C O M M U N I C A T I O N S
Scheme 2. Deracemization of rac-1a
CIDR was demonstrated in our first experiment when a THF-
hexane solution of ketimine 3a was allowed to crystallize (50 to
25 °C, 24 h). Assay of the 3a (90% isolated yield) indicated
approximately 3:1 dr (NMR in DMSO-d6). The dr slowly eroded
during NMR analysis, making accurate evaluations difficult.
Therefore, we used chiral GLC of the ketone or aldehyde after imine
hydrolysis for accurate determinations. The enantiomeric excesses
of ketones/aldehydes represented herein are a result of the two-
stage sequence of CIDR and hydrolysis.
In the CIDR of 3a, best results were obtained when the unpurified
solid imine was stirred as a solid-liquid mixture at 23 °C
(prolonged heating yielded minor decomposition which complicated
the crystallization). Polar solvents (e.g., methanol, ethanol, 2-pro-
panol, and acetonitrile) proved more effective than less polar
solvents (e.g., hexane, ether, and THF). Equilibration of 3a in
methanol and hydrolysis (vide infra) afforded (R)-1a with an ee of
90-92% in 91-94% overall yield from rac-1a (Table 1).
Of the numerous published methods for Schiff base hydrolysis,7
two methods worked best (Table 1). Biphasic hydrolysis of 3a with
hexane/acetic acid-sodium acetate buffer,8 yielded (R)-1a in 94%
yield and 90% ee. Under these conditions, (R)-1a was extracted
into the hexane phase as hydrolysis occurred and the acetate salt
of (R,R)-2 could be recovered from the water phase by merely
adjusting to pH 10 and filtering (95% average yield of (R,R)-2,
suitable for reuse). Hydrolytic conditions with hexane/aqueous
CuCl2 (initially introduced for the hydrolysis of hydrazones)9
afforded (R)-1a in 97% yield and 92% ee (Table 1).
Our deracemization protocol for d,l-ethylhexanal (rac-1b) proved
to be amazingly simple and provided enzyme-like selectivity.
Aldimine 3b was prepared by treating rac-1b with (R,R)-2 (1:1
diastereomers, approximately 100% yield based on (R,R)-2).6 A
simple “one-pot” procedure of imine formation and stirring/
concentration afforded pure 3b (dr 99:1). Hydrolysis with aqueous
CuCl2 afforded (R)-1b (98% ee, 94% overall yield) whereas
hydrolysis with NaOAc-HOAc (industrially advantageous) gave
a small amount of racemization (98% overall yield by quantitative
GLC, 90% ee). The yield of 1b was corroborated by subsequent
formation of the 2,4-DNP derivative.6 The critical nature of acid/
pH is demonstrated by the hydrolysis of 3b with four different acids
(Table 1).
The CIDR with three additional ketones (1c, 1d, 1e, Table 1)
suggests that the process is general. Deracemization of rac-1c is
difficult due to lability of the stereogenic center,10 and few reliable
methods exist for the preparation of ent-1c. The unoptimized CIDR
process afforded 3c (70% yield, dr ) 99%) and the ketone 1c in
98% ee (aqueous CuCl2 hydrolysis). Without optimization, imines
3d and 3e underwent CIDR to afford substantial enrichment (Table
1).
π-stacking of the (R,R)-2 and, in a nearly orthogonal fashion, a
hydrogen-bonding sheet11 in which the hydroxyl proton of (R,R)-2
is hydrogen bonded to an imine nitrogen (see ORTEP and crystal
packing data in the Supporting Information). This very rigid array
leads to a high degree of stereogenic discrimination during the
dynamic crystallization (e.g., ethyl vs butyl in 1b).
In summary, we have demonstrated unoptimized CIDR of five
ketones/aldehydes with (R,R)-2. Our results with 1b demonstrate
enzyme-like selectivity and industrial feasibility. Future endeavors
will focus on developing more general hydrolysis conditions as well
as superior chiral auxiliaries.
Acknowledgment. The authors thank Charles Held, Perry
Heath, Justin Smith, Marvin Hansen, Peter Wipf, William Roush,
Paul Wender, and Marvin Miller for helpful discussions.
Supporting Information Available: References on CIDR, experi-
mental procedures, ORTEP plot of 3b (PDF) and X-ray data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 25, 447-456.
(2) (a) Collins, A. N., Sheldrake, G. N., Crosby, J., Eds. Chirality in Industry
II; Wiley: Chichester, UK, 1997. (b) Astleford, B. A.; Weigel, L. O., in
ref 2a, Chapter 6.
(3) Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, A.;
Zwanenburg, B. Tetrahedron 1997, 53, 9417-9476.
(4) This protocol describes host-guest complexation but the method is limited
to 2-alkylcylcohexanones with n or π electrons in the R-substituent,
requires molar excesses of the chiral host (TADDOL), and requires
chromatographic separations (13 examples approximately 60% ee with
two examples exceeding 90% ee). (a) Kaku, H.; Ozako, S.; Kawamura,
S. Takatus, S.; Ishii, M.; Tsunoda, T. Heterocycles 2001, 55, 847-850.
(b) Tsunoda, T.; Kaku, H.; Nagaku, M.; Okuyama, E. Tetrahedron Lett.
1997, 38, 7759-7760. (c) Kaku, H., Takaoka, S., Tsunoda, T. Tetrahedron
2002, 58, 3401-3407.
(5) (a) Gruber et al. WO Patent 9951236, October 14, 1999. Also obtained
by resolution with mandelic acid, unpublished: Patterson, L.; Hansen,
M.; Kolis, S.; Ditsworth, T. Eli Lilly and Co., 2002. (b) THF, methanol,
ethanol, IPA, diglyme, hexane, triethyl orthoformate, ether, acetonitrile.
(c) HOAc, 4 Å sieves, TFA, silica gel, alumina, TsOH.
(6) Example synthesis of (R)-1b (all operations at 23 °C): A mixture of rac-
1b (7.05 g, 96% purity, 53 mmol) and (R,R)-2 (50 mmol) in THF (0.15
L) was stirred for 30 min. The volatile compounds were evaporated in a
stream of nitrogen (5 mL/h) to give 3b (dr 3:1). The enriched 3b was
stirred in methanol (0.1 L, 6 h) and evaporated (nitrogen stream) to afford
3b (dr 96:4). Repeating the above sequence twice (70 mL and 50 mL of
MeOH) resulted in 3b (dr 99:1), 100% yield based on (R,R)-2). The
aldimine 3b (20 mmol) was allowed to stir with hexane (0.24 L), diethyl
ether (0.1 L), and sodium acetate/acetic acid buffer (pH 3.8, 0.14 L; under
nitrogen, 1 h). The layers were separated and the aqueous layer was
extracted with hexane (3 × 50 mL). The standardized solution was
analyzed by quantitative GLC (98% yield (R)-1b based on input (R,R)-2;
reaction with 2,4-dinitrophenylhydrazine (2,4-DNP) yielded 93% of the
hydrazone), and by chiral GLC (90% ee (R)-1b).
(7) For recent review, see: Enders, D.; Wortmann, L.; Peters, R. Acc. Chem.
Res. 2000, 33, 157-169.
(8) Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger,
M. J. Am. Chem. Soc. 1981, 103, 3081-3087.
(9) Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976, 41, 3667-3668.
(10) Partridge, J. J.; Chada, N. K.; Uskokovic, M. R. J. Am. Chem. Soc. 1973,
95, 532-540.
To better understand the origin of this highly effective CIDR,
we analyzed 3b by single-crystal X-ray diffraction. Elucidation of
the crystal structure of 3b revealed an extremely ordered state with
(11) Kinbara, K.; Katsumata, Y.; Saigo K. Chem. Lett. 2002, 266-267.
JA029715N
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J. AM. CHEM. SOC. VOL. 125, NO. 11, 2003 3209