent stereocontrol occurs both with respect
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