Angewandte
Chemie
loadings of 5 mol%, electron-donating disubstituted aromatic
substrates suffered lower reactivities (Table 2, entries 7 and
8). It is noteworthy that excellent ee and d.r. values have been
achieved in the asymmetric Michael addition of heteroar-
omatic and aliphatic nitroolefins (up to 93% ee; Table 2,
entries 23–25) because the corresponding adducts have great
potential in natural product synthesis.
On account of the high efficiency in the guanidine
organocatalysis approach and the synthetic potential of the
Michael adducts, the reaction was carried out on a 7 mmol
scale in the presence of 1 f (1.8 mol%) with the cinnamonic
substrate 7u and gave the desired product in 99% yield and
with 99:1 d.r. and 93% ee (Table 2, entry21; Scheme 3). The
NH proton of the amide in 1 f showed a strong deshielding
effect, with a broad peak shape at d = 11.43 ppm due to the
characteristic strong intramolecular hydrogen bonding,[12]
À
which implies that the N H moiety of the amide in catalyst
1 f might act as a Brønsted acid.[13] Based on the X-ray
diffraction analysis of both the guanidine and the adducts, a
preliminary mechanism for this direct nitro-Michael reaction
of cyclic b-ketoesters has been proposed to illustrate the dual-
activation mode. As depicted in Figure 1, the intramolecular
Figure 1. The dual-activation mode of guanidine 1 f (TS) and the
ORTEP representation of product 8o (RC9,SC7) from the X-ray analy-
sis.[14]
H-bond of catalyst 1 f was released and transformed to
activate the two substrates simultaneously. The most favor-
able transition state (TS) shows the guanidine unit to be a
Brønsted base, on which strong zwitterionic hydrogen bonds
with the Michael donor can be built,[5,6f,i] while the NH moiety
of the amide acts as a Brønsted acid to activate the Michael
acceptor.[2d,6] This plausible TS leads to mostly syn products,
in accordance with the substrate generality.
Scheme 3. Large-scale synthesis of 8u and the ramipril analogues.
Boc=tert-butoxycarbonyl.
In conclusion, we have presented an example of the
introduction of amino amides into the guanidine framework
to create organocatalysts for the asymmetric Michael addition
of b-ketoesters to nitroolefins. Catalyst 1 f demonstrated high
stereoselectivities (up to > 99:1 d.r. and 97% ee) and yields
(up to 99%) for a wide range of substrates. The reaction could
be easily scaled up under mild conditions to facilitate a
concise synthesis of a bicyclic b-amino acid. The comparative
experiments and X-ray diffraction analysis of the catalyst
structures revealed both the guanidine group and the NH
proton of the amide are important for the dual-activation
mode.
optically pure (99% ee after a single recrystallization) prod-
uct 8u was successfully converted exclusively into the
corresponding aza-bicyclocarboxylate 9 in good yield by
zinc-mediated reduction[9] followed by an intramolecular aza-
cyclization without any loss of stereoselectivity.[10] Further
reductive addition of the imine with NaCNBH3 under weak-
acid conditions afforded a ramipril analogue, amino acid ester
10, which was then N-protected by using (Boc)2O. The N-Boc-
b-ramipril-type amino acid ester 11, featuring a chiral func-
tional group with an adjacent quaternary carbon stereocenter,
possesses great potential in pharmaceutical synthesis.
To gain insight into the dual-activation mode, comparative
À
experiments were carried out with the N Me derivative of the
amide catalyst.[11] Under optimal conditions, it gave 54%
yield, a syn/anti ratio of 93:7, and 71% ee for the major
product. These results indicate that the NH proton of the
amide moiety is vital for the high activity and stereoselectiv-
ity. Direct evidence was observed by NMR spectroscopy
analyses and deduced from experimental observations. The
Experimental Section
b-Ketoester 6b (27.6 mg, 0.15 mmol) was added to a stirred solution
of nitroolefin (1.33 equiv, 0.2 mmol) and guanidine 1 f (2 mol%,
1.5 mg, 0.005 mmol) in EtOAc (0.50 mL, analytical-reagent grade) at
À158C. After being stirred for 32 h, the reaction mixture was
Angew. Chem. Int. Ed. 2009, 48, 5195 –5198
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5197