5092 J. Am. Chem. Soc., Vol. 121, No. 21, 1999
Communications to the Editor
Figure 2. Bond distances (Å) for the (dimethylamino)pyridine fragment of (a) complex 1; (b) acetylated complex 1.
Table 3. Kinetic Resolutions of Propargylic Alcohols by 1% (-)-1
quantitative formation of the acylpyridinium salt. Disappointingly,
we were not able to obtain X-ray quality crystals of this salt.
However, exchange of chloride for SbF (through treatment with
AgSbF ) afforded a new acylpyridinium salt that proved to be
6
6
amenable to crystallization (Figure 1). To the best of our
knowledge, this is the first structural characterization of the
1
4
acylated form of a chiral, nonenzymatic acylation catalyst.
The NMe group, the pyridine ring, and the acetyl group of
2
the acylpyridinium ion lie approximately in a single plane, a
conformation consistent with extended conjugation (Figure 1).
The changes in bond lengths of the (dimethylamino)pyridine
fragment that are observed upon acylation are consistent with a
substantial contribution by resonance structure B (Figure 2).
Further support for significant conjugation is provided by the
increased rotational barrier about the Me N-C bond in the
2
‡
acetylated catalyst (∆G > 21 kcal/mol) as compared to the parent
‡
compound (∆G ≈ 10 kcal/mol).
Of the two possible rotamers of the acetyl group (about the
N(1)-C(11) bond, Figure 1), the one observed in the crystal
structure is consistent with minimization of steric interactions with
the fused five-membered ring (the oxygen of the acetyl is smaller
than the methyl).15 Finally, it is interesting to note that the two
cyclopentadienyl rings deviate from coplanarity by about 8°,
perhaps due to repulsion between the pyridine ring and the phenyl
a
The selectivity factors are averages of two runs.
5 5
substituents of the C Ph group; of course, sterically blocking one
In contrast to aryl alkyl carbinols, for which the selectivity factor
increases as the steric demand of the alkyl group increases,5a,b
for propargylic alcohols the selectivity factor decreases as the
steric demand increases (entries 1-4). Interestingly, substitutions
at positions far removed from the hydroxyl group can affect
enantioselection (entry 1 vs entries 5-7). Kinetic resolutions of
propargylic alcohols by catalyst 1 are more efficient when the
remote position of the alkyne is substituted with an unsaturated
group (e.g., aryl, carbonyl, alkynyl, alkenyl), rather than with an
alkyl group (selectivity factor for (()-3-octyn-2-ol: 3.9).
We have begun to pursue mechanistic studies of acylations
catalyzed by planar-chiral DMAP derivative 1. For reactions
catalyzed by DMAP itself, an acylpyridinium salt is believed to
be the active acylating agent.1 Unfortunately, for catalyst 1 as
face of the pyridine ring in an effective fashion is critical to the
asymmetry of these planar-chiral catalysts.16
In summary, we have described the first effective nonenzymatic
acylation catalyst for the kinetic resolution of propargylic alcohols.
This report thus adds a new family of substrates to the three
families that have previously been shown to be amenable to
kinetic resolutions of this type. In addition, we have provided
structural data regarding the acetylated form of catalyst 1, which
is likely a key intermediate in kinetic resolutions catalyzed by 1.
Future efforts will include studies directed at elucidating the origin
of enantioselectivity in these acylation processes.
Acknowledgment. We thank Michael Man-Chu Lo and Dr. William
M. Davis for assistance with X-ray crystallographic analysis. Support
has been provided by Bristol-Myers Squibb, Merck, the National Institutes
of Health (National Institute of General Medical Sciences, R01-
GM57034), the National Science Foundation (predoctoral fellowship to
J.C.R.), Pfizer, Pharmacia & Upjohn, and Procter & Gamble.
2,13
for DMAP, the equilibrium for a mixture of catalyst and Ac
(
2
O
1:1) strongly favors the starting materials.12 On the other hand,
use of a more reactive acylating agent such as AcCl leads to
(
10) Sample experimental: A vial containing 4-phenyl-3-butyn-2-ol (73.0
mg, 0.500 mmol) and catalyst (-)-1 (3.3 mg, 0.0050 mmol) in tert-amyl
Supporting Information Available: Experimental procedures, com-
pound characterization data, and X-ray crystallographic data (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
alcohol (1.0 mL) was capped with a septum and sonicated to help dissolve
the catalyst. The resulting purple solution was cooled to 0 °C, and Ac O (35.4
2
µL, 0.375 mmol) was added by syringe. After 49 h, the reaction was quenched
by the addition of a large excess of MeOH. The acetate was then separated
from the alcohol by column chromatography (10% f 50% EtOAc/hexanes;
JA9906958
the catalyst can be recovered by adding NEt
3
to the eluant). Analysis of the
(12) For reviews of the chemistry of DMAP, see: (a) Scriven, E. F. V.
Chem. Soc. ReV. 1983, 12, 129-161. (b) Hassner, A.; Krepski, L. R.;
Alexanian, V. Tetrahedron 1978, 34, 2069-2076. (c) H o¨ fle, G.; Steglich,
W.; Vorbr u¨ ggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569-583.
(13) For a crystal structure of acetylated DMAP, see: Jones, P. G.; Linoh,
K.; Blaschette, A. Z. Naturforsch. 1990, 45b, 267-270.
acetate by chiral GC revealed a 68.6% ee of the R enantiomer. The alcohol
was converted into the acetate and then analyzed by chiral GC, which revealed
a 96.0% ee of the S enantiomer. These ee values correspond to a selectivity
factor of 20.2 at 58.3% conversion.
(11) Notes: (a) The difference in selectivity factors that we report for the
kinetic resolution of 4-phenyl-3-butyn-2-ol (Table 1, entry 5 and Table 2,
entry 1: s ) 17; Table 3, entry 1: s ) 20) is due to a difference in the
concentrations at which the reactions were run (1.0 vs 0.5 M in 4-phenyl-3-
butyn-2-ol). (b) These reactions are not sensitive to small amounts of oxygen,
moisture, or adventitious impuritiessreactions run exposed to air with
unpurified reagents provide selectivities identical to those observed for
reactions run under an inert atmosphere with purified reagents. The catalyst
can be recovered in nearly quantitative yield at the end of the reaction. (c)
We observed lower selectivity when the kinetic resolutions were run in other
solvents.
(14) The SbF
chiral DMAP catalyst (s ) 2.1) preferentially acylate the same enantiomer of
4-phenyl-3-butyn-2-ol (CH Cl , NEt , rt; the comparison could not be
conducted in tert-amyl alcohol due to the insolubility of the SbF salt).
(15) NMR studies (presaturation difference NOE experiments in CD
indicate that this rotamer is also the only detectable rotamer in solution.
(16) For nonacylated catalyst 1, the cyclopentadienyl rings deviate from
6
acylpyridinium salt (s ) 2.5) and the corresponding planar-
2
2
3
6
2
2
Cl )
5 5
coplanarity by 10°; for the C Me analogue of catalyst 1, which provides
significantly lower selectivity factors in kinetic resolutions, the corresponding
angle is 2°.