Molecular-sieves controlled diastereo- and enantioselectivity: Unexpected effect in the organocatalyzed direct aldol reaction

Article abstract of DOI:10.1055/s-2008-1072586

An efficient asymmetric organocatalyst was developed for the direct aldol reaction between ketones and aldehydes to afford β-hydroxy ketones in high stereoselectivity (anti/syn up to 92:8, ee up to >99%). The key of the success was the use of activated molecular sieves (4 A? MS), which acted as a water scavenger. The influence of additives such as water or different types of molecular sieves on the reactivity and stereoselectivity of the reaction was also studied. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072586

LETTER
1255
Molecular-Sieves Controlled Diastereo- and Enantioselectivity: Unexpected
Effect in the Organocatalyzed Direct Aldol Reaction
O
rganocatalyze
d
D
i
irect
A
a
ldol
R
eact
o
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27403475; E-mail: majun_an68@tju.edu.cn
Received 28 December 2007
chiral prolinamide derivatives, we found, quite unexpect-
Abstract: An efficient asymmetric organocatalyst was developed
for the direct aldol reaction between ketones and aldehydes to af-
ford b-hydroxy ketones in high stereoselectivity (anti/syn up to
92:8, ee up to >99%). The key of the success was the use of activat-
edly, that the addition of molecular sieves (MS) resulted
in markedly enhanced diasteroselectivity as well as enan-
tioselectivity. To our knowledge, this is the first time that
ed molecular sieves (4 Å MS), which acted as a water scavenger. such an effect has been observed in organocatalytic syn-
thesis.6 Herein, we wish to present this intriguing finding
The influence of additives such as water or different types of molec-
ular sieves on the reactivity and stereoselectivity of the reaction was
also studied.
and disclose the origin of the favorable influence of the
molecular sieves.
The chiral organic catalysts 3a–e12 were prepared as
shown in Scheme 1. Reaction of Cbz-L-proline and trans-
Key words: asymmetric catalysis, aldol reaction, stereoselectivity,
molecular sieves, aldehyde
4-hydroxy-L-proline with binaphthyl-based axially chiral
amine 1 provided intermediate 2, subsequent deprotection
of the Cbz group then gave compound 3 in good yields.
The catalytic activities of these new organocatalysts were
then evaluated in a direct enantioselective aldol reaction
The asymmetric aldol condensation is one of the most
powerful tools for the carbon–carbon bond formation in
synthetic organic chemistry.1 Asymmetric organocataly-
sis, where small organic molecules catalyze the reactions
without the presence of any metal, has become an attrac-
of cyclohexanone with 4-nitrobenzaldehyde (Scheme 2).
tive strategy for the direct aldol reactions.2 The major
breakthrough came from a pioneering work by List3 and
Barbas4 that L-proline could act as a catalyst in intermo-
lecular direct aldol reaction where an enamine generated
in situ from a chiral amine and carbonyl compound under-
went an enantioselective nucleophilic attack on the elec-
trophilic aldehyde center. Since then, great emphases
have been given to the design of new chiral organocata-
lysts, and many proline derivatives have become popular
organocatalysts in this field.5 During our studies of enan-
tioselective direct aldol condensation of cyclohexanone
and 4-nitrobenzaldehyde catalyzed by the use of new
In our initial experiment, the direct aldol reaction was per-
formed in the presence of 4 Å molecular sieves using a
catalytic amount (10 mol%) of the prolinamides 3a–e
(Table 1). The two diastereomeric organocatalysts 3a and
3b maintained moderate reactivity, yet high diastereo- and
enantioselectivities were obtained, with catalyst 3b better
than 3a (entries 1 and 2). It was noteworthy that trans-4-
hydroxy-L-proline-derived organocatalysts 3c and 3d
gave the opposite sense of asymmetric induction (entries
3 and 4). Interestingly, both the yield and stereoselectivity
of the aldol reaction were decreased when the hydroxyl
group of 3d was replaced by a siloxy group (entry 5).
R
O
R
O
BOP-Cl, Et3N
CH2Cl2
HO
NH
+
N
N
N
Cbz
Cbz
2
1
R
O
3a: R = H, (Sax, 2Spro
)
N
3b: R = H, (Rax, 2Spro
3c: R = OH, (Rax, 2Spro, 4Rpro
3d: R = OH, (Sax, 2Spro, 4Rpro
)
N
)
)
H
3e: R = OTBS, (Sax, 2Spro, 4Rpro
)
Scheme 1 Synthesis of new organocatalysts
SYNLETT 2008, No. 8, pp 1255–1259
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072586; Art ID: W22307ST
© Georg Thieme Verlag Stuttgart · New York

1256
X.-J. Li et al.
LETTER
O
OH
O
OH
O
CHO
NO2
3 (10 mol%)
syn (minor)
+
+
+
THF, –20 °C, 72 h
NO2
NO2
(2R,1'S)
(2S,1'R)
anti
Scheme 2 Model reaction for screening of organocatalysts
Among these small organic molecules, compound 3d ex- Table 1 Evaluation of Organocatalysts and Effect of Molecular
Sieves in the Direct Aldol Reactiona
Entry Catalyst Additive
hibited a superior level of reactivity and stereoselectivity.7
In the absence of molecular sieves, it was quite unexpect-
edly found that the the aldol reactions proceeded more
quickly (within 16 h) with excellent yields, but the diaste-
reo- and enantioselectivities decreased dramatically (en-
try 6 vs. entry 2, and entry 7 vs. entry 4). Different kinds
of molecular sieves were also used in the presence of or-
ganocatalyst 3d, and their influence on the stereoselectiv-
ities of the aldol reaction was observed (entries 8–10). In
addition, diminishing the amount of 4 Å molecular sieves
from 60 to 50 mg led to a slight decrease in the selectivi-
ties (entry 11). The yields became poor when the amount
of molecular sieves was increased (entry 12 and 13). At
0 °C, although the reaction was complete within 24 hours
without loss of enantioselectivity, the dr value was slight-
ly lower (entry 14).
Yield
Ratio
ee (anti)c
(%)b
anti/sync
1
2
3
4
5
3a
3b
3c
3d
3e
4 Å MS
(60 mg)
35
89:11
80 (2S,1¢R)
>99 (2S,1¢R)
91 (2R,1¢S)
>99 (2R,1¢R)
77 (2R,1¢S)
4 Å MS
(60 mg)
31
42
93:7
4 Å MS
(60 mg)
87:13
92:8
4 Å MS
(60 mg)
>99
67
4 Å MS
(60 mg)
84:16
6d
7d
8
3b
3d
3d
–
–
95
>99
64
53:47
66:34
81:19
46 (2S,1¢R)
72 (2R,1¢S)
82 (2R,1¢S)
It is well known that adventitious water often results in a
less-than-satisfactory stereoselectivity for some transi-
tion-metal-catalyzed asymmetric reactions.
3 Å MS
(60 mg)
In contrast, organocatalytic aldol reactions can usually be
performed under an aerobic atmosphere with wet sol-
vents, and even in aqueous medium.8,9 However, water
might be the culprit for the lowering of diastereo- and
9
3d
3d
3d
3d
3d
3d
5 Å MS
(60 mg)
48
86
89:11
83:17
89:11
–
48 (2R,1¢S)
85 (2R,1¢S)
95 (2R,1¢S)
–
enantioselectivities in our organocatalytic system. There- 10
fore, the influence of water on the selectivity was investi-
13X MS
(60 mg)
gated in order to ascertain if the molecular sieves served
to eliminate moisture, and prevented water-mediated
background reactions. Significantly, we found that the
presence of water had a remarkable effect on the catalytic
activity and stereoselectivity (Table 2). With added water,
the reaction proceeded quickly but in moderate diastereo-
selectivities. Furthermore, the enantioselectivity tended to
decrease with increasing amount of water (entries 1–7).
Performing the same reaction in neat water leads to syn
product as the major diastereomer with 26% ee (entry 8).
11
4 Å MS
(50 mg)
98
12
4 Å MS
(100 mg)
33
13
4 Å MS
(120 mg)
13
–
–
14e
4 Å MS
(60 mg)
>99
87:13
>99 (2R,1¢S)
a The reactions were carried out with 3 (10 mol%), cyclohexanone (5.0
mmol), 4-nitrobenzaldehyde (1.0 mmol), and MS in THF at –20 °C
for 72 h.
In the presence of 4 Å molecular sieves, a representative
selection of cyclic ketones and aromatic aldehydes was
evaluated under the optimized conditions (Scheme 3) and
the results obtained are shown in Table 3. The direct aldol
reactions of ketones with the aldehydes bearing an elec-
tron-withdrawing group on the benzene ring took place
smoothly and were catalyzed by 10 mol% 3d to afford al-
dol adducts in moderate to high yields with high stereose-
lectivities (anti/syn up to 97:3, ee up to >99%; entries 1–
11).
b Yield of isolated product.
c Determined by HPLC analysis with a chiral column. The absolute
configuration was determined by comparison of the optical rotation
with the literature value.
d Reaction time: 16 h
e Reaction temperature and time: 0 °C, 24 h.
after 9 days to give the aldol product with excellent dia-
stereo- and enantioselectivities (entry 12). For aromatic
aldehydes with electron-neutral (H) or electron-donating
Interestingly, 4-tert-butylcyclohexanone, a conformation-
ally anchored substrate, also showed complete progress
Synlett 2008, No. 8, 1255–1259 © Thieme Stuttgart · New York

LETTER
Organocatalyzed Direct Aldol Reaction
1257
Table 3 Screening of Different Ketones and Aromatic Aldehydes in
the Presence of 4 Å MS
Table 2 Effect of the Amount of Water on the Direct Aldol Reac-
tiona
H2O–THF (vol.) Yield (%)b anti/sync
ee (anti)c
Entry Ar
X
Yield (%)a anti/synb ee (anti)b
Entry
1c
2
2-naphthyl
CH2
CH2
CH2
CH2
CH2
CH2
O
37
>99
45
79
90
84
78
95
34
35
43
78:22
92:8
>99
>99
94
87
93
83
92
84
84
89
96
95
1
2
3
4
5
6
7
8
1:100,000
1:10,000
1:1,000
1:100
72
83
61:39
54:46
55:45
66:34
83:17
56:44
64:36
42:58
85
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-NCC6H4
4-F3CC6H4
4-O2NC6H4
3-O2NC6H4
4-NCC6H4
4-O2NC6H4
3-O2NC6H4
4-O2NC6H4
82
3
94:6
93
85
4
91:9
>99
>99
>99
>99
>99
72
5d
6
80:20
87:12
65:35
56:44
82:18
60:40
97:3
10:90
38
40:60
66
7
70:30
63
8
O
100:0
54:26 (syn)
a The reactions were carried out with 3d (0.1 mmol), cyclohexanone
(5.0 mmol), aldehyde (1.0 mmol) in THF at –20 °C.
b Yield of isolated product.
9
O
10
S
c Determined by HPLC analysis with a chiral column.
11
12
S
O
X
OH
O
X
t-BuCH2 >99
98:2
3d (10 mol%)
4 Å MS (60 mg)
THF, –20 °C
O
a Yield of isolated product.
Ar
+
b Determined by HPLC analysis with a chiral column.
c Reaction temperature: r.t.
H
Ar
+
d Reaction temperature: 0 °C.
syn (minor)
Scheme 3 The reaction of different ketones and aromatic aldehydes
catalyzed by 3d in the presence of 4 Å MS
In summary, we found that the presence of 4 Å molecular
sieves increased the diastereo- and enantioselectivity in
the direct aldol reaction of cyclic ketones and various ar-
omatic aldehydes using of a series of L-prolinamide orga-
nocatalysts. The beneficial influence of the molecular
substituents (such as Me, MeO, and Cl), the desired aldol
adducts were not obtained.13
The stereochemical outcome in the above direct aldol re- sieves could be due to their water-trapping properties.
action catalyzed by 3d could be explained by the transi- Further investigations of the effect of the molecular sieves
tion state as depicted in Figure 1, which was based on the in other organocatalytic reactions are in progress and the
previous model supported by DFT calculations.5o,10 The results will be communicated in due course.
aldehyde was activated and oriented by hydrogen bonding
with the OH of the catalyst in a manner such that enamine
attacked the aldehyde from the re face, leading to the for-
Acknowledgment
This work was supported financially by NSFC, and NCET from the
Ministry of Education of China.
mation of the major stereoisomer. In addition, the p–p
stacking interaction might also play an important role in
stabilizing the transition state. In the presence of water,
the hydrogen-bonding interaction between water and al-
dehyde could result in a decrease of stereoselectivities.
References and Notes
(1) (a) Mahrwald, R. Modern Aldol Reactions, Vol. 1 and 2;
Wiley-VCH: Weinheim, 2004. (b)Berkessel, A.;Gröger, H.
Asymmetric Organocatalysis: From Biomimetic Concepts to
O
O
Application in Asymmetric Synthesis; Wiley-VCH:
Weinheim, 2005.
H
N
(2) For recent reviews, see: (a) List, B. Chem. Commun. 2006,
819. (b) Guillena, G.; Ramon, D. J. Tetrahedron: Asymmetry
2006, 17, 1465. (c) Marigo, M.; Jørgensen, K. A. Chem.
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F. III Acc. Chem. Res. 2004, 37, 580. (e) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(3) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395.
N
O
H
(4) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. III J. Am.
Chem. Soc. 2001, 123, 5260.
Figure 1 Transition-state model
Synlett 2008, No. 8, 1255–1259 © Thieme Stuttgart · New York

1258
X.-J. Li et al.
LETTER
(5) For some recent selected examples on aldol reaction
catalyzed by L-proline and its derivatives, see: (a) Wang,
X.-J.; Zhao, Y.; Liu, J.-T. Org. Lett. 2007, 9, 1343.
(b) Gryko, D.; Zimnicka, M.; Lipiński, R. J. Org. Chem.
2007, 72, 964. (c) Rodríguez, B.; Bruckmann, A.; Bolm, C.
Chem. Eur. J. 2007, 13, 4710. (d) Wang, C.; Jiang, Y.;
Zhang, X.-X.; Huang, Y.; Li, B.-G.; Zhang, G.-L.
K.; Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006,
128, 734. (i) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S.
Org. Lett. 2006, 8, 4417. (j) Jiang, Z.; Liang, Z.; Wu, X.; Lu,
Y. Chem. Commun. 2006, 2801. (k) Chimni, S. S.;
Mahajan, D. Tetrahedron: Asymmetry 2006, 17, 2108.
(l) Guillena, G.; Hita, M. D. C.; Nájera, C. Tetrahedron:
Asymmetry 2006, 17, 1493. (m) Pihko, P. M.; Laurikainen,
K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron
2006, 62, 317. (n) Font, D.; Jimeno, C.; Pericas, M. A. Org.
Lett. 2006, 8, 4653. (o) Torii, H.; Nakadai, M.; Ishihara, K.;
Saito, S.; Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43,
1983.
Tetrahedron Lett. 2007, 48, 4281. (e) Lei, M.; Shi, L.; Li,
G.; Shen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R.
Tetrahedron 2007, 63, 7892. (f) Revell, J. D.; Wennemers,
H. Tetrahedron 2007, 63, 8420. (g) Raj, M.; Maya, V.;
Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097.
(h) Tang, Z.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Org. Lett. 2006, 8, 1263. (i) Chen, J.-R.; Li, X.-
Y.; Xing, X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71, 8198.
(j) Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.;
Barbas, C. F. III J. Org. Chem. 2006, 71, 3822.
(10) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Córdova, A.
Angew. Chem. Int. Ed. 2005, 44, 7028.
(11) Maya, V.; Singh, V. K. Org. Lett. 2007, 9, 1117.
(12) Typical Procedure for the Preparation of Organocatalyst
To a stirred solution of the corresponding N-(benzyl-
oxycarbonyl)proline (2.5 mmol) and Et3N (0.9 mL, 6.8 mmol)
in anhyd CH2Cl2 (10 mL) and under an argon atmosphere,
were added bis(2-oxo-3-oxazolidinyl)phosphinic chloride
(BOPCl, 0.63 g, 2.6 mmol) at 0 °C. After 30 min of stirring,
the corresponding chiral amine (2.5 mmol) was added, and the
mixture was further stirred for 24 h. It was diluted with 10 mL
of CH2Cl2 and washed once with HCl (1 N), H2O, and brine.
Then, it was dried over MgSO4, and the solvent was removed
under reduced pressure to afford a residue. The resulting
residue was dissolved in EtOAc (10 mL) and Pd/C (10 wt%)
was added. The mixture was stirred at r.t. under hydrogen
atmosphere (1 atm) overnight. Then, the mixture was filtered
through Celite and the solvent evaporated under reduced
pressure to afford the title compounds, which were purified
over silica gel flash column chromatography [Et3N–EtOAc–
PE, 1:20:100 (vol.)].
(k) Rodríguez, B.; Rantanen, T.; Bolm, C. Angew. Chem. Int.
Ed. 2006, 45, 6924. (l) Guillena, G.; Hita, M. C.; Nájera, C.
Tetrahedron: Asymmetry 2006, 17, 1027. (m) Jiang, M.;
Zhu, S.-F.; Yang, Y.; Gong, L.-Z.; Zhou, X.-G.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2006, 17, 384. (n) Fu, Y.-Q.; Li,
Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S.
Tetrahedron: Asymmetry 2006, 17, 3351. (o) 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. 2005, 127, 9285.
(6) Effect of molecular sieves on the stereoselectivity in some
metal-catalyzed reactions, see: (a) Gao, Y.; Haneon, R. M.;
Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 6765. (b) Narasaka, K.;
Iwaaawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.;
Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340.
(c) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc.
1990, 112, 3949. (d) Gothelf, K. V.; Hazell, R. G.;
Compound 3a:11 yield 97%, mp 146–147 °C; [a]D20 –162.5 (c
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d = 1.82–1.89 (m,
1 H, pyrrolidine-H), 1.95–2.02 (m, 2 H, pyrrolidine-H), 2.50–
2.57 (m, 1 H, pyrrolidine-H), 3.03–3.07 (m, 1 H, pyrrolidine-
H), 3.16 (br, 1 H, NH), 3.27–3.32 (m, 1 H, pyrrolidine-H),
3.56 (d, J = 13.5 Hz, 1 H, NCH), 3.97 (d, J = 12.5 Hz, 1 H,
NCH), 4.19–4.22 (m, 1 H, pyrrolidine-H), 4.65 (d, J = 13.0
Hz, 1 H, NCH), 5.46 (d, J = 13.0 Hz, 1 H, NCH), 7.28–7.33
(m, 2 H, binaphthyl-H), 7.43 (d, J = 9.0 Hz, 1 H, binaphthyl-
H), 7.49–7.54 (m, 4 H, binaphthyl-H), 7.62 (d, J = 8.5 Hz, 1
Jørgensen, K. A. J. Org. Chem. 1998, 63, 5483. (e) Oi, S.;
Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue, Y.
J. Org. Chem. 1999, 64, 8660. (f) Desimoni, G.; Faita, G.;
Guala, M.; Pratelli, C. J. Org. Chem. 2003, 68, 7862.
(7) Screening of the other solvents for the model aldol reaction:
toluene (yield >99%, anti/syn = 82:18, anti = 82% ee),
DMSO (yield 98%, anti/syn = 74:26, anti = 77% ee), CHCl3
(yield 96%, anti/syn = 75:25, anti = 67% ee), neat (yield
>99%, anti/syn = 70:30, anti = 74% ee).
(8) For a very interesting discussion of enantioselective
organocatalysis ‘in water’ or ‘in the presence of water’, see:
(a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew.
Chem. Int. Ed. 2006, 45, 8100. (b) Hayashi, Y. Angew.
Chem. Int. Ed. 2006, 45, 8103. (c) Blackmond, D. G.;
Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem. Int.
Ed. 2007, 46, 3798. (d) Saito, S.; Yamamoto, H. Acc. Chem.
Res. 2004, 37, 570.
H, binaphthyl-H), 7.93–8.00 (m, 4 H, binaphthyl-H). 13
C
NMR (125 MHz, DMSO): d = 171.6, 135.2, 135.0, 133.6,
133.0, 132.9, 131.4, 131.3, 130.6, 129.9, 129.1, 128.9, 128.5,
128.3, 127.8, 127.5, 127.3, 127.2, 126.6, 126.3, 126.2, 59.1,
48.9, 47.9, 47.5, 30.9, 26.6. IR (KBr): n = 2927, 1641, 1508,
1453, 1398, 1249, 1211, 821, 752 cm–1. ESI-MS: m/z = 393.5
[M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O + H]:
393.1961; found: 393.1960.
(9) For some recent selected examples of the aldol reactions in
water or addition of water for increasing reaction rates and/
or selectivities via asymmetric organocatalysis, see:
(a) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.;
Shoji, M. Chem. Commun. 2007, 957. (b) Utsumi, N.; Imai,
M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas, C. F. III Org.
Lett. 2007, 9, 3445. (c) Chen, X.-H.; Luo, S.-W.; Tang, Z.;
Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Chem. Eur.
J. 2007, 13, 689. (d) Maya, V.; Raj, M.; Singh, V. K.
Org. Lett. 2007, 9, 2593. (e) Guizzetti, S.; Benaglia, M.;
Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247.
(f) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
958. (g) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
5527. (h) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
Compound 3b:11 yield 94%, mp 127–129 °C; [a]D20 +20.3 (c
1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 1.84–1.88 (m,
1 H, pyrrolidine-H), 1.96–2.02 (m, 2 H, pyrrolidine-H), 2.51–
2.55 (m, 1 H, pyrrolidine-H), 3.00–3.07 (m, 1 H, pyrrolidine-
H), 3.10 (br, 1 H, NH), 3.27–3.32 (m, 1 H, pyrrolidine-H),
3.56 (d, J = 13.5 Hz, 1 H, NCH), 3.96 (d, J = 12.5 Hz, 1 H,
NCH), 4.19–4.22 (m, 1 H, pyrrolidine-H), 4.65 (d, J = 13.0
Hz, 1 H, NCH), 5.46 (d, J = 13.0 Hz, 1 H, NCH), 7.27–7.33
(m, 2 H, binaphthyl-H), 7.42 (d, J = 9.0 Hz, 1 H, binaphthyl-
H), 7.47–7.54 (m, 4 H, binaphthyl-H), 7.61 (d, J = 8.5 Hz, 1
H, binaphthyl-H), 7.95–8.00 (m, 4 H, binaphthyl-H). 13
C
NMR (125 MHz, CDCl3): d = 170.8, 135.9, 135.1, 133.7,
133.6, 132.4, 131.7, 131.5, 131.4, 129.8, 129.6, 128.6, 128.5,
127.9, 127.7, 127.4, 126.7, 126.6, 126.5, 126.4, 126.2, 58.5,
48.8, 47.6, 47.0, 31.6, 26.3. IR (KBr): n = 3049, 2924, 1639,
1456, 1406, 1211, 1024, 819, 752 cm–1. ESI-MS: m/z = 393.5
Synlett 2008, No. 8, 1255–1259 © Thieme Stuttgart · New York

LETTER
[M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O + H]:
Organocatalyzed Direct Aldol Reaction
1259
J = 13.5 Hz, 1 H, NCH), 3.90 (d, J = 13.0 Hz, 1 H, NCH),
4.41–4.44 (m, 1 H, pyrrolidine-H), 4.69 (t, J = 8.0 Hz, 1 H,
pyrrolidine-H), 4.80 (d, J = 13.0 Hz, 1 H, NCH), 5.39–5.45
(m, 3 H, NCH, 2 × pyrrolidine-H), 7.27–7.31 (m, 2 H,
binaphthyl-H), 7.43–7.51 (m, 4 H, binaphthyl-H), 7.59 (d,
J = 8.0 Hz, 1 H, binaphthyl-H), 7.69 (d, J = 8.5 Hz, 1 H,
binaphthyl-H), 7.95–8.01 (m, 4 H, binaphthyl-H). 13C NMR
(125 MHz, CDCl3): d = 170.6, 135.4, 133.7, 133.6, 132.7,
131.9, 131.6, 131.5, 129.7, 129.6, 128.6, 128.5, 127.8, 127.7,
127.6, 127.4, 126.5, 126.4, 126.3, 126.2, 73.0, 57.5, 54.9,
48.9, 47.2, 40.1, 26.0, 18.2, –4.6, –4.5. IR (KBr): n = 2927,
1639, 1460, 1393, 1252, 1097, 827, 775 cm–1. ESI-MS: m/z =
523.6 [M+ – 1]. ESI-HRMS: m/z calcd for [C33H38N2O2Si +
H]: 523.2775; found: 523.2771.
393.1961; found: 393.1965.
Compound 3c: yield 81%, mp 123–125 °C; [a]D20 +52.0 (c
1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 1.92 (br, 1 H,
NH), 1.95–2.00 (m, 1 H, pyrrolidine-H), 2.82–2.87 (m, 1 H,
pyrrolidine-H), 3.28–3.36 (m, 2 H, pyrrolidine-H), 3.48 (d,
J = 13.5 Hz, 1 H, NCH), 3.92 (d, J = 13.0 Hz, 1 H, NCH),
4.54–4.71 (m, 3 H, NCH, 2 × pyrrolidine-H), 5.35 (d, J = 13.0
Hz, 1 H, NCH), 6.89 (br, 1 H, OH), 7.20–7.28 (m, 2 H,
binaphthyl-H), 7.34 (d, J = 8.5 Hz, 1 H, binaphthyl-H), 7.40–
7.48 (m, 3 H, binaphthyl-H), 7.53–7.59 (m, 2 H, binaphthyl-
H), 7.86–7.94 (m, 4 H, binaphthyl-H). 13C NMR (125 MHz,
CDCl3): d = 169.3, 135.6, 135.3, 133.7, 133.6, 131.9, 131.6,
131.5, 131.4, 129.8, 129.7, 128.6, 127.8, 127.6, 127.4, 126.7,
126.5, 126.4, 126.2, 57.6, 54.9, 48.8, 47.1, 46.0, 40.4. IR
(KBr): n = 3227, 2944, 1640, 1445, 1335, 1250, 1076, 820,
753 cm–1. ESI-MS: m/z 409.2 [M+ + 1]. ESI-HRMS: m/z calcd
for [C27H24N2O2 + H]: 409.1911; found: 409.1907.
(13) Representative Procedure for Organoatalyzed Direct
Aldol Reaction
The mixture of L-prolinamide derivative 3d (0.1 mmol),
cyclohexanone (5.0 mmol), 4-nitrobenzaldehyde (1.0
mmol), and MS in THF (1 mL) was stirred at –20 °C under
an argon atmosphere for 72 h. The reaction mixture was
directly purified through flash column chromatography on
silica gel [gradient increasing from 20 → 25 → 30% EtOAc
in PE (60–90 °C)] to give the adduct product; yield >99%;
anti/syn = 92:8.
Compound 3d: yield 82%, mp 212–215 °C; [a]D20 –119.4 (c
1.0, DMSO). 1H NMR (500 MHz, DMSO): d = 1.86–1.92 (m,
1 H, pyrrolidine-H), 2.47–2.51 (m, 1 H, pyrrolidine-H), 3.32–
3.35 (m, 1 H, pyrrolidine-H), 3.37–3.41 (m, 1 H, pyrrolidine-
H), 3.62 (d, J = 14.0 Hz, 1 H, NCH), 3.93 (d, J = 13.0 Hz, 1
H, NCH), 4.57 (t, 1 H, J = 4.0 Hz, pyrrolidine-CHNH), 4.81
(d, J = 13.0 Hz, 1 H, NCH), 5.11–5.15 (m, 1 H, pyrrolidine-
CHOH), 5.36 (d, J = 13.5 Hz, 1 H, NCH), 7.27–7.30 (m, 2 H,
binaphthyl-H), 7.37–7.40 (m, 2 H, binaphthyl-H), 7.49–7.52
(m, 2 H, binaphthyl-H), 7.58 (d, J = 8.5 Hz, 1 H, binaphthyl-
H), 7.76 (d, J = 8.0 Hz, 1 H, binaphthyl-H), 7.97–8.07 (m, 4
H, binaphthyl-H). 13C NMR (125 MHz, DMSO): d = 168.5,
134.5, 134.4, 133.0, 132.9, 132.0, 131.9, 130.7, 130.6, 129.4,
129.3, 128.5, 127.7, 127.0, 126.6, 126.5, 126.4, 126.2, 126.1,
70.3, 57.0, 54.2, 47.9, 46.1, 45.2. IR (KBr): n = 3300, 2845,
1652, 1459, 1372, 1212, 1085, 814, 753 cm–1. ESI-MS: m/z =
409.2 [M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O2 + H]:
409.1911; found: 409.1909.
anti-Diastereomer: 1H NMR (400 MHz, CDCl3): d = 1.35–
1.87 (m, 6 H), 2.09–2.13 (m, 2 H), 2.47–2.51 (m, 1 H), 4.08
(s, 1 H), 4.89 (d, J = 8.4 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H),
8.19 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d =
24.6, 27.4, 31.5, 42.0, 57.2, 73.9, 123.5, 127.6, 147.8, 148.5,
213.5. HPLC analysis Daicel Chiralpak AD-H, i-PrOH–
hexane (20:80), 254 nm, 0.5 mL/min, tR = 25.7 min (minor),
32.8 min (major); ee: >99%.
syn-Diastereomer: 1H NMR (400 MHz, CDCl3): d = 1.50–
1.89 (m, 6 H), 2.35–2.43 (m, 2 H), 2.57–2.62 (m, 1 H), 3.18
(s, 1 H), 5.48 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.4 Hz, 1 H),
8.21 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d =
24.8, 26.0, 28.4, 42.6, 57.0, 70.2, 123.4, 126.8, 147.0, 149.1,
213.8. HPLC analysis Daicel Chiralpak AD-H, i-PrOH–
hexane (20:80), 254 nm, 0.5 mL/min, tR = 21.7 min and 23.7
min.
Compound 3e: yield 51%, mp 84–86 °C. 1H NMR (500 MHz,
CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.88 [s,
9 H, SiC(CH3)3], 2.04 (br, 1 H, NH), 2.95–3.00 (m, 1 H,
pyrrolidine-H), 3.35–3.38 (m, 1 H, pyrrolidine-H), 3.57 (d,
Synlett 2008, No. 8, 1255–1259 © Thieme Stuttgart · New York

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