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DOI: 10.1002/anie.200502630

Asymmetric Catalysis

Catalytic Enantioselective Cross-Mannich Reaction

of Aldehydes
Maria Manuel B. Marques*
asymmetric catalysis C C coupling
enantioselectivity homogeneous catalysis
Mannich reaction

The Mannich reaction is one of the

most useful reactions for the synthesis of
nitrogen-containing compounds as well
as an effective method for the construction of C C bonds.[1] A wide variety of
natural products and drugs possessing
optically active, nitrogen-containing
molecules (proteins, nucleic acids, biologically active compounds) have attracted considerable attention from synthetic chemists and the pharmaceutical
industry, which has stimulated the development of asymmetric Mannich reactions.[1, 2] Mannich and aldol reactions
are both highly atom economic and
address the problem of stereocontrol,
and are therefore often used as key steps
in modern organic synthesis. Control
over the three components of the Mannich reaction (carbonyl donor, amine,
and aldehyde acceptor) constitutes one
of the main challenges, since side reactions such as the corresponding aldol
reaction might occur, thus lowering the
yield. Impressive achievements have
recently been made, in particular in
asymmetric catalysis, with regard to the
versatility of this reaction. Catalytic
direct and indirect enantioselective
methodologies have been developed.
While the direct Mannich reaction requires unmodified ketone donors,
amines, and aldehydes, the indirect
Mannich reaction uses preformed enolate equivalents and/or imines. Many

[*] Prof. Dr. M. M. B. Marques

REQUIMTEDepartamento de Qu6mica
Faculdade de Cincias e Tecnologia
Universidade Nova de Lisboa
2829-516 Caparica (Portugal)
Fax: (+ 351) 21-294-8300
E-mail: mmbmarques@dq.fct.unl.pt


catalytic asymmetric Mannich methods

have been reported over the last few
years.[3] Excellent indirect catalytic
methods, which involve the addition of

solvent (Scheme 1). It should be noted

that this method provides access to
either the syn or anti adducts stereospecifically from (E) or (Z)-enolates.[5]

Scheme 1. Enantio- and diastereoselective Mannich-type reactions in water. Bz = benzoyl,

SDS = sodium dodecyl sulfate, CTAB = cetyltrimethylammonium bromide, CPB = cetylpyridinium

enolates to imines in the presence of

metal catalysts, have been reported by
the Kobayashi, Sodeoka, and Lectka
research groups, who used chiral zirconium/binol, palladium(ii)/binap, and
copper(i)/binap complexes, respectively
(binol = 1,1-binaphthol,
binap = 2,2bis(diphenylphosphanyl)-1-1-binaphthyl).[4] Recently, Kobayashi and co-workers developed an efficient catalytic,
enantio- and diastereoselective Mannich-type reaction of a hydrazono ester
with silicon enolates using water as the

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Most of these methods have the

disadvantage that the preformed enolates are unstable. Thus, a direct methodology based on unmodified ketone
donors would enhance the efficiency of
the Mannich reaction. Direct and highly
enantioselective catalytic asymmetric
Mannich reactions were reported by
Trost and Terrell as well as by Shibasaki
and co-workers, who used a dinuclear
zinc catalyst and zinc combined with
(S,S)-linked-binol as the catalyst, respectively.[6] A new approach to a,bAngew. Chem. Int. Ed. 2006, 45, 348 352



diamino acid derivatives from imines of

glycine esters, catalyzed by a chiral
complex, was recently developed by Jrgensen and co-workers.[7]
Asymmetric organocatalysis has received much attention since it avoids the
use of expensive and/or toxic metals.
Moreover, Shibasaki and co-workers
very recently reported a highly efficient
syn-selective enantio- and diastereoselective catalytic Mannich-type reaction
of a glycine Schiff base using the chiral
two-center phase-transfer catalyst (S,S)tadias (5, Scheme 2).[8] This method

tion. Thus, organocatalytic asymmetric

Mannich reactions involving amino acid
derivatives as catalysts have been reported by the research groups of List,
Barbas, C@rdova, and Jacobsen.[11] Some
of these methods involve a catalytic
indirect asymmetric Mannich reaction,
while others involve direct methods.
Encouraged by the results obtained
by Kobayashi and co-workers in the
three-component Mannich reaction, and
the fact that l-proline promoted the
direct enantioselective aldol reaction,
List et al. explored the first l-prolinecatalyzed asymmetric three-component

Scheme 2. Enantio- and diastereoselective catalytic Mannich-type reactions of a glycine Schiff

base using (S,S)-tadias 5 as a phase-transfer catalyst. Boc = tert-butoxycarbonyl.

represents a simple and mild procedure

for the preparation of syn-a,b-diamino
acids, with the advantage of the facile
removal of the pivotal imine-protecting
group instead of the p-tosyl group used
by Jrgensen and co-workers.[7]
The use of unmodified ketones as
donors and metal-free catalystsin particular amine catalystsappeared to be
an excellent strategy and a promising
alternative. However, the use of amino
acid derivatives as catalysts has been the
method of choice. Proline was first used
as the catalyst in the HajosParrish
EderSauerWiechert reaction,[9] and
was subsequently employed in a broad
range of intermolecular aldol and crossaldol reactions.[10] During the last five
years, many research groups have applied this strategy to the Mannich reacAngew. Chem. Int. Ed. 2006, 45, 348 352

Mannich reaction of a free aldehyde

(instead of preformed imine equivalents
or paraformaldehyde) with an unmodi-

fied ketone and an imine, which is a

more atom-economic process. This approach led to the development of highly
enantioselective and efficient syntheses
of 1,2-amino alcohols using ketones as
donors. The main advantage of the
three-component procedure is that it
does not require any preformed imine
and enol equivalents; on the other hand,
the direct aldol and Mannich reaction
compete and are dependent on the
equilibrium ratio between the aldehyde
and imine (Kaldol versus KMannich).
Recently, the scope of the prolinecatalyzed asymmetric Mannich reaction
has been expanded[12] by applying a onepot, three-component procedure to unmodified aldehydes as donors. The 3amino adducts were reduced with
NaBH4 to the corresponding g-amino
alcohols to avoid epimerization and
racemization during the purification
process. A Mannich-type reaction to
afford g-amino alcohol derivatives 12
with high stereocontrol and in high yield
was also described (Scheme 3).
Moreover, Christmann and co-workers[13] recently developed a new and
efficient protocol for the construction
of azetidines, piperidines, and pyrrolidines by using a highly selective prolinecatalyzed Mannich reaction of functionalized aldehydes.
The development of a cross-Mannich reaction between two different
unmodified aldehydes provided a significant advancement to the synthetic
methodology. However, the use of an
aldehyde as the Mannich donor and
another aldehyde as the Mannich acceptor
(Scheme 4).

Scheme 3. One-pot direct asymmetric synthesis of g-amino alcohol derivatives catalyzed by

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim




Scheme 4. Possible different reaction pathways that might occur during the reaction between
two different unmodified aldehydes.

The challenge and fundamental

problem of a cross-Mannich reaction
consists of finding the right reaction
conditions (temperature, solvent, catalyst) that favors the cross-Mannich reaction and equilibrium rather than the
side pathways: cross-aldol, self-aldol,
self-Mannich, and enamine formation
(K3). The equilibrium constants as well
as the relative stabilitythe energy
gapof the competing transition states
are extremely important and determine
the course of the reaction. Imine formation must be specific for the aldehyde
acceptor and the formation of an enamine from an aldehyde donor must be
Nevertheless, Hayashi et al. and
C@rdova reported the one-pot, threecomponent enantioselective cross-Mannich reaction of aldehydes not only with
high syn diastereo- and enantioselectivity but also with low catalyst loading.[14, 15] Stimulated by the excellent
results reported by the research groups
of List and Barbas on proline-mediated
reactions, Hayashi and co-workers explored a new system for the reaction
between two different aldehydes. They
found higher reaction efficiency when
the reactions were performed at a lower
temperature: higher yields and enantioselectivities were achieved at 20 8C
(Scheme 5), and only the syn isomer
was observed. Indeed, lower temperature favors the Mannich reaction and
suppresses the aldol reaction (favored at



4 8C). Thus, proline was found to activate aldimines preferentially to aldehydes. The best results were reported
when aromatic and heteroaromatic acceptors were used instead of the aliphatic ones. The desired cross-Mannich
adducts were isolated after reduction to
the corresponding b-amino alcohol 15 to
avoid decomposition during purification.

ketones were used, however, absolute

stereocontrol was achieved when aldehydes were tested as acceptors and
donors, and the Mannich adducts could
be isolated in high yield (> 99 % ee and
> 19:1 d.r.). The role of the aldehyde
acceptor was also investigated, and it
was observed that proline exhibited a
higher selectivity for the cross-Mannich
instead of the cross-aldol reaction for
aromatic acceptors (lacking electronwithdrawing groups). In contrast, aliphatic acceptors only gave trace
amounts of the desired adduct. Thus,
the increased reactivity of the acceptor
results in a higher yield, as well as a
higher enantioselectivity of the Mannich
adducts. Another interesting observation was that a stable acceptor imine
favors the cross-Mannich reaction rather than the self-Mannich reaction. The
structural features of the aldehyde donor were also explored. The chain length
of the nucleophilic aldehyde influenced
the diastereoselectivity: lower ee valuess
were observed as the chain length of the
aldehyde donor increased. The results
obtained motivated the study of a onepot, direct catalytic asymmetric synthesis of each enantiomer of the unnatural
amino acid 18 using ethyl glyoxylate (17,
Scheme 6). The reaction proceeded with

Scheme 5. One-pot, direct cross-Mannich reaction of two different aldehydes with high
syn diastereo- and enantioselectivity by proline catalysis.

The scope, mechanism, applications,

and limitations of the cross-Mannich
reaction between two different unmodified aldehydes has been fully explored.[15] On the basis of previous
results and investigations,[12] it was later
realized that both (S)- and (R)-proline
could be used as catalysts for the crossMannich reaction. The chemoselectivity
was sometimes low when unmodified

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

excellent chemo- and enantioselectivities, and could be readily scaled up.

Different organic amines were also
tested, although the best results were
obtained with proline (> 90 % ee). However, all the catalysts exhibited syn
selectivity. It should be emphasised that
the main difference between the proline-catalyzed Mannich and aldol reactions in regard to stereoselectivity is that
Angew. Chem. Int. Ed. 2006, 45, 348 352



Scheme 6. One-pot, three-component, direct catalytic asymmetric synthesis of functional

a-amino alcohol derivatives. PMP = para-methoxyphenyl.

the Mannich reaction affords the syn adduct whereas the aldol reaction gives
the anti adduct (Scheme 7). List et al.
and C@rdova explored certain mechanistic features and found that a single
proline molecule is involved in the
transition state as well as in the mechanism. Since proline is a bifunctional
acid/base catalyst that acts like a Lewis
base type catalyst, and allows enamine
formation, and also like a general acid
(because of its increased pKa value relative to primary amino acids) it is
regarded as an artificial enzyme.
A plausible explanation was proposed for the observed diastereoselectivity in the (S)-proline-catalyzed direct
asymmetric Mannich reactions. They
were proposed to occur by the attack
of the si face of the enamine on the
si face of an imine with an E configuration, rather than the proposed re-face
attack in the cross-aldol reaction. Similar to the cross-aldol reaction, the
trasition statea six-membered metal-

systemis stabilized by hydrogen bonding between the
nitrogen atom (imine) and the
carboxylic acid (proline). The
attack of the imine at the
re face was considered disfavored because of steric congestion between the PMP
group and the pyrrolidine unit.
One of the drawbacks of
using proline as the catalyst is
the limited choice of solvent,
since only polar solvents such
as DMSO, DMF, N-methylScheme 8.
pyrrolidine (NMP), and N,Ndimethylacetamide (DMA)
can be used. More recently,
Ley and co-workers screened new catalysts and solvents for the catalytic asymmetric Mannich reaction.[16] Among the
catalysts tested, a new catalysttetrazole 21 (Scheme 8)was found to catalyze the asymmetric Mannich reactions
of ketone 19 and N-PMP-protected a-

Scheme 7. Proposed transition states of the cross-Mannich and cross-aldol reactions.

Angew. Chem. Int. Ed. 2006, 45, 348 352

imino ethyl glyoxalate 20 with high

enantioselectivity and high yield. This
catalyst is compatible with organic solvents such as dichloromethane and THF
and requires low catalyst loadings
(1 mol %), without affecting the enantioselectivety.
All the examples of the cross-Mannich reaction described herein are highly enantioselective (ee values up to
99 %), and under optimized reaction
conditions gave only the syn adduct,
although in only moderate to good

Asymmetric Mannich reaction using 21 as the catalyst.

Despite all the efforts devoted to

asymmetric organocatalysis during the
last few years, the search for a catalyst
that permits access to both syn and anti
adducts is still a problem waiting to be
solved, maybe the search for a catalyst
that stabilizes a Z configuration of the
imine in the transition state will allow
the formation of an anti-Mannich adduct. Another problem concerns the
search for other imine protecting
groups, since removal of the PMP group
requires oxidative procedures. Also the
scope of the aldehyde acceptor has to be
increased, since it is limited to aromatic
A non-enantioselective version of
the cross-Mannich reactions of aldehydes was recently applied to an efficient and elegant synthesis of symmetrically and unsymmetrically substituted
The cross-Mannich reaction of aldehydes, particularly the direct catalytic
asymmetric version, is a new valuable
method for the formation of C C bonds

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim



and permits access to a wide variety of
optically active compounds as well as
active compounds such as amino acid
derivatives. Remarkable advancements
have been reported over the last five
years, including one-pot, three-component procedures with absolute stereocontrol and high yields, and the competition between cross-aldol and crossMannich reactions could be overcome
by controlling the reaction conditions.
The success of this reaction will unquestionably prompt chemists to develop
new catalysts that will overcome the
limitations presented in this Highlight.


Published online: December 12, 2005

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