Kinetic Resolution of Arylalkylcarbinols Catalyzed by a Planar-Chiral Derivative of DMAP: A New Benchmark for Nonenzymatic Acylation

Full text of DOI:10.1021/jo980183w

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J . Org. Chem. 1998, 63, 2794-2795
phenylethanol are highly dependent on solvent (eq 3).
Although we have not yet been able to correlate stereose-
lectivity with any single solvent parameter, it is clear that
tert-amyl alcohol is the solvent of choice for acylations
catalyzed by 1. Interestingly, tert-amyl alcohol itself is not
acylated to any significant extent under these conditions.
Kin etic Resolu tion of Ar yla lk ylca r bin ols
Ca ta lyzed by a P la n a r -Ch ir a l Der iva tive of
DMAP : A New Ben ch m a r k for Non en zym a tic
Acyla tion
J . Craig Ruble, J ennifer Tweddell, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received February 4, 1998
The kinetic resolution of alcohols by nonenzymatic acyl-
ation catalysts has been the focus of intense interest, and
within the past 2 years the first catalysts have been
described that provide useful levels of selectivity (s )
selectivity factor g 10).1,2 Members of three families of
secondary alcoholssarylalkylcarbinols,3-5 cycloalkanols,4,6
and allylic alcohols5shave now been resolved with good to
excellent enantioselection. For the kinetic resolution of
arylalkylcarbinols, the most effective and the most versatile
acylation catalyst reported to date is planar-chiral DMAP
derivative 1 (s ) 12-52; eq 1).5 In this paper, we describe
The enhanced rate of acylation in tert-amyl alcohol,
relative to the Et2O that was used in our previous study,
has important practical consequences. We had determined
earlier that the selectivity in kinetic resolutions catalyzed
by 1 is temperature dependent, with higher selectivity
observed at lower temperature. Unfortunately, acylations
using 2% catalyst in Et2O at 0 °C are too slow to be
convenient (several days), thereby precluding exploitation
of this temperature effect. On the other hand, we have
established that acylations in tert-amyl alcohol proceed at
a convenient rate at 0 °C, even using only 1% catalyst
(typically <24 h), and we have observed a marked improve-
ment in the selectivity factor under these conditions (27 f
43 for (()-1-phenylethanol). Thus, the net effect of these
studies is a tripling of selectivity (13 f 43) with one-half of
the previous catalyst loading.
modified reaction conditions under which catalyst 1 displays
greatly enhanced enantioselectivity, thereby establishing a
new benchmark for kinetic resolutions of arylalkylcarbinols
(s ) 32-95; eq 2); furthermore, we apply this system for
the first time to racemic and meso diols.
As is evident in Table 1, this substantial increase in
selectivity when kinetic resolutions with catalyst 1 are
conducted in tert-amyl alcohol at 0 °C has proved to be
general. As a point of reference, for selectivity factors
greater than 49, unreacted alcohol of greater than 99% ee
is obtained at less than 55% conversion. These kinetic
resolutions 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 atmo-
sphere with purified reagents. To date, other nonenzymatic
acylation catalysts have been effective (s g 10) for the kinetic
resolution of only two arylalkylcarbinolssphenyl-tert-butyl-
carbinol (s ) 12-15;3 cf. entry 2) and o-tolylmethylcarbinol
(s ) 12;4 cf. entry 5).
A wide-ranging solvent study established that both the
rate and the enantioselectivity of the acylation of (()-1-
(1) Selectivity factor ) [(rate of fast-reacting enantiomer)/(rate of slow-
reacting enantiomer)]. For a review of kinetic resolution, see: Kagan, H.
B.; Fiaud, J . C. Top. Stereochem. 1988, 18, 249-330.
(2) For reviews of enantioselective acylation of alcohols by enzymes,
see: (a) Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic Synthesis:
A Comprehensive Handbook; VCH: New York, 1995. (b) Wong, C.-H.;
Whitesides, G. M. Enzymes in Synthetic Organic Chemistry; Pergamon: New
York, 1994; Chapter 2. (c) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114-
120. (d) Sih, C. J .; Wu, S.-H. Top. Stereochem. 1989, 19, 63-125.
(3) Vedejs, E.; Daugulis, O.; Diver, S. T. J . Org. Chem. 1996, 61, 430-
431.
(7) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1997, 119, 2584-2585.
(8) Procedure for
a preparative-scale reaction (eq 4): o-Tolylmethyl-
carbinol (1.11 g, 8.14 mmol), tert-amyl alcohol (16 mL), and triethylamine
(0.67 mL, 4.8 mmol) were added to a flask containing (-)-1 (27.7 mg, 0.0419
mmol). After gentle heating to dissolve the catalyst, the reaction mixture
was cooled in an ice bath, and acetic anhydride (0.46 mL, 4.9 mmol) was
added by syringe. After 25.5 h, the reaction was quenched with MeOH (5
mL). The mixture was passed through a short plug of silica (50% f 100%
EtOAc/hexanes, then 10% NEt3/EtOAc) to separate the alcohol and the
acetate from the catalyst. The solution of alcohol and acetate was concen-
trated, and the resulting oil was purified by flash chromatography (5% f
25% Et2O/pentane), which provided 639 mg of acetate and 517 mg of alcohol.
GC analysis of the alcohol revealed a 93% ee of the S enantiomer. A sample
of the acetate was reduced with LiAlH4 to the alcohol, which GC analysis
revealed to be the R enantiomer in 90% ee.
(4) Oriyama, T.; Hori, Y.; Imai, K.; Sasaki, R. Tetrahedron Lett. 1996,
37, 8543-8546.
(5) Ruble, J . C.; Latham, H. A.; Fu, G. C. J . Am. Chem. Soc. 1997, 119,
1492-1493.
(6) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J . Am. Chem. Soc.
1997, 119, 3169-3170.
S0022-3263(98)00183-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/02/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2795
Ta ble 1. Kin etic Resolu tion of Ar yla lk ylca r bin ols
resolve a racemic diol as well as desymmetrize a meso diol.
In the case of the racemic diol, the cumulative effect of two
sequential enantioselective processes affords both diol and
diacetate in very high ee (g98% ee; eq 5). In the case of the
meso diol, the high stereoselectivity of catalyst 1 provides
the desymmetrized monoacetate in excellent ee and high
yield (eq 6).10
Ca ta lyzed by (-)-1
In conclusion, we have demonstrated that planar-chiral
DMAP derivative 1 catalyzes the kinetic resolution of
arylalkylcarbinols with remarkable efficiency. Interestingly,
the optimum solvent for this process is a tertiary alcohol,
tert-amyl alcohol. Our results define a new benchmark for
the nonenzymatic asymmetric acylation of arylalkylcarbinols,
both in terms of scope and of enantioselectivity. Significant
from a practical point of view are the high catalyst turnover
and the catalyst recoverability, as well as the low sensitivity
of the reaction to oxygen, moisture, and adventitious impuri-
ties.
a
The selectivity factors are averages of two or more runs. The
ee data are for specific runs.
With such high selectivity factors, it is now possible to
obtain both alcohol and acetate in excellent ee without
relying upon more complicated strategies such as parallel
kinetic resolution.7 Thus, the preparative-scale reaction
illustrated in eq 4 provides o-tolylmethylcarbinol and its
acetylated derivative in >90% ee.8 The catalyst loading in
this kinetic resolution is low (0.5%), and the catalyst recovery
is high (89%).
Ack n ow led gm en t. We thank the Buchwald group
(MIT) for generously sharing their GC and HPLC equip-
ment. Support has been provided by the Alfred P. Sloan
Foundation, the American Cancer Society, the Camille and
Henry Dreyfus Foundation, Eli Lilly, Firmenich, Glaxo
Wellcome, the National Institutes of Health (National
Institute of General Medical Sciences, R01-GM57034), the
National Science Foundation (predoctoral fellowship to
J .C.R.; Young Investigator Award to G.C.F., with funding
from Merck, Pharmacia & Upjohn, Bristol-Myers Squibb,
DuPont, Bayer, Rohm & Haas, and Novartis), the Natural
Sciences and Engineering Research Council of Canada
(predoctoral fellowship to J .T.), Pfizer, Procter & Gamble,
and the Research Corporation. Acknowledgment is made
to the donors of the Petroleum Research Fund, adminis-
tered by the ACS, for partial support of this research.
To date, there have been no reports of highly effective
asymmetric acylation of a diol by a nonenzymatic catalyst.9
We have now established that 1 can efficiently kinetically
(9) The best selectivity reported to date is for the acylation of meso-
hydrobenzoin (product of 68% ee at 84% conversion; ref 3).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and compound characterization data (25 pages).
(10) (a) For
a discussion and leading references, see: Kroutil, W.;
Kleewein, A.; Faber, K. Tetrahedron: Asymmetry 1997, 8, 3251-3261,
3263-3274. (b) Guo, Z.-W.; Wu, S.-H.; Chen, C.-S.; Girdaukas, G.; Sih, C.
J . J . Am. Chem. Soc. 1990, 112, 4942-4945. (c) Reference 1.
J O980183W