Diastereoselective aldol reaction of N,N-dibenzyl-α-amino aldehydes with ketones catalyzed by proline

Article abstract of DOI:10.1021/ol049927k

(Equation presented) L-Proline-catalyzed direct aldol reaction of L-amino acid-derived N,N-dibenzyl amino aldehydes with acetone, cyclopentanone, or hydroxyacetone provides γ-amino-β-hydroxy- or γ-amino-α, β-dihydroxy-ketones with moderate to excellent yi

Full text of DOI:10.1021/ol049927k

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1009-1012
Diastereoselective Aldol Reaction of
N,N-Dibenzyl-r-amino Aldehydes with
Ketones Catalyzed by Proline
,‡
Qiangbiao Pan,† Benli Zou,† Yuji Wang,† and Dawei Ma*
Department of Chemistry, Fudan UniVersity, Shanghai 200433, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@pub.sioc.ac.cn
Received January 13, 2004
ABSTRACT
L-Proline-catalyzed direct aldol reaction of L-amino acid-derived N,N-dibenzyl amino aldehydes with acetone, cyclopentanone, or hydroxyacetone
provides γ-amino-â-hydroxy- or γ-amino-r,â-dihydroxy-ketones with moderate to excellent yields and diastereoselectivities.
Development of new asymmetric carbon-carbon formation
reactions is one of the most important problems of contem-
porary chemistry. Among recent achievements in this field,
proline-catalyzed direct enantioselective aldol reaction be-
tween aldehydes and ketones is more attractive because of
its operational simplicity and cheaper catalytic system.1,2
However, the scope of this catalytic reaction is still narrow
and more substrates, especially functionalized aldehydes or
ketones, need to be explored in order to expand its application
in the synthesis of useful chemicals.
several different nucleophiles have been investigated and
used for assembly of some biologically important molecules.3
However, these nucleophiles were limited to air- and
moisture-sensitive agents such as silyl ketene acetals,4
titanium homoenolates,5 as well as boron enolates.6 One
(3) For reviews, see: (a) Gryko, D.; Chalko, J.; Jurczak, J. Chirality
2003, 15, 514. (b) Reetz, M. T. Chem. ReV. 1999, 99, 1121. (c) Reetz, M.
T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. (d) Jurczak, J.; Golebiowski,
A. Chem. ReV. 1989, 89, 149.
(4) (a) Takemoto, Y.; Matsumoto, T.; Ito, Y.; Terashima, S. Tetrahedron
Lett. 1990, 31, 217. (b) Mikami, K.; Kaneko, M.; Loh, T.-P.; Terada, M.;
Nakai, T. Tetrahedron Lett. 1990, 31, 3909. (c) Kiyooka, S.; Suzuki, K.;
Shirouchi, M.; Kaneko, Y.; Tanimori, S. Tetrahedron Lett. 1993, 34, 5729.
(d) Kiyooka, S.; Goh, K.; Nakamura, Y.; Takeuse, H.; Hena, M. Tetrahedron
Lett. 2000, 41, 6599.
Due to their convenient availability, enantiopure R-amino
aldehydes have received considerable attention in organic
synthesis.3 Aldol-type reactions of R-amino aldehydes with
(5) (a) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.; Shinkai, I.
Tetrahedron Lett. 1991, 32, 1867. (b) Campbell, J. A.; Lee, W. K.; Rapoport,
H. J. Org. Chem. 1995, 60, 4602. (c) Armstrong, J. D.; Hartner, F. W.;
DeCamp, A. E.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1992, 33,
6599. (d) McWilliams, J. C.; Armstrong, J. D.; Zheng, N.; Bhupathy, M.;
Volante, R. P.; Reider, P. J. Am. Chem. Soc. 1996, 118, 11970.
(6) (a) Reetz, M. T.; Rivadeneira, E.; Niemeyer, C. Tetrahedron Lett.
1990, 31, 3863. (b) Hamada, Y.; Hayashi, K.; Shioiri, T. Tetrahedron Lett.
1991, 32, 931. (c) Hayashi, K.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1991, 32, 7287. (d) Gennari, C.; Moresca, D.; Vulpetti, A.; Pain, G.
Tetrahedron 1997, 53, 5593.
† Fudan University.
‡ Shanghai Institute of Organic Chemistry.
(1) For reviews, see: (a) List, B. Synlett 2001, 1675. (b) List, B.
Tetrahedron 2002, 58, 5573. (c) Alcaide B.; Almendros, P. Angew. Chem.,
Int. Ed. 2003, 42, 858.
(2) (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. 2000, 122, 7386. (c)
List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (d) Sakthivel,
K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260.
10.1021/ol049927k CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004

catalyzed reaction provided good diastereoselectivity in favor
of syn product 2d (entry 4), while D-proline-catalyzed
reaction gave poor diastereoselectivity in favor of anti
product 3d (entry 5). These results implied that (S)-N,N-
dibenzyl amino aldehydes and L-proline are a matched pair
for diastereoselectivity induction. In addition, the solvent was
another noticeable factor because a slightly lower yield was
obtained when mixed acetone and DMSO were utilized
(entry 6).
Table 1. Proline-Catalyzed Reaction of N-Protected
Phenylalaninals with Acetonea
In view of the above encouraging result, the scope of this
reaction was explored by varying ketones and N,N-dibenzyl
amino aldehydes, and the results are summarized in Table
2. Good to excellent yields were observed for reaction of
acetone with several N,N-dibenzyl amino aldehydes except
for valinal 6b (entries 1-6). We reasoned that this problem
resulted from steric hindrance of 6b. The ratios for syn
products 7 and anti products 8 were very close for simple
and some functionalized aldehydes (entries 1-5). However,
this value changed drastically when serine-derived aldehyde
6f was employed, which might be due to formation of
additional interaction of MOM group with catalyst in the
transition state.
We found that cyclopentanone also worked for this
reaction if DMSO was used as the solvent, producing
separable aldol products 7g-j in moderate yields, together
with some unidentified isomers (entries 7-10). The γ-amino
ketone 7j was subjected to a hydrogenolysis/cyclization/
hydrogenation process and afforded a fused bicyclic com-
pound 9. By NOE analysis of 9, we established the
stereochemistry of 7j (Scheme 2).
entry
aldehyde
catalyst
yield (%)b
2:3c
1
2
3
4
5
6
1a
1b
1c
1d
1d
1d
L-proline
L-proline
L-proline
L-proline
D-proline
L-proline
48
93
82
98
78
77
98:2
84:16
76:24
95:5
33:67
92:8d
a Reaction conditions: aldehyde (1 mmol), proline (0.25 mmol) in
acetone (10 mL). b Isolated yield for 2 and 3. c Determined by weighing
the separated isomers 2 and 3. d Reaction was carried out in a mixture of
2 mL of acetone and 8 mL of DMSO.
exception was nitroalkanes, which have been studied by
several groups to give Henry reaction products.7 In this
communication, we wish to describe a direct aldol reaction
of R-amino aldehydes with ketones catalyzed by proline,
which delivers synthetically useful γ-amino-â-hydroxy- or
γ-amino-R,â-dihydroxy-ketones diastereoselectively.
As summarized in Table 1, we initially checked the
proline-catalyzed direct aldol reaction of acetone with several
N-substituted phenylalaninals in order to identify a favored
N-protecting group. It was found that N-trityl phenylalaninal
gave the best diastereoselectivity but the lowest yield (entry
1). This drawback might come from its poor reactivity
resulting from the steric hindrance of the trityl group. Both
N-Boc phenylalaninal and N-Cbz phenylalaninal showed
lower diastereoselectivity, although their reaction yields were
satisfactory (entries 2 and 3). The most acceptable result was
observed in the case of N,N-dibenzyl phenylalaninal as a
substrate and L-proline as a catalyst, which provided aldol
products 2d and 3d in 98% combination yield and 90% de
(entry 4). To establish the stereochemistry of the major
product, 2d was subjected to Pt/C-catalyzed hydrogenation
to afford pyrrolidines 4 and 5 (Scheme 1). By NOE analysis
Scheme 2
Scheme 1
Proline-catalyzed aldol reaction of hydroxyacetone with
aldehydes is a more attractive transformation for organic
synthesis because, in this way, a 1,2-diol unit could be
formed concurrently with carbon-carbon bond formation.2b,d
We were pleased to find that L-proline-catalyzed reaction of
hydroxyacetone with N,N-dibenzyl phenylalaninal in DMSO
produced 7k in 79% yield, together with other minor isomers
(entry 11). The stereochemistry assignment of 7k was
it was found that the 2-benzyl group and the 3-hydroxy group
in 4 were trans to each other, which implied that the
configuration of the newly generated stereocenter in 2d was
R. The chirality of proline should be essential for diastereo-
selectivity because in the case of 1d as a substrate, L-proline-
(7) (a) Sasai, H.; Kim, W.-S.; Suzuki, T.; Shibasaki, M. Tetrahedron
Lett. 1994, 35, 6123. (b) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed.
1999, 38, 1931. (c) Misumi, Y.; Matsumoto, K. Angew. Chem., Int. Ed.
2002, 41, 1031. (d) Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43,
9401.
1010
Org. Lett., Vol. 6, No. 6, 2004

Table 2. L-Proline-Catalyzed Direct Aldol Reaction of N,N-Dibenzyl Aldehydes with Ketonesa
a Reaction conditions: aldehyde (1 mmol) with either L-proline (0.25 mmol) in 10 mL of acetone (entries 1-6), 2 mL of cyclopentanone and 8 mL of
DMSO (entries 7-10), 2 mL of hydroxyacetone and 8 mL of DMSO (entry 11), or 2 mL of HMPA (entries 12-16). b Isolated yield. c Yield was calculated
1
from the ratio of major product and its inseparable isomers determined by H NMR.
accomplished by hydrogenating it to pyrrolidine 10 as
indicated in Scheme 2. Among solvents tested, HMPA
showed some improvement for diastereoselectivity (compare
entries 11 and 12), while THF and CH2Cl2 gave worse
results. Using these conditions, we tested other amino
aldehydes and observed that good diastereoselectivities were
obtained for simple amino aldehydes (entries 12-14), while
functionalized amino aldehydes showed lower diastereose-
lectivities (entries 15 and 16).
As shown in Scheme 3, compound 7n, a major aldol
product of hydroxyacetone with N,N-dibenzyl isoleucinal,
was subjected to oxidative cleavage8 with sodium hypobro-
Org. Lett., Vol. 6, No. 6, 2004
1011

of the present reaction products to the polysubstituted
pyrrolidines10 as outlined in Schemes 1 and 2, clearly shows
that proline-catalyzed aldol reaction of N,N-dibenzyl amino
aldehydes with ketones could find considerable use in organic
synthesis. Further studies in this direction are in progress
and will be reported in due course.
Scheme 3
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (Grant 20242003), and Science and Technology
Commission of Shanghai Municipality (Grants 02JC14032
and 03XD14001) for their financial support.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 2d, 4, 7a-p,
and 9-11. This material is available free of charge via the
Internet at http://pubs.acs.org.
mite to produce an amino acid, which was treated with benzyl
bromide and K2CO3 in DMF to provide enantiopure
(2S,3S,4S)-4-amino-2,3-dihydroxyester 11 in 35% yield. This
compound is obviously a suitable intermediate for assembling
PM-94128, an antitumor agent synthesized by Vallee and
co-workers.9 This fact, together with the ready transformation
OL049927K
(9) Synthesis: (a) Patel, S. K.; Murat, K.; Py, S.; Vallee, Y. Org. Lett.
2003, 5, 4081. Isolation: (b) Canedo, L. M.; Fernandez Puentes, J. L.; Perez
Baz, J.; Acebal, C.; de la Calle, F.; Garcia Gravalos, D.; Garcia de Quesada,
T. J. Antibiot. 1997, 50, 175.
(10) For recent reviews on the biology and synthetic usages of polysub-
stituted pyrrolidines, see: (a) O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435.
(b) Broggini, G.; Zecchi, G. Synthesis 1999, 905.
(8) Stacy, G. W.; Klundt, I. L.; Davis, G. T.; Nielsen, N. A.; Power, M.
S.; Rector, D. L.; Razniak, S. L. J. Org. Chem. 1966, 31, 1753.
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Org. Lett., Vol. 6, No. 6, 2004