NOBIN-prolinamide organocatalyzed enantioselective direct aldol reaction: Remarkable activity in apolar medium

Article abstract of DOI:10.1055/s-2007-970765

Amides easily obtained from enantiopure (R)- and (S)-NOBIN and L-proline have been shown to promote the enantioselective direct aldol reaction under low catalytic loadings (5 mol%), in apolar hexane as the solvent and using only a slightly higher molar ex

Full text of DOI:10.1055/s-2007-970765

LETTER
795
NOBIN-Prolinamide Organocatalyzed Enantioselective Direct Aldol
Reaction: Remarkable Activity in Apolar Medium
N
A
OBIN-Prolinami
l
de Cata
e
lyzed Enan
s
tioselectiv
s
e
D
irect
A
i
ldol
R
o
eaction Russo, Giovanna Botta, Alessandra Lattanzi*
Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, 84084 Fisciano, Italy
Fax +39(089)969603; E-mail: lattanzi@unisa.it
Received 5 December 2006
Accordingly, Gong and co-workers demonstrated that
amide N–H and hydroxyl bonds, through a double hydro-
gen-bonding network, efficiently control catalyst activity
Abstract: Amides easily obtained from enantiopure (R)- and (S)-
NOBIN and L-proline have been shown to promote the enantiose-
lective direct aldol reaction under low catalytic loadings (5 mol%),
in apolar hexane as the solvent and using only a slightly higher and the stereochemical outcome of the aldol reaction as
molar excess of the acetone with respect to the aldehyde. Aldol illustrated in transition state TS (Figure 1). Notable re-
products are isolated in good to high yields and up to 77% ee at
room temperature.
sults were also reported by Xiao and co-workers by using
tunable bifunctional L-prolinamide derivatives. The axial
8
Key words: aldol reaction, asymmetric organocatalysis, prolin- motif was very recently introduced with BINAM–bis- and
amides, NOBIN, apolar solvent
monoprolinamides which were found to efficiently cata-
lyze direct aldol reactions either in polar solvents as DMF
and water or in ethereal and alogenated media affording
9
The enantioselective aldol reaction is one of the most good to high stereo- and regioselective control. Interest-
powerful approaches to the stereoselective construction of ingly, (R)- and (S)-BINOL additives were found to en-
1
carbon–carbon bonds. A great number of asymmetric hance the efficiency of L-proline-catalyzed direct aldol
methodologies have been developed to date, mainly start- reaction.10
ing from ketene silyl acetals or anion equivalent of the do-
As part of our ongoing project on designing new organo-
catalysts for asymmetric synthesis, we have designed
2
nor. More recently, organocatalyzed protocols have led
to excellent results in the practical and atom-efficient di-
rect aldol reaction of unmodified ketones or aldehydes as
11
L-proline-derived compounds having an axial element of
12
chirality provided by (R)- and (S)-NOBIN introduced as
3
donors. In this context, L-proline was recently discovered
the amide moiety (Figure 2). The higher acid strength of
NH and phenolic groups in NOBIN-prolinamides, that
would serve as hydrogen-bonding donors in the
postulated TS (Figure 1), should have furnished more
by List and Barbas as a catalyst able to successfully pro-
mote the direct asymmetric intermolecular aldol reaction.4
Along with it being a low-cost and easily available com-
pound, the catalyst is required in only substoichiometric
amounts (30 mol%). Because of the difficulty in realizing
structural modifications on the pyrrolidine ring, a great
deal of synthetic work has been directed toward the
6
active prolinamide organocatalysts. Diastereoisomeric
NOBIN-prolinamides 2 and 3 were easily synthesized
6,8
according to well-established procedures by coupling
commercially available N-benzyloxy-L-proline with (R)-
5
derivatization of the carboxylic acid moiety. Among the
13
and (S)-NOBIN. Successive deprotection through hy-
most efficient modified proline-based catalysts, Gong and
drogenation over Pd/C furnished compounds 2 and 3 in
6
co-workers reported prolinamides of type 1 (Figure 1),
14
5
4% and 51% yields for the two steps, respectively.
which afforded high yields and enantioselectivities. Houk
and List proposed a model for the L-proline-catalyzed
direct aldol reaction, where the transition state is stabi-
O
O
7
lized through hydrogen bonding.
N
N
N
N
H
H
H
H
HO
HO
O
R
R
O
N
R
H
O
N
L-Pro-Ra-NOBIN (2)
L-Pro-Sa-NOBIN (3)
N
H
R
N
H
O
H
Figure 2 NOBIN-based prolinamides
HO
1
H
TS
R
We first screened the reaction of p-nitrobenzaldehyde
with acetone under different conditions using catalysts 2
and 3 (Table 1). Under 10 mol% loading, they promoted
the reaction in neat acetone at room temperature in
satisfactory yields and moderate enantiomeric excess
Figure 1
SYNLETT 2007, No. 5, pp 0795–0799
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970765; Art ID: G34606ST
Georg Thieme Verlag Stuttgart · New York
(
entries 1 and 2). When using 20 mol% of catalyst loading
at –20 °C an improvement of the enantioselectivity was
©

7
96
A. Russo et al.
LETTER
observed for catalyst 3 (entry 4), moreover it proved to be improvement was observed under more concentrated
more active than compound 2 (entry 3). These results conditions (entry 6). In THF the ee was high, although the
indicated that the axial S-configured L-proline diastereo- yield of 5a was modest (entry 7); while in halogenated
isomer 3 has the matched combination of the chiral solvent, the product was isolated in modest yield and
elements. We next carried out a solvent screening with or- moderate ee (entry 8). In toluene, a significant improve-
ganocatalyst 3. When using DMF, the aldol product was ment in the yield and enantioselectivity was achieved
isolated in 81% ee, although in poor yield (entry 5); no (entry 9).
Table 1 Direct Aldol Reaction of p-Nitrobenzaldehyde with Acetone Using Catalysts 2 and 3a
O
O
O
OH
catalyst
NO2
+
H
NO2
4a
5a
Entry
Catalyst (mol%)
2 (10)
Time (h)
23
Solvent
–
Temp (°C)
r.t.
Yield of 5a (%)b ee of 5a (%)c
1
2
3
4
5
6d
7
8
9
40
63
40
71
14
25
32
36
65
99
99
57
57
22
56
57
58
68
81
78
85
56
62
68
70
61
69
66
3 (10)
21
–
r.t.
2 (20)
46
–
–20
–20
r.t.
3 (20)
66
–
3 (10)
28
DMF
DMF
THF
CH Cl
3 (10)
90
r.t.
3 (10)
29
r.t.
3 (10)
23
r.t.
2
2
3 (10)
23
toluene
hexane
hexane
hexane
hexane
hexane
r.t.
1
1
1
1
1
0
3 (10)
7
r.t.
1
3 (10)
12
4
2
2 (10)
18
4
3
3 (5)
66
–20
r.t.
4e
3 (0.5)
47
1 f
5
CO2H
70
8
hexane
hexane
r.t.
r.t.
55
98
18
5
N
H
O
1 f
6
NH2
N
H
O
Ph
1 f
7
11
21
hexane
hexane
r.t.
r.t.
99
38
24
62
N
H
Ph
Ph
N
H
HO
Ph
O
1 f
8
N
H
N
H
HO
a
b
c
Reaction conditions: 4a (0.2 mmol), acetone (0.6 mmol), solvent (400 mL).
Isolated yields after flash chromatography.
Determined by HPLC analysis using Chiracel AS-H column. Absolute configuration of the major enantiomer was determined to be R by
6,8
comparison of optical rotation with those reported in the literature.
d
The reaction was carried out using 200 mL of DMF.
Two equiv of acetone were used with respect to 4a.
The reaction was carried out using 10 mol% of catalyst.
e
f
Synlett 2007, No. 5, 795–799 © Thieme Stuttgart · New York

LETTER
NOBIN-Prolinamide Catalyzed Enantioselective Direct Aldol Reaction
797
The reaction carried out in an unusual solvent, the apolar the aldol product. To the best of our knowledge this is the
hexane, surprisingly proceeded in only 7 hours with com- first example of organocatalyzed direct aldol reaction that
plete conversion to the final product which was isolated in efficiently proceeds in hexane.
6
8% ee (entry 10). The reactions performed in hexane
To establish if the phenolic OH group was involved in hy-
with catalysts 2 and 3 at 4 °C (entries 11 and 12)
confirmed diastereoisomer 3 as the best promoter, but
the asymmetric induction did not increase. Catalyst 3
proved to be efficient in hexane even at 5 mol% loading
and –20 °C (entry 13). Although the activity decreased
when using only 0.5 mol% of the catalyst and 2 equiva-
lents of acetone at room temperature, the enantioselectiv-
ity was maintained (entry 14). To investigate if the
enhanced catalyst activity was a more general result, dif-
ferent proline-derived compounds were checked in hex-
ane. L-Proline was reacted under conditions reported in
entry 10, and after three days the product was isolated in
drogen-bonding activation, the O-methylated enantiomer
16
6
of the most active catalyst 3 was reacted with p-ni-
trobenzaldehyde and acetone under optimized conditions
Equation 1).
(
Catalyst 6 proved to be highly active, since the product
was isolated in quantitative yield, but the expected prefer-
entially enriched (S)-5a showed a markedly reduced ee
(
compare with entry 10 in Table 1). Even in the case of
NOBIN-prolinamides, the phenolic OH group was found
to be involved in the control of the asymmetric induction,
likely through double hydrogen-bonding activation of the
aldehyde as previously observed for catalysts of type 1
5
5% yield and 18% ee (entry 15). It is interesting to note
a,b
(
Figure 1).6
that this heterogeneous system, where L-proline is insolu-
ble in the reaction solvent, is more efficient than L-proline The scope of the aldol reaction of acetone with aromatic
used at the same loading (10 mol%) in very polar DMF– aldehydes was studied using 5 mol% of catalyst 3 in
water (1:1) solvent mixture, employing 27 equivalents of hexane at room temperature (Table 2).17
9
a
acetone with respect to 4a. In this case, after five days,
racemic 5a was isolated in 60% yield. Under the same
conditions, L-prolinamide showed to be a highly active
organocatalyst, although almost racemic aldol product
was recovered (entry 16). Finally, two diastereoisomeric
Aldehydes bearing electron-withdrawing groups in the
phenyl ring were converted into the corresponding aldol
products in high yields and satisfactory ee after relatively
short reaction times. Predictably, reduced efficiency was
observed when less activated aldehydes were reacted
6
a
prolinamides reported by Gong were tested (entries 17
and 18). In the first case, after a short reaction time, 5a
was isolated in quantitative yield, but the enantiomeric
excess significantly decreased from 49% observed in neat
(
entries 8 and 9).
A promising result has been achieved in the reaction of p-
nitrobenzaldehyde (4a, 1 equiv) and cyclohexanone (3
equiv) with catalyst 3 in hexane at room temperature
6
a
acetone to 24% (entry 17). The other diastereoisomer
(
Equation 2). The aldol product was isolated in quantita-
(
entry 18) proved to be less reactive, but the ee of 5a was
6
a
tive yield and fair diastereoisomeric ratio. The preferen-
almost maintained in hexane (64% ee in neat acetone ).
These data clearly indicate that the structure of the amide
tially formed anti-isomer was recovered in good ee.18
moiety is relevant in controlling the activity and the asym- In conclusion, NOBIN-prolinamides proved to be highly
metric induction. NOBIN-prolinamides 2 and 3 afforded active organocatalysts in the asymmetric direct aldol reac-
the best results among the different prolinamide promot- tion carried out in hexane. Significant practical improve-
ers employed in hexane. The use of such an apolar solvent ments over direct aldol reaction in conventional solvents/
led to a remarkable increase of the catalyst activity in the neat conditions have been achieved when working in hex-
presence of low amounts of acetone. These results can be ane: i) low catalytic loadings of NOBIN-prolinamide can
19
rationalized by the fact that being reactants insoluble in be conveniently used, ii) nearly stoichiometric amounts
hexane, they become dissolved and highly concentrated in of the donor are employed in comparison to high excess
the small polar portion of acetone. Enamine formation15 (≥20 equiv) generally reported. Furthermore, no aque-
would be facilitated and the equilibria then shifted toward ous work up is necessary, since the reaction mixture can
20
O
N
N
H
H
MeO
O
O
O
OH
H
+
6
(10 mol%)
hexane, r.t.
NO2
8
h
4a
5a
9%, 20% ee
NO2
9
Equation 1
Synlett 2007, No. 5, 795–799 © Thieme Stuttgart · New York

7
98
A. Russo et al.
LETTER
Table 2 Direct Aldol Reaction of Various Aromatic Aldehydes with
Acetone in Hexane at Room Temperature Catalyzed by 3a
(2) (a) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.;
Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 2169. (b) Evans, D. A.;
O
O
O
OH
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125,
3
(5 mol%)
8
706. (c) Mahrwald, R. Org. Lett. 2000, 2, 4011.
(d) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem.
000, 65, 9125. (e) Yamada, Y. M. A.; Yoshikawa, N.;
Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997,
6, 1871.
+
H
R
R
hexane, r.t.
4
5
2
Entry
R
Time (h)
Yield of 5 ee of 5
3
b
(%)c
70
71
71
70
59
53
77
60
57
(
%)
(
3) For selected examples, see: (a) Gröger, H.; Wilken, J.
Angew. Chem. Int. Ed. 2001, 40, 529. (b) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew.
Chem. Int. Ed. 2004, 43, 2152. (c) Northrup, A. B.;
MacMillan, D. W. C. Science 2004, 305, 1752.
1
2
3
4
5
6
7
8
p-NO C H
10
10
42
44
90
96
48
84
86
99
98
76
80
61
52
97
55
51
2
6
4
4
o-NO C H
2
6
6
p-CNC H4
(d) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254.
p-CF C H
4
3
6
(e) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem. Int. Ed. 2005, 44, 794. (f) Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem. Int. Ed. 2004, 43, 1983.
p-ClC H4
6
o-ClC H4
6
(
4) (a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395. (b) Notz, W.; List, B. J. Am. Chem. Soc.
2,6-Cl C H
3
2
6
2
000, 122, 7386. (c) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.
d) List, B. Acc. Chem. Res. 2004, 37, 548. (e) Notz, W.;
Tanaka, F.; Barbas, C. F. III Acc. Chem. Res. 2004, 37, 580.
p-BrC H4
6
(
9
Ph
a
Reaction conditions: 4 (0.2 mmol), acetone (0.6 mmol), 3 (0.01
mmol), hexane (400 mL).
(5) (a) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett.
2005, 7, 5321. (b) Berkessel, A.; Koch, B.; Lex, J. Adv.
Synth. Catal. 2004, 346, 1141. (c) Hartikka, A.; Arvidsson,
P. I. Tetrahedron: Asymmetry 2004, 15, 1983. (d) Lacoste,
E.; Landais, Y.; Schenk, K.; Verlhac, J.-B.; Vincent, J.-M.
Tetrahedron Lett. 2004, 45, 8035. (e) Cobb, A. J. A.; Shaw,
D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84. (f) Gryko, D.; Lipiński, R. Adv.
Synth. Catal. 2005, 347, 1948. (g) Vishnumaya, R. M.;
Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097.
b
Isolated yields after flash chromatography.
c
6
Determined by HPLC analysis using Chiracel AS-H column. Abso-
lute configuration of the major enantiomer was determined to be R by
comparison of the HPLC retention times and optical rotations with
6
,8
those reported in the literature.
O
O
OH
O
(
h) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang, S.-T.; Wang,
X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-A. Tetrahedron Lett.
006, 47, 7793. (i) Dinér, P.; Amedjkouh, M. Org. Biomol.
+
H
3 (10 mol%)
2
hexane, r.t.
42 h
NO2
NO2
Chem. 2006, 4, 2091. (j) Cheng, C.; Sun, J.; Wang, C.;
Zhang, Y.; Wei, S.; Jiang, F.; Wu, Y. Chem. Commun. 2006,
215. For L-proline derivatives modified in the pyrrolidine
ring used in direct aldol reaction, see: (k) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem. Int. Ed. 2006, 45, 958. (l) Gu, L.; Yu, M.;
Wu, X.; Zhang, Y.; Zhao, G. Adv. Synth. Catal. 2006, 348,
4a
98% yield
anti/syn 86:14
7% ee (anti): 29% ee (syn)
7
Equation 2 Aldol reaction of cyclohexanone with 4a catalyzed by 3
2223. For L-proline-catalyzed direct aldol reaction leading
to polyketide compounds, see: (m) Chowdari, N. S.;
Ramachary, D. B.; Córdova, A.; Barbas, C. F. III
Tetrahedron Lett. 2002, 43, 9591. (n) Casas, J.; Engqvist,
M.; Ibrahem, I.; Kaynak, B.; Córdova, A. Angew. Chem. Int.
Ed. 2005, 44, 1343. (o) Córdova, A.; Sundén, H.; Xu, Y.;
Ibrahem, I.; Zou, W.; Engqvist, M. Chem. Eur. J. 2006, 12,
be directly purified by flash chromatography. Further
work is now directed at investigating the potential of this
system using different donors and optimizing reaction
2
1
conditions to improve the enantioselectivity.
5
446.
Acknowledgment
(
6) (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,
MIUR is gratefully acknowledged for financial support.
5262. (b) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-
Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci.
U. S. A. 2004, 101, 5755. (c) 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.
References and Notes
(
1) (a) Modern Aldol Reactions, Vol. 2; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004, 197. (b) Johnson, J. S.;
Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(
(
7) (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am.
Chem. Soc. 2003, 125, 16. (b) Bahmanyar, S.; Houk, K. N.;
Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475.
8) (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543. (b) Chen, J.-R.; Li, X.-
Y.; Xing, X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71, 8198.
Synlett 2007, No. 5, 795–799 © Thieme Stuttgart · New York

LETTER
NOBIN-Prolinamide Catalyzed Enantioselective Direct Aldol Reaction
799
(
9) (a) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron:
1.54–1.48 (m, 1 H), 1.30–1.20 (m, 2 H). 13C NMR (100
Asymmetry 2006, 17, 729. (b) Guillena, G.; Hita, M. C.;
Nájera, C. Tetrahedron: Asymmetry 2006, 17, 1027.
MHz, CDCl ): d = 174.0, 151.9, 136.0, 133.3, 133.1, 132.8,
3
131.0, 130.6, 130.0, 129.3, 128.3, 128.1, 127.1, 127.0,
125.0, 124.9, 124.2, 123.7, 119.9, 117.8, 113.6, 60.6, 46.1,
(
c) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron:
+
Asymmetry 2006, 17, 1493. (d) Gryko, D.; Kowalczyk, B.;
Zawadzki, L. Synlett 2006, 1059. (e) Guizzetti, S.;
Benaglia, M.; Pignataro, L.; Puglisi, A. Tetrahedron:
Asymmetry 2006, 17, 2754.
30.6, 25.3. ESI-MS: m/z = 383 [MH ]. Anal. Calcd (%) for
C H N O : C, 78.51; H, 5.80; N, 7.32. Found: C, 78.39; H,
2
5
22
2
2
5.62; N, 7.20.
(15) (a) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci.
U. S. A. 2004, 101, 5839. (b) List, B. Chem. Commun. 2006,
819.
(
(
10) Zhou, Y.; Shan, Z. Tetrahedron: Asymmetry 2006, 17, 1671.
11) (a) Lattanzi, A. Org. Lett. 2005, 7, 2579. (b) Lattanzi, A.
Adv. Synth. Catal. 2006, 348, 339. (c) Lattanzi, A.
(16) Procedure for the Synthesis of Catalyst 6
N-Carbobenzyloxy-D-prolinamide-(R)-NOBIN (180 mg,
0.348 mmol) was stirred with Cs CO (566 mg, 1.74 mmol)
Tetrahedron: Asymmetry 2006, 17, 837. (d) Lattanzi, A.;
Russo, A. Tetrahedron 2006, 62, 12264.
2
3
(
12) Racemic NOBIN was synthesized according to procedures
reported in the following references: (a) Ding, K.; Xu, Q.;
Wang, Y.; Liu, J.; Yu, Z.; Du, B.; Wu, Y.; Koshima, H.;
Matsuura, T. Chem. Commun. 1997, 693. (b) Vyskočil, S.;
Smrčina, M.; Lorenc, M.; Kočovský, P.; Hanuš, V.; Polášek,
M. Chem. Commun. 1998, 585.
13) (R)- and (S)-NOBIN were obtained by optical resolution
according to the procedure reported in the literature: Ding,
K.; Wang, Y.; Yun, H.; Liu, J.; Wu, Y.; Terada, M.; Okubo,
Y.; Mikami, K. Chem. Eur. J. 1999, 5, 1734.
in MeCN (5 mL) at r.t. for 30 min. Then MeI (870 mL, 14
mmol) was added and the mixture was stirred for 18 h. The
solvent was removed, the crude mixture was diluted with
HCl solution (0.1 N) and extracted with CHCl (2 × 50 mL).
3
The organic phase was then dried over Na SO . The crude
2
4
mixture was purified by flash chromatography eluting with
PE–EtOAc (6:4) to give 124 mg (67%) of the methylated
product. Deprotection of this compound, carried out as
previously reported for compound 2 and 3, furnished 88 mg
(95%) of 6 as a white solid.
(
2
3
(
14) Procedure for the Synthesis of Catalysts 2 and 3
To a solution of N-carbobenzyloxy L-proline (320 mg, 1.26
mmol) in anyd CH Cl (4 mL) and MeCN (4 mL) was added
Compound 6: mp 167–171 °C (dec); [a]D +33.9 (c 0.25,
EtOH). IR (neat): 3443, 2927, 1658, 1507, 1249, 812, 753
–
1 1
cm . H NMR (400 MHz, CDCl ): d = 9.70 (br s, 1 H), 8.05–
2
2
3
DMAP (80 mg, 1 mmol), EDC·HCl (368 mg, 3 mmol) at
°C under argon atmosphere. Stirring was mantained for 1 h,
7.85 (m, 6 H), 7.56–7.17 (m, 6 H), 3.95 (s, 3 H), 3.50–3.45
(m, 1 H), 3.37–3.32 (m, 2 H), 2.17–1.98 (m, 2 H), 1.33–1.20
(m, 2 H). C NMR (100 MHz, CDCl ): d = 173.0, 154.9,
0
1
3
then (R)-or (S)-NOBIN (400 mg, 1.4 mmol) dissoved in
anhyd DMF (2 mL) was cannulated in the reaction vessel
and stirring was mantained for 3 d at r.t. The solvent was
removed, the crude mixture was diluted with HCl solution
3
138.2, 133.7, 133.0, 132.8, 131.0, 130.7, 129.5, 129.0,
128.5, 128.3, 127.6, 127.0, 126.0, 125.2, 125.1, 124.7,
124.0, 123.7, 115.5, 58.8, 58.3, 47.6, 29.9, 25.4. ESI-MS:
+
(
0.1 N) and extracted with CHCl (2 × 50 mL). The organic
m/z = 403 [M + H ]. Anal. Calcd (%) for C H N O : C,
3
26 24
2
2
phase was then dried over Na SO . The crude mixture was
78.76; H, 6.10; N, 7.07. Found: C, 78.92; H, 6.25; N, 7.21.
(17) Typical Procedure for the Aldol Reaction
2
4
purified by flash chromatography eluting with PE–Et O
2
(
3
1:1) to PE–EtOAc (2:1) mixtures to give 400 mg (60%) and
80 mg (57%) yield, respectively, as white gummy
In a capped vial under air catalyst 3 (3.8 mg, 0.01 mmol),
aldehyde (0.2 mmol) and hexane (400 mL) were added at r.t.
To this stirred mixture, acetone (44 mL, 0.6 mmol) was
added. Upon completion of the reaction, monitored by TLC,
the reaction mixture was directly purified by flash
compounds. To N-carbobenzyloxy-L-prolinamide (R)-
NOBIN (400 mg) dissolved in anhyd MeOH (8 mL) was
added Pd/C (10% w/w). The reaction mixture was stirred
under H (1 atm) at 50 °C for 3 h. After cooling, the mixture
was filtered over a pad of Celite . The solvent was removed
and the crude mixture was purified by flash chromatography
chromatography (PE–EtOAc 90:10 to 60:40 mixtures) to
provide aldol 5. Analytical data of aldols matched those
reported in the literature.
2
®
5
,6
eluting with CHCl –MeOH (2:1) mixture to give 2 (266 mg,
(18) For the sake of comparison, the optimized Gong’s catalyst at
–25 °C in cyclohexanone furnished the aldol product as anti/
syn 95:5 ratio in 83% yield. The anti-isomer was isolated in
3
90%) as a white solid. Compound 3 was obtained with the
same yield.
2
3
6c
Compound 2: mp 199–201 °C (dec.); [a]D –46.7 (c 0.25,
79% ee.
EtOH). IR (neat): 3203, 3056, 2870, 1670, 1506, 818, 751
(19) Asymmetric organocatalyzed aldol reactions are generally
performed using 10–30 mol% of catalyst loading. Few
examples reported lower amounts of the promoters, see:
(a) Córdova, A. Tetrahedron Lett. 2004, 45, 3949.
(b) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, O. Angew.
Chem. Int. Ed. 2005, 44, 3055. (c) Krattiger, P.; Kovasy, R.;
Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7,
1101. (d) Jiang, M.; Zhu, S.-F.; Yang, Y.; Gong, L.-Z.;
Zhou, X.-G.; Zhou, Q.-L. Tetrahedron: Asymmetry 2006,
17, 384. (e) Kano, T.; Tokuda, O.; Maruoka, K. Tetrahedron
Lett. 2006, 47, 7423. (f) See ref. 6c.
–
1 1
cm . H NMR (400 MHz, CDCl ): d = 9.70 (br s, 1 H), 8.62
3
(
d, 1 H, J = 9.0 Hz), 8.03–7.80 (m, 5 H), 7.41–7.31 (m, 4 H),
7
2
1
.25–7.21 (m, 1 H), 7.03–6.99 (m, 1 H), 3.55–3.50 (m, 1 H),
.58–2.53 (m, 1 H), 2.32–2.28 (m, 1 H), 1.90–1.87 (m, 1 H),
1
3
.81–1.76 (m, 1 H), 1.50–1.27 (m, 2 H). C NMR (100
MHz, CDCl ): d = 174.0, 152.0, 136.0, 133.3, 133.1, 132.8,
3
1
1
3
31.1, 130.6, 130.0, 129.3, 128.3, 128.1, 127.1, 127.0,
25.3, 125.2, 124.3, 123.6, 120.4, 117.8, 113.6, 60.5, 46.6,
+
0.6, 25.6. ESI-MS: m/z 383 [M + H ]. Anal. Calcd (%) for
C H N O : C, 78.51; H, 5.80; N, 7.32. Found: C, 78.70; H,
25
22
2
2
5
.96; N, 7.18.
(20) For the only example of stoichiometric use of the ketone
donors in organocatalyzed asymmetric aldol reaction, see:
Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006, 128,
734.
1
8
Compound 3: mp 215–218 °C (dec.). [a]D –25.8 (c 0.20,
EtOH). IR (neat): 3232, 3056, 2972, 1661, 1505, 865, 749
–
1 1
cm . H NMR (400 MHz, CDCl ): d = 9.72 (br s, 1 H), 8.75
3
(
d, 1 H, J = 9.0 Hz), 8.07–7.80 (m, 5 H), 7.43–7.31 (m, 4 H),
7
2
.24–7.20 (m, 1 H), 7.03–6.99 (m, 1 H), 3.57–3.52 (m, 1 H),
.35–2.31 (m, 1 H), 1.84–1.80 (m, 1 H), 1.69–1.62 (m, 1 H),
(21) One way to achieve this goal might be the employment of
proper mixtures of hexane and ethereal cosolvents.
Synlett 2007, No. 5, 795–799 © Thieme Stuttgart · New York

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