α-Lithiation-rearrangement of N-toluenesulfonyl aziridines with sec-butyllithium and (-)-sparteine: Opposite sense of asymmetric induction to epoxides

Article abstract of DOI:10.1016/S0040-4039(03)01677-0

The α-lithiation rearrangement of three cyclic N-toluenesulfonyl (tosyl) aziridines has been carried out using sec-butyllithium/(-)-sparteine. In each case, it was established that preferential lithiation of the S-aziridine stereocentre occurred. This is

Full text of DOI:10.1016/S0040-4039(03)01677-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6613–6615
a-Lithiation-rearrangement of N-toluenesulfonyl aziridines with
sec-butyllithium and (−)-sparteine: opposite sense of asymmetric
induction to epoxides
a,
a
b
Peter O’Brien, * Clare M. Rosser and Darren Caine
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 17 June 2003; accepted 3 July 2003
Abstract—The a-lithiation rearrangement of three cyclic N-toluenesulfonyl (tosyl) aziridines has been carried out using sec-butyl-
lithium/(−)-sparteine. In each case, it was established that preferential lithiation of the S-aziridine stereocentre occurred. This is
the opposite sense of asymmetric induction to that observed with epoxides.
©
2003 Elsevier Ltd. All rights reserved.
1
Since Cope’s seminal contribution in 1951, a wealth of
synthetic and mechanistic chemistry associated with
lithiated epoxides (oxiranyl anions) has been investi-
lacking an anion stabilising group are limited to Beak’s
6
a-lithiation-in situ trapping of N-Boc aziridines,
7
Vedejs’ use of N-alkyl aziridines complexed by borane,
2
,3
t
gated. Most recently, Hodgson and co-workers have
made significant progress in harnessing the synthetic
potential of enantioenriched lithiated epoxides gener-
ated by direct lithiation of epoxides using alkyllithiums
in the presence of (−)-sparteine. In all of the epoxides
studied by Hodgson, the use of (−)-sparteine as a chiral
ligand leads to preferential lithiation of the R-epoxide
stereocentre (to varying degrees, depending on the sub-
strate), thus generating lithiated epoxides 1 and 2.
Mordini’s reactions of superbases (e.g. LDA/KO Bu or
t
8
n-butyllithium/KO Bu) with N-tosyl aziridines and
M u¨ ller’s use of sec-butyllithium and (−)-sparteine to
9
desymmetrise N-tosyl aziridines. Due to our ongoing
interest in sparteine-like diamines and aziridines, we
became interested in further extending the pioneering
3–5
10
11
9
contribution of M u¨ ller and Nury. In particular, we
wished to establish the sense of asymmetric induction in
the proposed a-lithiation of cyclic N-tosyl aziridines, as
this had not been commented on in the original disclo-
sure. Herein, we present the results of this stereochemi-
cal study.
N-Tosyl aziridines 3, 5 and 7 were prepared by Sharp-
1
1,12
less aziridination of the corresponding cycloalkenes.
An Et O solution of each of these aziridines was added
2
to sec-butyllithium/(−)-sparteine (2.9 equiv.) in Et O at
2
In contrast, the chemistry of lithiated aziridines
−78°C. After 4 h at −78°C, the solution was allowed to
(
aziridinyl anions) has received much less attention and
warm to room temperature over 1 h. Standard aqueous
work-up and chromatography furnished the rearranged
products (R)-4, (R)-6 and 8 in the yields and ee’s
has generally involved the use of an anion stabilising
group attached directly to the aziridine. Examples of
2
the direct interaction of strong bases with aziridines
(
determined by chiral HPLC) indicated in Scheme 1.
Presumably, aziridine a-lithiation is followed by inser-
tion into an adjacent CꢀH bond to give (R)-4 and (R)-6
or into a transannular CꢀH bond to give 8. The ee’s
were dependent on the aziridine ring size and the
highest yields were obtained with the 6- and 8-ring
aziridines (5 and 7).
Keywords: aziridines; rearrangement; lithiation; sulfonamides; stereo-
chemistry.
*
Corresponding author. Tel.: +44-(0)1904-432535; fax: +44-(0)1904-
32516; e-mail: paob1@york.ac.uk
4
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01677-0

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P. O’Brien et al. / Tetrahedron Letters 44 (2003) 6613–6615
site sense of asymmetric induction to all of the epoxide
examples reported by the Hodgson group, which pro-
3–5
ceed through lithiated epoxides 1 and 2. The presence
of a N-tosyl group in aziridines permits a changeover of
the enantiodiscriminating interactions between the
alkyllithium–(−)-sparteine complex and the substrate.
With N-tosyl aziridines, it is possible that stereoselec-
tive complexation of the alkyllithium to one of the
enantiotopic SꢁO groups could be the source of the
reversal in stereoselectivity compared to epoxides.
Recent work from the M u¨ ller group has confirmed that
the S-aziridine stereocentre is lithiated preferentially in
1
5
three other related N-tosyl aziridine examples.
Scheme 1.
The stereochemistry of the major enantiomer of 4 and
In conclusion, the predominant sense of asymmetric
induction in the lithiation-rearrangement of N-tosyl
aziridines 3, 5 and 7 using sec-butyllithium/(−)-
sparteine is opposite to the corresponding epoxides. Fur-
ther work in our group will focus on rationalising the
difference in enantioselectivity between epoxides and
aziridines.
6
was assigned as (R) by conversion of each of them
13
into the corresponding known NHBoc compounds
Boc protection followed by Na/NH tosyl deprotec-
(
3
tion) and comparison of optical rotation data. The
stereochemistry of bicyclic sulfonamide 8 was estab-
lished by independent synthesis of ent-8 as described in
Scheme 2. Alcohol 9 (69% ee, prepared by sec-butyl-
lithium/(−)-sparteine rearrangement of cyclooctene
4
oxide ) was converted into alcohol 10 via Mitsunobu
inversion and reaction with KOH. Then, alcohol 10
Acknowledgements
1
4
was reacted with Weinreb’s TsNHBoc reagent to give
Boc protected sulfonamide 11 in a disappointing yield
of only 16% (despite an extended reaction time). No
other diastereomeric product was generated from this
reaction and the low yield reflects the difficulty of
We thank the EPSRC and GlaxoSmithKline for a
CASE award (to C.M.R.) and Professor P. M u¨ ller
(University of Geneva) for useful discussion and
exchange of unpublished results.
carrying out a S 2 reaction on the sterically hindered
N
endo-face of the bicyclic system. Finally, Boc deprotec-
tion of 11 using TFA gave sulfonamide ent-8, as judged
by the sign of the optical rotation and the chiral HPLC
retention times.
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