The Direct Catalytic Asymmetric Cross-Mannich Reaction: A Highly Enantioselective Route to 3-Amino Alcohols and α-Amino Acid Derivatives

Article abstract of DOI:10.1002/chem.200305646

The first proline-catalyzed direct catalytic asymmetric one-pot, three-component cross-Mannich reaction has been developed. The highly chemoselective reactions between two different unmodified aldehydes and one aromatic amine are new routes to 3-amino ald

Full text of DOI:10.1002/chem.200305646

FULL PAPER
The Direct Catalytic Asymmetric Cross-Mannich Reaction: A Highly
Enantioselective Route to 3-Amino Alcohols and a-Amino Acid Derivatives
Armando CÛrdova*[a]
Abstract: The first proline-catalyzed
direct catalytic asymmetric one-pot,
three-component cross-Mannich reac-
tion has been developed. The highly
chemoselective reactions between two
different unmodified aldehydes and
one aromatic amine are new routes to
3-amino aldehydes with dr>19:1 and
up to >99% ee. The asymmetric cross-
Mannich reactions are highly syn-selec-
tive and in several cases the two new
carbon centers are formed with abso-
lute stereocontrol. The reaction does
not display nonlinear effects and there-
fore only one proline molecule is in-
volved in the transition state. The reac-
tion was also catalyzed with good selec-
tivity by other proline derivatives. The
Mannich products were converted into
3-amino alcohols and 2-aminobutane-
1,4-diols with up to >99% ee. The first
one-pot, three-component, direct cata-
lytic asymmetric cross-Mannich reac-
tions between unmodified aldehydes,
p-anisidine, and ethyl glyoxylate have
been developed. The novel cross-Man-
nich reaction furnishes either enan-
tiomer of unnatural a-amino acid de-
rivatives in high yield and up to
>99% ee. The one-pot, three-compo-
nent, direct catalytic asymmetric reac-
tions were readily scaled up, operation-
ally simple, and conductible in environ-
mentally benign and wet solvents. The
mechanism and stereochemistry of the
proline-catalyzed, one-pot, three-com-
ponent, asymmetric cross-Mannich re-
action are also discussed.
Keywords: aldehydes ¥ asymmetric
synthesis
¥ catalysis ¥ Mannich
reaction ¥ proline
Introduction
cessfully employed numerous times, for example, as a key
step in natural product synthesis and in medicinal chemis-
try.[3] However, regardless of the immense importance of
this reaction only a few catalytic stereoselective Mannich-
type reactions have been developed.[4] One major obstacle is
the capability to control the roles of the three components
of the Mannich reaction: carbonyl donor, amine, and alde-
hyde acceptor. Failure leads to competing side-reactions and
decreases in product yield. Chemists have therefore devel-
oped several indirect methods that employ preformed enol
equivalents or imines.[5] The first successful examples of cat-
alytic asymmetric additions of enolates to imines were re-
ported by Kobayashi and co-workers, who used chiral zirco-
nium/BINOL complexes as catalysts.[6] Sodeoka et al.[7] and
Lectka et al.[8] reported that palladium(ii)/BINAP and cop-
per(i)/BINAP complexes, respectively, are excellent catalysts
for indirect asymmetric Mannich reactions with a-imino-
glyoxylates. However, a disadvantage of these stereoselec-
tive Mannich reactions can be the preparation and instabili-
ty of the preformed enolates used. An important advance
for this class of asymmetric reactions would therefore be a
catalytic stereoselective version employing unmodified car-
bonyl compounds.
One of the ultimate goals and challenges in chemistry is to
develop stereoselective transformations for the creation of
functionalized optically active molecules with structural di-
versity from simple and easily available starting materials.
Hence, during the last two decades, the synthesis of enantio-
merically pure or enriched compounds has emerged as one
of the most important fields in organic synthesis. Several
procedures to generate optically active molecules are
known, and among these, asymmetric catalysis is a highly
active research field.[1]
The Mannich reaction is a classic method for the prepara-
tion of nitrogen-containing compounds and therefore a very
important carbon carbon bond-forming reaction in organic
synthesis. The versatility and potential to create both func-
tional and structural diversity through this reaction have
long stimulated the creativity of chemists.[2] It has been suc-
[a]Prof. Dr. A. CÛrdova
Department of Organic Chemistry
The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46) 8154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
Recently, Shibasaki and co-workers reported that hetero-
dimetallic complexes are catalysts for the direct asymmetric
Mannich reaction.[9] Shibasaki et al.[10] and Trost et al.[11]
1987
Chem. Eur. J. 2004, 10, 1987 1997
DOI: 10.1002/chem.200305646
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

FULL PAPER
have also developed dinuclear zinc organometallic com-
plexes that catalyze highly enantioselective Mannich-type
reactions between hydroxyarylketones and preformed
imines. J˘rgensen et al. have developed direct asymmetric
Mannich reactions involving activated ketones as donors
and catalyzed by chiral copper(ii) bisoxazoline (BOX) com-
plexes.[12]
Results and Discussion
Scheme 2 depicts the different reaction pathways that could
occur in a reaction between two different unmodified alde-
hydes. In order to obtain the desired product, the catalyst
Asymmetric reactions catalyzed by metal-free organic cat-
alysts have received increased attention in recent years.[13]
Interestingly, after the discovery of amino acid catalyzed
stereoselective Robinson annulations in the early 1970s,[14]
there was no intensive research on this concept for other
À
C C bond-forming reactions for several decades, even
though the reaction is frequently used in the preparation of
building blocks for the total synthesis of natural products.[15]
It was not until recently that researchers demonstrated that
amino acid derivatives function as catalysts for direct asym-
23]
metric intermolecular C C bond-forming reactions.[16
Scheme 2. Potential different reaction pathways occurring in a reaction
between two different unmodified aldehydes.
À
Among these reactions, List et al.,[24] Barbas et al.,[25] and we
have developed organocatalytic asymmetric Mannich reac-
tions that involve unmodified ketones as donors.[26] During
our initial studies of proline-catalyzed, direct asymmetric
cross-aldol reactions, we realized the ability of small organic
molecules to activate unmodified aldehydes through an en-
amine mechanism for asymmetric additions to other electro-
philes.[16f] We thus applied this strategy in the first organoca-
talytic asymmetric Mannich-type reactions with unmodified
aldehydes as nucleophiles and preformed a-imino glyoxylate
esters as the electrophiles.[27] In addition, Wenzel and Jacob-
sen have reported indirect organocatalytic asymmetric Man-
nich-type reactions between silyl enol ethers and preformed
imines.[28] However, a more effective and atom-economic
process would be a catalytic enantioselective one-pot, three-
component cross-Mannich reaction with unmodified alde-
hydes, which would lead to a new route for the synthesis of
b-amino acids and g-amino alcohols (Scheme 1).[29]
and reaction conditions have to allow and favor specific re-
action pathways and equilibria. For example: 1) imine for-
mation has to occur specifically with the acceptor aldehyde
K1 @K2, 2) kcross-Mannich >kself-Mannich >kcross-aldol >kself-aldol
,
and
3) enamine formation (K3) between the donor aldehyde and
the amine component has to be avoided.
During our preliminary investigations of proline-catalyzed
stereoselective additions of unmodified aldehydes to pre-
formed imines we realized the potential of a small organic
catalyst able to catalyze direct one-pot, three-component,
asymmetric cross-Mannich reactions through an enamine
mechanism.[30] These studies revealed that (S)- and (R)-pro-
line were excellent catalysts for cross-Mannich-type reac-
tions, and that a variety of preformed imines could be used
as electrophiles. Moreover, we knew from previous Mannich
transformations with unmodified ketones that the imine can
26]
be generated in situ.[24
How-
ever, the chemoselectivity of
the amine-catalyzed, one-pot,
three-component Mannich reac-
tions with unmodified ketones
can at times be low, resulting in
the formation of significant
amounts of aldol products. Fur-
thermore, proline is also a cata-
lyst for cross-aldol and self-
Scheme 1. Catalytic enantioselective one-pot, three-component cross-Mannich reaction with unmodified alde-
hydes.
We therefore embarked on the quest to develop a novel
enamine-catalyzed asymmetric route for the synthesis of ni-
trogen-containing molecules. We have most recently dis-
closed the first one-pot, three-component, proline-catalyzed
asymmetric cross-Mannich reactions between two different
unmodified aldehydes and one amine, which provided Man-
nich adducts in up to >99% ee.[30] In this paper we describe
the scope, mechanism, and applications of this novel, highly
stereoselective, three-component, carbon carbon bond-
forming reaction.
aldol reactions and so it is not established whether kcross-Man-
[16f i]
would be higher than kcross-aldol and kself-aldol
.
Neverthe-
nich
less, we decided to develop a novel one-pot, three-compo-
nent, direct asymmetric Mannich reaction with unmodified
aldehydes. In an initial experiment, p-nitrobenzaldehyde
(1.0 mmol) and p-anisidine (1.1 mmol) were mixed in the
presence of a catalytic amount of (S)-proline (20 mol%) in
DMF at 48C for 15 minutes. Next, propionaldehyde
(3.0 mmol) in cold DMF was slowly added to the reaction
mixture by syringe pump over 4 h and the reaction was al-
lowed to run for an additional 16 h at 48C. The reaction was
quenched by extraction and, to our delight, 3-amino alde-
hyde 1 could be isolated in 81% yield (Scheme 3).[30] The
1988
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Asymmetric Cross-Mannich Reaction
1987 1997
loading could be reduced. Fur-
thermore, reactions with less
polar imines generated in situ
could be performed at higher
concentrations, since the imines
did not precipitate at the set
temperature. An alternative
method was therefore devel-
Scheme 3. In situ reduction of Mannich adduct 1, providing 3-amino propanol 2.
oped: the acceptor aldehyde
(1.0 mmol) and p-anisidine
corresponding cross-aldol product was also formed, but in a
much lower yield (<10%). Mannich adduct 1 was not sig-
nificantly stable and decomposed after its isolation. We
therefore decided to reduce 1 in situ with excess NaBH4
prior to workup and isolation of the corresponding 3-amino
alcohol derivative. Thus, 3-amino propanol 2 was isolated in
75% yield with dr>19:1 and 99% ee (Scheme 3, Meth-
od A).
(1.1 mmol) were mixed in the presence of a catalytic
amount of (S)-proline (10 mol%) in DMF at room tempera-
ture. After 20 30 minutes the reaction temperature was de-
creased to below freezing, and propionaldehyde (3.0 mmol)
was added in one portion to the reaction mixture, which was
stirred for an additional 20 h at below 08C. Next, the Man-
nich adduct was reduced in situ with NaBH4 prior to
workup and column chromatography (Method B). In addi-
tion, decreasing the reaction temperature from 4 to À208C
improved the yields and ees of Mannich adducts derived
from transformations with aromatic acceptor aldehydes
lacking an electron-withdrawing group. As an example, the
ee of Mannich adduct 3 was significantly increased from
78% to 93%. Interestingly, proline exhibits a higher selec-
tivity at temperatures below 08C, and kcross-Mannich >kcross-aldol
for aromatic acceptor aldehydes. Moreover, pyridinecarbal-
dehydes and furan-2-carbaldehyde were excellent electro-
philes, providing the corresponding 3-aminopropanol ad-
ducts 9 11 in good yields with ee values of up to >99%,
adding valuable new functionalities to the 3-aminopropanol
adducts. In general, the yields and enantioselectivities of the
Mannich adducts improved
In addition, the b-amino aldehydes can be extracted with
Et2O prior to reduction with NaBH4 or another chemical
manipulation of the propionaldehyde moiety.
Acceptor aldehyde component: Proline-catalyzed reactions
with propionaldehyde as the donor and other aromatic alde-
hydes as acceptors proceeded readily, affording 3-amino-3-
arylpropanols 2 11 with excellent chemo-, diastereo-, and
enantioselectivities (Table 1).
Optimization studies of the enantioselectivities of the
Mannich reactions with electron-rich aromatic acceptor al-
dehydes revealed that the use of a syringe pump was not es-
sential at temperatures below 08C and that the catalyst
with increased reactivity of the
Table 1. One-pot, three-component, direct catalytic asymmetric cross-Mannich reactions.[a]
acceptor aldehydes (imines
formed in situ). The reactions
were also readily scaled up to
multigram levels without the
yield or stereoselectivity being
affected. The direct asymmetric
cross-Mannich reactions pro-
ceeded with excellent chemose-
lectivity even though proline
was able to catalyze the two-
component self-Mannich reac-
tion between propionaldehyde
and p-anisidene to furnish the
Mannich adduct 14 in 82%
yield, dr>10:1, and 94% ee.
This indicated that proline ex-
[b]
Entry
R
Method
T [8C]Yield[%]
dr[c]
ee[d]
Product[e]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
C6H5
C6H5
C6H5
p-CNC6H4
p-CNC6H4
p-CIC6H4
p-BrC6H4
m-BrC6H4
p-MeOC6H4
furfuryl
2-pyridyl
3-pyridyl
cyclohexyl
isopropyl
Et
A
B
B
A
B
B
A
B
B
B
B
B
B
B
B
B
B
B
4
4
0
4
0
75
41
46
62
66
80
75
88
88
65
72
50
80
86
80
trace
trace
82
>19:1
>19:1
>19:1
4:1
99
99
2
2
2
3
3
4
4
4
5
6
7
8
9
10
11
12
13
14
>99
75
10:1
88
98
98
À20
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
4:1
>10:1
>10:1
n.d
n.d
>10:1
0
À20
À20
À10
À10
À20
À20
À20
À20
À20
À20
À20
>99
>99
99
99
55
84
hibits
a
higher kcross-Mannich >
kself-Mannich and that the equilibri-
um K1 favors a stable acceptor
imine. However, reactions with
aliphatic acceptor aldehydes
only afforded trace amounts of
the corresponding Mannich ad-
ducts. Cyclohexanecarboxalde-
hyde and isopropylaldehyde,
for example, provided a com-
>99
>99
n.d
n.d
94
[a]Reaction conditions: Method A or B was used; see the Experimental Section. [b]Isolated yields of the 3-
amino alcohol adduct after column chromatography. [c]Determined by NMR spectroscopy. [d]Determined by
chiral-phase HPLC. [e]The 3-amino alcohol product.
1989
Chem. Eur. J. 2004, 10, 1987 1997
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. CÛrdova
FULL PAPER
plex reaction mixture mostly containing the corresponding
cross-aldol products and self-aldol products from the donor.
Perhaps for these substrates proline preferentially mediates
the addition to the carbonyl moiety rather than the imine
functionality (kcross-aldol >kcross-Mannich) and/or the equilibrium
(K1) does not favor a stable imine formation.
of the aldehyde donor component (Table 3). We found that
a-unbranched aliphatic aldehydes with a chain length of
more than two carbons were excellent nucleophiles for the
proline-catalyzed direct asymmetric, one-pot, three-compo-
nent cross-Mannich reactions, furnishing Mannich adducts
21 23 in high yields and with excellent enantioselectivities
(Table 3). For example, amino alcohol 23 was isolated in
78% yield with dr>19:1 and 99% ee. The diastereoselectiv-
ity of the reaction varied slightly depending upon the chain
length of the nucleophilic aldehyde. Cross-Mannich reac-
tions with n-butanal provided a lower dr in the 3-amino al-
cohol adduct than were obtained with n-heptanal and propa-
nal. The ees of the Mannich adducts could also slightly de-
crease with increasing chain length of the aldehyde donor,
depending upon the reactivity of the acceptor aldehyde
(imine) (Entry 4). Interestingly, acetaldehyde and 2-substi-
tuted acetaldehydes only provided trace amounts of the de-
sired cross-Mannich adducts and mainly self-aldol condensa-
tion products (entry 1, Table 3). Hence, in this case,
Amine component: The amine component of the asymmet-
ric Mannich reaction can be regarded either as an ™ammo-
nia∫ equivalent or as an additional element of structural di-
versity, which is highly useful in drug development. The
former requires a functional amine that can readily be con-
verted into the free amine through deprotection. For this
purpose, p-anisidine was used as the amine component, thus
introducing a p-methoxyphenyl-protected (PMP-protected)
amino group into the Mannich adducts. The PMP group is
readily removed under oxidative conditions with cerium(iv)
ammonium nitrate (CAN) or PhI(OAc)2.[24,26,30a,b] Further
introduction of structural diversity into the three-compo-
nent, direct cross-Mannich reactions was achieved with ex-
cellent selectivity by use of proline and different aromatic
amines, Mannich adducts 15 18 being obtained in high
yields and with superb chemo- and enantioselectivities
(Table 2). Cross-Mannich reactions with para-substituted
anilines provided 3-amino alcohol derivatives with slightly
kcross-aldol >kcross-Mannich.
One-pot direct catalytic asymmetric synthesis of either
enantiomer of an unnatural amino acid: Up to this point, we
had established that reactions with aromatic aldehydes pro-
vided excellent results, in contrast to reactions with aliphatic
acceptor aldehydes. We were therefore not certain whether
a-glyoxylate esters might serve as electrophiles for the one-
pot, three-component, direct catalytic cross-Mannich reac-
tion. However, retrosynthetic analysis as depicted in
Scheme 1 and previous Mannich-type reactions with N-pro-
tected iminoglyoxylates had indicated that our synthetic
strategy should be applicable to a direct multicomponent
route for the synthesis of unnatural amino acid deriva-
tives.[26,27] We thus treated different aldehydes with p-anisi-
dine and ethyl glyoxylate in the presence of 10 mol% of
either (S)- or (R)-proline in DMF at 48C (Table 4).
Table 2. One-pot, three-component, direct catalytic asymmetric cross-
Mannich reactions with aromatic amines.[a]
Entry
R
Yield [%][b]
dr[c]
ee [%][d]
Product
1
2
3
4
5
p-MeOC6H4
C6H5
p-BrC6H5
m-BrC6H4
p-IC6H4
85
78
82
56
65
>19:1
>19:1
>10:1
>10:1
>10:1
>99
>99
>99
99
10
15
16
17
18
To our delight, proline was able to catalyze the synthesis
of b-formyl-a-amino acid derivatives 24 29 in good yield
and with excellent chemo- and enantioselectivities. The
products were more stable than the aromatic 3-amino alde-
hydes and subsequent reduction was not required. However,
the dr values of the aldehyde-functionalized amino acid de-
>99
[a]Reaction conditions: see Method B in the Experimental Section.
[b]Isolated yields of the 3-amino alcohol adduct after silica gel column
chromatography. [c]Determined by NMR spectroscopy. [d]Determined
by chiral-phase HPLC.
Table 3. One-pot, three-component, direct catalytic asymmetric cross-Mannich reactions with aldehydes.[a]
higher yields and ees than those
derived from meta-substituted
anilines. For example, the re-
action with p-bromoaniline
afforded the corresponding
3-amino propanol 16 in 82%
yield
with
dr>10:1
and
Entry
R
R’
Yield [%][b]
dr[c]
ee [%][d]
Product
>99% ee, while the reaction
with m-bromoaniline furnished
the 3-amino propanol deriva-
tive 17 in 56% yield with
dr>10:1 and 99% ee.
1
2
3
4
5
2-pyridyl
2-pyridyl
2-pyridyl
p-NO2C6H4
2-pyridyl
H
Me
Et
n-pent
n-pent
trace
85
n.d
>99
>99
94[e]
19
10
21
22
23
>19:1
2:1
80
77[e]
78[e]
>10:1[e]
>10:1[e]
>99[e]
[a]Reaction conditions: see Method B in the Experimental Section. [b]Isolated yields of the 3-amino alcohol
adduct after silica gel column chromatography. [c]Determined by NMR spectroscopy. [d]Determined by
Aldehyde donor component:
We next investigated the scope chiral-phase HPLC. [e]Reaction performed with 20 mol% proline and 10 equiv of heptanal.
1990
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Chem. Eur. J. 2004, 10, 1987 1997

Asymmetric Cross-Mannich Reaction
1987 1997
Table 4. One-pot, three-component, direct catalytic asymmetric synthesis of functional a-amino alcohol deriv-
alysts for the one-pot, three-
component Mannich reactions
(Table 5). Of the limited
number of catalysts screened,
proline provided the highest ee
of 10, closely followed by hy-
droxyproline derivatives, which
furnished 10 with >90% ee. In
addition, all the successful cata-
lysts exhibit syn diastereoselec-
tivity for the cross-Mannich re-
actions, as determined by NMR
spectroscopy. Interestingly, pi-
colic acid was not a catalyst for
the reaction, establishing the
importance of the cyclic five-
atives.[a]
Entry
Catalyst
R
Yield [%][b]
dr[c]
1.5:1
>10:1
7:1
>10:1
>10:1
>19:1
ee [%][d]
Product
1
3
4
5
6
7
(S)-proline
(R)-proline
(S)-proline
(S)-proline
(S)-proline
(S)-proline
Me
Bu
67
80
77
78
70
70
>99
99
99
>99
98
>99
24
ent-25
26
CH2=CHCH2
pentyl
isopropyl
27
28
29
CH3(CH2)CH=CHCH2
[a]Reaction conditions: see the Experimental Section. [b]Isolated yields after silica gel column chromatogra-
phy. [c]Determined by NMR spectroscopy. [d]Determined by chiral-phase HPLC.
Table 5. Catalyst screen.[a]
rivatives decreased slightly during workup and isolation.
This is, to the best of our knowledge, the first one-pot,
three-component, direct catalytic asymmetric synthesis of
either enantiomer of a-amino acid derivatives. The reaction
circumvents the preparation of the imine and can readily be
coupled with other nucleophilic carbon carbon bond-form-
ing reactions.[27b,c] We also developed a novel one-pot direct
asymmetric synthesis of enantiomerically pure N-PMP-pro-
tected 2-aminobutane-1,4-diols such as 30, which are useful
precursors for the stereoselective synthesis of substituted 2-
aminopyrrolidines (Scheme 4). In addition, b-cyanohydroxy-
Entry
1
Catalyst
Yield [%][b]
85
dr[c]
ee [%][d]
>99
>19:1
2
63
>19:1
94
3
4
66
>19:1
96
trace
n.d
n.d
6
7
20
1:1
n.d
<5
trace
n.d
[a]Reaction conditions: see Method B in the Experimental Section.
[b]Isolated yields of the 3-amino alcohol adduct after silica gel column
chromatography. [c]Determined by NMR spectroscopy. [d]Determined
by chiral-phase HPLC.
Scheme 4. One-pot direct catalytic asymmetric synthesis of functional a-
amino acid derivatives. i: a) Ethyl glyoxylate, 2 equiv isovaleraldehyde,
1.1 equiv p-anisidine, 10 mol% (S)-proline, 48C. ii: either b) LAH, THF,
08C, 85% yield two steps, or c) Et2AlCN, THF, À758C, 66% yield two
steps.
membered, secondary amine structural motif. A similar ob-
servation has also been encountered in amine-catalyzed
direct asymmetric aldol reactions.[16c] Furthermore, (S)-3-me-
thoxymethylpyrrolidine (SMP) only provided trace amounts
of product 2 under the set reaction conditions, due mainly
to low imine formation.[27b]
methyl amino acid derivative 31, with three contiguous ste-
reocenters, was prepared through a tandem three-compo-
nent, cross-Mannich cyanation reaction.
Catalyst: In our earlier studies of amine-catalyzed direct
asymmetric cross-Mannich-type reactions, we discovered
that other proline-derived amines are catalysts as well and
can switch the diastereoselectivity of the products.[27] We
therefore screened different organic amines as potential cat-
Solvent screen: We also performed a solvent screen of the
one-pot, three-component, proline-catalyzed direct asym-
metric cross-Mannich reaction between propionaldehyde, p-
anisidine, and 2-pyridinecarbaldehyde (Table 6).
1991
Chem. Eur. J. 2004, 10, 1987 1997
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. CÛrdova
FULL PAPER
Table 6. Solvent screen of the proline-catalyzed, one-pot, three-compo-
nent cross-Mannich reaction.[a]
this revealed that (2S,3S)-2 was formed by proline catalysis.
Furthermore, subsequent deprotection of 3 by CAN afford-
ed the known 3-amino alcohol 3a.[32] Hence, (S)-proline af-
fords (2S,3S)-3-amino 2-alkyl aldehydes and (S)-a-amino
acid derivatives with syn relative stereochemistry.[33] In addi-
tion, NMR analyses revealed that the chemical shift of the
doublet corresponding to the RNHPMP proton of the 3-
amino alcohols and b-formyl amino acid derivatives were
between d=4.52 4.81 ppm with J=3.0 6.5 Hz and d=4.18
4.44 ppm with J=6.2 8.1 Hz for the syn and anti isomers, re-
spectively.
[b]
Entry
1
Solvent
dioxane
T [8C]Yield [%]
ee [%][c]
10
32
99
(99)[d]
99
(65)[d]
2
3
4
5
ether
À20
À20
À20
4
<10
(40)[d]
39
(99)[d]
>99
(99)[d]
>99
(99)[d]
n.d
THF
Mechanism: The mechanism of the proline-catalyzed Man-
nich reactions is depicted in Scheme 6. The aldehyde donor
reacts with proline, resulting in an enamine. Next, the imine,
(50)[d]
85
DMF
toluene
(81)[d]
<10
(45)[d]
88
(99)[d]
>99
>99
(99)[d]
6
7
NMP
DMA
À20
À20
79
(84)[d]
[a]Reaction conditions: see Method B in the Experimental Section.
[b]Isolated yields of the corresponding 3-amino alcohol adduct after in
situ reduction and silica gel column chromatography. [c]Determined by
chiral-phase HPLC of the corresponding amino alcohol 10. [d]( S)-Pro-
line-catalyzed direct asymmetric cross-Mannich-type reactions between
propionaldehyde and preformed N-PMP-protected p-nitrobenzaldimine
according to Refs. [30a,b].
The reaction worked well in polar aprotic solvents such as
DMF, N-methylpyrrolidinone (NMP), and DMA, with DMF
and NMP providing the highest yields and ees. The one-pot,
three-component, catalytic cross-Mannich transformations
in other solvents provided low yields and chemoselectivity.
This contrasts with direct asymmetric cross-Mannich-type
reactions with N-PMP-protected p-nitrobenzaldimine, which
could be performed in a broader range of solvents.[30a,b]
Hence, carbon carbon bond-formation between the alde-
hyde and the imine could occur in solvents with smaller die-
lectric constants, which suggests that the in situ generation/
stability of the imine was the predominant limiting factor.
Scheme 6. The reaction mechanism for the proline-catalyzed one-pot
direct asymmetric cross-Mannich reaction.
generated in situ, reacts with the enamine to give (after hy-
drolysis) the enantiomerically enriched Mannich adduct and
the catalytic cycle can be repeated.
We did not observe any nonlinear effect in the proline-
catalyzed reaction (Figure 1).[34] Thus, a single proline mole-
cule is involved in the transition state and mechanism,
acting as a molecular robot/enzyme. Furthermore, NMR
analysis revealed that almost complete imine formation be-
tween PMP and aromatic acceptor aldehydes had taken
place within five minutes at room temperature. The process
was mediated by proline, since
Determination of absolute configuration: Synthesis and
comparison with literature data established the absolute
stereochemistry
of
the
proline-catalyzed
reaction
(Scheme 5). Hence, 3-amino alcohol 3 was synthesized ac-
no significant amount of imine
was formed in DMF in the ab-
sence of the catalyst. Impor-
tantly, only trace amounts of
the cross-aldol products were
observed at À208C for the (S)-
proline-catalyzed direct catalyt-
Scheme 5. Determination of the absolute configuration of amino alcohol adduct 3 and its deprotection.
a) i) (S)-proline (10 mol%), DMF, À208C, 20 h, ii) NaBH4, MeOH/Et2O, 0 8C, 10 minutes. b) LiAlH4, THF,
08C, 3 h. c) CAN, CH3CN, 08C, 10 minutes.
ic cross-Mannich reactions with
aromatic acceptor aldehydes
(imines). Hence, proline exhib-
ited a much higher kcross-Mannich
cording to procedures developed by Viccario et al. and com-
pared to the proline-derived 3.[31] The amino alcohol adducts
were compared by NMR spectroscopy and HPLC analyses;
than kcross-aldol for these substrates under the set reaction con-
ditions. In contrast, significant amounts of cross-aldol prod-
ucts were formed when aliphatic aldehydes were treated
1992
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1987 1997

Asymmetric Cross-Mannich Reaction
1987 1997
has been explained by density functional theory calculations
of the respective transition states.[24,26,35]
Conclusion
The first one-pot, three-component, direct catalytic asym-
metric cross-Mannich reactions have been described. The
highly chemoselective, proline-catalyzed reactions between
two different unmodified aldehydes and one aromatic amine
are new routes to b-amino aldehydes with dr values of
>19:1 and up to >99% ees. The asymmetric cross-Mannich
reactions are highly syn-selective and in several cases the
two new carbon centers are formed with almost absolute
stereocontrol. The aldehyde moiety of the Mannich products
is readily exploitable in other reactions in one-pot fashion.
Furthermore, the b-amino aldehyde adducts are readily con-
vertible into 1,3-amino alcohol derivatives and 2-aminobu-
tane-1,4-diols with up to >99% ees in one-pot operations.
In addition, the first one-pot, three-component, direct cata-
lytic asymmetric syntheses of unnatural amino acid deriva-
tives have been developed. The novel cross-Mannich reac-
tions between unmodified aldehydes, p-anisidine, and ethyl
glyoxylate can furnish either enantiomer of unnatural a-
amino acid derivatives in high yield and with up to
>99% ees. The one-pot, three-component, direct catalytic
asymmetric reactions were readily scaled up, operationally
simple, and did not require an inert atmosphere. In addition,
the reactions could be conducted in environmentally benign
and wet solvents. The reaction was also catalyzed with good
selectivity by other proline derivatives. The reaction does
not display nonlinear effects, and so only one proline mole-
cule was involved in the transition state. In addition, proline
activates aldimines preferentially to aldehydes at low reac-
tion temperatures. The mechanisms and transition-state
model have been discussed on the basis of the stereochemis-
try of the Mannich adducts. Taken as a whole, the reported
transformation should be an inexpensive and useful route
for the synthesis of optically active nitrogen-containing mol-
ecules.
Figure 1. Linear effect in the (S)-proline-catalyzed cross-Mannich reac-
tion of propionaldehyde with p-anisidine and 2-pyridylcarbaldehyde in
DMF (y=0.99x + 1.02, R2 =0.996).
with propionaldehyde under our reaction conditions, indicat-
ing that proline exhibits a higher kcross-aldol for aliphatic ac-
ceptor aldehydes than for the aromatic acceptor aldehydes.
The stereochemical outcome of the (S)-proline-catalyzed
direct asymmetric Mannich reactions was explained in terms
of a si-facial attack on the imine with a trans configuration
by the si-face of the enamine (Figure 2, I). The six-mem-
Figure 2. Postulated transition states of the cross-Mannich (I) and cross-
aldol (II) reactions.
Experimental Section
General methods: Chemicals and solvents were either purchased puriss
p.A. from commercial suppliers or purified by standard techniques. For
thin-layer chromatography (TLC), silica-gel plates (Merck 60 F254) were
used and compounds were visualized by irradiation with UV light and/or
bered metal-free Zimmermann Traxler transition state is
stabilized by hydrogen bonding between the nitrogen atom
of the imine and the carboxylic group of proline. A switch
of the facial selectivity is disfavored due to steric repulsion
between the PMP group of the imine and the pyrrolidine
moiety of the enamine. Interestingly, this is the opposite of
what is observed in similar proline-catalyzed direct asym-
metric cross-aldol reactions in which a re-facial attack
occurs on the carbonyl from the si-face of the enamine
by treatment with
a solution of phosphomolybdic acid (25 g),
Ce(SO4)2¥H2O (10 g), conc. H2SO4 (60 mL), and H2O (940 mL) followed
by heating or by treatment with a solution of p-anisaldehyde (23 mL),
conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL), fol-
lowed by heating. Flash chromatography was performed on silica gel
(Merck 60, particle size 0.040 0.063 mm), 1H NMR and 13C MR spectra
were recorded on a Varian AS 400 instrument. Chemical shifts are given
in d relative to tetramethylsilane (TMS), the coupling constants J are
given in Hz. The spectra were recorded in CDCl3 or CD3OD as solvents
1
i]
(Figure 2, II).[16g Hence, (S)-proline affords b-amino alde-
at room temperature, TMS served as internal standard (d=0 ppm) for H
NMR, and CDCl3 was used as internal standard (d=77.0 ppm) for 13C
NMR. HPLC was carried out with a Hitachi organizer consisting of a D-
2500 Chromato-Integrator, an L-4000 UV-Detector, an L-6200A Intelli-
gent Pump, and a Waters 2690 Millennium with photodiode array detec-
hydes with syn configurations and b-hydroxy aldehydes with
anti sterochemistry. This switch of selectivity has also been
observed in Mannich reactions with unmodified ketones and
1993
Chem. Eur. J. 2004, 10, 1987 1997
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. CÛrdova
FULL PAPER
tor. Optical rotations were recorded on a Perkin Elmer 241 Polarimeter
(l=589 nm, 1 dm cell). High-resolution mass spectra were recorded on
an IonSpec FTMS mass spectrometer with a DHB matrix.
flow rate 1.0 mLminÀ1, l=254 nm): major isomer: tR =14.02 min; minor
isomer: tR =12.18.
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(4-cyanophenyl)propan-1-
ol (4): [a]D =À63.7 (c=0.1 in CHCl3); 1H NMR (CD3OD): d=0.85 (d,
J=7.0 Hz, 3H), 1.98 (m, 1H), 3.32 (dd, 1H), 3.45 (dd, 1H), 3.67 (s, 3H;
OMe), 4.47 (d, J=4.0 Hz, 1H), 6.38 (d, J=8.8 Hz, 2H), 6.68 (d, J=
8.8 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.54 ppm (d, J=8.0 Hz, 2H); 13C
NMR: d=12.3, 43.4, 56.1, 60.7, 65.5; 115.6, 115.7, 129.5, 133.1, 143.2,
151.3, 153.1 ppm; HR-MS: m/z calcd for C18H20N2O2: 297.1583; found:
297.1597 ([M+H]+ ; HPLC (Daicel Chiralpak AD, hexanes/iPrOH=99:1,
flow rate 1.0 mLminÀ1, l=254 nm): major isomer: tR =28.86 min; minor
isomer: tR =19.31 min.
Typical one-pot, three-component experimental procedure for the cata-
lytic asymmetric cross-Mannich reaction of aldehydes and p-anisidine
Method A: A mixture of the acceptor aldehyde (1.0 mmol) and p-anisi-
dine (1.1 mmol) in DMF (8.0 mL) was stirred for 15 min in the presence
of a catalytic amount of proline (20 mol%) at 48C. Next, a cold solution
of the corresponding donor aldehyde (3.0 mmol) in DMF (2.0 mL) was
slowly added by syringe pump over 4 5 h at 48C. After an additional 15
16 h reaction time, the temperature was decreased to 08C, followed by
dilution with anhydrous Et2O or MeOH (2.0 mL) and careful addition of
excess NaBH4 (0.4 g). The reaction was quenched after 10 minutes by
pouring the reaction mixture into a vigorously stirred biphasic solution of
Et2O and 1m aqueous HCl. The organic layer was separated and the
aqueous phase was extracted thoroughly with ethyl acetate. The com-
bined organic phases were dried (MgSO4), concentrated, and purified by
flash column chromatography (silica gel, mixtures of hexanes/ethyl ace-
tate) to afford the desired b-amino alcohols. The enantiomeric excesses
of the products were determined by HPLC analysis on chiral stationary
phases.
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(4-chlorophenyl)propan-
1-ol (5): [a]D =À29.6 (c=1.9 in CD3OD); 1H NMR (CD3OD): d=0.93
(d, J=7.0 Hz, 3H), 2.02 (m, 1H), 3.38 (m, 1H), 3.53 (m, 1H), 3.67 (s,
3H; OMe), 4.45 (d, J=4.8 Hz, 1H), 6.47 (d, J=8.4 Hz, 2H), 6.62 (d, J=
9.2 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.31 ppm (d, J=8.4 Hz, 2H); 13C
NMR: d=12.7, 43.6, 56.3, 60.7, 65.8, 115.7, 115.9, 129.3, 130.2, 133.3,
143.6, 153.1 ppm; HR-MS: m/z calcd for C17H20ClNO2: 305.1182; found:
305.1173 [M]+
; HPLC (Daicel Chiralpak AD, hexanes/iPrOH=99:1,
flow rate 1.0 mLminÀ1, l=254 nm): major isomer: tR =15.15 min; minor
isomer: tR =10.84 min.
Method B: A mixture of the acceptor aldehyde (1.0 mmol) and p-anisi-
dine (1.1 mmol) in DMF (1.0 mL) was stirred for 20 30 minutes in the
presence of a catalytic amount of proline (10 mol%) at room tempera-
ture. Next, the temperature of the reaction mixture was decreased to
À208C, and the donor aldehyde (3.0 mmol) was added to the reaction
mixture in one portion. After 20 h vigorous stirring at À208C, the solu-
tion was diluted with Et2O (2.0 mL) and MeOH (2.0 mL), followed by
the addition of excess NaBH4 (0.4 g), and the reaction temperature was
increased to 08C. The reaction was quenched after 10 minutes by pouring
the reaction mixture into a vigorously stirred biphasic solution of Et2O
and 1m aqueous HCl. The organic layer was separated, and the aqueous
phase was extracted thoroughly with ethyl acetate.[36] The combined or-
ganic phases were dried (MgSO4), concentrated, and purified by flash
column chromatography (silica gel, mixtures of hexanes/ethyl acetate) to
afford the desired b-amino alcohols. The enantiomeric excesses of the
products were determined by HPLC analysis on chiral stationary phases.
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(4-bromophenyl)propan-
1-ol (6): [a]D =À38.9 (c=0.6 in CHCl3); 1H NMR (CD3OD): d=0.94 (d,
J=7.3 Hz, 3H), 2.03 (m, 1H), 3.37 (dd, 1H), 3.55 (dd, 1H), 3.62 (s, 3H;
OMe), 4.43 (d, J=5.1 Hz, 1H), 6.47 (d, J=9.2 Hz, 2H), 6.61 (d, J=
8.8 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.40 ppm (d, J=8.4 Hz, 2H); 13C
NMR: d=12.7, 43.6, 56.3, 60.8, 65.8, 115.7, 115.9, 130.6, 132.3, 143.7,
144.1, 153.2 ppm; HR-MS: m/z calcd for C17H20BrNO2: 350.0753; found:
350.0753 [M+H]+ ; HPLC (Daicel Chiralpak AD, hexanes/iPrOH=99:1,
flow rate 1.0 mLminÀ1, l=254 nm): major isomer: tR =14.00 min; minor
isomer: tR =10.14 min.
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(3-bromophenyl)propan-
1
1-ol (7): [a]D =À28.6 (c=1.7 in MeOH); H NMR (CD3OD): d=0.85 (d,
J=7.0 Hz, 3H), 1.98 (m, 1H), 3.32 (dd, 1H), 3.45 (dd, 1H), 3.54 (s, 3H;
OMe), 4.35 (d, J=5.9 Hz, 1H), 6.39 (d, J=9.2 Hz, 2H), 6.52 (d, J=
9.2 Hz, 2H), 7.15 (dd, J=8.1 Hz, J=7.5 Hz, 2H), 7.21 (m, 2H), 7.42 ppm
(brs, 1H); 13C NMR: d=12.5, 43.5, 56.2, 60.6, 65.7, 115.6, 115.7, 127.3,
130.6, 130.8, 131.6, 147.0, 147.6, 153.0 ppm; HR-MS: m/z calcd for
C17H20BrNO2: 350.0753; found: 350.0753 [M+H]+ ; HPLC (Daicel Chiral-
Typical one-pot, two-component catalytic asymmetric self-Mannich reac-
tion: A mixture of the aldehyde (3.0 mmol) and p-anisidine (1.1 mmol)
in DMF (1.0 mL) was stirred for 20 h in the presence of a catalytic
amount of proline (10 mol%) at À208C. Next, the solution was diluted
with Et2O or MeOH (2.0 mL), followed by addition of excess NaBH4
(0.4 g), and the reaction temperature was increased to 08C. The reaction
was quenched after 10 minutes by pouring the reaction mixture into a
vigorously stirred biphasic solution of Et2O and 1m aqueous HCl. The or-
ganic layer was separated, and the aqueous phase was extracted thor-
oughly with ethyl acetate. The combined organic phases were dried
(MgSO4), concentrated, and purified by flash column chromatography
(silica gel, mixtures of hexanes/ethyl acetate) to afford the desired b-
amino alcohols. The enantiomeric excesses of the products were deter-
mined by HPLC analysis on chiral stationary phases.
pak OD-H, hexanes/iPrOH=99.5:0.5, flow rate 1.0 mLminÀ1
,
l=
254 nm): major isomer: tR =24.90 min; minor isomer: tR =21.71 min.
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(4-methoxyphenyl)pro-
pan-1-ol (8): [a]D =À6.6 (c=2.7 in MeOH); 1H NMR (CDCl3): d=0.92
(d, J=7.0 Hz, 3H), 2.15 (m, 1H), 3.64 (d, J=6.4 Hz, 2H), 3.69 (s, 3H;
OMe), 3.78 (s, 3H; OMe), 4.45 (d, J=4.4 Hz, 1H), 6.54 (d, J=8.8 Hz,
2H), 6.69 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.24 ppm (d, J=
8.8 Hz, 2H); 13C NMR: d=12.6, 41.6, 55.4, 56.0, 66.4, 114.0, 114.2, 114.9,
115.7, 128.4, 128.5, 133.6, 158.8 ppm; HR-MS: m/z calcd for C18H23NO3:
302.3968; found: 302.3969 [M+H]+ ; HPLC (Daicel Chiralpak OD-H,
hexanes/iPrOH=99.5:0.5, flow rate 1.0 mLminÀ1
isomer: tR =14.90 min; minor isomer: tR =11.71 min.
, l=254 nm): major
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(4-nitrophenyl)propan-1-
ol (2): [a]D =À65.2 (c=0.2 in MeOH); 1H NMR (CDCl3): d=0.91 (d,
J=7.0 Hz, 3H), 2.21 (m, 1H), 3.64 (m, 2H), 3.67 (s, 3H; OMe), 4.65 (d,
J=4.0 Hz, 1H), 6.42 (d, J=8.8 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 7.51 (d,
J=8.8 Hz, 2H), 8.17 ppm (d, J=8.8 Hz, 2H); 13C NMR: d=11.9, 41.6,
56.0, 60.8, 66.0, 115.0, 115.1, 123.9, 128.3, 141.0, 147.3, 150.6, 152.6 ppm;
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(2-pyridinyl)propan-1-ol
(10): [a]D =À28.9 (c=1.2 in MeOH); 1H NMR (CD3OD): d=0.85 (d,
J=7.0 Hz, 3H), 2.11 (m, 1H), 3.32 (dd, 1H), 3.45 (dd, 1H), 3.54 (s, 3H;
OMe), 4.53 (d, J=5.9 Hz, 1H), 6.51 (d, J=9.2 Hz, 2H), 6.63 (d, J=
9.2 Hz, 2H), 7.21 (m, 1H), 7.42 (m, 1H), 7.70 (m, 1H), 8.48 ppm (m,
1H); 13C NMR: d=12.7, 42.7, 56.3, 62.8, 66.0, 115.7, 116.0, 123.5, 123.8,
138.5, 143.6, 149.7, 153.4, 164.3 ppm; HR-MS: m/z calcd for
HR-MS: m/z calcd for C17H20N2O4: 317.1496;found: 317.1496 [M+H]+
;
C16H20N2O2Na: 295.3321; found: 295.3307 [M+Na]+
Chiralpak AD, hexanes/iPrOH=90:10, flow rate 0.5 mLminÀ1
254 nm): major isomer: tR =42.57 min; minor isomer: tR =36.85 min.
;
HPLC (Daicel
l=
HPLC (Daicel Chiralpak AD, hexanes/iPrOH=99:1, flow rate
1.0 mLminÀ1, l=254 nm): major isomer: tR =36.10 min; minor isomer:
tR =21.49 min.
,
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-phenylpropan-1-ol
(3):
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-(3-pyridinyl)propan-1-ol
(11): [a]D =À33.7 (c=1.2 in MeOH); 1H NMR (CD3OD): d=0.97 (d,
J=7.0 Hz, 3H), 2.09 (m, 1H), 3.39 (dd, 1H), 3.56 (dd, 1H), 3.58 (s, 3H;
OMe), 4.57 (d, J=5.9 Hz, 1H), 6.51 (d, J=9.2 Hz, 2H), 6.61 (d, J=
9.2 Hz, 2H), 7.26 (m, 1H), 7.78 (m, 1H), 8.31 (m, 1H), 8.51 ppm (m,
1H); 13C NMR: d=12.8, 43.5, 56.4, 59.1, 65.6, 115.9, 116.2, 125.1, 137.5,
137.7 143.3, 148.4, 149.8, 153.4 ppm; HR-MS: m/z calcd for
[a]D =À6.2 (c=1 in MeOH); 1H NMR (CD3OD): d=0.95 (d, J=7.0 Hz,
3H), 2.05 (m, 1H), 3.38 (dd, 1H), 3.56 (dd, 1H), 3.62 (s, 3H; OMe), 4.43
(d, J=4.0 Hz, 1H), 6.38 (d, J=8.8 Hz, 2H), 6.50 (d, J=8.8 Hz, 2H), 7.12
(m, 1H), 7.24 (m, 2H), 7.31 ppm (d, J=7.7 Hz, 2H); 13C NMR: d=12.8,
43.7, 56.3, 61.4, 66.0; 115.7, 116.0, 127.7, 128.6, 129.3, 143.9, 144.6, 151.9,
153.1, 157.7 ppm; HR-MS: m/z calcd for C17H21NO2: 272.1645;found:
272.1647 [M+H]+ ; HPLC (Daicel Chiralpak AD, hexanes/iPrOH=99:1,
C16H20N2O2Na: 295.3321; found: 295.3320 [M+Na]+
; HPLC (Daicel
1994
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1987 1997

Asymmetric Cross-Mannich Reaction
1987 1997
Chiralpak AD, hexanes/iPrOH=90:10, flow rate 0.5 mLminÀ1
254 nm): major isomer: tR =43.56 min; minor isomer: tR =37.88 min.
,
l=
[M+H]+ ; HPLC (Daicel Chiralpak AD, hexanes/iPrOH=98:2, flow rate
0.5 mLminÀ1, l=254 nm): major isomer: tR =154.7 min; minor isomer:
tR =94.3 min.
(2S,3S)-2-Methyl-3-(4-methoxyphenylamino)-3-pentan-1-ol (14): [a]D =+
8.5 (c=1 in MeOH); 1H NMR (CD3OD): d=0.92 (t, J=6.9 Hz, 3H),
0.95 (d, J=7.7 Hz, 3H), 1.52 (m, 2H), 1.87 (m, 1H), 3.50 (dd, 1H), 3.66
(dd, 1H), 3.68 (s, 3H; OMe), 6.70 (d, J=8.8 Hz, 2H), 6.81 ppm (d, J=
8.8 Hz, 2H); 13C NMR: d=11.9, 12.3, 26.7, 40.0, 56.4, 58.8, 66.3, 115.9,
116.0, 145.3, 153.0 ppm; HR-MS: m/z calcd for C13H21NO2: 224.1645;
General procedure for the direct catalytic synthesis of b-formyl amino
acid derivatives
Ethyl (2S,3S)-3-formyl-2-(4-methoxyphenylamino)butanoate (24): Ethyl
glyoxylate (2.5 mmol) and p-anisidine (2.8 mmol) were stirred in the
presence of
a catalytic amount of (S)-proline (10 mol%) in DMF
found: 224.1645 [M+H]+
; HPLC (Daicel Chiralpak AD, hexanes/
(2.5 mL) for 30 minutes at room temperature. Next, the temperature was
decreased to 48C, followed by addition of the propanal (5 mmol). After
stirring for 20 24 h, the reaction was quenched by addition of aqueous
NH4Cl solution, followed by extraction with EtOAc. The combined or-
ganic layers were dried (MgSO4), filtered, and concentrated. Purification
of the residue by flash column chromatography (pentanes/ethyl acetate=
5:1) afforded the corresponding b-formyl amino acid derivative 24
(0.38 g, 65%): ꢀ1.5:1 mixture of diastereoisomers, * denotes the anti dia-
iPrOH=99:1, flow rate 1.0 mLminÀ1, l=254 nm): major isomer: tR =
8.09 min; minor isomer: tR =12.18 min.
(2S,3S)-2-Methyl-3-(phenylamino)-3-(2-pyridinyl)propan-1-ol (15): [a]D =
À34.1 (c=1.6 in MeOH); 1H NMR (CD3OD): d=0.96 (d, J=7.0 Hz,
3H), 2.21 (m, 1H), 3.41 (dd, 1H), 3.59 (dd, 1H), 4.60 (d, J=5.9 Hz, 1H),
6.54 (m, 2H), 7.18 (d, 2H), 7.42 (m, 1H), 7.63 (m, 1H), 8.47 ppm (m,
1H); 13C NMR: d=12.8, 42.7, 61.9, 65.9, 114.6, 118.2, 123.6, 130.0, 138.6,
143.6, 149.4, 149.7, 164.3 ppm; HR-MS: m/z calcd for C15H18N2O:
243.1497; found: 243.1495 [M+H]+ ; HPLC (Daicel Chiralpak AD, hex-
anes/iPrOH=90:10, flow rate 0.5 mLminÀ1, l=254 nm): major isomer:
tR =28.87 min; minor isomer: tR =25.34 min;.
1
stereomer. H NMR (CDCl3): d=1.10 1.40 (m, 12H), 2.87 (m, 2H), 3.73
(brs, 3H, 3H*; OMe), 3.91 (d, 1H, 1H*), 4.16 (m, 2H, 2H*), 4.38 (d,
J=6.6 Hz, 1H*), 4.49 (d, J=3.4 Hz, 1H), 6.67 (m, 2H, 2H*), 6.77 (m,
2H, 2H*), 9.72 ppm (brs, 1H, 1H*); 13C NMR: d=9.0, 9.8, 14.1, 14.1,
48.1, 48.4, 55.5, 55.6, 58.4, 58.6, 61.5, 61.6, 114.7, 114.8, 115.6, 116.3, 140.1,
140.4, 153.1, 153.4, 171.7, 172.3, 201.7, 201.8 ppm; HR-MS: m/z calcd for
C14H19NO4Na: 265.1309; found: 265.1316 [M+Na]+ ; HPLC (Daicel Chir-
(2S,3S)-2-Methyl-3-(4-bromophenylamino)-3-(2-pyridinyl)propan-1-ol
(16): [a]D =À29.1 (c=2.1 in MeOH); 1H NMR (CD3OD): d=0.97 (d,
J=7.0 Hz, 3H), 2.19 (m, 1H), 3.40 (m, 1H), 3.53 (m, 1H), 4.61 (d, J=
5.9 Hz, 1H), 6.49 (m, 2H), 7.10 (m, 2H), 7.21 (m, 1H), 7.42 (m, 1H),
7.67 (m, 1H), 8.48 ppm (m, 1H); 13C NMR: d=12.7, 42.7, 61.9, 65.7,
114.6, 118.1, 123.5, 123.7, 130.0, 138.5, 149.7, 149.7 d, 164.3 ppm; HR-MS:
m/z calcd for C15H17BrN2O: 321.0602; found: 321.060 [M+H]+ ; HPLC
alpak AS, hexanes/iPrOH=99:1, flow rate 1.0 mLminÀ1
, l=254 nm):
major isomer: tR =18.82 min, major isomer*: tR =20.12 min, minor
isomer: tR =23.11 min, minor isomer: tR =27.01 min.
(2S,3S)-3-Hydroxymethyl-2-(4-methoxyphenylamino)-4-methylpentan-1-
ol (30): Ethyl glyoxylate (2.5 mmol) and p-anisidine (2.8 mmol) were stir-
red in the presence of a catalytic amount of (S)-proline (10 mol%) in
DMF (2.5 mL) for 30 minutes at room temperature. Next, the tempera-
ture was decreased to 48C, followed by addition of isovaleraldehyde
(5 mmol). After stirring for 20 h, the reaction mixture was diluted with
THF (30 mL), and LiAlH4 (50 mL, 1m solution in THF) was added. The
reaction mixture was allowed to reach room temperature and stirred for
1 h. The mixture was cooled and quenched by careful addition of aque-
ous NH4Cl solution, followed by 3m HCl, and extraction with Et2O. The
combined organic layers were dried (MgSO4), filtered, and concentrated.
Purification of the residue by flash column chromatography (hexanes/
ethyl acetate 1:5) afforded diol 30 as a pale yellow oil (0.7 g, 85%): 1H
NMR (CDCl3): d=0.93 (d, J=7.9 Hz, 3H), 1.02 (d, J=7.9 Hz, 3H), 1.55
(m, 1H), 1.92 (m, 1H), 3.55 (m, 1H), 3.63 (m, 1H), 3.71 3.3.83 (m, 6H),
6.58 (d, J=8.8 Hz, 2H), 6.76 ppm (d, J=8.8 Hz, 2H); 13C NMR: 20.1,
21.3, 25.9, 47.5, 55.2, 55.7, 59.1, 60.8, 115.0, 115.2, 141.1, 152.1 ppm; HR-
(Daicel Chiralpak AD, hexanes/iPrOH=90:10, flow rate 0.5 mLminÀ1
l=254 nm): major isomer: tR =29.59 min; minor isomer: tR =39.57 min.
,
(2S,3S)-2-Methyl-3-(4-iodophenylamino)-3-(2-pyridinyl)propan-1-ol (18):
[a]D =À31.2 (c=0.6 in MeOH); 1H NMR (CD3OD): d=0.99 (d, J=
7.0 Hz, 3H), 2.21 (m, 1H), 3.41 3.59 (m, 2H), 4.58 (d, J=5.1 Hz, 1H),
6.40 (m, 2H), 7.26 (m, 3H), 7.45 (m, 1H), 7.75 (m, 1H), 8.52 ppm (m,
1H); 13C NMR: d=9.9, 39.8, 58.8, 62.8, 114.0, 120.7, 120.8, 135.7, 135.8,
146.4, 146.8, 147.0 ppm; HR-MS: m/z calcd for C15H17IN2O: 350.0753;
found: 350.0751 [M+H]+
; HPLC (Daicel Chiralpak AD, hexanes/
iPrOH=90:10, flow rate 0.5 mLminÀ1, l=254 nm): major isomer: tR =
38.22 min; minor isomer: tR =29.18 min.
(1S,2S)-1-(4-Methoxyphenylamino)-1-(2-pyridyl)-2-hydroxymethylbutane
(21): ꢀ2:1 mixture of diastereoisomers, * denotes the anti diastereomer;
1H NMR (CD3OD): d=0.88 (t, J=7.0 Hz, 1.5H*), 0.90 (t, J=7.0 Hz,
3H), 1.39 1.61 (m, 2H, 1H*), 1.85 1.98 (m, 1H, 1H*), 3.51 (dd, 1H*),
3.53 (dd, 2H), 3.61 (s, 3H, 1.5H*; OMe), 4.34 (d, J=7.0 Hz, 1H*), 4.59
(d, J=4.0 Hz, 1H), 6.48 (dd, 2H, 1H*), 6.61 (dd, 2H, 1H*), 7.19 (m, 1H,
0.5H*), 7.42 (m, 1H, 0.5H*), 7.67 (m, 1H, 0.5H*), 8.47 ppm (m, 1H,
0.5H*); 13C NMR: d=12.2, 12.4, 20.4, 22.4, 49.8, 56.3, 62.4, 63.0, 115.5,
115.8, 115.9, 116.0, 116.1, 123.5, 123.6, 124.0, 124.1, 138.4, 138.5, 143.6,
149.7, 153.5, 164.2, 164.5 ppm; HR-MS: m/z calcd for C17H22N2O2:
272.1645; found: 2721645 [M+H]+ ; HPLC (Daicel Chiralpak AD, hex-
anes/iPrOH=98:2, flow rate 0.5 mLminÀ1, l=254 nm): major isomer:
tR =59.35 min; minor isomer: tR =46.47 min; major isomer*: tR =
61.17 min; minor isomer*: tR =59.35 min.
MS: m/z calcd for C14H32NO3: 254.1751; found: 254.1752 [M+H]+
;
HPLC (Daicel Chiralpak AS, hexane/iPrOH=99:1, flow rate
1.0 mLminÀ1, l=254 nm): tR (major)=23.12 min; tR (minor)=26.64 min.
Ethyl (2S,3S)-3-[(R)-cyanohydroxymethyl)-2-(4-methoxyphenylamino]-4-
methylpentanoate (31): Ethyl glyoxylate (2.5 mmol) and p-anisidine
(2.8 mmol) were stirred in the presence of a catalytic amount of (S)-pro-
line (10 mol%) in DMF (2.5 mL) for 30 minutes at room temperature.
Next, the temperature was decreased to 48C, followed by addition of iso-
valeraldehyde (5 mmol). After stirring for 20 h, the reaction mixture was
diluted with THF (7.5 mL) and the temperature was decreased to
À758C. Next, Et2AlCN (1m solution in toluene, 10 mmol) was added,
and the solution was stirred for 2.5 h. The mixture was quenched by addi-
tion of 1m NaHCO3 and extracted with EtOAc. The combined organic
layers were dried (MgSO4), filtered, and concentrated. Purification of the
residue by flash column chromatography (pentanes/ethyl acetate=4:1)
afforded cyanohydrin 31 as a clear oil (0.52 g, 66%): [a]D =À13.3 (c=2.5
in CH2Cl2); 1H NMR (CDCl3): d=1.10 (d, J=5.5 Hz, 3H), 1.16 (d, J=
5.5 Hz, 3H), 1.28 (t, 3H), 2.18 (brs, 2H), 3.74 (s, 3H; OMe), 4.22 (q,
2H), 4.39 (d, J=6.3 Hz, 1H), 4.87 (brs, 1H), 6.70 (d, J=8.8 Hz, 2H),
6.79 ppm (d, J=8.8 Hz, 2H); 13C NMR: 13.9, 20.7, 21.4, 26.3, 50.7, 55.6,
57.8, 61.2, 61.6, 114.8, 116.4, 119.2, 139.9, 153.4, 173.4 ppm; HR-MS: m/z
calcd for C14H32NO3: 321.1809; found: 321.1811 [M+H]+ ; HPLC (Daicel
(1S,2S)-1-(4-Methoxyphenylamino)-1-(4-nitrophenyl)-2-hydroxymethyl-
heptane (22): [a]D =À24.7 (c=0.2 in MeOH); 1H NMR (CD3OD): d=
0.83 (t, J=7.0 Hz, 3H), 1.22 1.55 (m, 8H), 2.08 (m, 1H), 3.54 (d, J=
3.3 Hz, 1H), 3.68 (s, 3H; OMe), 3.73 (d, J=3.3 Hz, 1H), 4.71 (d, J=
3.3 Hz, 1H), 6.48 (d, J=8.8 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 7.51 (d, J=
8.8 Hz, 2H), 8.17 ppm (d, J=8.8 Hz, 2H); 13C NMR: d=14.4, 22.9, 27.8,
29.7, 46.4, 56.1, 63.9, 96.6, 115.3, 124.1, 128.7, 147.5 ppm; HR-MS: m/z
calcd for C21H28N2O4: 373.2122; found: 373.2120 [M+H]+ ; HPLC (Daicel
Chiralpak AD, hexanes/iPrOH=90:10, flow rate 1.0 mLminÀ1
254 nm): major isomer: tR =17.79 min; minor isomer: tR =7.43 min.
, l=
(1S,2S)-1-(4-Methoxyphenylamino)-1-(2-pyridyl)-2-hydroxymethylhep-
tane (23): [a]D =À33.9 (c=0.3 in MeOH); 1H NMR (CD3OD): d=0.82
(t, J=7.0 Hz, 3H), 1.22 1.55 (m, 8H), 2.08 (m, 1H), 3.54 (d, J=3.3 Hz,
1H), 3.59 (d, J=3.3 Hz, 1H), 3.59 (s, 3H; OMe), 4.64 (d, J=3.3 Hz, 1H),
6.51 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H) 7.16 (m, 1H), 7.41 (m,
1H), 7.65 (m, 1H), 8.46 ppm (m, 1H); 13C NMR: d=14.6, 23.7, 27.3,
28.5, 33.2, 48.8, 56.3, 62.5, 63.5, 123.5, 124.1, 138.4, 143.6, 149.7, 153.4,
164.2 ppm; HR-MS: m/z calcd for C20H28N2O4: 373.2122; found: 373.2120
Chiralcel OD-H, hexane/iPrOH 98:2, flow rate 1.0 mLminÀ1
254 nm): tR (major) =8.32 min; tR (minor) =12.59 min.
, l=
Synthesis of (2S,3S)-2-methyl-3-(4-methoxyphenylamino)-3-phenylpro-
pan-1-ol and (2R,3S)-2-methyl-3-(4-methoxyphenylamino)-3-phenylpro-
pan-1-ol: A diastereomeric mixture (syn/anti 0.9:1) of methyl (3S)-2-
1995
Chem. Eur. J. 2004, 10, 1987 1997
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. CÛrdova
FULL PAPER
methyl-3-(4-methoxyphenylamino)-3-phenylpropanoate (0.1 mmol) in
THF (5 mL), synthesized according to ref. [31], was reduced by addition
of LiAlH4 (1 mmol) at 08C. After 4 h at this temperature the reaction
mixture was allowed to reach room temperature and quenched by addi-
tion of Na2SO4¥10H2O and filtered through Celite. Next, the filtrate was
diluted with ether and washed with brine. The organic layer was separat-
ed, and the aqueous phase was extracted thoroughly with ethyl acetate.
The combined organic phases were dried (MgSO4), concentrated, and pu-
rified by flash column chromatography (silica gel, mixtures of hexanes/
ethyl acetate) to afford b-amino alcohol 3 as an inseparable mixture of
diastereomers (dr=0.9:1, syn/anti) in 72% yield. 1H NMR (CD3OD): (*
denotes the anti diastereomer) d=0.79 (d, J=7.0 Hz, 3H*), 0.95 (d, J=
7.0 Hz, 3H), 2.05 (m, 1H, 1H*), 3.38 (dd, 1H), 3.56 (dd, 1H), 3.61 (d,
J=5.9 Hz, 2H*), 3.62 (s, 3H, 3H*; OMe), 4.27 (d, J=7.0 Hz, 1H*), 4.43
(d, J=4.0 Hz, 1H), 6.50 (dd, 2H, 2H*), 6.61 (dd, 2H, 2H*), 7.12 (m, 1H,
1H*), 7.24 (m, 2H, 2H*), 7.31 ppm (m, 2H, 2H*); 13C NMR: d=12.8,
14.6, 42.8, 43.6, 56.2, 56.3, 61.4, 66.0, 66.3, 115.6, 115.7, 116.0, 116.5, 127.7,
127.9, 128.6, 129.2, 129.3, 143.9, 144.4, 153.2, 153.4 ppm; HR-MS: m/z
calcd for C17H21NO2: 272.1645; found: 272.1647 [M+H]+ ; HPLC (Daicel
8215; i) C. Palomo, M. Oiarbide, A. Landa, Gonzales-M. C. Rego,
J. M. Garcia, A. Gonzales, J. M. Odriozola, Martin-M. Pastor, A.
Linden, J. Am. Chem. Soc. 2002, 124, 8637, and references therein.
[6]a) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
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[7]a) E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120,
2474; b) A. Fujii, E. Hagiwara, M. Sodeoka, J. Am. Chem. Soc.
1999, 121, 545; c) Y. Hamashima, K. Yagi, H. Tamas, M. Sodeoka, J.
Am. Chem. Soc. 2002, 124, 14530; d) Y. Hamashima, M. Hotta, M.
Sodeoka, J. Am. Chem. Soc. 2002, 124, 11240.
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1998, 120, 4548; b) D. Ferraris, B. Young, C. Cox, W. J. Drury III, T.
Dudding, T. Lectka, J. Org. Chem. 1998, 63, 6090; c) D. Ferraris, B.
Young, C. Cox, T. Dudding, W. J. Drury III, L. Ryzhkov, T. Taggi, T.
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[10]S. Matsunaga, N. Kumagai, N. Harada, S. Harada, M. Shibasaki, J.
Am. Chem. Soc. 2003, 125, 4712.
[11]B. M. Trost, L. M. Terrell, J. Am. Chem. Soc. 2003, 125, 338.
[12]a) K. Juhl, N. Gathergood, K. A. J˘rgensen, Angew. Chem. 2001,
113, 3083; Angew. Chem. Int. Ed. 2001, 40, 2995; b) M. Marigo, A.
Kjaersgaard, K. Juhl, N. Gathergood, K. A. J˘rgensen, Chem. Eur. J.
2003, 9, 2395; c) L. L. Bernardi, A. S. Gothelf, R. G. Hazell, K. A.
J˘rgensen, J. Org. Chem. 2003, 68, 2583.
[13]a) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840; Angew.
Chem. Int. Ed. 2001, 40, 3726; b) B. List, Tetrahedron 2002, 58, 5573;
c) J. Grˆger, J. Wilken, Angew. Chem. 2001, 113, 545; Angew. Chem.
Int. Ed. 2001, 40, 529; d) E. R. Jarvo, S. J. Miller, Tetrahedron 2002,
58, 2481; e) R. O. Duthaler, Angew. Chem. 2003, 115, 1005; Angew.
Chem. Int. Ed. 2003, 42, 975.
Chiralpak AD, hexanes/iPrOH=99:1, flow rate 1.0 mLminÀ1
,
l=
254 nm): major isomer: tR =14.02 min; minor isomer: tR =12.18 min;
major isomer*: tR =15.55 min; minor isomer*: tR =13.55 min.
(2S,3S)-3-Amino-2-methyl-3-phenylpropan-1-ol (3a): CAN (386 mg) in
H2O (1.74 mL) was added to a solution of b-amino alcohol 3 (87.5 mg) in
acetonitrile (5.7 mL) at À158C. After 15 min the reaction mixture was di-
rectly purified by flash column chromatography (silica gel, mixtures of
hexanes/ethyl acetate) to afford 3a in 65% yield (35 mg). 1H NMR
(CD3OD): d=1.10 (d, J=4.4 Hz, 3H), 2.35 (m, 1H), 3.44 (d, J=5.14 Hz,
1H), 3.48 (d, J=6.6 Hz, 1H), 4.35 (d, J=6.6 Hz, 1H), 7.54 ppm (m, 5H);
13C NMR: d=12.0, 40.9, 59.1, 66.2, 126.9, 127.1, 128.2, 143.9 ppm. Com-
parison of the NMR data with those previously reported for 3-amino-2-
methyl-3-phenylpropan-1-ol revealed a syn relationship of the substitu-
ents.[32]
[14]a) Z. G. Hajos, D. R. Parrish, Asymmetric Synthesis of Optically
Active Polycyclic Organic Compounds. German Patent.
DE-
2102623, July 29, 1971; b) Z. G. Hajos, D. R. Parrish, J. Org. Chem.
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Acknowledgement
A.C. thanks the Swedish Natural Science Research Council for financial
support. The author is grateful to Jan-Erling B‰ckvall, Hans Adolfsson,
and their respective groups for sharing chemicals.
[15]For example, the total synthesis of taxol: S. J. Danishefsky, J. Am.
Chem. Soc. 1996, 118, 2843.
[16]Aldol reactions, see: a) B. List, R. A. Lerner, C. F. Barbas III, J.
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C. F. Barbas III, J. Org. Chem. 2002, 67, 301; e) B. List, P. Pojarliev,
C. Castello, Org. Lett. 2001, 3, 573; f) A. CÛrdova, W. Notz, C. F.
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N. Kumaragurubaran, K. A. J˘rgensen, Chem. Commun. 2002, 620;
h) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
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[17] a-Aminations, see: a) A. B˘gevig, K. Juhl, N. Kumaragurubaran, W.
Zhuang, K. A. J˘rgensen, Angew. Chem. 2002, 114, 1868; Angew.
Chem. Int. Ed. 2002, 41, 1790; b) B. List, J. Am. Chem. Soc. 2002,
124, 5656; c) N. Kumaragurubaran, K. Juhl, W. Zhuang, A. B˘gevig,
K. A. J˘rgensen, J. Am. Chem. Soc. 2002, 124, 6254; a-Oxidations,
see: d) G. Zhong, Angew. Chem. 2003, 115, 4379; Angew. Chem. Int.
Ed. 2003, 42, 4247; e) S. P. Brown, M. P. Brochu, C. J. Sinz, D. W. C.
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[2]The first example of the application of the Mannich reaction to nat-
ural product synthesis is attributed to Robinson in his synthesis of
tropinone: R. Robinson, J. Chem. Soc. 1917, 762.
[3]For excellent reviews see: a) E. F. Kleinmann, in Comprehensive Or-
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[4]S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069 and references
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1987 1997

Asymmetric Cross-Mannich Reaction
1987 1997
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Received: October 21, 2003 [F5646]
1997
Chem. Eur. J. 2004, 10, 1987 1997
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