These studies prompted us to explore fully the opportunities
for further transformations of the lactam products and
asymmetric synthesis. Herein we report the first examples
of stereocontrol from chiral anhydrides and chiral imines in
the formation of tetra- and pentasubstituted γ-lactams.
Scheme 2. Alkylation at the R-Carbona
Scheme 1. Reactions of Achiral Imines and Cyanosuccinic
Anhydride
Our efforts in the development of asymmetric imineÀ
anhydride reactions stemmed from our development
of modifications to the γ-lactam products of the imineÀ
anhydride reaction. We initially explored the preparation
of R-substituted γ-lactams though alkylation (Scheme 2).
Lactam 53d was methylated using LHMDS to give 6a with
95:5 diastereoselectivity, and X-ray crystallographic anal-
ysis4 indicated that the incoming electrophile approached
opposite to the adjacent carboxymethyl group. Unfortu-
nately, other electrophiles (6bÀc) gave poor yields. In the
case of benzyl bromide, the gem-alkylated product 6c,
which was determined by X-ray analysis,4 resulted from
the elimination of the cyano group. The limited scope of
alkylating the lactam compounds led us to pursue the use
of disubstituted anhydrides and the possibility of forming
enantiopure compounds.
a Reaction conditions: 1 equiv of 5, 2.5 equiv of n-BuLi, 3.0 equiv of
hexamethyldisilazane, and 2.6 equiv of the alkyl halide in tetrahydro-
furan (0.6 M). Ar = 4ClÀC6H4.
Scheme 3. Synthesis of 3,4-Disubstituted Succinic Anhydrides
We synthesized disubstituted succinic anhydrides for
use in imineÀanhydride reactions (Scheme 3). Following
literature conditions, diester 8a was synthesized in two steps
from ethyl lactate.5 Subsequent hydrolysis and cyclization
gave anhydride 9. In order to explore the scope and
diastereoselectivity of the disubstituted anhydrides, the
isobutyl, benzyl, and phenyl analogs (10À12) were also
prepared.
We explored the scope of the imineÀanhydride reaction
with respect to various imines and chiral disubstituted
succinic anhydrides (Scheme 4). Using methyl-substituted
cyanosuccinic anhydride 9, the reaction produced 13aÀf in
82À98% yield and up to 95% selectivity for the formation
of one major product out of the four possible diastereo-
mers. The products (13gÀi) from 10À12 gave similarly
high selectivities. The analogous reaction of enantiomeri-
cally pure 9, prepared from (S)-ethyl lactate, demonstrated
that the stereogenic center was preserved through the lactam-
forming reaction.6 X-ray crystallographic analysis4 (Figure2)
revealed that the major isomer is 13f-syn, complementing the
outcome of the alkylation reaction. The stereochemistry of
the major diastereomer of 13aÀh was assigned by comparing
1H NMR coupling constants. For product 13i, X-ray analysis
showed a different major diastereomer from 13aÀh. Further-
more, when (S)-ethyl mandelate was used to make anhydride
12, chiral HPLC analysis of the resulting 13i showed a
racemic mixture of products. Although the synthesis of
pentasubstituted γ-lactams is suitable for various alkyl sub-
stituents, the increased acidity of the R-H of 8d from the
anion-stabilizing phenyl group makes this substrate suscep-
tible to racemization.
(3) (a) Gonzalez-Lopez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164.
(b) Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999. (c) Ng,
P. Y.; Tang, Y. C.; Knosp, W. M.; Stadler, H. S.; Shaw, J. T. Angew.
Chem., Int. Ed. 2007, 46, 5352. (d) Tan, D. Q.; Atherton, A. L.; Smith,
A. J.; Soldi, C.; Hurley, K. A.; Fettinger, J. C.; Shaw, J. T. ACS Comb.
Sci. 2012, 14, 218. (e) Tang, Y.; Fettinger, J. C.; Shaw, J. T. Org. Lett.
2009, 11, 3802. (f) Castagnoli, N.; Cushman, M. J. Org. Chem. 1971, 36,
3404. (g) Castagnoli, N. J. Org. Chem. 1969, 34, 3187. (h) Cushman, M.;
Castagnoli, N. J. Org. Chem. 1973, 38, 440. (i) Cushman, M.; Madaj,
E. J. J. Org. Chem. 1987, 52, 907.
(4) CCDC 916580À916584 and 934180 contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
We next examined the possibility of asymmetric induc-
tion from imines derived from chiral amines to synthesize
(5) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron
1997, 53, 13633.
(6) See Supporting Information.
B
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