J. Am. Chem. Soc. 1997, 119, 3169-3170
3169
Nonenzymatic Kinetic Resolution of Racemic
Alcohols through an “Induced Fit” Process
Takeo Kawabata, Minoru Nagato, Kiyosei Takasu, and
Kaoru Fuji*
Institute for Chemical Research
Kyoto UniVersity, Uji, Kyoto 611, Japan
Figure 1. 1H NMR study of 1 (A) and its acyliminium ion (B) in
CDCl3 at 20 °C. Arrows denote the observed NOEs. In A, protons Ha,
Hb, and Hc, Hd appear at δ 8.01 and 6.37 ppm, respectively. In B,
protons Ha, Hb, Hc, and Hd appear independently at δ 7.45, 8.73, 5.69,
and 6.87 ppm, respectively.
ReceiVed September 17, 1996
Enzymatic kinetic resolution of racemic alcohols through
acylation or deacylation has been extensively studied1 and
established as one of the most effective methods for the
preparation of optically active alcohols.2 Nonenzymatic alterna-
tives in this field have also been developed recently. Use of
stoichiometric amounts of chiral acylating agents effected the
kinetic resolution with high stereoselectivity.3 On the other
hand, the corresponding catalytic process is still in the devel-
opmental stage. The first example was reported by Vedejs et
al. that chiral phosphines catalytically promoted the kinetic
resolution in 9-81% ee (s value4 ) 1.2-15).5 We report here
a development of a new nucleophilic catalyst 1. Catalyst 1
promotes the kinetic resolution of racemic alcohols through
enantioselective acylation at ambient temperature. Use of 5 mol
% of the catalyst leads to the recovery of optically active
alcohols of 92 to >99% ee at 68-77% conversion (s ) 4.7-
12.3). Investigation of the reaction mechanism suggests that 1
acts through an “induced fit” mechanism like natural enzymes,
despite its low molecular weight (C23H24N2O ) 344).
Catalyst 1 was prepared from a racemic ketone 4.7 Addition
of 2-(lithiomethyl)naphthalene (prepared from 2-methylnaph-
thalene and n-BuLi) to 4 followed by hydrogenolysis gave 5 in
80% yield. Racemic 5 was resolved by recrystallization of the
salt obtained with (-)-camphorsulfonic acid to give 5 in
enantiomerically pure form (>99% ee; absolute configuration:
see Supporting Information). A pyridine moiety was introduced
into 5 by treatment with 4-chloropyridine and tripropylamine
17
to give 1 in 46% yield, [R]D -188° (c 1.0, CHCl3). The
absolute configuration of levorotatory 1 was determined to be
1S,5R,8S since (1S,5R)-47 afforded levorotatory 1 through the
same sequence as above. With the use of catalyst 1, the kinetic
resolution of racemic alcohols 6 and 8-11 was examined (Table
1).8 Treatment of racemic 6a with 5 mol % of 1 and 0.7 molar
equiv of isobutyric anhydride9 in toluene at ambient temperature
gave 7a (R ) iPr) and recovered 6a in yields of 60% and 27%,
respectively. The optical purity of recovered 6a was 76% ee
(s ) 4.3, entry 1). With pivaloate 6b, the enantioselectivity
increased to 94% ee (s ) 8.3, entry 2). When benzoate and
substituted benzoates 6c-f were used as substrates, a clear
tendency was observed: the stronger the electron-donating
ability of the aromatic ring, the higher the enantioselectivity of
the reaction (s ) 2.4-12.3, entries 3-6). The enantiomerically
pure (>99% ee) 6f was recovered from the kinetic resolution
of racemic p-(dimethylamino)benzoate 6f with 5 mol % of 1 at
72% conversion (entry 6). Even with 0.5 mol % of catalyst 1
(substrate/catalyst, 200:1), the optical purity of the recovered
6f was 93% ee (entry 7). The kinetic resolution of several
racemic mono[p-(dimethylamino)benzoate] of diols was exam-
ined with 5 mol % of 1. In both cyclic diol-monoesters 8-10
and the acyclic variant 11, acylation proceeded enantioselec-
tively to give the recovered alcohols with 92-97% ee at 70-
77% conversion (s ) 4.7-8.3).
In designing the catalyst, we focused on how strict stereo-
control could be realized without retarding its catalytic activity.
We chose 4-pyrrolidinopyridine (PPY) (2) as a model of the
active site because it is known to be the most effective catalyst
for the acylation of alcohols.6 To achieve effective stereocon-
trol, a conventional strategy would involve the introduction of
sterically demanding asymmetric center(s) near the active site
(pyridine nitrogen). However, this would lead to a dramatic
reduction in the catalytic activity. For example, the chiral
analogue 3, recently reported by Vedejs,3c does not have
catalytic activity for the acylation of alcohols, although it does
promote the kinetic resolution of secondary alcohols with high
stereoselectivity when used in stoichiometric amounts. To
overcome the selectiVity-reactiVity dilemma, we designed
catalyst 1 in which stereocontrolling chiral centers are located
far from the active site. This catalyst is expected to cause
remote asymmetric induction through chirality transfer from the
C(1) and C(8) chiral centers to the active site (N-acyliminium)
in the reactive intermediate (Figure 1).
1
Toward grasp of the reaction mechanism, the H NMR of 1
and its N-acyliminium ion were examined in CDCl3 at 20 °C
(Figure 1).10 The observed NOEs suggest that the preferred
conformation for 1 is an “open conformation” (A), in which
(7) Corey, E. J.; Chen, C.-P.; Reichard, G. A. Tetrahedron Lett. 1989,
30, 5547.
(8) Typical experimental procedure for the kinetic resolution: To a
solution of racemic 6f (132 mg, 0.50 mmol) and 1 (8.6 mg, 0.025 mmol)
in 3 mL of toluene was added 2,4,6-collidine (66 µL, 0.50 mmol) and
isobutyric anhydride (58 µL, 0.35 mmol). After 3 h of stirring at ambient
temperature, the reaction mixture was treated with 0.1 M HCl aqueous
solution and extracted with ethyl acetate. The organic layer was washed
with sat aq NaHCO3 and brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by preparative TLC (hexane/ethyl acetate,
1:1) to give (1R,2S)-6f (29 mg, 22% yield) and 7 (R ) p-Me2NC6H4) (97
mg, 58% yield). The optical purity of 6f was determined to be >99% ee
by HPLC analysis with Daicel Chiralpak AD (iPrOH/hexane, 10:90).
(9) Use of acetic anhydride instead of isobutyric anhydride usually results
in the less effective kinetic resolution. For example, kinetic resolution of
6f using acetic anhydride under otherwise identical conditions in Table 1
gave (1R,2S)-6f in 35% ee at 38% conversion, which corresponds to s )
4.9.
(1) For reviews: (a) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl.
1989, 28, 695. (b) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114. (c)
Roberts, S. M. Chimia 1993, 47, 85.
(2) For reviews on preparation of optically active alcohols, see: (a)
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1978, 10, 175. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York,
1994.
(3) (a) Evans, D. A.; Anderson, J. C.; Taylor, M. K. Tetrahedron Lett.
1993, 34, 5563. (b) Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1994,
611. (c) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809.
(4) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(5) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430.
(6) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed. Engl.
1978, 17, 569.
(10) Even in CHCl3, 1 could effectively catalyze the kinetic resolution
of 6f (s ) 9.9).
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