esters are inexpensive and the commonly used benzophenone
protecting/activating group is readily removed. Surprisingly,
however, only a handful of efficient catalytic asymmetric
reactions based on this strategy have been reported.
enantioselectivities.8 In this approach, however, the diaste-
reoselectivities were not satisfactory, and the use of azi-
doketones on a large scale might not be practical.
It is apparent from both our own studies and the studies
of others that significant improvements in this reaction are
needed. Although organocatalytic phase-transfer reactions
have shown promise, organocatalytic routes not based on
PTC have not been explored. Finally, the protecting group
employed on the imine is critical. N-Carbamoylimines are
known to be sensitive and unstable, but recent advances allow
for the in situ generation of N-carbamoylimines from bench-
stable R-amido sulfones.9,10 Herein, we describe our con-
tributions to the development of practical and efficient
syntheses of the R,ꢀ-diamino derivatives and report the first
examples of bifunctional alkaloid thiourea catalysts for highly
enantio- and diastereoselective organocatalytic direct Man-
nich reactions of a glycine Schiff base with in situ generated
N-carbamoylimines.11
In order to address the stability issue of tert-butoxycar-
bonyl (N-Boc) imines while preserving the advantages of
the N-Boc protecting group, we decided to base our approach
on R-amido-sulfone precursors. As a model reaction we
chose to study the reaction of glycine methyl ester 112 with
the bench-stable R-amido sulfone derived from benzaldehyde
2. We focused our catalyst screening efforts on thiourea
catalysts13,14 and performed the reaction in the presence of
a saturated solution of Na2CO3 to facilitate in situ generation
of the N-Boc-imine of benzaldehyde (Scheme 1).
The use of glycine Schiff bases in asymmetric phase
transfer catalysis (PTC) was pioneered by O’Donnell.5
Recently, there have been advances in asymmetric Lewis
acid and PTC catalyzed Mannich reactions of glycine Schiff
bases. Copper salt catalyzed Mannich reactions of glycine
Schiff bases with toluene-4-sulfonyl (Ts) imines suffer the
drawbacks of an air-sensitive catalyst and the difficulties
inherent with the Ts protecting group that is only removed
under very harsh reaction conditions.3a,e Maruoka has
reported a spiro quaternary ammonium salt based phase-
transfer catalyst that works with a limited number of PMP-
protected glyoxylate imine acceptors to provide Mannich
products with moderate diastereomeric ratios and
enantioselectivity.3d Other quaternary ammonium salts have
been reported by Shibasaki as catalysts of the Mannich
reaction of a glycine Schiff base with N-Boc-imines to
provide R,ꢀ-diamino acids with moderate ee’s.3b,c Finally,
Liu et al. have reported Mannich reactions of preformed
chiral Ni complexes of glycine with R-amido sulfones;6
however, this methodology suffers with respect to efficiency
and practicality. As an alternative to either of these ap-
proaches, we have previously explored organocatalytic direct
asymmetric Mannich reactions7 of azidoketones with imines.
These reactions afforded R,ꢀ-diamino acids with excellent
Gratifyingly, the desired product was obtained with good
enantiomeric excess. The ee was 88% when a thiourea catalyst
prepared from the cinchona alkaloid dihydroquinine (DHQ)14
was used (3a). The reaction, however, did not go to comple-
tion.15 Takemoto’s catalyst 3b gave the best conversion to the
(4) Direct nitro-Mannich reactions of nitro compounds with imines: (a)
Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866. (b) Rueping,
M.; Antonchick, A. P. Org. Lett. 2008, 10, 1731. (c) Chen, Z. H.; Morimoto,
H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (d)
Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007,
129, 3466. (e) Cutting, G. A.; Stainforth, N. E.; John, M. P.; Kociok-Kohn,
G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10632. (f) Knudsen, K. R.;
Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jorgensen, K. A. J. Am. Chem.
Soc. 2001, 123, 5843.
(8) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas,
C. F. Org. Lett. 2006, 8, 2839.
(5) For reviews and selected examples concerning catalysis with glycine
Schiff base substrates, see: (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. D.
J. Am. Chem. Soc. 1989, 111, 2353. (b) O’Donnell, M. J. Acc. Chem. Res.
2004, 37, 506. (c) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3. (d) Lygo,
B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
(9) For a comprehensive review of use of R-amido sulfones as stable
precursors of N-acylimino derivatives, see: Petrini, M. Chem. ReV. 2005,
105, 3949
.
(10) For examples of R-amido sulfones as imine precursors in Mannich-
type reactions, see: (a) Song, J.; Shih, H. W.; Deng, L. Org. Lett. 2007, 9,
603. (b) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem. Soc.
2005, 127, 17622. (c) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007,
72, 9998. (d) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi,
(6) Wang, J.; Shi, T.; Deng, G. H.; Jiang, H. L.; Liu, H. J. Org. Chem.
2008, 73, 8563.
(7) For select studies concerning organocatalytic direct asymmetric
Mannich reactions reported by this laboratory, see: (a) Zhang, H.; Mitsumori,
S.; Utsumi, N.; Imai, M.; Garcia-Delgado, N.; Mifsud, M.; Albertshofer,
K.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2008, 130, 875. (b) Utsumi, N.; Kitagaki, S.; Barbas, C. F., III.
Org. Lett. 2008, 10, 3405. (c) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas,
C. F., III. Angew. Chem., Int. Ed. 2007, 46, 1878. (d) Ramasastry, S. S. V.;
Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129,
288. (e) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 9630. (f) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk,
K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040.
(g) Cheong, P. H.-Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk,
K. N.; Barbas, C. F., III. Org. Lett. 2006, 8, 811. (h) Notz, W.; Watanabe,
S.-i.; Chowdari, N. S.; Zhong, G.; Betancort, J. M.; Tanaka, F.; Barbas,
C. F., III. AdV. Synth. Catal. 2004, 346, 1131. (i) Notz, W.; Tanaka, F.;
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (j) Chowdari, N. S.;
Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507. (k) Notz, W.; Tanaka,
F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.;
Barbas, C. F. J. Org. Chem. 2003, 68, 9624. (l) Chowdari, N. S.; Ramachary,
D. B.; Barbas, C. F., III. Synlett 2003, 1906. (m) Watanabe, S.; Cordova,
A.; Tanaka, F.; Barbas, C. F. Org. Lett. 2002, 4, 4519. (n) Cordova, A.;
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J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (p) Notz, W.;
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(11) For thiourea catalyzed 1,3-dipolar cycloaddition of azomethine
ylides of glycine Schiff bases with nitroalkenes, see: Xue, M. X.; Zhang,
X. M.; Gong, L. Z. Synlett 2008, 691.
(12) When glycine tert-butyl ester was employed in the Mannich reaction
with in situ generated N-carbamoylimines in the presence of thiourea catalyst
and base under the same conditions, little of the desired product was ob-
tained.
(13) Reviews on organocatalysts, including urea and thiourea catalysts:
(a) Connon, S. J. Synlett 2009, 354. (b) Miyabe, H.; Takemoto, Y. Bull.
Chem. Soc. Jpn. 2008, 81, 785. (c) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520. (d) Doyle, A. G.; Jacobsen, E. N. Chem.
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see: (a) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44,
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