Communications
and particularly 4d, are attributed to the relative conforma-
catalyzed conjugate addition reaction. As shown in Table 3,
the enantioselective conjugate addition reaction is remark-
ably general: under the optimized conditions, the full
spectrum of substrates underwent the reaction in 30 minutes
or less and afforded the products in good yields with 96–99%
ee, regardless of the electronic properties and locations of
substituents. The parent reaction of the simple nitrostyrene
can be scaled up without untoward effect on either the yield
or enantioselectivity (Table 3, entry 1). It is worth noting that
even substrates containing acidic protons, such as 1 l
tional rigidity of these substituents, which allows a more
organized transition state that better discriminates between
the two sides of trans-b-nitrostyrene. After a brief investiga-
tion of different substituents on the aryl moiety, we chose
catalyst 5 for further study owing to its ease of preparation
and high enantioselectivity (Table 1, entry 5). Catalyst 5 can
be prepared in three steps from commercial starting materials
(Scheme 1).
and 1q, which are capable of forming competing
hydrogen bonds, were tolerated by this procedure
and afforded the expected products in 98% ee
(Table 3, entries 12 and 17).
Among the most challenging substrates for the
organocatalyzed phosphite conjugate addition reac-
tion are alkyl-substituted nitroalkenes.[9,10] The high-
est enantioselectivity recorded in the literature for
such substrates is 87% ee.[19] To evaluate the
effectiveness of catalyst 5 in these reactions, several
alkyl-substituted nitroalkenes were subjected to the
Scheme 1. Synthesis of catalyst 5.
optimized conditions. As summarized in Table 4,
A survey of solvents showed that the phosphite conjugate
addition reaction is relatively insensitive to the solvent used
(Table 2). The enantioselectivity observed when the reaction
was performed in toluene was essentially the same as that
obtained in ether solvents, including tetrahydrofuran
(Table 2, entries 1–4).[18] Even highly polar solvents, such as
acetonitrile and acetone, afforded the addition product with
ee values of at least 90%(Table 2, entries 5 and 6). The best
solvent was found to be dichloromethane, in which, as noted
earlier, reaction at room temperature gave the product in
96% ee (Table 2, entry 7). As expected, the enantioselectivity
increased as the reaction temperature was lowered (Table 2,
entries 8–10). Given the practical advantages of carrying out
the reaction at 08C, this temperature was used for evaluating
the scope of the method.
excellent enantioselectivities were obtained even for aliphatic
nitroalkenes (95–97% ee). Compared to aryl-substituted
substrates, the reactions of alkyl substrates were slower,
presumably owing to steric and electronic factors. To circum-
vent the slow rate of reaction of substrates with secondary and
tertiary alkyl groups, the catalyst loading was increased to 20
mol% (Table 4, entries 4-6). With this modification, even the
highly hindered tert-butyl-containing substrate 3w reacted to
completion, giving the phosphite addition product in 83%
yield and 96% ee (Table 4, entry 6).
The results above show squaramide 5 to be a remarkably
effective catalyst for the enantioselective Michael addition
reactions of diphenyl phosphite to nitroalkenes. The reaction
provides a simple, highly enantioselective synthesis of chiral
b-nitro phosphonates, which are precursors to biologically
active b-amino phosphonic acids. The high yields and
uniformly excellent enantioselectivities obtained for both
aryl- and alkyl-substituted nitroalkenes, including those
bearing acidic protons or sterically-demanding substituents,
point to the unique capability of the squaramide scaffold.
Given the simple, modular assembly of squaramides, and the
ready availability of its precursors, this scaffold is expected to
provide many further opportunities in asymmetric catalysis.
A diverse range of aryl-substituted nitroalkene substrates
were selected to evaluate the scope of the squaramide
Table 2: Michael addition of diphenyl phosphite 2 to trans-b-nitrostyrene
1a, catalyzed by 5.[a]
Entry
Solvent
T [8C]
t
Conversion [%][b]
ee [%]
1
2
3
4
5
6
7
8
9
toluene
Et2O
tBuOMe
THF
MeCN
acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
RT
RT
RT
RT
RT
RT
RT
0
1 h
1 h
1 h
1 h
1 h
90
81
71
99
89
94
93
94
93
90
93
96
97
98
98.4
Experimental Section
Representative procedure (3a): Compound 1a (30 mg, 0.20 mmol)
and catalyst (R,R)-5 (8.4 mg, 0.020 mmol) was added to dichloro-
methane (1.0 mL) at room temperature. The stirred mixture was
cooled in an ice-water bath for 10 min before addition of 2 (48 mL,
0.25 mmol). After 30 min, the reaction mixture was loaded directly
onto a flash chromatography column. Elution with hexanes/ethyl
acetate (10:1 to 6:1 to 3:1) afforded the title compound as a white
solid: 73 mg, 95% yield, 97% ee. On a 1 mmol scale, the product was
obtained in 99% yield, 97% ee.
1 h
64
99
15 min
30 min
1 h
99 (95[c])
99
À10
10
À20
2 h
99
[a] Reactions were carried out on 0.20 mmol of 1a, with 1.25 equiv of 2
and 10 mol% 5, in 1.0 mL solvent. [b] Reaction conversions were
determined by H NMR spectroscopy. [c] Yield of isolated product.
Received: August 26, 2009
Published online: November 30, 2009
1
154
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Angew. Chem. Int. Ed. 2010, 49, 153 –156