A Reactivity/Affinity Switch for Parallel Kinetic Resolution: α-Amino Acid Quasienantiomers and the Resolution of Cyclopropene Carboxylic Acids

Article abstract of DOI:10.1021/ja049779t

A new type of parallel kinetic resolution (PKR) is reported in which quasienantiomers with very similar reactivities give products whose chromatographic properties diverge upon the addition of fluoride. This concept of a reactivity/affinity switch is applied to the PKR of cyclopropene carboxylic acids with all-carbon quaternary centers. This is the first application of α-amino acid quasienantiomers in PKR, and it is a complementary approach for acyltransfer systems where the asymmetry is induced by the nucleophile rather than the leaving group. Excellent diastereoselectivities (ranging from 90:10 to 99.5:5) and good yields were obtained for both quasienantiomeric products, and the reactions can be run on significant scale because the separation is trivial. High-level DFT calculations (B3LYP functional with the 6-31+G(d,p) basis set) provided transition-state structures with relative energies that are in accord with the experimental observations. Copyright

Full text of DOI:10.1021/ja049779t

Published on Web 03/20/2004
A Reactivity/Affinity Switch for Parallel Kinetic Resolution: r-Amino Acid
Quasienantiomers and the Resolution of Cyclopropene Carboxylic Acids
Lian-an Liao, Fan Zhang, Olga Dmitrenko, Robert D. Bach, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received January 13, 2004; E-mail: jmfox@udel.edu
We report here a new type of parallel kinetic resolution1 (PKR)
Scheme 1. Reactivity/Affinity Switch for PKR
in which quasienantiomers2 with very similar reactivities give
products whose chromatographic properties diverge upon the
addition of fluoride ion (Scheme 1). This idea of a reactivity/affinity
switch represents a complementary approach for acyltransfer
systems where the asymmetry is induced by the nucleophile rather
than the leaving group.1 This concept should be applicable to a
broad range of problems in kinetic resolution because the reactants
are derived from readily available amino acidssubiquitous as
sources of chirality in asymmetric synthesis but novel as reagents
for PKR. The specific application pursued in this contribution is
the PKR of cyclopropene carboxylic acids with all carbon quater-
nary centers. With high-level DFT calculations, we also make the
novel observation that the acyl transfer of an N-lithiated amide to
an anhydride proceeds by a concerted SN2 transition state in the
absence of the anticipated tetrahedral intermediate.
The inherent limitation of kinetic resolution is that both reactant
and product cannot be obtained in good yield and high ee unless
the efficiency of the reaction is exceptional [selectivity factor3 (s)
g100]. Quasienantiomersstetrahedral molecules that differ in
absolute stereochemistry and in the composition of one substitutents
can be powerful tools for overcoming this limitation through the
parallel kinetic resolution of a racemate.1 For idealized quasienan-
tiomers, the intrinsic diastereoselectivity can be observed regardless
of conversion; the dependence of ee and conversion3 is ameliorated
because both enantiomeric reactants are depleted simultaneously
to give separable quasienantiomeric products.
There are two fundamental requirements for a useful pair of
quasienantiomeric resolving agents: (1) both should react with
nearly identical rates and selectivities (i.e. chemo-, regio-, and
diastereoselectively) and (2) the quasienantiomeric products should
be easily separable on large scale. Designing an appropriate pair
of quasienantiomers is nontrivial because many functional groups
(e.g. hydroxyl, amino) that dramatically alter the solubilities and
chromatographic affinities of molecules also tend to alter their
reactivities. This dichotomy is further complicated by the practical
consideration that the quasienantiomers must be readily available.
Thus, while some elegant systems for quasienantiomer PKR have
been reported1a,4sincluding a three-phase catalytic system4asit is
still an infrequently used tool for synthesis.
Table 1. One-Pot Parallel Kinetic Resolution of Cyclopropenes
Although R-amino acids provide the basis for a remarkable
spectrum of asymmetric transformations, they have not been applied
in PKR. We recognized the potential utility of a number of
inexpensive amino acid quasienantiomers such as L-phenylalanine/
D-tyrosine, L-valine/D-threonine, and L-phenylglycine/D-p-hydroxy-
phenylglycine. For these pairs of amino acids, we reasoned that
the hydroxyl group of the latter quasienantiomer would significantly
alter the chromatographic affinity relative to the former. Moreover,
we felt that we could equate their reactivity by masking the hydroxyl
of the latter quasienantiomer as a silyl ether. This concept of using
a reactivity/affinity switch in PKR is outlined in Scheme 1 with
the specific example of oxazolidinone quasienantiomers in the PKR
of cyclopropene carboxylic acids. This approach is complementary
to that of Vedejs in which the asymmetry is derived from the
nucleofuge, and the products are distinguished through differential
reactivity of the transferred acyl groups.1 The strategy outlined here
should be generally useful when the asymmetry is induced by the
nucleophilesa situation where it is difficult to distinguish the
products through selective reactivity of their carbonyl groups.
The development of new methods for preparing enantiomerically
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J. AM. CHEM. SOC. 2004, 126, 4490-4491
10.1021/ja049779t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Diastereomeric Transition States from B3LYP
Scheme 2. Kinetic Resolution of Cyclopropene Mixed Anhydrides
[6-31+G(d,p)]
pure cyclopropenes fits within the context of our research program
to use the thermodynamic “currency” of high-strain molecules to
quickly generate molecular complexity. For example, we and others
have shown that cyclopropene carbometalation5a,b and hydro-
metalation5c,d reactions can be used to access highly functionalized
chiral cyclopropenes that cannot be prepared by cyclopropanation
of alkenes. Although racemic cyclopropene carboxylic esters can
be prepared easily and in quantity by the reactions of stabilized
diazo compounds with alkynes,6 methods that produce enantio-
merically enriched cyclopropenes are rare.7 The groups of Doyle,
Mu¨ller, and Shapiro have described catalytic asymmetric cyclo-
propenation reactions using chiral Rh-catalysts.7 For intermolecular
catalytic asymmetric cyclopropenation reactions, excellent en-
antioselectivities have been obtained for the reactions of several
terminal alkynes using [MEPY]4Rh2.7a.c.d Still, reactions that
produced enantiomerically enriched cyclopropenes with quaternary
centers were unknown prior to this work of our group and
concurrent work carried out by Davies and co-workers.8
transition state that leads to the major product is calculated to be
lower in energy by 1.1 kcal. Both transition structures are
characterized by single imaginary frequencies around 172i cm-1
,
the animation of which indicates both concerted C-N bond
formation and C-O bond cleavage. A notable difference between
the two structures is the distances between the alkene hydrogen
and that of C5 of the oxazolidinone. Efforts are underway to use
this observation in a predictive manner to further enhance selectiv-
ity.
We recently showed that oxazolidinones are remarkably useful
reagents for resolving diverse types of cyclopropene carboxylic
acids.9a The merits of this method are simplicity and generality,
while the limitation is that it is not amenable to multigram scale.
The optimized procedure included DMAP to catalyze the acyl-
transfer reaction. Serendipitously, we discovered a kinetic resolution
that took place when the DMAP was excluded from the reactions
an optimized example is shown in Scheme 2. Although the product
(2) was formed in a respectable 94:6 dr, the unreacted starting
material showed only 60% ee, as determined by conversion to 3.
The result could not be improved by changing the chiral oxazoli-
dinone. To make this a useful process for the resolution of
cyclopropenes, we applied the idea outlined in Scheme 1. Com-
mercially available oxazolinone 5S is inexpensive when purchased
in quantity, and quasienantiomer 6R can be synthesized on a 15-g
scale by a straightforward method. For a variety of cyclopropene
carboxylic acids that have all-carbon quaternary centers, the
diastereoselectivity is excellent (Table 1). Importantly, the parallel
kinetic resolutions can be carried out on significant scale by a simple
one-pot procedure. Thus, nearly 4 g of the quasienantiomers 7 and
8 were obtained after separation on a 1-in. diameter column of silica.
It is also shown in Table 1 that the oxazolidinone 6R can be
recovered in high yield upon LiBH4 cleavage (to give useful
3-hydroxymethylcyclopropenes5a) and treatment with TBSCl.
We have developed a model for the diastereomeric transition
states that are involved in the kinetic resolution of 4 with 5S
(Scheme 3). Calculations were performed with the B3LYP func-
tional with the 6-31+G(d,p) basis set. The development of the
models in Scheme 3 was multilayered and began with calculations
on acetic anhydride and oxazolidinone.9b For the present system
(with the minor modification from the experimental system that
t-Bu replaces adamantyl), multiple trajectories of nucleophilic attack
were studied. The lowest-energy transition states for each diaste-
reomer are displayed in Scheme 3. Concerted SN2-like addition to
carbonyl systems is well documented computationally and experi-
mentally (both solution and gas phase) for acyl transfer reactions
of strong nucleophiles with leaving groups that are better than
alkoxide.9b,c In accord with the experimental observation, the
Acknowledgment. This work was supported by NIH Grant
Number P20 RR017716-01 from the COBRE Program of the
NCRR. The computational work was supported by the NSF (CHE-
0138632) and by National Computational Science Alliance under
CHE990021N and utilized the NCSA SGI Origin2000 and Uni-
versity of Kentucky HP Superdome.
Supporting Information Available: Full experimental and char-
1
acterization details, H and 13C NMR spectra; archive data, Cartesian
coordinates, and total energies for the minima and transition states
described in this work. This material is available free of charge via the
Internet at http://pubs.acs.org.
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