Enantioselective Lithiation of N-Boc-pyrrolidine
A R T I C L E S
responsible for the observed high enantioselectivity in the
lithiation of N-Boc-pyrrolidine 1. Why does (-)-sparteine
occupy such a privileged position in terms of asymmetric
induction in this reaction? In an attempt to address this issue,
we have compared the experimental results for the lithiation of
N-Boc-pyrrolidine 1 using diamines ent-2a-e (with substituents
R of different steric demands) with the results generated from
a computational study using diamines 2a, 2b, and 2e. In addition,
three modified diamines have been investigated solely from a
theoretical perspective. Ligand variation in combined experi-
mental/computational studies using alkyllithium/(-)-sparteine
systems has been somewhat limited in previous reports (pre-
sumably due to size of the complexes involved in the calcula-
tions): O-alkyl carbamates [(R,R)-1,2-bis(N,N-dimethylamino)-
cyclohexane only],4 N-Boc-pyrrolidine 1 [(-)-sparteine and
(R,R)-1,2-bis(N,N-dimethylamino)cyclohexane]10 and N-Boc-
piperidine [(-)-sparteine only].16 This is the first detailed study
of ligand Variation using a combined experimental and com-
putational approach in an alkyllithium/(-)-sparteine-mediated
process.
level and opposite sense of enantioselectivity to (-)-sparteine.7,8
Thus, use of (+)-sparteine-like diamine ent-2a to lithiate N-Boc-
pyrrolidine 1 produced a substitution product with er ) 95:5
and the opposite sense of asymmetric induction compared to
that obtained with (-)-sparteine.7,9 Second, we are applying ab
initio molecular orbital theory to a range of enantioselective
lithiation processes, and our computational results on the
lithiation of N-Boc-pyrrolidine 1 using isopropyllithium and (-)-
sparteine were recently reported.10 The experimental results were
accurately reproduced by ab initio calculations at the B3P86/
6-31G* level,11 and the interactions that lead to the enantiose-
lectivity were shown to be mainly steric in origin by application
of the ONIUM model of Morokuma et al.12 in which the N-Boc-
pyrrolidine 1 and isopropyllithium were treated quantum
mechanically and the (-)-sparteine ligand and its interaction
with the rest of the complex were treated by molecular
mechanics. As well as information from ligand variation and
computational studies, reports on solution13,14 and solid-state15
structures of alkyllithium/(-)-sparteine complexes also provide
useful insight into reactivity.
Results and Discussion
Enantioselective Lithiation of N-Boc-pyrrolidine Using
Sparteine-like Diamines. A range of diamines ent-2a-e with
N-alkyl groups of different steric sizes was prepared from (-)-
cytisine extracted from Laburnum anagyroides seeds.17 The
preparation of diamines ent-2a-d using a simple three-step route
(N-acylation, pyridone hydrogenation, and lithium alumi-
num hydride reduction) has been described previously.7,18 Di-
amine ent-2e was prepared by modifications of this approach
(as noted by Kann et al.19): (i) reductive alkylation of (-)-
cytisine (to give the N-iPr derivative); (ii) pyridone hydrogena-
tion under acidic conditions, and (iii) lithium aluminum hydride
reduction.
Despite all of the previous efforts, there remains the intriguing
question of exactly what portion of (-)-sparteine’s structure is
(7) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870. (b) Hermet, J.-P. R.; Porter, D. W.; Dearden,
M. J.; Harrison, J. R.; Koplin, T.; O’Brien, P.; Parmene, J.; Tyurin, V.;
Whitwood, A. C.; Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003, 1,
3977.
(8) The most detailed study of ligand variation in the asymmetric lithiation-
substitution of N-Boc-pyrrolidine 1 has been carried out by Beak et al.,
but none of the ligands could match the efficacy of (-)-sparteine (no
substitution products were obtained with >75% ee and most were <40%
ee). Similarly, Kozlowski et al. had limited success (26% ee substitution
product) using 1,5-diaza-cis-decalins. See: (a) Gallagher, D. J.; Wu, S.;
Nikolic, N. A.; Beak, P. J. Org. Chem. 1995, 60, 8148. (b) Li, X.; Schenkel,
L. B.; Kozlowski, M. C. Org. Lett. 2000, 2, 875. (c) Xu, Z.; Kozlowski,
M. C. J. Org. Chem. 2002, 67, 3072.
(9) The result we obtained using diamine ent-2a for the lithiation-substitution
of N-Boc-pyrrolidine 1 has also been verified using diamine 2a (prepared
by a different synthetic approach). See: Danieli, B.; Lesma, G.; Passarella,
D.; Piacenti, P.; Sacchetti, A.; Silvani, A.; Virdis, A. Tetrahedron Lett.
2002, 43, 7155.
(10) (a) Wiberg, K. B.; Bailey, W. F. Angew. Chem., Int. Ed. 2000, 39, 2127.
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Diamines ent-2a-e and (-)-sparteine were evaluated in the
lithiation-substitution of N-Boc-pyrrolidine 1 (Table 1). The
typical procedure, analogous to that described by Beak et al.,5
involved lithiation of N-Boc-pyrrolidine 1 using 1.3 equiv of
sec-butyllithium and diamine in diethyl ether at -78 °C for 5
h followed by trapping with Me3SiCl. The trimethylsilyl adduct
3 and any recovered starting material were then isolated by
chromatography. For direct comparison of the experimental
results with those obtained from the computational study (vide
infra), we also carried out some reactions using isopropyllithium.
The yield and er of adduct (S)-3 obtained using (-)-sparteine
(entries 1 and 2) are comparable to those reported previously
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