Development of Chiral Nucleophilic Pyridine Catalysts: Applications in Asymmetric Quaternary Carbon Synthesis

Article abstract of DOI:10.1021/ja037223k

TADMAP (1a), a new chiral DMAP catalyst, has been designed to place a C(3)-benzylic trityl group over one face of the pyridine ring, while a C(3)-benzylic acetoxy group creates a chirotopic environment on the other face. TADMAP was prepared in four steps

Full text of DOI:10.1021/ja037223k

Published on Web 10/11/2003
Development of Chiral Nucleophilic Pyridine Catalysts: Applications in
Asymmetric Quaternary Carbon Synthesis
Scott A. Shaw, Pedro Aleman, and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received July 11, 2003; E-mail: edved@umich.edu
Organocatalysis is an important strategy in asymmetric synthesis.1-8
One of the most intensively studied areas is acyl transfer using
chiral nucleophiles,6-8 including chiral trialkylamines,9 synthetic
peptides,10 and phosphines.11 Chiral (dimethylamino)pyridine (DMAP)
analogues have been particularly attractive targets, in view of
DMAP’s broad utility.12 Early work with chiral 2-substituted DMAP
derivatives13 demonstrated that the derived N-alkoxycarbonyl
pyridinium salts are enantioselective carboxylating agents. However,
steric hindrance from the 2-substituent inhibits catalytic turnover.
Soon thereafter, Fu and co-workers reported the synthesis of a
family of ferrocene-fused DMAPs14 and demonstrated their use in
Figure 1. Ab initio geometry of acyl pyridinium 2.19
Enantiomerically pure 1a was obtained via classical resolution.
a variety of catalytic asymmetric processes with impressive levels
of stereocontrol. Examples of atropisomeric biaryl DMAPs6,15 and
DMAP analogues containing chiral amino groups16-18 have since
been reported. Several of these newer catalysts are capable of
moderate to high levels of selectivity in acyl transfer reactions.
With the goal of developing an enantioselective DMAP catalyst
that would be easily synthesized in enantiomerically pure form,
we chose to study a new class of chiral pyridine derivatives 1. It
was hypothesized that the corresponding N-acylpyridinium inter-
mediate 2 would be restricted to a geometry where the dialkylamino
group is nearly coplanar with the pyridine ring, thereby maximizing
nitrogen lone pair delocalization. The benzylic substituents would
rotate to place the bulky trityl group on one open face of the pyridine
ring and orient the benzylic hydrogen toward the ortho-dialkylamino
group. In this conformer, the acetoxy group creates a chirotopic
environment on the other face of the pyridine ring. Support for
this geometry is provided by an ab initio evaluation of pyridinium
ion 2 (Figure 1), shown as the most stable conformer located thus
far.19 Catalysts 1 should be readily available in modular fashion
from 3-halopyridines, triarylacetaldehydes, and anhydrides and
should therefore be amenable to easy variation.
Treatment of racemic 1a with 0.5 equiv of (-)-camphorsulfonic
acid (CSA) in toluene produced enantiomerically enriched crystals
of [(R)-1a‚(-)-CSA] that were neutralized using NaOH. Repeating
this procedure on the scalemic material led to (R)-1a in >99% ee.22
The (S)-1a enriched mother liquor of the initial crystallization was
treated analogously with (+)-CSA, producing (S)-1a in >96% ee.
When this procedure was used, 7.4 g of racemate was resolved to
give 0.7 g of (R)-1a (>99% ee) and 1 g of (S)-1a (98.3% ee), with
4.7 g of scalemic 1a available for further resolution (>85% recovery
through the crystallization sequence).
The first test of catalyst 1a was the enantioselective Steglich
rearrangement of enol carbonates 423 to azlactones 5, containing
an asymmetric quaternary carbon.24 Fu and Ruble have reported
good results in this reaction using a chiral pyridine catalyst.25
Treating alanine derived oxazoles 4a or 4b with catalyst 1a (room
temperature, CH2Cl2) showed that phenoxycarbonyl migrates with
higher selectivity than benzyloxycarbonyl (5a, 73% ee vs 5b, 30%
ee). As in the analogy of Fu and Ruble,25 t-amyl alcohol at 0 °C
gave the best results overall, affording 5a in 92% yield and 91%
ee (1 mol % of catalyst 1a), but the solvent effect was small.26
With these optimized conditions, a variety of oxazole enol
carbonates 4a-j were tested (Table 1), comparing the results with
those using the nucleophilic phosphabicyclooctane (PBO) catalyst
6, developed earlier in our laboratory for enantioselective acyl
transfer.11b The benzyloxycarbonyl group was better suited for
migration reactions catalyzed by 6, in contrast to the result with
1a (best with phenoxycarbonyl). The migration reactions proceeded
in excellent yield and enantioselectivity using either 1a or 6 as the
catalysts for substrates having an unbranched methylene side chain
(4a-h). For phenyl-substituted oxazoles 4i-j, the selectivity was
diminished.
The synthesis of racemic 1a (“TADMAP”; short for 2,2,2-
triphenyl-1-acetoxyethyl DMAP) began with the conversion of
triphenylacetic acid to triphenylacetaldehyde (eq 1).20 This aldehyde
To probe the sense of absolute stereochemistry for the carboxyl
migrations, the azlactone products ent-5a (from 4a and (S)-1a)
and 5b (from 4b and 6) were converted into the same disubsti-
tuted malonate 7 (Figure 2). This was accomplished via nucleophilic
ring opening, starting from ent-5a and benzyl alcohol, or from 5b
and phenol. The stereochemistry of the TADMAP-catalyzed
process could then be deduced from the sign of optical rotation
reported for 5b.25
was then treated with the aryllithium derived from 3-bromo-4-
(dimethylamino)pyridine,21 and the resulting alkoxide was quenched
with acetic anhydride. Racemic 1a was prepared on gram scale in
four steps (37% overall yield). No chromatography was required
until the final aryllithium coupling reaction.
The scope of asymmetric carboxyl migration with TADMAP
(1a) was briefly explored using several heteroaromatic enol
9
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J. AM. CHEM. SOC. 2003, 125, 13368-13369
10.1021/ja037223k CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Spanish Ministry of Education and Culture. The authors also thank
Mr. J. Christy and Mr. P. Va for their contributions to carboxyl
migration experiments.
Supporting Information Available: Experimental procedures and
characterization (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Table 1. Azlactone Acyl Migration
substrate
R
R′
catalysta
% yield
% ee
References
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
Me
Bn
Ph
Bn
Ph
Bn
Ph
Bn
Ph
Bn
Ph
Bn
1a
6
1a
6
1a
6
1a
6
95
88
99
90
90
91
90
87
95b
96
91
89
95
90
91
90
91
92
58
20
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Bn
allyl
allyl
iBu
iBu
Ph
1a
6
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Ph
2003, 125, 1192 and references therein.
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a 1 mol % (R)-1a or 10 mol % 6, t-amyl alcohol, 0 °C. b Yield determined
by NMR.
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7394.
Figure 2. Determination of product stereochemistry.
carbonates. Furan enol carbonate 8 rearranged (eq 3) to give a 10:1
mixture of R- and γ- C-carboxylated isomers 9 (83%; 90% ee) and
10 (7%; 80% ee). Furanone 9 is potentially useful, as three of the
quaternary carbon substituents should be readily elaborated.
Analogous DMAP-catalyzed carboxyl migrations of benzofuran and
indole derived enol carbonates related to 11 have also been
reported.14g,27,28 Preliminary results using our catalyst 1a are
promising. Fair to excellent levels of enantioselectivity were
observed in the benzofuranone and oxindole products (Table 2),
although the reactions from 11c (24 h) or 11d (18 h) were relatively
slow using 10% of the catalyst.
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(19) This conformer is representative of several local energy minima found
for 2 (R ) Me, R′ ) OPh, Ar ) Ph) that have similar geometry (B3LYP/
6-31G*).
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Table 2. Benzofuranone and Oxindole Acyl Migration
substrate
solvent
temp (°C)
% yield
% ee
(21) Groziak, M. P.; Melcher, L. M. Heterocycles 1987, 26, 2905.
(22) Absolute stereochemistry determined by X-ray crystallography for the salt
of dibenzoyl-(L)-tartaric acid with (S)-1.
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(26) Toluene, Et2O, and THF also produced acceptable results (84-89% ee).
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Chem. 1987, 52, 5425.
11aa
11bb
11cc
11dc
Et2O
23
-40
23
92
92
92
86
49
86
CH2Cl2
t-amyl alc.
t-amyl alc.
40
93
a 1 mol % 1a. b 20 mol % 1a, 95% cat. recovered. c 10 mol % 1a.
Work is underway to further develop the new family of chiral
catalysts, to expand the scope of acyl migration applications, to
better understand the basis for enantioselectivity, and to evaluate
several options for the enantioselective synthesis of 1.
(28) Porcs-Makkay, M.; Argay, G.; Ka´lma´n, A.; Simig, G. Tetrahedron 2000,
56, 5893.
Acknowledgment. This work was supported by the National
Science Foundation, and by a fellowship provided to P.A. by the
JA037223K
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