Synthesis of chiral organocatalysts derived from aziridines: Application in asymmetric aldol reaction

Article abstract of DOI:10.1021/jo8019863

(Chemical Equation Presented) We report the synthesis of a new series of highly efficient chiral organocatalysts derived via the regio-and stereoselective ring opening of chiral aziridines with azide anions. The catalysts have proved to be very efficient

Full text of DOI:10.1021/jo8019863

Synthesis of Chiral Organocatalysts derived from Aziridines:
Application in Asymmetric Aldol Reaction
Shikha Gandhi and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Vinodks@iitk.ac.in
ReceiVed September 9, 2008
We report the synthesis of a new series of highly efficient chiral organocatalysts derived via the regio-
and stereoselective ring opening of chiral aziridines with azide anions. The catalysts have proved to be
very efficient for a direct asymmetric aldol reaction, both with cyclic as well as acyclic ketones in brine
with 2 mol % of catalyst loading, and afforded the products in excellent yields (up to 99%) and
enantioselectivities (up to >99%). The chiral aldol adduct obtained has further been converted to a chiral
azetidine ring via a convenient pathway.
Introduction
pharmacologically useful compounds.1,5 For the last decade, we
have been actively involved in the chemistry of aziridines.3,4a,b
Since these small molecules possess many interesting properties,
in the past few years, the chemistry of chiral, nonracemic
aziridines has also attracted much interest.1b,6 The ability of these
molecules to undergo regio- and stereoselective ring opening
has been widely exploited for the synthesis of biologically active
chiral compounds.6a,c,7 An important transformation is the ring
opening of chiral aziridines by using azides as nucleophiles that
leads to the formation of products which can easily be converted
to chiral functionalized amines. We have, hence, applied this
chemistry for an efficient synthesis of a series of chiral
compounds which have the potential to act as chiral organo-
catalysts in asymmetric synthesis.
Aziridines, small three-membered heterocycles, have attracted
considerable attention owing to their striking chemical proper-
ties.1 The high strain energy associated with the aziridine ring
enables easy cleavage of the C-N bond. Therefore, aziridines
can either undergo ring cleavage reactions with a range of
nucleophiles2,3 or cycloaddition reactions with dipolarophiles.4
Both of these reactions have been extensively explored in
organic synthesis leading to the formation of synthetically and
(1) (a) Aziridines and epoxides in organic synthesis; Yudin, A. K., Ed.; Wiley-
VCH: Weinheim, Germany, 2006. (b) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599–619.
(2) (a) Sun, X.; Sun, W.; Fan, R.; Wu, J. AdV. Synth. Catal. 2007, 349, 2151–
2155. (b) Rinaudo, G.; Narizuka, S.; Askari, N.; Crousse, B.; Bonnet-Delpon,
D. Tetrahedron Lett. 2006, 47, 2065–2068. (c) Fan, R. H.; Hou, X. L. J. Org.
Chem. 2003, 68, 726–730. (d) Watson, I. D. G.; Yudin, A. K. J. Org. Chem.
2003, 68, 5160–5167. (e) Riego, E.; Concello´n, J. M. J. Org. Chem. 2003, 68,
6407–6410.
(3) (a) Kumar, M.; Gandhi, S.; Kalra, S. S.; Singh, V. K. Synth. Commun.
2008, 38, 1527–1532. (b) Bisai, A.; Pandey, M. K.; Singh, V. K. Tetrahedron
Lett. 2004, 45, 9661–9663. (c) Prasad, B. A. B.; Sanghi, R.; Singh, V. K.
Tetrahedron Lett. 2002, 58, 7355–7363. (d) Anand, R. V.; Pandey, G.; Singh,
V. K. Tetrahedron Lett. 2002, 43, 3975–3976. (e) Prasad, B. A. B.; Sekar, G.;
Singh, V. K. Tetrahedron Lett. 2000, 41, 4677–4679.
(4) (a) Gandhi, S.; Bisai, A.; Prasad, B. A. B.; Singh, V. K. J. Org. Chem.
2007, 72, 2133–2142. (b) Prasad, B. A. B.; Pandey, G.; Singh, V. K. Tetrahedron
Lett. 2004, 45, 1137–1141. (c) Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Synlett 2004,
1691–1694. (d) Sudo, A.; Morioko, Y.; Koizumi, E.; Sanda, F.; Endo, T.
Tetrahedron Lett. 2003, 44, 7889–7891. (e) Madhushaw, R. J.; Hu, C.-C.; Liu,
R.-S. Org. Lett. 2002, 4, 4151–4153.
(5) (a) Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2005, 70,
5508–5518. (b) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetra-
hedron Lett. 2002, 43, 2827–2830. (c) Bergmeier, S. C. Tetrahedron 2000, 56,
2561–2576. (d) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012. (e) Ager, J. D.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835–875.
(f) Gilman, A. G.; Goodman, L. S. The Pharmacological Basis of Therapeutics,
10th ed.; Macmillan: New York, 2001.
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2004, 6, 2377–2380, and references cited therein. (b) Sim, T. B.; Kang, H. S.;
Lee, K. S.; Yun, H.; Dong, Y.; Ha, H.-J. J. Org. Chem. 2003, 68, 104–108. (c)
Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R.; Davis, F. A. J. Org. Chem. 2003,
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10.1021/jo8019863 CCC: $40.75 2008
Published on Web 11/04/2008
J. Org. Chem. 2008, 73, 9411–9416 9411

Gandhi and Singh
SCHEME 1
FIGURE 1. Organocatalysts derived from L-proline and ꢀ-amino
sulfonamides.
Remarkable advances have been made in the field of
asymmetric organocatalysis over the past few years.8 In the
realm of reactions catalyzed by organic molecules, the asym-
metric aldol reaction has been an area of intense research.9 The
recent trend is toward the use of organocatalysts which can
efficiently catalyze the aldol reaction in an aqueous medium
since water is a safe, economical, and environmentally benign
solvent.10,11a We have recently reported an asymmetric aldol
reaction catalyzed by an organocatalyst derived from L-proline
and a ꢀ-amino alcohol.11 It will be interesting to study the
change in performance of the catalyst when the ꢀ-amino alcohol
in the same catalyst is replaced by a ꢀ-amino sulfonamide. Here,
we disclose the synthesis of an organocatalyst derived from
L-proline and a ꢀ-amino sulfonamide (Figure 1) and its
application in a direct asymmetric aldol reaction. Gratifyingly,
the catalyst has worked remarkably well in an aqueous medium,
making it further useful from the perspective of green chemistry.
We have further shown the application of aldol adduct by
converting it to a chiral azetidine ring. This N-containing four-
membered heterocycle is one of the important structural motifs
in modern synthetic chemistry.12 The aldol adduct obtained by
the reaction between a cyclic ketone and aldehyde was converted
to a bicyclic fused ring system. A cyclohexane ring fused with
an azetidine ring finds applications in the synthesis of analogues
of paclitaxel (Taxol) and docetaxel (Taxotere).13
Results and Discussion
The chiral aziridines, required as precursors for the synthesis
of organocatalysts, were synthesized in two steps starting from
(1S,2R)-norephedrine as per the literature known procedure.4a
Thus, a series of chiral aziridines 1a-g with different N-sulfonyl
groups was prepared. The azidolysis of activated aziridines was
carried out with NaN3. The reaction proceeded in a regio- and
a stereoselective manner, leading to diastereomerically pure
ꢀ-azido sulfonamides 2a-g. The reduction of the azide group
with triphenylphosphine led to the synthesis of ꢀ-amino
sulfonamides, which were then directly coupled to (S)-N-Boc
proline. The Boc protecting group was then cleaved by using
formic acid leading to the synthesis of final catalysts in high
yields. A series of catalysts 3a-g with different sulfonamide
groups was thus prepared (Scheme 1).
(8) For reviews on organocatalysis, see: (a) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638–4660. (b) Mukherjee, S.; Yang, J. W.; Hoffmann,
S.; List, B. Chem. ReV. 2007, 107, 5471–5569. (c) Pellisier, H. Tetrahedron
2007, 63, 9267–9331. (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138–5175.
(9) (a) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.; Feng, X.;
Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654–5655. (b) Luo, S.; Xu, H.;
Zhang, L.; Li, J.; Cheng, J.-P. Org. Lett. 2008, 10, 653–656. (c) Chen, J.-R.;
An, X.-L.; Zhu, X.-Y.; Wang, X.-F.; Xiao, W.-J. J. Org. Chem. 2008, 73, 6006–
6009. (d) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III J. Am.
Chem. Soc. 2007, 129, 288–289. (e) Samanta, S.; Zhao, C.-G. Tetrahedron Lett.
2006, 47, 3383–3386. (f) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543–4545. (g) Tang, Z.; Yang, Z.-H.; Chen,
X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005,
127, 9285–9289. For reviews on organocatalytic asymmetric aldol reaction, see:
(h) List, B. Acc. Chem. Res. 2004, 37, 548–557. (i) Notz, W.; Tanaka, F.; Barbas,
C. F., III Acc. Chem. Res. 2004, 37, 580–591. (j) Allemann, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37,
558–569. (k) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579.
(10) (a) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas, C. F.,
III Org. Lett. 2008, 10, 1621–1624. (b) Zhu, M.-K.; Xu, X.-Y.; Gong, L.-Z.
AdV. Synth. Catal. 2008, 350, 1390–1396. (c) Aratake, S.; Itoh, T.; Okano, T.;
Usui, T.; Shoji, M.; Hayashi, Y. Chem. Commun. 2007, 2524–2526. (d) Font,
D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653–4655. (e) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am.
Chem. Soc. 2006, 128, 734–735. (f) Hayashi, Y. Angew. Chem., Int. Ed. 2006,
45, 8103–8104. (g) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
T.; Shoji, M. Angew. Chem. 2006, 118, 972–975.
(11) (a) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595. (b)
Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097–4099.
(12) (a) Couty, F.; Evano, G.; Vargaz-Sanchez, M.; Bouzas, G. J. Org. Chem.
2005, 70, 9028–9031, and references cited therein. (b) Burtoloso, A. C. B.;
Correia, C. R. D. Tetrahedron Lett. 2004, 45, 3355–3358, and references cited
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Tetrahedron 2002, 58, 7303–7313. (d) Iwao, O.; Mangzhu, Z.; Takehiko, Y.;
Kazuaki, N.; Mitsuo, Y.; Rumiko, A. J. Org. Chem. 1991, 56, 5263–5277.
(13) (a) Cheng, Q.; Kiyota, H.; Yamaguchi, M.; Horiguchi, T.; Oritani, T.
Bioorg. Med. Chem. Lett. 2003, 13, 1075–1077. (b) Marder, R.; Dubois, J.;
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6637. (c) Fenoglio, I.; Nano, G. M.; Velde, D. G. V.; Appedino, G. Tetrahedron
Lett. 1996, 37, 3203–3206.
For catalyst 3, the chirality of proline will dictate the
stereochemistry of the product. But there are two other chiral
centers C-1 and C-2 in the catalyst. To figure out the stereo-
chemistry at C-1 and C-2 that will match/mismatch with the
stereochemistry of proline to effect stereoselectivity in the
reaction, catalysts 6a-d were synthesized (Scheme 2). The
synthesis started with the two enantiomers of 2-amino-1,2-
diphenylethanol. The amino group was first sulfonylated with
benzenesulfonyl chloride. The four diastereomers of ꢀ-azido
sulfonamide were then prepared via two different reaction
sequences. The sulfonamide protected amino alcohols were
cyclized to form C-2 symmetric aziridine rings (4a and 4b)
which were then opened up with NaN3 to form 5a and 5b,
respectively. In the second pathway, the alcohols were first
mesylated and then knocked off by using azide as a nucleophile
forming 5c and 5d. Starting from the two pure enantiomers of
amino alcohol, these two pathways led to the synthesis of four
diastereomers of ꢀ-azido sulfonamides (5a-d). Further, fol-
lowing the same reaction sequence as in the synthesis of
catalysts 3a-g, the synthesis of four diastereomers 6a-d was
accomplished.
After successful completion of the synthesis of the catalysts,
we decided to evaluate their role in a direct organocatalytic aldol
reaction. At the outset, to optimize the reaction conditions, a
series of reactions were carried out between cyclohexanone and
4-fluorobenzaldehyde as the substrates and 3a as the catalyst.
9412 J. Org. Chem. Vol. 73, No. 23, 2008

Synthesis of Chiral Organocatalysts
SCHEME 2
TABLE 1. Optimization of Reaction Conditions
TABLE 2. Catalyst Screeninga
entry
catalyst
% yield
anti/synb
% ee (anti)c
catalyst
% ee
entry mol % solvent x:y time, h % yield anti/syna (anti)b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
6a
6b
6c
6d
87
82
85
69
76
71
78
75
75
78
76
94:6
93:7
91:9
91:9
92:8
92:8
92:8
91:9
92:8
92:8
92:8
86
84
83
86
87
88
84
89
87
90
87
1
2
3
4
5
6
7
8
15
15
15
5
2
2
2
1
5
2
CHCl3
DMF
H2O
H2O
H2O
H2O
H2O
H2O
4:1
4:1
4:1
4:1
4:1
10:1
2:1
4:1
4:1
4:1
4:1
72
72
12
16
24
20
30
30
22
24
36
91
82
82
85
73
78
85
87
75
73:27
87:13
93:07
93:07
90:10
92:08
89:11
94:06
93:07
48
75
80
79
76
84
84
86
89
9
10
11
9
10
11
brine
brine
brine
a Ratio of ketone:aldehyde was 4:1 in all the cases. b Determined by
1H NMR analysis. c Determined by HPLC with chiral column.
1
a Determined by 1H NMR analysis. b Determined by HPLC with
chiral column.
was still further enhancement in ee (Table 1, entries 9-11).
Best results were obtained when 2 mol % of the catalyst was
used in brine, which was thus used for further studies (Table 1,
entry 10).
After optimizing the reaction conditions, the series of catalysts
3a-g and 6a-d were then evaluated for the reaction (Table
2). However, to our surprise, all the catalysts gave the products
in high ee, yield as well as diastereoselectivity. Catalyst 6c being
slightly superior to the others was thus used for further studies
(Table 2, entry 10).
To improve the enantioselectivity, we then studied the effect
of temperature on the reaction (Table 3). Decreasing the
temperature from rt to 0 °C-rt and then to 0 °C increased the
ee as well as diastereoselectivity (Table 3, entries 1-3). Best
results were obtained when the reaction was carried out at -5
No product was formed when the reaction was carried out in
organic solvents such as CHCl3 and DMF with 15 mol % of
the catalyst (Table 1, entries 1 and 2). However, on changing
the reaction medium to water, the product was formed in high
yield and moderate enantio- and diastereoselectivity (Table 1,
entry 3). When the catalyst loading was decreased to 5 mol %,
a major enhancement in ee was observed (Table 1, entry 4).
There was still further enhancement in ee on decreasing the
catalyst loading to 2 mol % without any loss in yield (Table 1,
entry 5). No positive effect was observed on the reaction when
the ratio of cyclohexanone to 4-fluorobenzaldehyde was changed
from 4:1 to 10:1 (Table 1, entry 6). Decreasing the amount of
cyclohexanone had a negative effect on both ee as well as yield
(Table 1, entry 7). When brine was used as the solvent, there
J. Org. Chem. Vol. 73, No. 23, 2008 9413

Gandhi and Singh
TABLE 5. Reaction of Acetone with Different Aldehydesa
TABLE 3. Temperature Studya
entry
R
product
% yield
% eeb
entry
temp, °C
time, h
% yield
anti/synb
% ee (anti)c
1
2
3
4
5
6
7
C6H5
4-F-C6H4
8a
8b
8c
8d
8e
8f
75
80
72
78
70
68
93
89
86
86
82
84
88
67
1
2
3
4
5
rt
0 to rt
0
-5
-10
24
28
30
40
48
78
73
71
67
55
92:8
94:6
96:4
96:4
97:3
90
94
95
>99
96
3-OMe-C6H4
4-Cl-C6H4
3-Br-C6H4
3-Me-C6H4
4-CF3-C6H4
8g
a Ratio of ketone:aldehyde was 4:1 in all the cases. b Determined by
1H NMR analysis. c Determined by HPLC with chiral column.
a Ratio of ketone:aldehyde was 4:1 in all the cases. b Determined by
HPLC with chiral columns.
TABLE 4. Reaction of Cyclic Ketones with Different Aldehydesa
TABLE 6. Screening of Organic Solventsa
entry
X
R
product % yield anti/synb % ee (anti)c
entry
catalyst mol %
solvent
time, h
% yield
% eeb
1
2
3
4
5
6
CH2 4-F-C6H4
CH2 C6H5
7a
7b
7c
7d
7e
7f
67
82
60
99
92
95
75
99
82
77
75
83
96:4
98:2
93:7
93:7
97:3
90:10
97:3
97:3
98:2
98:2
92:8
94:6
>99
96
85
82
94
81
95
90
93
92
93
89
1
2
3
4
5
6
7
8
9
10
15
15
15
15
15
15
15
10
20
25
pyridine
DMF
DMSO
acetonitrile
THF
dioxane
24
48
48
36
30
48
12
36
10
8
66
53
45
74
78
68
84
74
78
68
74
72
70
73
79
75
77
72
71
68
CH2 4-OMe-C6H4
CH2 4-CN-C6H4
CH2 4-Cl-C6H4
CH2 4-NO2-C6H4
CH2 4-Me-C6H4
CH2 4-CF3-C6H4
CH2 2-naphthyl
CH2 2-furyl
7
7g
7h
7i
7j
7k
7l
c
c
c
c
8d
9
10
11e
12e
4-NO2-C6H4
a Ratio of ketone:aldehyde was 4:1 in all the cases. b Determined by
HPLC with chiral column. c Reaction was carried out in neat acetone
(1 M).
S
C6H5
a Ratio of ketone:aldehyde was 4:1 in all the cases. b Determined by
1H NMR analysis. c Determined by HPLC with chiral columns.
d Reaction was carried out at -25 °C. e Ratio of ketone:aldehyde was
2:1.
takes place from the re-face of aldehyde as shown in TS1. When
the reaction is carried out in an aqueous medium, the water
molecules form H-bonding with the amide groups and the
aldehyde as shown in TS3. There was no effect of stereochem-
istry at C-1 and C-2 on ee of the reaction when the reaction
was carried out in an aqueous medium (Table 2). We anticipated
that in organic solvents, since there is a direct H-bonding
between the aldehyde and the N-H groups of amide and
sulfonamide, there may be an observed effect of stereochemistry
at C-1 and C-2 on the reaction. We studied a variety of organic
solvents for the reaction between acetone and benzaldehyde to
find a suitable solvent for study (Table 6). Best results were
obtained in neat acetone. We then carried out the reaction with
catalysts 6a-d, in both acetone as well as brine, and compared
the two results (Table 7). As expected, there was no effect of
changing stereochemistry at C-1 and C-2 on ee of the reaction
when the reaction was carried out in an aqueous medium (Table
7, condition B). Surprisingly, the change in stereochemistry at
C-1 had no effect on ee of the reaction when an excess of
acetone was used as the solvent (Table 7, condition A, entries
1 and 3). However, the change in stereochemistry at C-2 had a
significant effect on ee of the reaction under the same conditions
(Table 7, condition A, entries 2 and 4). The results can be
explained by transition state models TS4 and TS5. When the
stereochemistry at C-2 is inversed from R to S, there is a
possibility of C-H-π interaction between the phenyl group at
C-2 and hydrogen of the aromatic ring of benzaldehyde if the
attack takes place from the si-face of aldehyde rather than the
re-face (TS5). This interaction stabilizes TS5 to a certain extent
°C and the ee increased to >99% (Table 3, entry 4). Further
decrease in temperature resulted a drop in both ee as well the
yield of the reaction (Table 3, entry 5).
A variety of aromatic aldehydes were then tested by using
cyclic ketones as donors (Table 4). High enantioselectivities
were obtained in almost all the cases. Aldehydes such as
naphthaldehyde and furaldehyde also formed the products in
high yields and enantioselectivities (Table 4, entries 9 and 10).
Apart from cyclohexanone, cyclic ketones such as cyclopen-
tanone and tetrahydrothiopyran-4-one also afforded the aldol
adducts in high enantio- and diastereoselectivities (Table 4,
entries 11 and 12).
The reaction was then extended to acetone and a variety of
aromatic aldehydes were explored (Table 5). Again, high
enantioselectivities were obtained in almost all the cases. The
aldehyde having an electron-withdrawing group gave low
enantioselectivity as compared to all other aldehydes (Table 5,
entry 7).
The proposed transition state model to explain the stereo-
chemical outcome of the reaction is shown in Figure 2. The
model has been explained by using benzaldehyde as the
electrophile and can be generalized to all other aromatic
aldehydes. The aldehyde is activated by bifurcated H-bonding
with NH of amide as well as NH of sulfonamide as shown in
TS1 and TS2. TS2 is unfavored because of nonbonding
interactions between the aromatic ring of aldehyde and the bulky
amino sulfonamide moiety. Therefore, the C-C bond formation
9414 J. Org. Chem. Vol. 73, No. 23, 2008

Synthesis of Chiral Organocatalysts
FIGURE 2. Proposed transition state model.
TABLE 7. Comparison of Results in Acetone and Brine
cyclohexanone and 4-fluorobenzaldehyde was converted to a
six- and a four-membered fused ring system.
The keto group was first converted to an oxime to form
compound 9, which was then reduced to form an amino
alcohol (Scheme 3). Initial attempts to cyclize the amino
alcohol to the azetidine ring failed. Even the use of benzoyl
or benzyl as protecting groups for amine was not successful
since the protected amine could not be cyclized. Finally, the
amino alcohol was tosylated and cyclized in situ with KOH.
The stereochemistry at the new chiral center was then
assigned by NOE experiments (Figure 3). On irradiation of
H1, there was an enhancement in the peak intensity of H2
and vice versa. This confirmed the stereochemistry at the
new chiral center.
condition Aa
condition Bb
entry catalyst time, h % yield % ee time, h % yield % ee
1
2
3
4
6a
6b
6c
6d
24
12
8
78
84
93
85
82
51
82
55
30
26
24
30
70
80
75
70
82
81
89
82
12
a Condition A: catalyst (15 mol %), acetone (1 M). b Condition B:
catalyst (5 mol %), acetone:benzaldehyde (4:1), brine.
SCHEME 3
FIGURE 3. NOE studies for compound 10.
Conclusion
In conclusion, we have synthesized a new series of highly
efficient organocatalysts by regio- and stereoselective ring opening
of aziridines with azide anions. The synthesis has been ac-
complished by coupling L-proline with a chiral ꢀ-amino sulfona-
mide. The catalysts have been evaluated for a direct asymmetric
aldol reaction. The catalysts work efficiently in an aqueous medium
and offer high yield and diastereo- and enantioselectivities. The
results obtained have been rationalized on the basis of a proposed
transition state model. Furthermore, the chiral aldol adduct has been
derivatized to a chiral azetidine ring that finds a variety of
applications in asymmetric organic synthesis.
and hence leads to a drop in ee of the product. This C-H-π
interaction is disturbed when the reaction is carried out in an
aqueous medium because water molecules enter into the spaces
between the catalyst and participate in H-bonding with the
substrates and the catalyst. Hence, there is no observed effect
of changing stereochemistry at C-1 and C-2 on the reaction in
brine.
ꢀ-Hydroxy ketones, obtained as the products of the direct
aldol reaction, contain two modifiable functional groups, which
makes them highly valuable in organic synthesis. To show their
applicability, the aldol adduct was converted to a chiral azetidine
ring. The aldol adduct obtained by the reaction between
Experimental Section
General Procedure for the Synthesis of Catalysts 3a-g.
Formic acid (4.0 mL) was slowly added to N-Boc protected catalyst
(1.0 mmol) at 0 °C and the mixture was subsequently stirred at rt
for 12 h. Formic acid was then evaporated and reaction mixture
J. Org. Chem. Vol. 73, No. 23, 2008 9415

Gandhi and Singh
was neutralized with aqueous ammonia at 0 °C. The product was
extracted with dichloromethane and the organic layer was washed
with water and brine and dried over anhydrous Na2SO4. The organic
layer was then concentrated and purified by column chromatography
(10% MeOH-DCM) to give the pure catalyst.
(4 mmol) and the catalyst (0.02 mmol) in brine (1.0 mL) at the
required temperature. The reaction mixture was stirred and the
progress of the reaction monitored by TLC. After the completion
of the reaction, the reaction mixture was diluted with EtOAc. The
organic layer was separated, dried over anhydrous Na2SO4, and
concentrated to give the crude product that was purified over silica
gel by column chromatography. The enantiomeric excess (ee) of
the aldol product was determined by chiral HPLC analysis.
Procedure for the Synthesis of Oxime 9. Hydroxylamine
hydrochloride (1.5 mmol) was added to a solution of aldol adduct
7a (1.0 mmol) in ethanol (4 mL). Sodium acetate (4.0 mmol) and
pyridine (0.1 mmol) were then added and the solution was refluxed
for 3 h. After the completion of the reaction, ethanol was evaporated
under reduced pressure. The residue was diluted with water and
extracted three times with DCM. The organic layer was washed
with brine, dried over anhydrous Na2SO4, and concentrated to give
the crude product. Column chromatography over silica gel (20%
EtOAc/Hexane) gave the pure product.
(S)-N-((1S,2R)-2-(4-Methylphenylsulfonamido)-1-phenylpro-
pyl)pyrrolidine-2-carboxamide (3a). Yield 89%; mp 160-162 °C;
[R]25D -5.4 (c 1.0, CHCl3); FT IR (KBr) 3357, 3326, 3212, 1658,
1511, 1332, 1152 cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.65 (d, J
) 8.3 Hz, 1H), 7.75 (d, J ) 8.0 Hz, 2H), 7.31 (m, 5H), 7.18 (m,
2H), 4.84 (dd, J ) 8.8, 2.9 Hz, 1H), 4.70 (m, 1H), 3.81 (dd, J )
9.0, 5.6 Hz, 1H), 3.70 (m, 1H), 3.04 (m, 1H), 2.96 (m, 1H), 2.43
(s, 3H), 2.17-2.01 (m, 2H), 1.84 (m, 1H), 1.69 (m, 2H), 0.80 (d,
J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 175.1, 143.5,
137.6, 137.1, 129.7, 128.6, 127.9, 127.4, 127.1, 60.6, 56.4, 53.2,
47.1, 30.4, 26.0, 21.5, 17.8; HRMS (ESI) exact mass calcd for
C21H27N3O3S [M + H]+ 402.1852, found 402.1852.
(S)-N-((1S,2R)-1-Phenyl-2-(phenylsulfonamido)propyl)pyr-
rolidine-2-carboxamide (3b). Yield 74%; mp 85-87 °C; [R]25
(R)-2-((R)-(4-Fluorophenyl)(hydroxy)methyl)cyclohexanone
D
oxime (9). Yield 75%; mp 124-125 °C; [R]25 +107.4 (c 0.85,
-11.2 (c 1.0, CHCl3); FT IR (KBr) 3284, 3063, 1656, 1517, 1324,
1164 cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.64 (d, J ) 7.6 Hz, 1H),
7.88 (m, 2H), 7.55 (m, 3H), 7.31 (m, 3H), 7.16 (m, 2H), 4.83 (dd, J
) 8.5, 2.9 Hz, 1H), 4.74 (d, J ) 9.5 Hz, 1H), 3.80 (dd, J ) 9.1, 5.6
Hz, 1H), 3.72 (m, 1H), 3.03 (m, 1H), 2.94 (m, 1H), 2.08 (m, 2H),
1.83 (m, 1H), 1.69 (m, 2H), 0.82 (d, J ) 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 175.2, 140.5, 136.9, 132.7, 129.2, 128.7, 127.9,
127.4, 127.1, 60.5, 56.4, 53.3, 47.1, 30.4, 26.1, 17.9; HRMS (ESI)
exact mass calcd for C20H25N3O3S [M + H]+ 388.1696, found
388.1691.
D
CHCl3); FT IR (KBr) 3268, 1604, 1512, 1432, 1223 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 7.31 (m, 2H), 7.03 (m, 2H), 4.76 (d, J ) 9.0
Hz, 1H), 3.30 (m, 1H), 2.41 (m, 1H), 1.84-1.68 (m, 3H), 1.45-1.12
(m, 5H); 13C NMR (CDCl3, 125 MHz) δ 163.0, 137.2, 128.8, 128.7,
115.2, 115.0, 74.9, 49.9, 30.0, 25.6, 24.7, 24.3. Anal. Calcd for
C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.93; H, 6.83;
N, 5.92.
Procedure for the Synthesis of Product 10. LiAlH4 (3.0 mmol)
was added to THF (3.0 mL) at 0 °C. Oxime 9 (1.0 mmol) dissolved
in THF (3.0 mL) was then added dropwise at the same temperature.
The reaction mixture was allowed to warm to room temperature
and then refluxed for 4 h. After the completion of reaction, the
reaction mixture was cooled and quenched with ethyl acetate, 10%
NaOH, and water. The solution was stirred for 30 min and filtered
over celite. The residue was washed with ethyl acetate. Anhydrous
Na2SO4 was added to the filterate, which was subsequently
concentrated in vacuo to give the crude amino alcohol.
The crude amino alcohol was dissolved in DCM:water (1:1) (5
mL) and the solution was cooled to 0 °C. Potassium hydroxide
(2.0 g) and p-toluenesulfonyl chloride (2.5 mmol) were then added
and the solution was stirred at room temperature for 12 h. After
the completion of reaction, the solution was diluted with DCM.
The organic layer was extracted and washed with brine, dried over
anhydrous Na2SO4, and concentrated to give the crude product,
which on purification over silica gel (10% EtOAc/hexane) gave
the pure compound 10.
(1R,8S)-8-(4-Fluorophenyl)-7-tosyl-7-azabicyclo[4.2.0]octane (10).
Yield 42%; dr >99:1; mp 90-92 °C; [R]25D +37.7 (c 0.3, CHCl3);
FT IR (KBr) 2925, 1337, 1154 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 7.30 (m, 2H), 7.08 (m, 4H), 6.80 (m, 2H), 4.91 (d, J ) 7.5 Hz,
1H), 4.38 (m, 1H), 2.51 (m, 1H), 2.33 (s, 3H), 2.18 (m, 1H), 2.10
(m, 1H), 1.62 (m, 3H), 1.20 (m, 3H); 13C NMR (CDCl3, 125 MHz)
δ 163.5, 161.6, 143.0, 137.5, 134.3, 129.2, 129.1, 127.4, 115.2,
115.0, 69.2, 61.9, 38.5, 26.9, 23.7, 21.5, 20.9, 20.1; HRMS (ESI)
exact mass calcd for C20H22FNO2S [M + H]+ 360.1435, found
360.1434.
(S)-N-((1S,2R)-2-(2-Nitrophenylsulfonamido)-1-phenylpropyl)-
pyrrolidine-2-carboxamide (3f). Yield 74%; mp 85-87 °C; [R]25
D
-86.0 (c 1.0, CHCl3); FT IR (KBr) 3356, 1661, 1540, 1452, 1345,
1167 cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.62 (m, 1H), 8.16 (m,
1H), 7.86 (m, 1H), 7.75 (m, 2H), 7.31 (m, 5H), 4.89 (dd, J ) 8.2,
3.2 Hz, 1H), 3.95 (m, 1H), 3.78 (dd, J ) 9.2, 5.6 Hz, 1H), 3.00
(m, 1H), 2.94 (m, 1H), 2.12 (m, 2H), 1.81 (m, 1H), 1.68 (m, 2H),
0.92 (d, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 175.0,
147.8, 136.6, 134.4, 133.6, 133.0, 130.8, 128.8, 128.1, 127.4, 125.5,
60.5, 56.1, 53.6, 47.2, 30.4, 26.1, 18.1; HRMS (ESI) exact mass
calcd for C20H24N4O5S [M + H]+ 433.1546, found 433.1548.
General Procedure for the Synthesis of Catalysts 6a-d. The
same procedure was followed as in the case of synthesis of catalysts
3a-g.
(S)-N-((1S,2R)-1,2-Diphenyl-2-(phenylsulfonamido)ethyl)pyr-
rolidine-2-carboxamide (6a). Yield 91%; mp 180-182 °C; [R]25
D
-22.4 (c 0.3, THF); FT IR (KBr) 3197, 1656, 1549, 1324, 1156
1
cm-1; H NMR (CDCl3, 400 MHz) δ 8.53 (d, J ) 8.5 Hz, 1H),
7.66 (d, J ) 7.3 Hz, 2H), 7.39 (m, 1H), 7.26 (m, 5H), 7.07 (m,
3H), 6.79 (d, J ) 6.7 Hz, 2H), 6.68 (d, J ) 7.1 Hz, 2H), 5.20 (dd,
J ) 8.6, 3.4 Hz, 1H), 4.79 (m, 1H), 3.81 (dd, J ) 9.3, 5.4 Hz, 1H),
2.99 (m, 1H), 2.85 (m, 1H), 2.08 (m, 1H), 1.83 (m, 1H), 1.64 (m,
2H); 13C NMR (CDCl3, 125 MHz) δ 175.7, 140.3, 136.5, 136.1,
132.4, 128.8, 128.5, 128.1, 128.0, 127.7, 127.4, 127.1, 125.6, 62.2,
60.5, 57.7, 47.2, 30.4, 26.2; HRMS (ESI) exact mass calcd for
C25H27N3O3S [M + H]+ 450.1852, found 450.1850.
(S)-N-((1R,2R)-1,2-Diphenyl-2-(phenylsulfonamido)ethyl)pyr-
rolidine-2-carboxamide (6c). Yield 92%; mp 135-137 °C; [R]25
D
Acknowledgment. V.K.S. thanks the Department of Science
and Technology, India, for a research grant. S.G. thanks the
Council of Scientific and Industrial Research, New Delhi, for a
senior research fellowship.
-6.3 (c 1.0, CHCl3); FT IR (KBr) 3197, 1656, 1549, 1324, 1156
1
cm-1; H NMR (CDCl3, 500 MHz) δ 8.48 (d, J ) 8.3 Hz, 1H),
7.64 (d, J ) 7.8 Hz, 2H), 7.39 (m, 1H), 7.24 (m, 5H), 7.07 (m,
3H), 6.79 (d, J ) 7.2 Hz, 2H), 6.67 (d, J ) 7.5 Hz, 2H), 5.82 (m,
1H), 5.18 (dd, J ) 8.5, 3.2 Hz, 1H), 4.78 (m, 1H), 3.82 (dd, J )
9.1, 5.5 Hz, 1H), 2.99 (m, 1H), 2.85 (m, 1H), 2.10 (m, 1H), 1.80
(m, 2H), 1.69-1.40 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 175.4,
140.2, 136.3, 136.0, 132.3, 128.7, 128.5, 128.0, 127.8, 127.6, 127.3,
127.0, 62.1, 60.3, 57.7, 47.1, 30.4, 26.6; HRMS (ESI) exact mass
calcd for C25H27N3O3S [M + H]+ 450.1852, found 450.1851.
A Representative Procedure for the Direct Aldol Reaction
in Brine. An aldehyde (1.0 mmol) was added to a mixture of ketone
Supporting Information Available: General experimental
1
procedures, characterization data including H NMR spectra,
13C NMR spectra for all compounds, and HPLC chromatograms
for compounds 7a-l and 8a-g. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO8019863
9416 J. Org. Chem. Vol. 73, No. 23, 2008