Direct, pyrrolidine sulfonamide promoted enantioselective aldol reactions of α,α-dialkyl aldehydes: Synthesis of quaternary carbon-containing β-hydroxy carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2005.05.067

A procedure has been developed for direct, asymmetric aldol reactions of α,α-dialkyl aldehydes with aromatic aldehydes, which produces quaternary carbon-containing β-hydroxy carbonyl compounds. The processes, promoted by the organocatalyst (S) pyrrolidine sulfonamide, take place in high yields with exceptionally high levels of enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2005.05.067

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 5077–5079
Direct, pyrrolidine sulfonamide promoted enantioselective aldol
reactions of a,a-dialkyl aldehydes: synthesis of quaternary
carbon-containing b-hydroxy carbonyl compounds
a,b,
a
a
*
Wei Wang,
Hao Li and Jian Wang
a
Department of Chemistry, University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001, USA
School of Pharmacy, East China University of Science & Technology, PO Box 268, Shanghai 200237, China
b
Received 28 April 2005; revised 10 May 2005; accepted 16May 2005
Available online 9 June 2005
Abstract—A procedure has been developed for direct, asymmetric aldol reactions of a,a-dialkyl aldehydes with aromatic aldehydes,
which produces quaternary carbon-containing b-hydroxy carbonyl compounds. The processes, promoted by the organocatalyst (S)
pyrrolidine sulfonamide, take place in high yields with exceptionally high levels of enantioselectivities.
Ó 2005 Elsevier Ltd. All rights reserved.
The aldol reaction is one of the most powerful methods
to form C–C bonds in complex organic substances. Con-
sequently numerous procedures to perform asymmetric
quaternary carbon-containing b-hydroxycarbonyl com-
pounds with exceptionally high levels of enantioselectiv-
ity. To our knowledge, this is the first example in which
a bifunctional organocatalyst is employed without the
need for acid additives.
1
,2
aldol reactions have been uncovered. Direct aldoliza-
tion processes are atom economic, and thus they serve as
attractive approaches for the synthesis of versatile poly-
oxygenated compounds. Recently, a great effort has
been made to the development of chiral organocatalysts
for the asymmetric version of this process. Most studies
have focused on reactions that produce either b-hydroxy
The motivation for this investigation came from our re-
cent study in exploring the utility of pyrrolidine sulfon-
amide I to catalyze highly efficient Michael addition
reactions of a,a-dialkyl aldehydes with b-nitrostyrenes
3
–11
13
carbonyls or a-alkyl-b-hydroxy carbonyls.
However,
(Fig. 1, Eq. 1). In the process, I effectively catalyzes
organocatalyst promoted asymmetric synthesis of
a,a-dialkyl-b-hydroxyl carbonyl compounds remains a
challenge since low reaction yields and poor enantio-
selectivities are typically observed. The major reason
for this is the general inaccessibility of either starting
a,a-disubstituted aldehydes or their stereochemically
defined enolates. The only method that can be used
for this purpose was uncovered by Barbas and co-work-
ers and it relies on the use of a chiral diamine as the
enolization of an a,a-dialkyl aldehyde to form an elec-
tron-rich enamine, which then adds to the nitroolefin
electrophile. Intrigued by the possibility that this mech-
anistic scenario might be expanded to encompass other
electrophilic forms such as aldehydes, we postulated that
organocatalyst I promoted aldol reactions of a,a-dialkyl
aldehydes as donors with aldehyde acceptors, would
generate products containing quaternary carbon centers
(Fig. 1, Eq. 2). The results of this effort on exploring
this proposal have demonstrated that the asymmetric al-
dol reactions using 20 mol % of (S) pyrrolidine sulfon-
amide I take place to form b-hydroxyaldehydes in high
yields (81–97%) and excellent enantioselectivities (91–
97% ee).
1
4
6
a,12
organocatalyst.
In this letter, we report a new, direct pyrrolidine sulfon-
amide promoted asymmetric aldol reaction that occurs
with sterically hindered a,a-dialkyl aldehydes to provide
Initial studies, testing the feasibility of this catalytic
process, focused on the reaction of iso-butyraldehyde
1a as an aldol donor and p-nitrobenzaldehyde 2a as an
acceptor in the presence of 20 mol % I in DMSO at
room temperature. The reaction took place smoothly
Keywords: Aldehyde; Aldol reaction; Asymmetric catalysis; Organo-
catalyst; Pyrrolidine sulfonamide.
*
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 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.067

5078
W. Wang et al. / Tetrahedron Letters 46 (2005) 5077–5079
alized aldehyde acceptors (Table 2, entries 1–10). In all
NH
O
cases, high levels of enantioselectivities (91–97%) and
high reaction yields (81–97%) were observed. Interest-
ingly, only one of the aldehyde groups in terephthalalde-
hyde participated in the reaction with iso-butyraldehyde
1a to give the mono-aldol addition product exclusively
in excellent yield (97%) and enantioselectivity (97% ee),
N
H
S
O
Ar
O
NO2
I
O
CF3
R1
20 mol%
NO2
H
H
+
R1 R2
Eq. 1
Ar
o
R2
0 C, iPrOH
8
9-99% ee
1
R : H, alkyl
>
20:1 dr
2
R : alkyl
63-99% yield
Table 2. Synthesis of aldol products by forming quaternary carbon
a
centers catalyzed by pyrrolidine sulfonamide I
O
NH
O
O
OH
N
H
R1
O
I
S
O
H
+
CF
3
H
Ar Eq. 2
NH
R2
Ar
H
R2
O
R1
O
N
H
I
S
O
OH
O
O
R1
CF
3
20 mol%
DMSO, rt
I
+
H
Ar
H
H
Ar
R1 R2
R2
1
2
3
N
O
O
N
O
O
N
H
b
c
S
N
H
S
Entry
Product 3
t (h)
Yield (%)
83
ee (%)
O
+
R1
CF3
R1
Ar
H
O
CF3
O
OH
R2
2Ar
H
H
1
43
91
R
Me Me
NO
2
3a
Figure 1. Pyrrolidine sulfonamide I catalyzed enolization of a,a-
dialkyl aldehydes.
O
OH
H
2
24
83
95
94
Me Me
CF
3
and afforded the aldol adduct 3a in a good yield (83%)
and a high enantioselectivity (91% ee) (Table 1, entry
3b
O
OH
1). The absolute configuration at the chiral center in al-
dol product 3a was determined to be S configuration by
H
H
3
4
84
94
Me Me
1
comparison of the H NMR and optical rotation data
Br
Cl
3c
6
a,15
for 3a with those of the known compound.
A poor
O
OH
reaction rate, yield, and enantioselectivity was observed
when other solvents were used for this process (Table 1,
entries 2–6). Thus, DMSO was selected as a reaction
medium for reactions probing the scope of the asymmet-
ric aldol processes.
9696
94
Me Me
3
d
O
OH
H
H
5
6
7
9681
72
93
Me Me
F
A number of aldol reactions were carried out under the
reaction conditions described above in the presence of
20 mol % I in DMSO. Examination of the results reveals
that the (S) pyrrolidine sulfonamide I promoted aldol
processes are generally applicable to variously function-
3e
O
OH
95
81
93
97
85
95
93
94
97
93
Me Me
CN
3f
O
OH NO
2
Table 1. Effect of the solvents on the asymmetric aldol reaction of iso-
butyraldehyde 1a with p-nitrobenzaldehyde 2a by pyrrolidine sulfon-
H
H
72
Me Me
a
3g
amide I
O
OH
NH
d
O
O
O
O
OH
8
9
1
144
72
N
H
Me Me
S
I
CH3
O
CO
2
Me
CF3
H
+
H
20 mol%
H
3h
H C CH3
CH
solvent, rt
3
O
OH
3
NO2
3a
NO
2
1
a
2a
H
H
b
c
Me Me
Entry
Solvent
t (h)
Yield (%)
ee (%)
CHO
3i
1
2
3
4
5
DMSO
DMF
1,4-Dioxane
43
72
72
72
72
37
83
77
41
63
68
91
81
80
48
79
O
OH
e
0
168
Me Et
3
CH CN
NO
2
3j
THF
6MeOH
72
18
a
b
c
See footnote a in Table 1.
Isolated yield after chromatographic purification.
Determined by chiral HPLC analysis (Chiralpak AS-H or Chialcel
a
Unless otherwise specified, the reaction was carried out using 1a
4.0 mmol) and 2a (0.4 mmol) in the presence of 20 mol % I in 1.0 mL
of solvent at room temperature.
(
OJ-H).
The reaction was run at 0 °C in DMF.
dr determined by H NMR with a ratio of 6/1 anti/syn.
b
c
d
e
Isolated yields after chromatographic purification.
Determined by chiral HPLC analysis (Chiralpak AS-H).
1

W. Wang et al. / Tetrahedron Letters 46 (2005) 5077–5079
5079
even when an excess of 1a (10 equiv) was used (Table 2,
entry 9). Moreover, two stereogenic centers were formed
simultaneously in a high diastereo-controlled manner
Chem. Soc. 2001, 123, 5260; (e) Thayumanavan, R.;
Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541; (f)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2
002, 124, 6798; (g) Northrup, A. B.; Mangion, I. K.;
Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
004, 43, 2152; (h) Northrup, A. B.; MacMillan, D. W. C.
(
93% ee, 6/1 anti/syn) when unsymmetric dialkyl aldehyde
a-ethyl-b-methyl aldehyde was used (Table 2, entry 10).
2
Science 2004, 305, 1752; (i) Enders, D.; Grondal, C.
Angew. Chem., Int. Ed. 2005, 44, 1210; (j) Casas, J.;
Sunden, H.; C o´ rdova, A. Tetrahedron Lett. 2004, 45, 6117;
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In conclusion, we have observed that the bifunctional
(
S) pyrrolidine trifluoromethanesulfonamide I is an
effective organocatalyst for promoting direct, asymmet-
ric aldol reactions of a,a-dialkyl aldehydes. These pro-
cesses, which lead to formation of quaternary carbon
centers, take place in high yields and exceptionally high
enantioselectivities. Further studies are underway to
investigate the full scope of the reaction and to explore
its applications in synthesis of biologically active targets.
6
2
004, 43, 2420; (b) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260; (c)
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Acknowledgements
(
d) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron
002, 58, 8167.
2
Financial support from the Department of Chemistry
and the Research Allocation Committee, University of
New Mexico, is greatly acknowledged. We thank Profes-
sor Patrick S. Mariano for making critical editorial com-
ments about the manuscript.
7. For amine alcohol catalyzed aldol reactions, see: (a) Tang,
Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
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U.S.A. 2004, 101, 5755; (c) Zhong, G.; Fan, J.; Barbas, C.
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8
. For peptide catalyzed aldol reactions, see: (a) Tang, Z.;
Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang,
Y.-Z. Org. Lett. 2004, 6, 2285; (b) Krattiger, P.; Kovasy,
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
7, 1101.
2
005.05.067.
9. For pyrrolidine tetrazole catalyzed aldol reactions, see:
Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yama-
moto, H. Angew. Chem., Int. Ed. 2004, 43, 1983.
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1
1
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3
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4
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2
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2
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1
2
5
15. In Ref. 6a, the authors did not give the data of the optical
rotation for compound 3a. We used the chiral diamine as a
catalyst to produce compound 3a in 95% ee and then
22, 2395; (b) List, B.; Pojarliev, P.; Castello, C. Org. Lett.
001, 3, 573; (c) Pidathala, D.; Hoang, L.; Vignola, N.;
2
D
5
determined its optical value: ½aꢀ +35.7 (c 1.0, CHCl
3
); the
2
5
List, B. Angew. Chem., Int. Ed. 2003, 42, 2785; (d)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
data obtained by using pyrrolidine sulfonamide I is: ½aꢀ
D
+31.6( c 1.0, CHCl ).
3