SCHEME 1. Substrate Steric and Electronic Preferences of
Previously Reported Catalyst 1a
which are very difficult for the acylated catalyst to distinguish
in the enantiodiscriminating acylation event; to the best of our
knowledge, no examples of the effective enantioselective
acylation of any such substrate promoted by a small molecule
nucleophilic catalyst is known.10 We have recently developed
a highly active, chiral 4-N,N-dialkylaminopyridine catalyst 1a
for the acylative kinetic resolution (KR)11 of sec-alcohols with
moderate to excellent enantioselectivity (up to s ) 30)12 which
exhibited an unusually strong preference for substrates contain-
ing either electron-rich carbonyl or aromatic moieties (Scheme
1).12 Attracted to the twin catalytic challenges of asymmetric
catalysis of BHRs involving electron-rich substrates (either
Michael acceptor or aldehyde) and the nonenzymatic KR of
sp2-sp2 sec-carbinols outlined above, we therefore decided to
evaluate 1a (and analogues) as a promoter of the KR of BH
adducts difficult to synthesize in high enantiopurity using current
benchmark catalytic methods.
In previous studies12 investigating the mode of action of 1a,
we demonstrated that both the catalyst hydroxyl group and
pendant aromatic moieties were required for high catalyst
selectivity. A π-π interaction between the phenyl and pyridine
rings (which strengthens considerably on either N-alkylation
or N-acylation of 1a) was also detected;12 however, its bearing
on the stereochemical outcome of the acylation event was not
fully explored. Given the inherent unsuitability of BHR adducts
as substrates in acylative KR processes (vide supra), we decided
to first investigate the influence of the steric/electronic properties
of the aromatic substituents on catalyst performance so that an
optimal catalyst structure could be identified for application in
the KR of BHR adducts.
Catalysts 1b-e were prepared13 and evaluated as promoters
of the KR of sec-alcohols 2, 7, and 8 (Table 1). It was expected
that significant augmentation of the steric bulk of the aromatic
substituents (i.e., catalyst 1b) would lead to more enantiose-
lective acylation (entries 1, 2, 6, and 7). However, in view of
the proposed contribution of a π-pyridinium cation interaction
to selectivity in reactions catalyzed by 1a,12 the clear, (reproduc-
ible) superiority of the catalyst equipped with electron-
withdrawing trifluoromethyl substituents (1e, entries 5 and 10)
over more electron-rich analogues (1c and 1d, entries 3, 4, 8,
and 9) was somewhat surprising.14 Gratifyingly, the readily
prepared catalyst 1e proved capable of resolving substrates
incorporating Lewis basic carbonyl moieties with synthetically
useful selectivity (s > 10, entries 10-12) at either 0 or
-78 °C, which allowed the recovery of either enantioenriched
or enantiopure (87-99.9% ee) alcohols with reasonable ef-
ficiency (23-40%).
With a superior catalyst (to 1a) in hand, attention now turned
to the question of the KR of BHR adducts. To examine the
potential utility of the proposed KR strategy, we decided to focus
on the resolution of adducts currently difficult to synthesize in
high enantiopurity using direct catalytic asymmetric BHRs.
Bearing this in mind, we selected BH adducts 9-12 (Table 2)
as candidates; these are derived from the coupling of Michael
acceptor substrates which (to the best of our knowledge) do
not readily participate in highly enantioselective organocatalytic
asymmetric BHRs, such as methyl acrylate and acrylonitrile,
with challenging, deactivated aromatic aldehydes (benzaldehyde
and o-anisaldehyde). We were pleased to find that both 1a and
1e were compatible with these aryl vinyl carbinol substrates;
treatment of acrylate 9 with substoichiometric loadings of
isobutyric anhydride and amine base in the presence of 1a or
(7) (a) Brown, J. M.; Cutting, I. J. Chem. Soc., Chem. Commun. 1985,
578. (b) Yamamoto, K.; Takagi, M.; Tsuji, J. Bull. Chem. Soc. Jpn. 1988,
61, 319. (c) Takaya, H.; Kitamura, M.; Kasahara, I.; Manabe, K.; Noyori,
R. J. Org. Chem. 1988, 53, 710. (d) Bailey, M.; Staton, I.; Ashton, P. R.;
Marko´, I. E.; Ollis, W. D. Tetrahedron: Asymmetry 1991, 2, 495. (e) Oishi,
T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6, 1241. (f)
Adam, W.; Hoch, U.; Saha-Mo¨ller, C. R.; Schreier, P. Angew. Chem., Int.
Ed. 1993, 32, 1737. (g) Burgess, K.; Jennings, L. D. J. Org. Chem. 1990,
55, 1138. (h) Basavaiah, D.; Dharma Rao, P. Synth. Commun. 1994, 24,
917. (i) Hayashi, H.; Yanagihara, K.; Tsuboi, S. Tetrahedron: Asymmetry
1998, 9, 3825. (j) Trost, B. M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc.
2000, 122, 3534. (k) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett.
2004, 6, 1337. (l) Du, Y.; Han, X.; Lu, X. Tetrahedron Lett. 2004, 45,
4967.
(8) Recent reviews: (a) Connon, S. J. Lett. Org. Chem. 2006, 3, 333.
(b) Jarvo, E. R.; Miller, S. J. In ComprehensiVe Asymmetric Catalysis,
Supplement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, Heidelberg, 2004; Chapter 43. (c) Miller, S. J. Acc. Chem.
Res. 2004, 37, 601. (d) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(9) Selected leading references: (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. 2003,
125, 4166. (d) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230. (e)
Garrett, C. E.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 7479.
(f) Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc. 1999,
121, 5091. (g) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem.
Soc. 1997, 119, 3169. (h) Kawabata, T.; Yamamoto, Y.; Yoshida, H.;
Nagaoka, Y.; Fuji, K. Chem. Commun. 2001, 2700. (i) Spivey, A. C.; Fekner,
T.; Adams, H. Tetrahedron Lett. 1998, 39, 8919. (j) Spivey, A. C.; Leese,
D. P.; Zhu, F.; Davey, S. G.; Jarvest, R. L. Tetrahedron 2004, 60, 4513.
(k) Oriyama, T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron Lett. 1998,
39, 3529. (l) Terakado, D.; Koutaka, H.; Oriyama, T. Tetrahedron:
Asymmetry 2005, 16, 1157. (m) Miller, S. J.; Copeland, G. T.; Papaioannou,
N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629. (n)
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6496. (o) Priem,
G.; Pelotier, B.; Macdonald, S. J. F.; Anson, M. S.; Campbell, I. B. J. Org.
Chem. 2003, 68, 3844. (p) Ishihara, K.; Kosugi, Y.; Akahura, M. J. Am.
Chem. Soc. 2004, 126, 12212. (q) Suzuki, Y.; Yamauchi, K.; Muramatsu,
K.; Sato, M. Chem. Commun. 2004, 2770. (r) Kano, T.; Sasaki, K.; Maruoka,
K. Org. Lett. 2005, 7, 1347. (s) Notte, G. T.; Sammakia, T.; Steel, P. J. J.
Am. Chem. Soc. 2005, 127, 13502. (t) Setizberg, J. G.; Dissing, C.; Søtofte,
I.; Norrby, P.-A.; Johannsen, M. J. Org. Chem. 2005, 70, 8332. (u) D´ıez,
D.; Gil, M. J.; Moro, R. F.; Garrido, N. M.; Marcos, I. S.; Basabe, P.;
Sanz, S.; Broughton, H. B.; Urones, J. G. Tetrahedron: Asymmetry 2005,
16, 2980. (v) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett. 2005,
46, 2239. (w) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C.
J. J. Am. Chem. Soc. 2004, 126, 12227. (x) Birman, V. B.; Jiang, H. Org.
Lett. 2005, 7, 2445. (y) Poisson, T.; Penhoat, M.; Papamicae¨l, D. G.; Dalla,
V.; Marsais, F. Synlett 2005, 2285.
(10) For (a lone) example, Vedejs et al. (ref 9c) have reported a phosphine
catalyst capable of promoting the enantioselective acylation of alkyl aryl
carbinols with outstanding selectivity (s ) 15-390). This catalyst promotes
the acylation of methyl mandelate with s ) 3.0 at rt.
(11) Kagan H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(12) (a) OÄ Da´laigh, C.; Hynes, S. J.; Maher, D. J.; Connon, S. J. Org.
Biomol. Chem. 2005, 3, 981. (b) (a) OÄ Da´laigh, C.; Hynes, S. J.; O’Brien,
J. E.; McCabe, T.; Maher, D. J.; Watson, G. W.; Connon, S. J. Org. Biomol.
Chem. 2006, 4, 2785.
(13) See Supporting Information for details.
(14) The reasons for this are unclear at present; however, it should be
noted that the electronic character of the aromatic substituents would also
influence the hydrogen bond donating/accepting characteristics of the
influential hydroxyl group.
J. Org. Chem, Vol. 72, No. 18, 2007 7067