Communications
Table 2: Catalytic enantioselective Mannich reactions of sulfonylacetates 1, followed by reductive
desulfonylation or a modified Julia olefination.[a]
possible hydrogen-bond network
involving the ortho substituent,
the oxygen atom of the hydroxy
group, and a molecule of water
(Scheme 3), as observed in the
solid state.[13] This interaction can
help to rigidify the system and thus
augment its effectiveness in dis-
criminating the two prochiral faces
of the imine.
In summary, arylsulfonylace-
tates 1 have been used for the
first time in a catalytic asymmetric
reaction, namely, an enantioselec-
tive Mannich addition to N-carba-
moyl imines. Reductive removal of
the sulfonyl group of the Mannich
adducts gave a range of b3-amino-
ester derivatives 4 through a very
simple two-step procedure in
which the hydrolytic, oxidative, or
thermal conditions typically used
in previously reported related
Entry
Cat.
2, Ar
R
Pg
4[b] Yield [%][c] ee [%][d] 6[e] Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
2a, p-Tol Ph(CH2)2
2b, p-Tol Ph(CH2)2
2c, p-Tol Me
Boc 7e
Cbz 7e
Boc 7e
Cbz 7e
Cbz 7e
Boc 7e
Boc 7d
Boc 7d
Boc 7d
Boc 7d
4a 82
4b 70
4c 88
4d 71
4e 62
4 f 68
4g 65[i]
4h 78
4i 75
4j 76
4k 70
4 l 89
92
77
6a 85
6b 74
91
78
90[h]
84
88
96
87
92
91[h]
84
89
80
94
78[f,g,h]
87
6c
88
2d, Ph
2e, Ph
2 f, Ph
2g, Ph
2h, Ph
2i, Ph
2j, Ph
iBu
6d 76
n-pentyl
n-hexyl
iPr
cyclohexyl
Ph
85
6e
6 f
79
91
95[g]
80[g,h]
91[g]
92[h]
85
6g 74
6h 84[j]
6i
6j
6k
6l
85
84
63
70
2-naphthyl
2k, p-Tol p-MeOC6H4 Boc 7d
90[g]
83
–
2l, Ph
2m, Ph
p-ClC6H4
o-BrC6H4
Boc 7d
Cbz 7d
–
–
6m 75[j]
[a] Reactions were carried out with 2a–m (0.15 mmol), 1a or 1b (0.225 mmol), 7 (5 mol%), and
aqueous K3PO4 (50% w/w, 210 mL, 0.75 mmol for 1a; 105 mL, 0.37 mmol for 1b) in toluene (3.0 mL) at
À308C for 16–60 h. [b] After plug filtration, the crude products of the catalytic reaction were treated with
Mg powder (109 mg, 4.5 mmol) in CH3OH (1.5 mL) overnight. [c] Yield of the isolated product (two
steps) after chromatography on silica gel. [d] The ee value was determined by HPLC on a chiral
stationary phase. [e] After plug filtration, the crude products of the catalytic reaction were treated with
aqueous HCHO (37% w/w, 57 mL, 0.75 mmol) and Cs2CO3 (123 mg, 0.37 mmol) in DMF (1.5 mL)
overnight. [f] Catalyst 7d was used. [g] The ee value was determined after conversion into the Cbz
derivative.[12] [h] The absolute configuration was assigned by comparison of the optical rotation with a
known value.[12] [i] Acetate 1b was used. [j] Reaction time for the olefination step: 48 h.
transformations
ed.[7a–c,11] Similarly, an oxidative
desulfonylation furnished b-
were
avoid-
a
amino-a-hydroxyester 5, whereas
a Julia-type olefination provided
access to aza-MBH products 6. In
sulfonylacetate
1
to the Re face of the intermediate
contrast to the more common aza-MBH approach,[10] in which
preformed N-tosyl imines are typically employed, this proce-
dure enables the use of highly unstable imines through their
generation in situ; furthermore, the enantiomerically
enriched products contain a readily removable protecting
group on the nitrogen atom.
N-carbamoyl imine. The inefficiency of O-alkylated and
O-acylated catalysts in this[12] and related transformations[9]
suggests a crucial hydrogen-bond interaction between the
hydrogen atom of the hydroxy group of the catalyst and one
of the reagents; such an interaction was rationalized very
convincingly for the related aza-Henry reaction by a compu-
tational study.[21] On the basis of these considerations, we
tentatively propose an intermediate in which the catalyst
coordinates the deprotonated sulfonylacetate through the
hydrogen atom of the hydroxy group to give the tight ionic
couple depicted in Scheme 3. Additional hydrogen-bond
interactions between the incoming imine and the hydrogen
atoms a to the quaternary nitrogen atom in the catalyst (not
shown)[21] force the imine to approach from the back side and
thus favor selective addition to its Re face. The superior
efficiency of catalysts containing an ortho-substituted ben-
zylic moiety in these reactions, when used in combination with
aqueous inorganic bases, can be interpreted by considering a
Received: February 5, 2009
Published online: May 7, 2009
Keywords: amino acids · asymmetric catalysis · Mannich bases ·
.
organocatalysis · sulfones
[1] a) N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon,
Oxford, 1993; b) Organosulfur Chemistry in Asymmetric Syn-
thesis (Eds.: T. Toru, C. Bolm), Wiley-VCH, Weinheim, 2008.
[2] C. Nꢀjera, M. Yus, Tetrahedron 1999, 55, 10547.
[3] J. C. Carretero, R. Gꢁmez Arrayꢀs, J. Adrio in Organosulfur
Chemistry in Asymmetric Synthesis (Eds.: T. Toru, C. Bolm),
Wiley-VCH, Weinheim, 2008, p. 291.
[4] For example, for conjugate additions, see: a) L. Hongming, J.
Song, X. Liu, L. Deng, J. Am. Chem. Soc. 2005, 127, 8948; b) S.
Sulzer-Mossꢂ, A. Alexakis, Chem. Commun. 2007, 3123, and
references therein; c) P. Mauleꢁn, I. Alonso, M. R. Rivero, J. C.
Carretero, J. Org. Chem. 2007, 72, 9924, and references therein;
for reductions, see: d) T. Llamas, R. Gꢁmez Arrayꢀs, J. C.
cycloadditions, see: f) A. Lꢁpez-Pꢂrez, J. Adrio, J. C. Carretero,
J. Am. Chem. Soc. 2008, 130, 10084.
Scheme 3. Proposed reaction intermediate.
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5694 –5697