ceptors. Accordingly, we have studied amino aldehydes as
acceptors. Herein, we report L-proline-catalyzed direct asym-
metric assembly reactions involving three different compo-
nents, namely, aldehydes, ketones, and azodicarboxylic acid
esters, to provide optically active functionalized â-amino
alcohols in an enzyme-like assembly process. To the best of
our knowledge, these are the first examples of assembly
reactions that use directly both aldehydes and ketones as
donors in one pot.
Table 1. Proline-Catalyzed Asymmetric Assembly Reaction of
Acetone, Propionaldehyde, and Dibenzyl Azodicarboxylate in
Various Solvents
To develop the targeted assembly reaction, we first studied
the L-proline-catalyzed aldol reaction of acetone with (R)-
amino aldehyde (1). To our surprise the aldol product was
formed with reduced facial selectivity as compared to that
observed in other known proline-catalyzed aldol reactions
(Scheme 1). Since amino aldehydes such as 1 are accessible
entry
solvent
yield (%) dr (anti:syn) eea (%) (anti/syn)
1
2
3
4
6
5
7c
8d
DMSO
DMF
72
79
75
77
68
80
82
80
13:87
28:72
62:38
44:56
55:45
56:44
28:72
43:57
>99/74 (>99/98)b
>99/65
>99/49
>99/49
>99/28
>99/54
98/78
99/55
CH2Cl2
dioxane
acetone
CH3CN
CH3CN
CH3CN
Scheme 1. L-Proline-Catalyzed Aldol Reactions: (a) Previous
Work and (b) Present Work
a Ee determined by HPLC analysis on a Chiralcel OD-R column using
35% CH3CN in water (0.1% TFA) as an eluent; flow rate ) 1 mL/min.
b Ee of the enantioenriched mother liquor obtained after crystallization of
racemate from CH2Cl2-hexane. c This experiment was carried out in tandem
d
using D,L-proline for amination and L-proline for aldol reaction. D-Proline
is used as a catalyst, and ees are provided for the opposite enantiomers.
The success of this assembly reaction can be attributed to
the higher reactivity of propionaldehyde over acetone in the
proline-catalyzed R-amination reaction. When we compared
the reactivity of these two donors in the proline-catalyzed
R-amination reaction, propionaldehyde exhibited a 100-fold
higher reactivity than acetone when the reactions were
performed under identical conditions in CH3CN. The reaction
conditions for the assembly reaction are very simple: the
reactants are mixed in the presence of catalyst and stirred.
The products are readily purified, and the syn diastereomer
can be enantioenriched by recrystallization from CH2Cl2-
hexane. The two diastereomers can also be separated by
recrystallization from CH2Cl2-hexane. Under D-proline
catalysis, amino alcohols with the opposite stereoconfigu-
rations were obtained.
To further understand the diastereoselectivity and reaction
mechanism, additional experiments were performed. When
we treated racemic aminated propionaldehyde (1) with
acetone in the presence of L-proline, products 2 and 3 were
obtained with yield, diastereoselectivity, and enantioselec-
tivity identical to those found in the reaction involving (R)-
amino aldehyde (1) (Table 1, entry 7, and Scheme 2). Next
we performed a reaction with propionaldehyde and azo-
dicarboxylate for 3 days and determined that the resulting
amino aldehyde was racemic. Thus, proline can act to
racemize the amino aldehyde over time. These two findings
suggest that the reaction proceeds as outlined in Scheme 2.
Amination of propionaldehyde using D,L-proline or L-proline
with extended reaction times (3 days) provides racemic
amino aldehyde (1). The reaction of rac-amino aldehyde (1)
with acetone in the presence of L-proline in CH3CN afforded
through proline catalysis,8 we studied the reaction of acetone,
propionaldehyde, and dibenzyl azodicarboxylate in one pot
with L-proline (20 mol %) in DMSO at room temperature
for 3 days. The functionalized amino alcohol diastereomers
(anti/syn ) 13:87) 2 and 3 were obtained in good yield (72%)
and with an enantioselectivity of >99% for the anti product
(Table 1, entry 1). Given the solvent dependence we have
noted in organocatalytic reactions, we investigated a variety
of solvents for this one-pot reaction. Interestingly the reaction
works well in a range of solvents such as DMSO, DMF,
CH2Cl2, dioxane, acetone, and CH3CN. The use of acetone
as a reactant-solvent also afforded the expected â-amino
alcohols in 68% yield along with aminated acetone in 9%
yield. With the exception of the use of acetone as a solvent,
other solvents suppressed the formation of aminated acetone.
Scaling of the reaction to 20 mmol of reactants afforded
identical results (Table 1, entry 1). Significantly, the use of
DMSO or DMF as solvents enhances the syn selectivity of
the reaction.
(6) (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C.
F., III. Tetrahedron Lett. 2001, 42, 4441. (b) Betancort, J. M.; Barbas, C.
F., III. Org. Lett. 2001, 3, 3737. (c) Enders, D.; Seki, A. Synlett 2002, 26.
(7) (a) Thayumanavan, R.; Ramachary, D. B.; Sakthivel, K.; Tanaka,
F.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817. (b) Ramachary, D.
B.; Chowdari, N. S.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 6743.
(8) (a) Bogevig, A.; Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (b) Kumaragu-
rubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen, K. A. J. Am.
Chem. Soc. 2002, 124, 6254. (c) List, F. J. Am. Chem. Soc. 2002, 124,
5656.
(9) Chowdari, N. S.; Ramachary, D. B.; Co´rdova, A.; Barbas, C. F., III.
Tetrahedron Lett. 2002, 43, 9591.
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Org. Lett., Vol. 5, No. 10, 2003