Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1759–1761
Nucleophilic synthesis of enantiopure
2-(tributylstannyl)pyrrolidines and piperidinesq
a
b
a
Robert E. Gawley,a,b, Graciela Barolli, Sachin Madan, Michele Saverin
*
and Sean OꢀConnora
aDepartment of Chemistry, University of Miami, Coral Gables, FL 33124, USA
bDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA
Received 25 November 2003; revised 11 December 2003; accepted 12 December 2003
Abstract—trans-Cumylcyclohexanol (TCC) is used as a chiral auxiliary for the stereoselective addition of tributyltinlithium to
N-acylpyrrolidinium/piperidinium ion with 70–80% diastereoselectivity at 0 ꢀC. After removal of the minor diastereomer by radial
chromatography, enantiopure N-methyl-2-(tributylstannyl)pyrrolidine and piperidine were produced by reductive removal of the
auxiliary.
ꢁ 2003 Elsevier Ltd. All rights reserved.
Stannylpyrrolidines have become important tools for
asymmetric synthesis, primarily via tin–lithium
exchange, and sometimes tandem transmetalations such
as Sn fi Li fi Cu or Pd.1 Tin–lithium exchange2 is the
most common method to generate an unstabilized a-
aminoorganolithium. For example, scalemic 2-(tributyl-
stannyl)pyrrolidines are precursors of unstabilized
a-aminoorganolithiums that have been used for enan-
tioselective alkylation, anionic cyclizations, and sigma-
tropic rearrangements.1 On the other hand, scalemic
stannylpiperidines have not enjoyed similar success
because of the difficulty in making them.3
tivity with electrophiles when compared to the lithiated
N-Boc heterocycles.3;6
A significant bottleneck to further development and
implementation of 2-(stannyl)pyrrolidines in asymmetric
synthesis is the dearth of methods for synthesis. To date,
only deprotonation/stannylation routes have been reported
for the preparation of these compounds. Asymmetric
deprotonation is the only route to enantioenriched
2-(metalated)pyrrolidines (maximum er ¼ 97:3), but this
route fails with piperidines!7 So far, ())-sparteine is the
only commercially available chiral ligand suitable for
this reaction, although (+)-sparteine can be made by
total synthesis,8 and OꢀBrien has reported a (+)-sparte-
ine surrogate that selectively produces R-2 in a similar
deprotonation.9 Deprotonation and stannylation of
piperidines equipped with a chiral oxazoline auxiliary
affords a 50:50 dr; separation of diastereomers is
tedious, and removal of the auxiliary requires two
steps.3;6
Following earlier work from the Hoppe group in
a-alkoxy systems,4 Kerrick and Beak made the impor-
tant discovery that the s-BuLiÆsparteine complex
enantioselectively deprotonated N-Boc pyrrolidine 3
(Eq. 1), and that the resultant organolithium S-2 could
be stannylated to afford S-1 in up to 97:3 enantiomer
ratio (er).5 Subsequently, we showed that reduction of
the N-Boc to a methyl gave a precursor to a-amino-
organolithium compounds that possess exceptional
configurational stability, and exhibit broadened reac-
(CH2)n
N-CO2t-Bu
(CH2)n
N-CO2t-Bu
(CH2)n
N-CO2t-Bu
+ s-BuLi·L
Li
SnBu3
3
n = 1, L = (−)-sparteine
n = 2, L = TMEDA
S-1; n = 1
rac-1; n = 2
S-2; n = 1
rac-2; n = 2
Keywords: (Stannanyl)pyrrolidines; TCC; N-Acyliminium ion; Asym-
metric synthesis.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.12.080
* Corresponding author. Tel.: +1-479-575-6933; fax: +1-479-575-5178;
ð1Þ
We asked whether it would be possible to generate
2-(tributylstannyl) heterocycles, 4, from lactams by
0040-4039/$ - see front matter ꢁ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.080