J. Am. Chem. Soc. 1996, 118, 3757-3758
3757
Communications to the Editor
with ee’s of 88%, 66%, 66%, 71%, and 24%, respectively. The
reaction in THF does not show the solvent-controlled reversal
of enantioselectivity recently reported for reactions of lithiated
N-Boc-N-methylbenzylamine.4b,d The absolute configuration of
(S)-3 is assigned by comparison of CSP-HPLC retention times
with authentic material and of (S)-4 by conversion to a known
amino acid (Vide infra). The assignments to (S)-5 and (S)-6
are based on a correspondence with (S)-3 and (S)-4 as the more
retained enantiomer on the CSP-HPLC column.8
The use of benzophenone as the electrophile in the sequence
gives the oxazolidinone (R)-7 in high yield and 92% ee. The
imine N-benzylideneaniline (Y ) NC6H5; R1, R2 ) C6H5, H)
affords the imidazolidinones 8 in a diastereomeric ratio of 20:1
with the major isomer (R,R)-8 obtained in 78% yield and 73%
ee. In each case one recrystallization gave (R)-7 and (R,R)-8,
respectively, with >95% ee.
(-)-Sparteine-Mediated r-Lithiation of
N-Boc-N-(p-methoxyphenyl)benzylamine:
Enantioselective Syntheses of (S) and (R) Mono-
and Disubstituted N-Boc-benzylamines
Yong Sun Park, Mark L. Boys,1 and Peter Beak*
Department of Chemistry
UniVersity of Illinois at Urbana-Champaign
Urbana, Illinois 61801
ReceiVed NoVember 20, 1995
Asymmetric syntheses which begin with prochiral substrates
and involve reactions of organolithium reagents or intermediates
under the influence of enantioenriched ligands are being reported
at an increasing pace.2-4 The approach has proven useful for
enantioselective syntheses of secondary amines, but extensions
to primary amines have not been known.3-6 In this com-
munication we report controlled asymmetric syntheses of both
enantiomers of mono- and disubstituted N-Boc-benzylamines
with high enantioenrichments from N-Boc-N-(p-methylphenyl)-
benzylamine (1) in lithiation-substitution sequences mediated
by (-)-sparteine (2). One application of the approach is
illustrated by the preparation of an enantioenriched amino acid.
Addition of a solution of 1 in toluene to a mixture of 1.2
equiv of n-butyllithium/2 at -78 °C in toluene followed by
stirring for 10 h, with subsequent addition of methyl and primary
alkyl triflates, gives highly enantioenriched alkylation products.
These compounds undergo oxidative cleavage of the p-meth-
oxyphenyl group with ceric ammonium nitrate (CAN)7 to
provide the N-Boc-benzylamines (S)-3, (S)-4, (S)-5, and (S)-6
with 93-96% ee in 69-81% yields. Alkyl triflates give
superior results to alkyl halides. Use of methyl iodide as the
electrophile for reactions in toluene, ether, tert-butyl methyl
ether, 1:1 mixture of tert-butyl methyl ether and n-pentane, and
THF gives (S)-3 in yields of 80%, 71%, 81%, 79%, and 81%
With benzaldehyde as the electrophile, a mixture of the
â-amino alcohol (R,S)-9 and (R,R)-10 is obtained. The amino
alcohol is produced in 73% yield and 93% ee and the trans-
oxazolidinone in 18% yield and 83% ee.6 When the reaction
is quenched with aqueous methanol, a 3:1 mixture of 9 and 10
is obtained, in which (R,S)-9 is one isomer and 10 is produced
in a 6:1 ratio of (R,R) isomer and (R,S) isomer. Cyclization of
(R,S)-9 to the corresponding oxazolidinone, followed by removal
of the p-methoxyphenyl group with CAN, produced (4R,5S)-
cis-4,5-diphenyl-2-oxazolidinone. Removal of the p-methox-
yphenyl group of (R,R)-10 afforded (4R,5R)-trans-4,5-diphenyl-
2-oxazolidinone. Comparisons with authentic materials provided
the assignments of the absolute stereochemistry.9 The configu-
rations shown for 7 and 8 (Vide supra) are based on analogy to
the formations of (R,S)-9 and (R,R)-10.10,11 These assignments
are consistent with the same sense of asymmetric substitution
for reactions with alkyl triflate, alkyl halide, carbonyl, and imine
electrophiles.
(1) Present address: Department of Chemical Sciences, G. D. Searle and
Co., Skokie, IL.
(2) (a) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc.
1994, 116, 9755. (b) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Haller,
J.; Guarnieri, W.; Kolczewski, S.; Hense, T.; Hoppe, I. Pure Appl. Chem.
1994, 66, 1479. (c) Klein, S.; Marek, I.; Poisson, J. F.; Normant, J. F. J.
Am. Chem. Soc. 1995, 117, 8853. (d) Muci, A. R.; Campos, K. R.; Evans,
D. A. J. Am. Chem. Soc. 1995, 117, 9075. (e) Tsukazaki, M.; Tinkl, A.;
Roglans, A.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. J. Am. Chem. Soc.
1996, 118, 685.
(3) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231 and references cited therein.
(4) For applications to enantioselective syntheses of enantioenriched
derivatives of N-Boc-N-alkylbenzylamines; see: (a) Voyer, N.; Roby, J.
Tetrahedron Lett. 1995, 36, 6627. (b) Schlosser, M.; Limat, D. J. Am.
Chem. Soc. 1995, 117, 12342. (c) Wu, S.; Lee, S.; Beak, P. J. Am. Chem.
Soc. 1996, 118, 715. (d) We observed a result similar to Schlosser’s report4b
in the enantiomeric excesses for the lithiation-substitution of N-Boc-N-
methylbenzylamine with s-BuLi/(-)-sparteine and methyl iodide. In THF,
two regioisomers were produced in 85% yield in a ratio of 1.3:1. The major
isomer, (R)-N-Boc-N-methyl-R-methylbenzylamine, from the lithiation-
substitution at the benzylic position was obtained with -36% ee, and the
minor product as N-Boc-N-ethylbenzylamine from lithiation-substitution
at the N-methyl group. In toluene, only (S)-N-Boc-N-methyl-R-methyl-
benzylamine was obtained with 92% ee. Park, Y. S.; Beak, P. Unpublished
Results.
(8) Pirkle, W. H.; Pochapsky, T. C.; Mahler, G. S.; Corey, D. E.; Reno,
D. S.; Alessi, D. M. J. Org. Chem. 1986, 56, 4991.
(9) Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1983, 48, 2520.
Murthy, K. S. K.; Dhar, D. N. J. Heterocycl. Chem. 1984, 21, 1721.
Stefanovsky, J. N.; Spassov, S. L.; Kurtev, B. J.; Balla, M.; Otvos, L. Chem.
Ber. 1969, 102, 717.
(10) We have also found the same sequence for 1 with the imine
N-benzylidene-p-methoxyaniline gave i, which is transformed to ii by
reaction with CAN, consistent with the trans geometry assigned to (R,R)-
8.11
(5) For applications and comparisons to alternative methodology, see:
Elworthy, T. R.; Meyers, A. I. Tetrahedron 1994, 50, 6089. Gawley, R.
E.; Zhang, O. J. Org. Chem. 1995, 60, 5763.
(6) During the reviewing process, the reaction of 1 with s-BuLi followed
by addition to imines was reported to give a racemic product with high
diastereoselectivity, while addition to benzaldehyde showed little diaste-
reoselectivity. Kise, N.; Kashiwagi, K.; Watanabe, M.; Yoshida, J. J. Org.
Chem. 1996, 61, 428.
(11) Sankhavasi, W.; Yamamoto, M.; Kohmoto, S.; Yamada, K. Bull.
Chem. Soc. Jpn. 1991, 64, 1425.
(7) Tomioka, K.; Inoue, I.; Koga, K. Tetrahedron Lett. 1990, 31, 6681.
0002-7863/96/1518-3757$12.00/0 © 1996 American Chemical Society