C O M M U N I C A T I O N S
we expected that choosing a substituent with an intermediate σ
value8 would be optimal both for the overall catalytic activity and
for the enantioselectivity. Indeed, CF3-PIP 1d9 fulfilled our expecta-
tions (s ) 14 and 38% conversion after 1 h, entry 4).
not only as a novel structural basis for rationally designing new
catalysts, but also as a tool for probing the details of the mechanism
of asymmetric recognition. Further studies aimed at refining the
current model and exploration of the use of DHIP-based catalysts
in asymmetric catalysis are currently underway in our laboratory.
Addition of i-Pr2NEt as an auxiliary base significantly increased
the reaction rate, so that it became possible to use only 2 mol %
catalyst loadings and lower the reaction temperature to 0 °C. Under
these conditions, acetylation of PhCH(OH)Et proceeded with 17:1
selectivity and reached 43% conversion after 8 h. Selectivity was
lower in the case of PhCH(OH)Me and higher in the acetylation
of PhCH(OH)-i-Pr (entries 5-7). Judging from these data, the
discrimination appeared to take place between the hydrogen and
the alkyl group of the substrate, rather than between the phenyl
and the alkyl. As a working hypothesis, we proposed that the aryl
group of the substrate stacks on top of the pyridinium ring of the
catalyst,10 while the alkyl group is repelled from the acyl portion
for steric reasons (Figure 1).
Acknowledgment. V.B.B. thanks Drs. S. R. Gilbertson, T. J.
Kappock, G.R. Marshall, K. D. Moeller, and J.-S. Taylor for
stimulating discussions and equipment. This study was sponsored
by Washington University.
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
References
(1) (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (b) Sih,
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Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769.
(2) For reviews, see: (a) Jarvo, E. R.; Miller, S. J. Asymmetric Acylation. In
ComprehensiVe Asymmetric Catalysis, Supplement 1; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Heidelberg,
2004; Chapter 43. (b) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. ReV. 2003, 103, 2985. (c) Spivey, A. C.; Maddaford, A.; Redgrave,
A. J. Org. Prep. Proced. Int. 2000, 32, 331. (d) Somfai, P. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2731.
(3) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (b) Vedejs,
E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430. (c) Vedejs,
E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813. (d) Shaw, S. A.;
Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368. (e) Ruble,
J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230. (f) Ruble, J. C.; Latham,
H. A.; Fu, G. J. Am. Chem. Soc. 1997, 119, 1492. (g) Fu, G. C. Acc.
Chem. Res. 2000, 33, 412. (h) Oriyama, T.; Hori, Y.; Imai, K.; Sasaki, R.
Tetrahedron Lett. 1996, 37, 8543. (i) Oriyama, T.; Taguchi, H.; Terakado,
D.; Sano, T. Chem. Lett. 2002, 26. (j) Kawabata, T.; Nagato, M.; Takasu,
K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. (k) Kawabata, T.; Stragies,
R.; Fukaya, T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron Lett. 2003,
44, 1545. (l) Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann,
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Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154. (o) Spivey, A. C.;
Maddaford, A.; Fekner, T.; Redgrave, A. J.; Frampton, C. S. J. Chem.
Soc., Perkin Trans. 1 2000, 14, 3460. (p) Spivey, A. C.; Zhu, F.; Mitchell,
M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68, 7379. (q)
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Figure 1. Transition state model.
On the basis of this model, increasing the size of R′ was expected
to result in a greater steric repulsion of the R2 group. Indeed, the
use of propionic anhydride instead of Ac2O resulted in a consider-
able improvement of selectivity (entries 8-10).11 Under these
conditions, phenyl t-butyl carbinol was resolved with selectivity
factor of 85 (entry 11). Substitution of the aromatic ring was varied
to investigate the influence of the electronic and steric factors on
the selectivity and the reaction rates (entries 12-17). Not unexpect-
edly, cyclohexyl methyl carbinol containing no aromatic ring and
1-indanol, which cannot adopt the required conformation in the
transition state, proved to be ineffective substrates (entries 18 and
19).12 Chloroform is currently the solvent of choice, producing both
high reaction rates and selectivities (Table 2). Kinetic resolutions
using CF3PIP can be easily scaled up13 and are carried out using
reagent grade solvents under air atmosphere.
(4) AM1 calculations indicated ca. 4.5 kcal/mol preference for rotamer 2b
over 2a (X ) CF3, R ) Ph, R′ ) Et).
(5) (a) Bremer, O. Annalen 1936, 521, 286. (b) Copp, F. C.; Timmis, G. M.
J. Chem. Soc. 1955, 2021. (c) Weiner, N.; Kaye, I. A. J. Org. Chem.
1949, 14, 868. (d) For general reviews of DHIP derivatives, see: Sulojeva,
E.; Yure, M.; Gudriniece, E. Chem. Heterocycl. Compd. 1999, 35, 1121
and 2000, 36, 885.
(6) Canibano, V.; Rodriguez, J. F.; Santos, M.; Sanz-Tejedor, M. A.; Carreno,
M. C.; Gonzalez, G.; Garcia-Ruano, J. L. Synthesis 2001, 2175.
(7) Prepared by arylation of 3a with 2-chloro-5-nitropyridine (NEt3, EtOH,
reflux, 92% yield) followed by cyclization (98%).
Table 2. Selectivities in Different Solventsa
(8) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96.
entry
solvent
conversion %
selectivity
(9) Prepared by arylation of 3a with 2-chloro-5-trifluoromethylpyridine
(i-Pr2NEt, neat, 110 °C, 66% yield) followed by cyclization (85%). Both
reagents are available from Aldrich. (R)-Phenylglycinol costs $215.30/
25 g and 2-chloro-5-trifluoromethylpyridine costs $58.70/50 g.
(10) For reviews of π-π and cation-π interactions, see: (a) Hunter, C. A.;
Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc., Perkin Trans. 2
2001, 651. (b) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303.
(11) Further increase in the size of R′ (using (n-PrCO)2O, (i-BuCO)2O, and
(i-PrCO)2O) led to lower selectivities than with (EtCO)2O.
1
2
3
4
5
6
CHCl3
Et2O
PhMe
CH2Cl2
tert-amyl alcohol
MeCN
39
27
30
30
18
20
36
40
36
24
23
11
(12) Similar observations have been made using Vedejs’s phosphine catalyst3c
and Fu’s planar-chiral catalyst: Ruble, J. C. Ph.D. Thesis, Massachusetts
Institute of Technology, Cambridge, MA, 1999.
a Conditions: 1M (()-PhCH(OH)Et, 0.75 M (EtCO)2O, 0.75 M i-Pr2NEt,
0.02M 1d, 0 °C, 8 h.
(13) Preparative-scale resolution of 1-naphthyl methyl carbinol (2.416 g, 14.0
mmol) gave the ester in 52% yield and 82.5% ee and the unreacted alcohol
in 45% yield and 98.8% ee, which corresponds to 54% conversion and
52:1 selectivity. 68% of the catalyst was recovered. See Supporting
Information for more details.
In conclusion, we have developed a new class of effective
enantioselective acylation catalysts based on the previously unex-
plored 2,3-dihydroimidazo[1,2-a]pyridine structure. The ease of
preparation of chiral derivatives of the DHIP core make it valuable
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