Catalysis of highly stereoselective Mannich-type reactions of ketones with ?±-imino esters by a pyrrolidine-sulfonamide. Synthesis of unnatural α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2004.08.032

The novel pyrrolidine-sulfonamide I has been prepared and used successfully to catalyze Mannich-type reactions between ketones and α-imino esters. The process is used to efficiently synthesize functionalized α-amino acid derivatives with excellent levels

Full text of DOI:10.1016/j.tetlet.2004.08.032

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7243–7246
Catalysis of highly stereoselective Mannich-type reactions of
ketones with a-imino esters by a pyrrolidine-sulfonamide.
Synthesis of unnatural a-amino acids
*
Wei Wang, Jian Wang and Hao Li
Department of Chemistry, University of New Mexico, MSC03 2060 Albuquerque, NM 87131-0001, USA
Received 24 June 2004; accepted 5 August 2004
Abstract—The novel pyrrolidine-sulfonamide I has been prepared and used successfully to catalyze Mannich-type reactions between
ketones and a-imino esters. The process is used to efficiently synthesize functionalized a-amino acid derivatives with excellent levels
of regio-, diastereo-, and enantio-selectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
1
3,14
Asymmetric synthesis of optically active natural and
unnatural a-amino acids has been of long-standing
interest to organic chemists since these substances are
versatile synthetic building blocks for the preparation
Several catalytic systems including L-proline,
16,17
pep-
have been re-
1
5
tides, and small organic molecules
ported for the Mannich reactions. L-Proline and its
derivative pyrrolidine tetrazole catalyzed process have
been reported for promoting direct Mannich-type reac-
1
of an assortment of biologically important molecules.
1
4,16
In this regard, the enantioselective Mannich-type reac-
tions of enolates or enolate equivalents with a-imino
esters constitutes a powerful approach to the synthesis
of novel functionalized c-keto-a-amino acid deriva-
tions of ketones and aldehydes with a-imino esters.
As part of a program aimed at developing new and
broadly useful organocatalysts for asymmetric synthesis,
we recently uncovered a pyrrolidine-sulfonamide org-
anocatalyst I, which promotes direct a-aminoxylation
reactions of ketones and aldehydes with nitrosobenzene
2
tives. Over the past few years, catalytic, enantioselective
versions of this process has received great attention with
a major emphasis being given to the development of
1
8
in a highly enantio-and regioselective manner (Eq. 1).
3
–6
organometallic catalysis. These metal-based catalysis
methods rely on the use of preformed enolates or eno-
late equivalents. An effective, atom-economic asymmet-
ric version of this reaction, employing unmodified
carbonyl compounds would be more attractive. Exam-
ples of Mannich reactions catalyzed by organometal-
lic-based chiral catalysts have been described by
To our knowledge, this is the first example of the use of
an amine sulfonamide organocatalyst for catalysis of
organic transformations.
We envisioned that enamines formed from ketones and I
would also add to electrophilic a-imino ester in Man-
nich-type reactions to provide novel functionalized c-
keto-a-amino acids (Eq. 2). Studies testing this proposal
have demonstrated that pyrrolidine-sulfonamide I cata-
lyzes reactions of unmodified ketones with a-imino
esters in a highly efficient manner with excellent levels
of regio-, diastereo-, and enantio-selectivity.
7
8
Shibasaki and co-workers, Trost and Terrell, and
9
Jørgensen and co-workers.
The development of metal-free organocatalysts has
emerged as a new frontier in asymmetric catalysis, pio-
10
1
1
12
neered by List et al. and MacMillan and co-workers.
Keywords: Asymmetric catalysis; Ketones; Mannich reaction; Amino
acids; Pyrrolidine-sulfonamide.
ð1Þ
*
Corresponding author. Tel.: +1 505 277 0756; fax: +1 505 277
609; e-mail: wwang@unm.edu
2
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.032

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W. Wang et al. / Tetrahedron Letters 45 (2004) 7243–7246
Table 2. Effect of catalyst loadings on the Mannich-type reaction
between 1f and 2
a
b
c
Entry Mol% I Reaction time (h) % Yield
% ee
dr
1
2
3
4
20
10
5
2.0
3.5
90
90
86
81
>99
96
>95:5
>95:5
>95:5
>95:5
ð2Þ
14
50
96
91
2
a
b
c
Isolated yields.
Determined by chiral HPLC analysis (Chiralpak AS-H).
1
dr = syn/anti As determined by H NMR.
1
8
by I, a variety of solvents can be employed for the
Mannich-type process. The catalyst exhibited high activ-
ities in all solvents explored; in every case, good to high
yields (76–90%), high levels of enantioselectivities (95%
to >99% ee), and high diastereoselectivities (P95:5
syn/anti) were observed. Based on this study, DMSO
was selected as the solvent used for the further examina-
tion of this process.
An exploratory study was conducted to evaluate the
proposed enantioselective Mannich-type reactions cata-
lyzed by I. Initial studies of the reaction of cyclohexa-
none 1f with the N-PMP (p-methoxyphenyl) protected
a-imino ethyl glyoxylate 2 in the presence of 20mol%
of I in DMSO (Table 1, entry 1) revealed that the Man-
nich-type reaction took place rapidly (2h) at room tem-
perature and with excellent enantioselectivity (>99% ee).
Catalyst I displayed a higher level of catalytic activity
and higher yield (90% vs 81%) than L-proline. Signifi-
The effect of catalyst loading on the reaction efficiency
was probed. A variety of catalyst loadings (2–
20mol%) were employed to catalyze reaction of cyclo-
hexanone 1f with a-imino ethyl ester 2 in DMSO (Table
2). As expected, the time to bring about complete reac-
tion increased with a decrease in catalyst loading. How-
ever, the reaction yields (81–90%) and enantio-and
diastereoselectivities remained high or only slightly
decrease (91% to >99% ee, and >95:5 dr) when the
amount of catalyst was lowered. From an operational
perspective, use of 10mol% of catalyst I is optimal to en-
sure high levels of enantio-and stereoselectivities (96%
ee, >95:5 dr) and efficiency (90% yield) while maintain-
ing a reasonable reaction time (3.5h, Table 2, entry 2).
1
cantly, H NMR analysis of the product mixture showed
that the syn-diastereomer was formed predominantly
(
dr >95:5). The observed stereochemical outcome,
that is, 3f with (S,S) configuration, matched that of
proline-catalyzed Mannich-type reactions, presumably
a consequence of the energetic similarities of their dia-
1
7
stereomeric transition states (Eq. 2).
Solvent effects on this process were examined next
Table 1). In a similar manner to enantioselective a-ami-
nooxylations of ketones with nitrosobenzene catalyzed
(
Having established optimal reaction conditions, we next
explored the scope of the organocatalytic Mannich-type
reactions between a-imino ester 2 and various ketones
Table 1. Effect of solvent on the Mannich reaction of cyclohexanone 1f
a
with a-imino ethyl 2
(Table 3). Significantly, we observed that pyrrolidine-
sulfonamide catalyzed Mannich-type reactions
O
O
NHPMP
I
occurred with both acyclic (entries 1–5) and cyclic
PMP
H
N
catalyst I (20% mol)
+
S CO Et
S
2
ketones (entries 6–8), affording adducts 3 in good yields
(74–91%) with high syn diastereo-and enantioselectivi-
EtO C
RT, solvent
2
1f
2
3f
ties (>95:5 dr and 96% to >99% ee). In the case of
ketones 2–8 (Table 3, entries 2–8), two adjacent stereo-
genic centers were generated simultaneously with com-
plete (S,S)-stereocontrol. More importantly, reactions
of unsymmetric ketones (entries 2, 4, and 5) resulted in
the highly regioselective production of adducts 3b,d,e
resulting from reaction at the more substituted a-sites
with excellent stereoselectivities as well (P96% ee and
P95/5 dr syn/anti). Studies with differently a-substituted
carbonyl substrates (entries 2, 4, and 5) reveal that
methyl, allyl, and hydroxyl substituents provided the
greatest degree of stereochemical control (96% to
b
c
d
Entry
Solvent
DMSO
Reaction
time (h)
% Yield
% ee
dr
1
2
3
4
5
6
7
8
2.0
7.0
2.5
4.5
3.5
5.5
5.5
2.0
90
86
82
89
88
84
76
89
>99
95
97
97
98
98
98
97
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
CHCl
DMF
THF
3
CH
EtOAc
CH NO
1,4-Dioxane
3
CN
3
2
a
Reaction conditions: a solution of cyclohexanone 1f:a-imino ethyl
ester 2:catalyst I = 10:1:0.2 (mole ratio) in a solvent (table) was run
>
99% ee and dr P95:5 (syn/anti)). Finally, changes in
2.0–7.0h.
Isolated yields.
Enantiomeric excess (ee) determined by chiral HPLC analysis
b
c
the electronic properties of ketones (Table 3, entries 5,
7, and 8) had only a small effect on the process.
(Chiralpak AS-H).
dr = syn/anti As determined by H NMR after column chromato-
graphy.
d
1
In summary, the study described above has uncovered a
novel pyrrolidine-sulfonamide catalyst I that can be

W. Wang et al. / Tetrahedron Letters 45 (2004) 7243–7246
7245
Table 3. Catalyst I catalyzed the reactions of various ketones 1 with a-
imino ester 2
We thank Professor Patrick S. Mariano for making criti-
cal editorial comments about the manuscript.
PMP
O
PMP
O
HN
N
catalyst I (10% mol)
+
Supplementary data
CO Et
2
EtO C
H
RT, DMSO
2
R1 R2
R1 R2
2-20 h
1
2
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.08.032.
3
a
b
c
dr
Entry
Product
% Yield
% ee
O
NHPMP
1
91
>99
97
––
CO Et
2
3
a
References and notes
O
NHPMP
1
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2
3
4
84
83
88
>95:5
CO Et
2
3
b
O
O
NHPMP
97
96
>95:5
>95:5
CO Et
2
3
c
2
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NHPMP
2
. Reviews on the Mannich reactions, see: (a) Denmark, S.
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d
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NHPMP
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6
74
90
>99
96
>95:5
>95:5
CO Et
2
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OH 3e
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NHPMP
CO Et
2
3
f
4. (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem.
Soc. 1997, 119, 7153–7154; (b) Kobayashi, S.; Hamada,
T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640–5641;
O
O
NHPMP
(
2
c) Ishitani, H.; Ueno, S.; Kobayashi, S. J. Am. Chem. Soc.
000, 122, 8180–8186.
7
8
CO Et
83
78
>99
>95:5
>95:5
2
3
g
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O
NHPMP
6
. (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J.
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2
96
3
h
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O
2
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. Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett.
999, 40, 307–310.
. Trost, B. M.; Terrell, L. M. J. Am. Chem. Soc. 2003, 125,
38–339.
a
b
c
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7
8
9
1
1
dr = syn/anti As determined by H NMR.
3
. Juhl, K.; Gathergood, N.; Jorgensen, K. A. Angew. Chem.,
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0. Excellent reviews on organocatalysts: a general review,
1
used to promote highly efficient, direct, asymmetric
Mannich-type reactions of ketones with a-imino esters
to produce functionalized a-amino acid esters. In this
process, I exhibits high catalytic activity and excel-
lent levels of regio-, diastereo-, and enantio-selectivity.
Further applications of this catalyst to other syn-
thetically useful transformations are currently being
investigated.
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2
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1
1
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9
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