The direct catalytic asymmetric three-component Mannich reaction [21]

Full text of DOI:10.1021/ja001923x

9336
J. Am. Chem. Soc. 2000, 122, 9336-9337
lessons we have learned from aldolase antibody 38C2,5 and our
own finding that proline catalyzes the direct asymmetric aldol
reaction.6 According to our mechanistic hypothesis, proline reacts
with ketones to form a chiral enamine. We reasoned that (a) the
nucleophilic addition of the proline enamine would be faster to
an imine than to an aldehyde and (b) that imine formation with
a primary amine would be faster than concurrent aldolization.
Consequently, a Mannich reaction catalyzed by proline or another
chiral amine can be performed as a three-component reaction
utilizing an aldehyde, a ketone, and a primary amine.
The Direct Catalytic Asymmetric Three-Component
Mannich Reaction
Benjamin List*
Departments of Molecular Biology and Chemistry,
The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed June 1, 2000
We found that after stirring proline (35 mol %),7 p-nitrobenz-
aldehyde (1 eq), and p-anisidine (1.1 eq) in acetone/DMSO (1:4)
for 12h, the corresponding Mannich product 1 was formed in 50%
yield and 94% ee (eq 2).
The Mannich reaction is enormously useful for the construction
of nitrogenous molecules.1 In this transformation, three compo-
nents, a ketone, an aldehyde, and an amine, react to form a
â-amino-ketone. The increasing popularity of the Mannich
reaction has been fueled by the ubiquitous nature of nitrogen in
drugs and natural products as well as by the potential of this
multicomponent reaction to generate diversity. Both direct variants
with unmodified ketone donors and indirect variants utilizing
preformed enolate equivalents have been described.1 In addition,
the imine intermediate may be preformed or its amine and
aldehyde precursors used directly (eq 1).
The aldol addition and condensation products were observed
as side products in this reaction. Similarly, if 2-naphthaldehyde
was used, â-amino ketone 2 was obtained in excellent enantio-
selectivity (96% ee), albeit in modest yield (35%) (Table 1, entry
2). Both R-substituted and R-unsubstituted aldehydes gave the
corresponding â-amino ketones in good to excellent yields and
with ee’s of up to 93% (Table 1, entries 3-6).8 Moreover, the
reactions with R-unsubstituted aldehydes were performed in pure
acetone, and after completion, proline could be recovered from
the reaction mixture in almost quantitative yield by filtration.
These reactions can also be performed in chloroform containing
20 vol % of acetone (Table 1, entry 3).
Only a handful of catalytic asymmetric Mannich reactions have
been reported,2 and all but one of these are indirect.2f Here we
report direct proline-catalyzed highly enantioselective three-
component Mannich reactions.
Few reports concerning asymmetric Mannich reactions exist.3
Catalytic methods have been introduced only very recently by
the groups of Tomioka, Kobayashi, Sodeoka, Lectka, and Shiba-
saki.2 Noncatalytic enantioselective methods include the addition
of chiral preformed enamines to imines.3 Our interest in testing
whether chiral amines or amino acids would also catalyze the
Mannich reaction is based on these reports, Kobayashi’s elegant
work on three-component Mannich reactions,4 the pioneering
The PMP (p-methoxyphenyl) amine protecting group has been
chosen because it can readily be removed under oxidative
conditions (Scheme 1),9 although other anilines can be used.10
Furthermore, we found that ketones other than acetone furnish
the desired Mannich products in excellent yields and enantiose-
lectivities.11,12 Most importantly, hydroxyacetone is an efficient
and selective donor. For example, in the reaction with isobu-
tyraldehyde, syn-amino alcohol 9 was formed within 12 h as the
only detectable regioisomer in good ee (65%) and dr (17:1)
(1) Reviews: (a) Kleinnmann, E. F. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 2, Chapter 4.1.
(b) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044-1070.
(5) Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Grama-
tikova, S.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 1998, 120,
2768-2779, and references therein.
(2) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060-2061. (b) Ishitani, H.; Ueno, M.; Kobayashi, S.
J. Am. Chem. Soc. 1997, 119, 7153-7154. (c) Kobayashi, S.; Ishitani, H.;
Ueno, M. J. Am. Chem. Soc. 1998, 120, 431-432. (d) Hagiwara, E.; Fujii,
A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474-2475. (e) Ferraris, D.;
Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-
4549. (f) For the only method that utilizes unmodified ketones, see the
following: Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40,
307-310 and Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999, 55,
8857-8867. This report describes asymmetric three-component Mannich
reactions. However, yields (e16%) and ee’s (e64%) were modest.
(3) For asymmetric Mannich reactions utilizing stoichiometric chiral
controller, see, for example: (a) Kober, R.; Papadopoulus, K.; Miltz, W.;
Enders, D.; Steglich, W.; Reuter, H.; Puff, H. Tetrahedron 1985, 41, 1693-
1701 (b) Corey, E. J.; Decicco, C. P.; Newbold, R. C. Tetrahedron Lett. 1991,
32, 5287-5290. (c) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto,
H. J. Am. Chem. Soc. 1994, 116, 10520-10524. (d) Enders, D.; Ward, D.;
Adam, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 981-984. (e)
Zarghi, A.; Naimi-Jamal, M. R.; Webb, S. A.; Balalaie, S.; Saidi, M. R.;
Ipaktschi, J. Eur. J. Org. Chem. 1998, 197-200. For diastereoselective
Mannich reactions, se, for example: (f) Seebach, D.; Betschart. C.; Schiess,
M. HelV. Chim. Acta 1984, 67, 1593-1597. (g) Risch, N.; Arend, M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2422-2423.
(6) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395-2396. (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-
7387. Our studies are based on the landmark contributions by Wiechert and
Hajos and their collegues: Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 496. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,
39, 1615.
(7) We have screened various other catalytic proline derivatives. All of
these gave lower yields and ee’s. See Supporting Information.
(8) The absolute configuration of â-amino ketone 6 has been determined
by correlation (chiral-phase HPLC) with aldol 7:6a
(9) For example, see: Bravo, P.; Guidetti, M.; Viani, F.; Zanda, M.;
Markovsky, A. L.; Sorochinsky, A. E.; Soloshonok, I. V.; Soloshonok, V. A.
Tetrahedron 1998, 54, 12789-12806.
(10) We investigated three different anilines in Mannich reactions with
isovaleraldehyde in pure acetone: p-chloroaniline (56% yield, 84% ee),
o-anisidine (43% yield, < 10% ee), and 2-aminophenol (51% yield, < 10%
ee).
(4) Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965-1967.
10.1021/ja001923x CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9337
Table 1. Products from the Proline-Catalyzed Asymmetric
Three-Component Mannich-Reaction
Scheme 1. Three-Component Mannich Reaction with
Hydroxyacetone
boron enolates.3b The geometry of the enamines from substituted
ketones (X * H) is (E) in A and (Z) in B. These transition states
readily explain the observed si-facial enantioselectivity. The
opposite selectivity (re) has previously been observed in proline-
catalyzed aldol reactions.6 The additional nitrogen substituent of
the imine may destabilize the corresponding chairlike transition
state of the aldol reaction.
a PMP ) p-methoxyphenyl. b The ee’s of compounds 1-6 were
determined by chiral-phase HPLC analysis using Chiralpak AD and
AS columns (Daicel Chemical Industries, Ltd.) with hexane/2-propanol
mixtures as eluents. c Reactions in DMSO/acetone 4:1. d Reactions in
pure acetone. e Reaction in CHCl3/acetone 4:1.
In summary, we have shown the first examples of the proline-
catalyzed asymmetric three-component Mannich reaction. Im-
portant features of this new transformation are the following: (1)
The reactions typically display high enantioselectivity (up to 99%
ee)11 and yield. (2) The inexpensive catalyst proline is available
in both enantiomeric forms and can be recovered from the reaction
mixture via filtration. (3) The PMP group can be readily removed
after further transformations. (4) Aliphatic unbranched aldehydes
can be utilized in this process. (5) The reactions do not require
preformed enolate equivalents or preformed imine equivalents.
Future studies will aim to shed light on the mechanism and
scope of this reaction and on further applications of proline and
other chiral amines in important carbon-carbon bond-forming
reactions.15
(Scheme 1). The relative and absolute configuration was deter-
mined from the X-ray structure of cyclic derivative 10a and via
conversion to enantiomerically pure N-(BOC)-D-valinol (11),
respectively. The Mannich reactions with hydroxyacetone comple-
ment the Sharpless asymmetric aminohydroxylation (AA)13 for
the construction of chiral nonracemic Vic-amino alcohols.14
Currently we speculate that this reaction follows an enamine
mechanism and involves either a boatlike transition state A or
chairlike transition state B. Both transition states include a (Z)-
imine, which has been implicated earlier in related reactions with
(11) The following products were obtained via the reaction:
Acknowledgment. Generous support by Richard A. Lerner and The
Scripps Research Institute is most gratefully acknowledged. We thank
Reza M. Ghadiri for critical review of the manuscript and Raj K. Chadha
for the X-ray structural analysis of 10a.
Supporting Information Available: Experimental procedures, char-
acterization of new compounds, determination of absolute configurations,
and X-ray structural analysis of oxazolidine 10a (print/PDF). This material
is available free of charge via the Internet at http://pubs.acs.org. See any
current masthead page for ordering information and Web access
instructions.
12a (R1 ) H, R2 ) Me), dr > 20:1, ee ) 99% and 12b (R1 ) Me, R2 ) H),
ee ) 94%, 96% combined yield from 2-butanone. 13 (R1 ) H, R2 ) OMe),
dr > 20:1, ee ) 98%, 93% yield from methoxyacetone. 14 (R1 ) R2 ) CH2-
CH2CH2), dr ) 2:1, ee ) 84% (major diastereomer), ee ) 23% (minor
diastereomer), 50% combined yield from cyclohexanone. 3-Pentanone and
3-methyl-butan-2-one did not react under these conditions.
(12) In all these reactions, we used the ketone component in excess.
However, Mannich reactions in which all three components are used
stoichiometrically have been reported. See ref 4.
JA001923X
(15) For amine-catalyzed asymmetric Diels-Alder reactions, see: (a)
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000,
122, 4243-4244. (b) Serebryakov, E. P.; Nigmatov, A. G.; Shcherbakov, M.
A.; Struchkova, M. I. Russ. Chem. Bull. 1998, 47, 82-90.
(13) Review: O’Brien, P. Angew. Chem., Int. Ed. Engl. 1999, 38, 326-
329.
(14) Review: Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.