Kinetic resolution of alcohols using a 1,2-dihydroimidazo[1,2-a]quinoline enantioselective acylation catalyst

Article abstract of DOI:10.1021/ol051063v

(Chemical Equation Presented) A new enantioselective acylation catalyst (CI-PIQ), designed to provide enhanced π-stacking with benzylic and cinnamyl alcohol substrates, was found to give considerably increased reaction rates and selectivities compared with the first-generation catalyst CF₃-PIP.

Full text of DOI:10.1021/ol051063v

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3445-3447
Kinetic Resolution of Alcohols Using a
1,2-Dihydroimidazo[1,2-a]quinoline
Enantioselective Acylation Catalyst
Vladimir B. Birman* and Hui Jiang
Department of Chemistry, Washington UniVersity, Campus Box 1134,
One Brookings DriVe, St. Louis, Missouri 63130
birman@wustl.edu
Received May 9, 2005
ABSTRACT
A new enantioselective acylation catalyst (Cl-PIQ), designed to provide enhanced
π-stacking with benzylic and cinnamyl alcohol substrates,
was found to give considerably increased reaction rates and selectivities compared with the first-generation catalyst CF3-PIP.
We have recently reported a new class of enantioselective
acylation catalysts based on the 2,3-dihydroimidazo[1,2-a]-
pyridine (DHIP) core. One of these easily accessible
compounds, 2-phenyl-6-trifluoromethyl-dihydroimidazo[1,2-
a]pyridine (1, abbreviated as CF3-PIP), proved to be par-
ticularly effective in kinetic resolution of secondary benzylic
alcohols (Figure 1). Our experimental data suggested that
Having achieved good selectivities with benzylic alcohols
(s ) 20-85), we decided to explore kinetic resolution of
other classes of secondary alcohols that are capable of
π-stacking.4,5 In particular, we were curious whether cin-
(2) For leading references to other nonenzymatic asymmetric acylation
catalysts, see: (a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (b) Vedejs, E.;
Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166. (c) Kawabata, T.; Stragies,
R.; Fukaya, T.; Nagaoka, Y.; Schedel, H.; Fuji, K. Tetrahedron Lett. 2003,
44, 1545. (d) Terakado, D.; Koutaka, H.; Oriyama, T. Tetrahedron:
Asymmetry 2005, 16, 1157. (e) Miller, S. J. Acc. Chem. Res. 2004, 37,
601. (f) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R.
L. J. Org. Chem. 2003, 68, 7379. (g) Naraku, J.; Shimomoto, N.; Hanamoto,
T.; Inanaga, J. Enantiomer 2000, 5, 135. (h) Lin, M.-H.; RajanBabu, T. V.
Org. Lett. 2002, 4, 1607. (i) Priem, G.; Pelotier, B.; Macdonald, S. J. F.;
Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003, 68, 3844. (j) Jeong,
K.-S.; Kim, S.-H.; Park, H.-J.; Chang, K.-J.; Kim, K. S. Chem. Lett. 2002,
1114. (k) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am.
Chem. Soc. 2003, 125, 2052. (l) Mizuta, S.; Sadamori, M.; Fujimoto, T.;
Yamamoto, I. Angew. Chem., Int. Ed. 2003, 42, 3383. (m) Suzuki, Y.;
Yamauchi, K.; Muramatsu, K.; Sato, M. Chem. Commun. 2004, 2770. (n)
Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004, 126, 12212.
(o) Dalaigh, C. O.; Hynes, S. J.; Maher, D. J.; Connon, S. J. Org. Biomol.
Chem. 2005, 3, 981. (p) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005,
7, 1347. (q) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett. 2005, 46,
2239.
Figure 1. CF3-PIP, the best first-generation catalyst.
the chiral recognition in this process was dependent on the
π-π and cation-π interactions between the reactive acylated
intermediate and the aryl moiety in the substrate. This led
us to propose transition state model 1a.1-3
(3) Recent reviews: (a) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
2005, 44, 3974. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138. (c) 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. (d) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003,
103, 2985. (e) Spivey, A. C.; Maddaford, A.; Redgrave, A. J. Org. Prep.
Proc. Int. 2000, 32, 331.
(1) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J.
Am. Chem. Soc. 2004, 126, 12226.
10.1021/ol051063v CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/14/2005

cinnamyl substrate, â-styryl methyl carbinol 6, proceeded
much more slowly and less selectively than that of phenyl
methyl carbinol 12 (Table 1, entries 1 and 7). This result is
not surprising considering that the phenyl group in 6 is
positioned too far to interact with the pyridinium moiety of
the catalyst, while π-stacking with the olefin is less efficient
than with an aromatic ring. It occurred to us that extending
the π-system of the catalyst might provide a simple and
effective solution to this problem (Figure 2).
Table 1. Kinetic Resolution of Alcohols Catalyzed by CF3-PIP
1 and Cl-PIQ 2
Figure 2. Design of the second-generation catalyst.
On the basis of our experience with catalysts in the DHIP
series, where variation of the electron-withdrawing group at
C6 was used to fine tune the system to achieve the maximum
catalytic activity and the phenyl group at the C2 chiral center
proved to be optimal for the enantioselectivity,6 we decided
to prepare and test the 2-phenyl-7-chloro derivative of the
1,2-dihydroimidazo[1,2-a]quinoline (DHIQ) tricyclic core.7
Its synthesis from the commercially available 2,6-dichloro-
quinoline 3 and (R)-phenylglycinol 4 was achieved in excel-
lent yield via the standard two-step procedure previously used
to obtain DHIP derivatives1 (Scheme 1). We were pleased
Scheme 1. Preparation of Cl-PIQ (2)a
a Reagents and conditions: (a) i-Pr2NEt, 130 °C, 2.5 days, 87%,
(b) SOCl2, CHCl3, reflux, then NaHCO3, NaOH, 91%.
to observe that both the selectivity and the reaction rate
improved dramatically when the kinetic resolution of 6 was
a Conditions: 1.0 M substrate, 0.75 M (EtCO)2O, 0.75 M i-Pr2NEt, 0.02
M catalyst, CHCl3, 0 °C. b Conditions: 1.0 M substrate, 0.75 M (EtCO)2O,
0.75 M i-Pr2NEt, 0.1 M catalyst, CDCl3, 0 °C. c Data from previous work.1
(4) Allylic alcohols, both with and without aryl substituents, have been
previously resolved via catalytic enantioselective acyl transfer: (a) Ruble,
J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492. (b)
Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794. (c)
Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.; Fu, G.
C. Chem. Commun. 2000, 1009. (d) Vedejs, E.; MacKay J. A. Org. Lett.
2001, 3, 535; (e) ref 2p. (f) ref 2q.
namyl alcohols would be resolved with useful levels of
enantioselectivity. Under the standard set of conditions, CF3-
PIP-catalyzed enantioselective acylation of the simplest
(5) Propargylic alcohols have also been resolved: (a) Tao, B.; Ruble, J.
C.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 5091; (b) ref 2q.
3446
Org. Lett., Vol. 7, No. 16, 2005

performed using the new catalyst (2, abbreviated Cl-PIQ)
instead of CF3-PIP (entry 1). At this point, we decided to
compare the two catalysts systematically, using both cin-
namyl (entries 1-6) and benzylic (entries 7-12) substrates.
As can be seen from the data collected in Table 1, the use
of Cl-PIQ results in acceleration of the reaction rates relative
to those with CF3-PIP in all cases studied. The enantiose-
lectivities are also noticeably enhanced in most of the cases
(up to 5-fold, in entry 5).
As may be expected, the influence of the substitution
pattern of the substrates on the selectivity follows roughly
similar trends with both of the catalysts. However, several
cases are worthy of special comment.
Comparison of the results obtained with o-methoxyphenyl
substrate 10 and its conformationally restricted analogue 11
(entries 5 and 6, respectively) suggests that the coplanarity
of the aromatic ring and the double bond is important for
both the reaction rate and the enantioselectivity. This factor
probably contributes to the generally lower conversions and/
or selectivities observed with cinnamyl alcohols (entries 1-4)
compared with their benzylic counterparts (entries 7 and 9),
especially when a methyl group is introduced cis to the
phenyl (entries 3 and 4).
2-Naphthyl methyl carbinol 16, which we had expected
to provide “the perfect fit” with the quinolinium moiety of
Cl-PIQ, was indeed resolved with excellent selectivity (s )
74) and reached 51% conversion in only 2 h using the new
catalyst. This result constituted a significant improvement
over that obtained with CF3-PIP (entry 11). In contrast,
1-naphthyl methyl carbinol, in which the second benzene
ring cannot participate in π-stacking effectively, produced
similar conversions and selectivities with both catalysts (entry
12).
Finally, we decided to test whether an unconjugated allylic
alcohol could be resolved using our catalysts. Cyclohexenyl
methyl carbinol 18 was found to react much more slowly
than benzylic or cinnamyl alcohols, as might be expected
on the basis of the proposed model and earlier observations
by Fu et al.4c Therefore, increased catalyst loadings (10 mol
%) were employed to obtain comparable reaction rates (entry
13). Once again, Cl-PIQ proved to be more effective than
CF3-PIP. Although the conditions have not yet been opti-
mized, these results demonstrate that the new catalyst is
suitable for the kinetic resolution of allylic alcohols lacking
an aryl substituent. A detailed investigation of the structure-
selectivity trends in this series will be the subject of future
studies.
In conclusion, the second generation catalyst Cl-PIQ,
rationally designed to address certain limitations of CF3-PIP,
has fulfilled our expectations. Studies aimed at the explora-
tion of its usefulness in enantioselective acylation of other
classes of substrates, as well as further optimization of the
DHIQ-based catalyst design, are currently underway.8
Acknowledgment. We thank NIGMS (NIH Grant R01
GM072682) and Washington University for providing fi-
nancial support for this study. Mass spectrometry was
provided by the Washington University Mass Spectrometry
Resource, an NIH Research Resource (Grant P41RR0954).
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(6) Birman, V. B.; Li, X.; Jiang, H.; Uffman, E. W. Tetrahedron 2005,
Symposium-in-Print on Organocatalysis, in press.
OL051063V
(7) (a) Preparation of the unsubstituted DHIQ: Grout, R. J.; Hynam, B.
M.; Partridge, M. W. J. Chem. Soc., Perkin Trans. 1 1973, 1314. (b)
Preparation of racemic 2-phenyl-DHIQ: Cookson, R. F.; Nowotnik, D. P.;
Parfitt, R. T.; Airey, J. E.; Kende, A. S. J. Chem. Soc., Perkin Trans. 1
1976, 201.
(8) Part of this work has been presented: Birman, V. B.; Jiang, H.
Abstracts of Papers, 229th National Meeting of the American Chemical
Society, San Diego, CA, March 13-17, 2005; American Chemical
Society: Washington, DC, 2005; ORGN 313.
Org. Lett., Vol. 7, No. 16, 2005
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