asymmetric Pd-TMM cycloadditions with such highly
substituted substrates is relatively limited. While we have
demonstrated highly efficient reactions with both 3-alky-
lidene oxindoles9 and ketimines,4b these reactions required
the use of a cyano donor to achieve high ee. Herein, we
describe our efforts to expand the scope of this reaction to
include β,β-disubstituted nitroalkenes, a type of substitu-
tion rarely examined due to the anticipated low reactivity
of such acceptors. These studies also revealed, for the first
time, an unusual reversal of asymmetric induction as a
function of the substitution on the TMM donor.
Figure 1. Chiral ligands explored during optimization.
Our study was initiated using trans-R-methyl-β-nitro-
styrene (2) as a model substrate (Table 1). Surprisingly, the
reaction provided a pair of diastereomeric products under
all conditions examined, in contrast to all previous studies
using standard donor 1a in asymmetric cycloadditions.
These cycloadducts were fully separable by chromatogra-
phy and were later identified as epimeric at the quaternary
stereocenter (vide infra). Interestingly, ligand L1 (Figure 1)
gave predominately the cis product 3b, albeit in poor ee
(entry 1). On the other hand, phosphoramidites L2 and L3,
bearing a cyclic amine bound to the phosphorus, favored
formation of trans-3a (entries 2ꢀ3). While the diastereo-
and enantioselectivity were highest with the latter, the yield
under these conditions was modest, and there was evidence
of an open-chain side product10 that appeared to poison
the catalyst as unreacted donor 1a was always observed in
the crude reaction mixture. A slight improvement in yield
was observed upon increasing the concentration in toluene
to 0.5 M (entry 4), or by increasing the catalyst loading to
7.5 mol % (entry 5). Alternatively, we found that the use of
dioxane suppressed formation of the open-chain impurity,
allowing good yields of the product without requiring a
higher catalyst loading (entry 7).
We were able to determine which of the stereocenters in
3a and 3b was epimeric by performing a Michael addition
with methyl vinyl ketone on the diastereomeric mixture
(Scheme 1). In the event, 4 was obtained in 87% yield as a
1
7.5:1 mixture of diastereomers, as determined by the H
NMR signals for the diastereomeric methyl groups at
δ 1.58 (major) and δ 1.41 (minor). Upon irradiation of
the ring-bound methyl group in the major diastereomer, a
2.1% enhancement was observed at the proton β to the
ketone, suggesting the trans configuration as depicted.
Surprisingly, the major diastereomer was formed in only
57% ee; given the high yield, it seemed unlikely that kinetic
discrimination was responsible for the poor ee. In the
Michael addition, only the configuration at the quaternary
carbon is expected to control the facial selectivity of alkyla-
tion; therefore, the ee of the product will be preserved if
both diastereomers 3a and 3b have the same stereochem-
istry at the quaternary center. The observed 57% ee for 4,
however, indicates that the quaternary stereocenters in 3a
and 3b have opposite absolute configurations. In addition,
the absolute configuration for 3a was established by pre-
paring diastereomeric mandelamide derivatives and corre-
lating their relative 1H NMR shifts.11 We note that
the sense of stereoinduction is consistent with our pre-
vious efforts.8
Table 1. Initial Reaction Optimizationa
Scheme 1. Functionalization and Subsequent Assignment of
Diastereoselectivity
entry
ligand
solvent
% yield
drb
1:3
% eec
1
L1
L2
L3
L3
L3
L3
L3
toluene
toluene
toluene
toluene
toluene
THF
89
78
52
57
66
38
75
83, 29
83, 48
89, 45
92, 53
90, 56
93, 55
92, 43
2
1.2:1
3:1
3
4d
5e
6
3:1
3:1
3:1
7
dioxane
2:1
(10) A species tentatively assigned as 30 was observed in the crude
reaction mixture by 1H NMR. It likely arises via deprotonation of the
nitroalkene by Pd-TMM, where the allylic anion thus formed is alky-
lated by the palladium-π-allyl. Such a pathway has been previously
observed: Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105,
2326.
a All reactions were conducted at 0.15 M in the indicated solvent, at
50 °C, with 1.6 equiv of 1a, 5 mol % Pd(dba)2, and 10 mol % ligand.
Yields are isolated, combined values; ee’s were determined by chiral
HPLC. b dr’s are reported as the ratio of 3a:3b. c ee’s shown for 3a and 3b,
respectively. d Reaction conducted at 0.5 M. e Reaction conducted using
7.5 mol % Pd(dba)2 and 10 mol % ligand at 0.33 M.
(9) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396.
(11) See Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX