Angewandte
Chemie
acceptor that could intercept the nucleophilic enamine
intermediate A generated in situ by the condensation of
catalyst 1 with the a,b-unsaturated ketones 2a–i (Figure 1).
The resulting carbon nucleophile B should then selectively
engage in an intramolecular, iminium-catalyzed conjugate
addition to afford the derivatives 4a–i. Therefore, the
reaction between acyclic a,b-unsaturated ketones 2a–i and
nitroalkenes 3 to furnish complex cyclohexanones 4a–i was
studied (Table 1).
cascade.[12] By carrying out the reaction in the presence of
30 mol% salicylic acid, a very high diasterocontrol and an
increased reaction rate were obtained, albeit with slightly
lower enantioselectivity (compare Table 1, entries 4,5 and
7,8). Interestingly, the use of enones that bear an ethyl a-
substituent (R2 = Me, Table 1, entries 9–11) promotes the
selective formation of cyclic products 4g–i, which have four
stereogenic centers.
The relative and absolute configuration of the trisubsti-
tuted cyclohexanone 4c and the tetrasubstituted compound
4h was unambiguously determined to be 3S,4R,5S and
2R,3S,4R,5S, respectively, by anomalous dispersion X-ray
crystallography.[13]
Table 1: Organocascade with chiral primary amine 1: combinations of
linear a,b-unsaturated ketones and nitroalkenes.[a]
The unique reaction pathway imparted by catalyst 1
introduces important features from both synthetic and
mechanistic standpoints. The primary amine catalyzed orga-
nocascade furnishes a complementary approach to the
classical Diels–Alder reaction for the asymmetric, one-step
synthesis of complex cyclohexane scaffolds with multiple
stereocenters. For example, the present reaction manifold
allows the highly stereoselective access to the chiral com-
pound 4a, which has identical R1 and R3 substituents (Table 1,
entry 1), whereas a cycloaddition path would lead to the
meso-isomer cis-4a.[9a] On the basis of the experimental
observations made thus far, we propose that the formal Diels–
Alder reaction proceeds by the enamine–protioiminium
mechanism depicted in Figure 1. In addition, to account for
the unexpected stereochemical outcome of the process, this
mechanistic scenario is consistent with the fact that the rate
and enantioselectivity of the reaction strictly depend on the
identity of the carboxylic acid cocatalyst,[12] a parameter that
can strongly facilitate the equilibrium between imine (gen-
erated by catalyst condensation with enone 2) and secondary
enamine A during the reaction. Moreover, the catalytic
activity of primary amine 1 is completely suppressed when
carrying out the reaction in polar solvents (e.g., MeOH or
H2O), whereas a concerted cycloaddition pathway is generally
accelerated in such reaction media.[7,8c,9] The proposed
stepwise double-Michael sequential mechanism is finally
corroborated by the isolation of the corresponding Michael
adducts of a,b-unsaturated ketones and nitrostyrene[14] (see
the Supporting Information for details).
Entry
4
R1
R2
R3
Yield
[%][b] trans/cis [%][d]
d.r.[c] ee
1
2
3
4
a
b
c
d
d
e
f
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Ph
78
>19:1 96
3:1 93
4-MeO-C6H4 69[e]
2,6-Cl2-C6H3 85
13:1 95
2:1 94
>19:1 90
>19:1 96
3:1 96
>19:1 88
15:1 99
6:1 99
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
thiophenyl
thiophenyl
Ph
Ph
Ph
77[e]
40
5[f]
6
2,6-Cl2-C6H3 92
Ph
Ph
7
50
53
58
47
65
8[f]
9
f
g
h
i
Me Ph
Me 4-Br-C6H4
10
11
Ph
thiophenyl Me Ph
14:1 99
[a] Reactions conducted on a 0.2 mmol scale with 2 equiv of 2 and [3]0 =
1m. [b] Yield of the isolated single, major diastereoisomer. The yields
reflect the degree of conversion. [c] Determined by H NMR analysis of
the crude mixture. [d] Determined by HPLC analysis on chiral stationary
phases. [e] Yield refers to the sum of diastereoisomers. [f] Reaction
carried out at RT using 30 mol% of salicylic acid (2-OH-C6H4CO2H) as
cocatalyst.
1
Barbas and co-workers[9a] used the same transformation to
demonstrate, for the first time, the ability of chiral secondary
amine catalysts to activate linear enones toward a Diels–
Alder process, thus exploiting the transient formation of the
activated diene A (Figure 1). Such a type of [4+2] cyclo-
addition reaction led to the selective formation of the
expected exo cycloadducts cis-4 with very poor enantioselec-
tivity (38% ee).[9a] We were pleased to find that the reaction
catalyzed by the chiral primary amine 1 (20 mol%), in
combination with 30 mol% of 2-fluorobenzoic acid as the
cocatalyst, showed a very high enantiocontrol and the
opposite stereochemical behavior, with preferential forma-
tion of the formal endo product trans-4. As highlighted in
Table 1, the combination of a series of acyclic enones 2 and
aromatic nitroalkenes 3 afforded complex cyclohexanones 4
with high diastereomeric ratio and in almost enantiomerically
pure form (ee values ranging from 93 to 99%). We also found
that the nature of the acidic cocatalyst strongly influences
both the reactivity and the stereochemical outcome of the
A central goal of our organocascade catalysis studies has
been to demonstrate the potential of this simple methodology
to solve challenging synthetic problems. We thus applied the
primary amine catalyzed organocascade strategy to target
daunting issues in asymmetric synthesis, namely the gener-
ation of all-carbon quaternary stereocenters, and the asym-
metric construction of polycyclic structures. These cyclic
structures often pose distinct challenges owing to the unique
strain and steric elements imparted by their connectivity.
Meanwhile, the generation of a quaternary chiral carbon
atom is always a demanding task, mainly because of the
À
sterically congested environment in which C C bonds must
be formed and stereochemical information must be trans-
ferred.[15]
As shown in Table 2, our cascade-catalysis strategy
provides a flexible and direct approach to innovate around
the highly stereoselective construction of all-carbon quater-
Angew. Chem. Int. Ed. 2009, 48, 7196 –7199
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7197