Kinetic resolution of atropisomeric amides

Article abstract of DOI:10.1021/ja026436r

We have demonstrated the feasibility of the kinetic resolution of atropisomeric amides using the commercially avaliable AD-mix. To our knowledge, this methodology represents the first catalytic kinetic resolution of such compounds. Relative rates of up to

Full text of DOI:10.1021/ja026436r

Published on Web 08/10/2002
Kinetic Resolution of Atropisomeric Amides
Ramon Rios, Ciril Jimeno, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diane T. Vagelos Laboratories, UniVersity of PennsylVania, Department of Chemistry,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received April 5, 2002
Table 1. Kinetic Resolution of Atropisomeric Amides with the
Sharpless Asymmetric Dihydroxylation
As the field of asymmetric catalysis has matured, several types
of ligands have emerged that consistently form highly enantiose-
lective catalysts.1,2 The biaryl atropisomers BINOL3-5 and BI-
NAP3,6,7 are prominent members of this elite class. It is, therefore,
surprising that nonbiaryl atropisomers have only recently been
examined in asymmetric synthesis.8,9 The pioneering work of Curran
using atropisomeric anilides and imides showed that atropisomeric
compounds could exhibit excellent diastereoselectivity.10-12 Impres-
sive diastereoselectivity with nonbiaryl atropisomers has also been
realized by Simpkins,13,14 Clayden,15-17 and Taguchi.18-20 The
perpendicular architecture of atropisomeric anilides and benzamides
exerts powerful control over the generation of new stereogenic
centers.
The successful application of nonbiaryl atropisomers as chiral
auxiliaries alludes to the great potential of these, and related
compounds, as axially chiral ligands and catalysts.17,21 An impedi-
ment to the examination of this potential is the generation of
enantiopure atropisomers. Routes to benzamides and naphthamides
of high enantiopurity are currently based on enantio-13,17,22 or
diastereoselective15,16 reactions requiring stoichiometric chiral
reagents.10-12 With the goal of developing simple and direct
methods for the resolution of these compounds, we focused on their
catalytic kinetic resolution.23,24 To our knowledge there are no such
previous reports. This efficient kinetic resolution has allowed us
to isolate atropisomeric amides in high enantiopurity and to
determine their barriers to racemization.
Kinetic resolution of the olefins 1-8 was performed with the
Sharpless asymmetric dihydroxylation reaction (AD)25 employing
the commercially avaliable AD-mix-R and AD-mix-â [with (DHQ)2-
PHAL and (DHQD)2-PHAL ligands, respectively]. The AD has
been used with varying degrees of success in kinetic resolutions.26-31
We hoped that the preexisting chiral axis in the olefin substrates
would affect the relative rates of dihydroxylation of the enantiomers.
The reactions were performed at 0 °C or room temperature in
t-BuOH-H2O (1:1) at a concentration of 0.1 M substrate.25
Reactions were followed by removal of samples, workup, and
analysis. The extent of conversion was measured by 1H NMR, and
the ee’s of the olefins were determined by HPLC (Chiralcel OD-H
1, 4, 5, and 8; Pirkle 7) and shift reagent (2, 3, 6). Low-to-excellent
levels of kinetic enantioselection with krel up to 32 were realized
under these conditions (Table 1).
The krel values in Table 1 are particularly important because they
are the relative rates of oxidation of the fast- versus slow-reacting
enantiomers. The relative rate constants (krel) enable one to calculate
the degree of conversion necessary to obtain the desired enantiopu-
rity.24 Our most impressive results were obtained for R,â-unsatur-
ated ester 2, affording a krel of 32 (AD-mix R). Thus, at 57%
a Syntheses of 1-8 are outlined in the Supporting Information.
conversion, 2 would have 98% ee. By reacting 5 with AD-mix-R,
we isolated 5 of 94% ee in 36% yield.
Several trends are apparent from the data in Table 1. Kinetic
resolutions with (DHQ)2-PHAL are more effective with benzamides
while the diastereomer (DHQD)2-PHAL is more efficient with
naphthamides. In general, benzamide derivatives are superior
substrates for the kinetic resolution with the Sharpless AD than
are analogous naphthamides. Decreasing the size of the N,N-dialkyl
groups from isopropyl to ethyl resulted in lower krel values for the
benzamide 3 (vs 2) and higher values for the naphthamide 8 (vs
7). The presence of the o-trimethylsilyl group in 6 significantly
lowers the barrier to atropisomerization, and no kinetic resolution
of 6 was detected. It is possible that the silicon facilitates
racemization by coordinating the carbonyl oxygen in the transition
state.32
An intriguing result was realized in the kinetic resolution of
terminal olefin 1. Examination of the diol products after consump-
tion of the olefin was complete indicated that the initial diastereo-
selectivity was 4.8:1. It decreased slightly after 24 h at 23 °C to
4.1:1 due to slow epimerization about the chiral axis. Heating the
* Author to whom correspondence may be addressed. E-mail: pwalsh@
sas.upenn.edu.
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J. AM. CHEM. SOC. 2002, 124, 10272-10273
10.1021/ja026436r CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
In summary, we have demonstrated the feasibility of the kinetic
resolution of atropisomeric amides using the commercially avaliable
AD-mix. To our knowledge, this methodology represents the first
catalytic kinetic resolution of such compounds. The resolution of
the amides examined here would be difficult to otherwise achieve.
Their half-lives to racemization range from 7 to 135 h at 23 °C.
Such data is essential in the construction of ligands for asymmetric
catalysis from these precursors.
Acknowledgment. This paper is dedicated to Professor Charles
L. Perrin (UCSD) for his inspirational teaching and research. This
work was supported by the Petroleum Research Fund.
Supporting Information Available: Substrate preparation, AD
procedure, and ee analyses (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Figure 1. The X-ray structures of 1 and the major diastereomer formed
on its dihydroxylation are shown (top). The proposed reactive conformation
of 1, B, is illustrated (bottom).
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