J. Am. Chem. Soc. 1997, 119, 8209-8216
8209
Two Different Pathways of Stereoinformation Transfer:
Asymmetric Substitutions in the (-)-Sparteine Mediated
Reactions of Laterally Lithiated
N,N-Diisopropyl-o-ethylbenzamide and
N-Pivaloyl-o-ethylaniline
S. Thayumanavan, Amit Basu, and Peter Beak*
Contribution from the Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
ReceiVed March 24, 1997X
Abstract: Highly enantioenriched substitution products can be obtained by the (-)-sparteine mediated lithiation-
substitution reactions of the laterally lithiated intermediates 3‚1 and 14‚1 derived from the amides 2 and 13. Either
enantiomer of the products can be obtained with high enantioenrichment using (-)-sparteine as the ligand by appropriate
choice of the protocol. The enantiodetermining step in both sequences occurs after deprotonation. Enantioenrichment
in the sequence with 3‚1 arises from a dynamic kinetic resolution, whereas enantioenrichment in the sequence with
14‚1 arises from a dynamic thermodynamic resolution.
Introduction
of the stereoinformation transfer in these asymmetric substitu-
tions which establish that the reactions proceed by mechanisti-
cally different pathways.4
Enantioselective lithiation-substitution sequences mediated
by (-)-sparteine have been shown to provide efficient meth-
odology for asymmetric synthesis. A quarter century ago,
Nozaki first reported the use of (-)-sparteine as a chiral ligand
in a lithiation-substitution sequence.1 Hoppe’s more recent
application of this ligand to asymmetric deprotonations of
carbamates to afford oxygen dipole stabilized carbanions with
high enantioselectivities has stimulated interest in (-)-sparteine
mediated lithiations.2,3
Asymmetry can be introduced in a lithiation-substitution
sequence by energy differences in either the formation or
reaction of the diastereomeric lithiated intermediates.4 The
pathway of asymmetric deprotonation is well recognized, but
transfer of stereoinformation in a post-deprotonation step, the
pathway of asymmetric substitution, while known, is less
developed. Asymmetric substitutions can be more permissive
than asymmetric deprotonations. The substitutions are ap-
plicable to organolithium intermediates regardless of their mode
of formation and can involve configurationally labile carban-
ions.4,5 We have communicated preliminary studies of enan-
tioselective (-)-sparteine induced lithiation-substitutions of two
benzylic organolithium species.6 We now report full studies
Results
Methodology. Lateral lithiation of the N,N-diisopropyl(o-
ethyl)benzamide(2) effected by s-BuLi in the presence of (-)-
sparteine (1) at -78 °C affords the putative organolithium
complex 3‚1. Treatment of 3‚1 with the variety of electrophiles
provides the products 4-11 with a enantiomeric ratios (er) and
yields shown in Table 1.
Alkylation, stannylation, and silylation provide products with
high enantiomeric ratios (ers) in useful yields. The use of
chlorides afford higher enantiomeric ratios and yields than
bromide or iodide. Acetone as an electrophile provides the
tertiary alcohol 12 with poor enantioselectivity. The absolute
configuration of (R)-8 was determined by independent synthesis
from (R)-3-phenylbutyric acid.7,8 The absolute configuration
of 11 was determined by Tamao-Fleming oxidation and
X Abstract published in AdVance ACS Abstracts, August 15, 1997.
(1) Nozaki, H.; Aratani, T.; Toraya, T.; Noyori, R. Tetrahedron 1971,
27, 905-913.
(2) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl. 1990,
29, 1422. Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.;
Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri, W.; Kolcazewski,
K.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479.
(3) (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231. (b) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996,
118, 3757 (c) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715.
(d) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 12218.
(e) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075. (f) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor,
N. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685. (g) Thayumanavan,
S.; Beak, P.; Curran, D. P. Tetrahedron Lett. 1996, 37, 2899. (h) For earlier
cases, see: Byrne, L. T.; Engelhardt, L. M.; Jacobsen, G. Z.; Leung, W.-
P.; Papasergio, R. I.; Raston, C. L.; Skelton, B. W.; Twiss, P.; White, A.
H. J. Chem. Soc., Dalton Trans. 1989, 105 and references cited therein.
(4) For a recent discussion of the different pathways, see: Beak, P.; Basu,
A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 29, 552.
(5) (a) Gallagher, D. J.; Du, H.; Long, S. A.; Beak, P. J. Am. Chem.
Soc. 1996, 118, 11391. (b) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.;
Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2158. (c) Schlosser, M.;
Limat, D. J. Am. Chem. Soc. 1995, 117, 12342. (d) Voyer, N.; Roby, J.
Tetrahedron Lett. 1995, 36, 6627. (e) Hoppe, D.; Zschage, O. Angew Chem.,
Int. Ed. Engl. 1989, 28, 69. (f) Zchage, O.; Hoppe D. Tetrahedron 1992,
48, 5657.
(6) (a) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc.
1994, 116, 9755. (b) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 1575.
(c) Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718.
(7) For a comprehensive chapter on lateral lithiation reactions, see: Clark,
R. D.; Jahangir, A. Org. React. 1996, 47, 1.
(8) Experimental details are provided as Supporting Information.
S0002-7863(97)00930-X CCC: $14.00 © 1997 American Chemical Society