Controlling stereoselectivity in the aminocatalytic enantioselective mannich reaction of aldehydes with in situ generated N-carbamoyl imines

Article abstract of DOI:10.1002/chem.200903217

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines has been developed. Both α-imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N-tert-butoxycarbonyl (Boc) or N-carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configura-tion and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N-carbamate-protected imines are generated in situ from stable and easily handled aamido sulfones. 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/chem.200903217

FULL PAPER
DOI: 10.1002/chem.200903217
Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich
Reaction of Aldehydes with In Situ Generated N-Carbamoyl Imines
Patrizia Galzerano,[c] Dario Agostino,[c] Giorgio Bencivenni,[c] Letizia Sambri,[c]
Giuseppe Bartoli,[c] and Paolo Melchiorre*[a, b]
Abstract:
A
simple and convenient
selective access to the desired stereo-
isomer of the N-tert-butoxycarbonyl
(Boc) or N-carbobenzyloxy (Cbz)
Mannich adducts, with high control
over the syn or anti relative configura-
tion and almost perfect enantioselectiv-
ity. Besides the possibility to fully con-
trol the stereochemistry of the Man-
nich reaction, the main advantage of
this method lies in the operational sim-
plicity; the highly reactive N-carba-
mate-protected imines are generated in
situ from stable and easily handled a-
amido sulfones.
method for the direct, aminocatalytic,
and highly enantioselective Mannich
reactions of aldehydes with in situ gen-
erated N-carbamoyl imines has been
developed. Both a-imino esters and ar-
omatic imines serve as suitable electro-
philic components. Moreover, the judi-
cious selection of commercially avail-
able secondary amine catalysts allows
Keywords: asymmetric catalysis
·
imines · Mannich reaction · organo-
catalysis · sulfones
Introduction
tion modes of carbonyl compounds that have enabled previ-
ously unknown transformations. To the same extent, the
design of novel structural classes of organic catalysts has
also ignited the field and enabled the activation of more
challenging carbonyl substrates. Within this context, venera-
ble chemical transformations that lead to the preparation of
useful chiral building blocks have been generally chosen as
benchmarks for developing novel, more effective aminocata-
lysts. Among them, the catalytic asymmetric Mannich reac-
tion has been considered a point of reference for measuring
the progress of aminocatalysis.[3] The discovery that chiral
secondary amines, such as proline and its derivatives, are
able to catalyze the direct addition of unmodified carbonyl
compounds to N-PMP imines (PMP=p-methoxyphenyl)
with very high stereoselectivity[4] has greatly contributed to
the development of new atom-economy-based Mannich
strategies.[5] While proline-catalyzed addition of aldehydes
to N-PMP imines affords syn-b-amino aldehydes with high
diastereo- and enantiocontrol,[4,5] the development of an ef-
fective anti-Mannich protocol has represented a challenging
synthetic problem for a long time. Only by the rational
design of specific, novel, chiral amine catalysts, which often
required several synthetic steps for their preparation, was it
possible to partially address this synthetic challenge.[6] Re-
cently, an important advance was introduced by List and co-
workers,[7] who identified suitable reaction conditions that
involve the use of a preformed aromatic N-Boc imine
(Boc=tert-butoxycarbonyl) in proline-catalyzed syn-Man-
Asymmetric aminocatalysis is nowadays recognized as a fun-
damental and reliable synthetic strategy for the stereoselec-
tive construction of chiral molecules.[1] The rapid affirmation
of organocatalysis over the last decade has been warranted
by its efficiency, cost-effectiveness, low environmental
impact, and operational simplicity. All of these features
have generated a remarkable scientific competition, which
has guided asymmetric aminocatalysis towards excellent
levels of development and opened new synthetic opportuni-
ties that were considered inaccessible only a few years ago.[2]
The extraordinary pace of innovation and progress has been
mainly dictated by the discovery of generic catalytic-activa-
[a] Prof. Dr. P. Melchiorre
ICREA - Instituciꢀ Catalana de Recerca i Estudis AvanÅats
Pg. Lluꢁs Companys 23, 08010 Barcelona (Spain)
[b] Prof. Dr. P. Melchiorre
ICIQ - Institute of Chemical Research of Catalonia
Av. Paꢂsos Catalans 16, 43007 Tarragona (Spain)
Fax : (+34)977-920-823
E-mail: pmelchiorre@iciq.es
[c] P. Galzerano, D. Agostino, Dr. G. Bencivenni, Dr. L. Sambri,
Prof. G. Bartoli
Dipartimento di Chimica Organica “A. Mangini”
Universitꢃdi Bologna, Viale Risorgimento 4-40136 Bologna (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903217.
Chem. Eur. J. 2010, 16, 6069 – 6076
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6069

nich reactions of aldehydes. This study provided important
synthetic benefits due to the easy removal of the N-protect-
ing group to directly deliver unfunctionalized chiral amines.
In the frame of our studies on aminocatalysis,[8] we were
interested in expanding the synthetic potential and the
scope of the asymmetric aminocatalytic Mannich reaction.
Specifically, we focused on the development of highly ste-
reoselective enamine-catalyzed additions of unmodified al-
dehydes to N-carbamoyl imines to promote the formation of
versatile N-Boc- or N-Cbz-protected (Cbz=carbobenzyl-
Moreover, we recognized the development of a syn-Man-
nich version as a crucial target, because it would allow selec-
tive access to all four stereoisomers of the valuable b-amino
aldehydes by simply selecting the appropriate organocatalyst
for use in a very simple protocol. We found that the com-
mercially available proline-derived tetrazole catalyst C is
able to promote the enantioselective syn-Mannich addi-
tion[12] to aromatic N-carbamoyl imines generated in situ
from stable a-amido sulfones 1 (Scheme 1). We believe that
the described approach provides an easy and convenient
protocol, which significantly expands the synthetic potential
of the asymmetric aminocatalytic Mannich reaction of alde-
hydes.
ACHTUNGTRENNUNGoxy) adducts. To be broadly applicable and useful to the
synthetic community, such a methodology should also be
simple and reliable. The main drawback associated with the
use of N-carbamoyl imines is their inherent high reactivity,
which introduces practical complications. They are rather
sensitive to moisture and air, as a result their preparation
and storage can be quite disadvantageous, and the catalytic
reaction requires strictly controlled conditions. To greatly
simplify the procedure, we sought to introduce the use of
stable a-amido sulfones 1 as imine precursors for the design
of a more efficient asymmetric Mannich methodology. Re-
cently, the benefit of using stable a-amido sulfones 1 as
imine surrogates[9] has been exploited in phase-transfer-cata-
lyzed Mannich-type reactions[9b,c] and later extended to
chiral-base catalysis,[9d] with important procedural simplifica-
tion. Inspired by these studies and convinced of the compat-
ibility between a chiral secondary amine (able to activate
the aldehydic component by induction of enamine forma-
tion) and an inorganic base (necessary for the in situ genera-
tion of N-carbamoyl imines from 1), we developed a simple
protocol for the first anti-selective addition of aldehydes to
N-Cbz and N-Boc-protected a-imino esters, catalyzed by the
commercially available TMS-diaryl prolinol-derived cata-
lysts A and B (TMS=trimethylsilyl).[10,11] Herein, we de-
scribe our contribution to the progress of the aminocatalytic
Mannich transformation by reporting the application of our
approach to the hitherto difficult anti- and highly enantiose-
lective Mannich reactions of N-carbamoyl aromatic imines
(Scheme 1).
Results and Discussion
Aminocatalytic anti-selective Mannich reaction of in situ
generated N-carbamoyl a-imino ethyl glyoxylate:[10] The cat-
alytic asymmetric Mannich reaction constitutes one of the
most powerful synthetic routes for the construction of chiral
nitrogen-containing molecules. Therefore, much effort has
been devoted toward the development of new and effective
catalytic and asymmetric methodologies.[3] Within this con-
text, the proline-catalyzed, direct, highly enantioselective
addition of unmodified carbonyl compounds to N-PMP
imines[4,5] has represented a cornerstone reaction. Succes-
sively, the identification of more efficient aminocatalytic tac-
tics has been mainly focused on the ability to selectively
access syn- or anti-b-amino aldehydes with high levels of ab-
solute and relative stereocontrol, as well as the possibility to
use easily removable N-protecting groups. Accordingly,
some anti-selective asymmetric Mannich reactions with N-
PMP-protected imines, catalyzed by carefully engineered
catalysts, have recently been reported.[6,10,11] The power of
proline to catalyze the direct addition of aldehydes to pre-
formed N-Boc-protected imines, leading to syn-b-amino al-
dehydes, has been recently established.[7] Very recently, we
focused our attention upon the, at that time,[10,11] unprece-
dented anti-selective direct addition of aldehydes to N-Cbz-
and N-Boc-protected imines, a method that would allow
easy access to unfunctionalized chiral amines due to the
easy removal of the N-protecting group. However, because
of their inherent high reactivity, the preparation and use of
N-carbamoyl imines requires particular operational condi-
tions. To us, a useful synthetic method should be reproduci-
ble and easily executed. Toward this aim, we sought to de-
velop a simple protocol for the aminocatalytic anti-Mannich
reaction of aldehydes using stable a-amido sulfones 1 as
imine precursors. This approach would introduce important
synthetic advantages by avoiding the requirement to prepare
and isolate the unstable imines.
For the exploratory studies, we selected the reaction be-
tween hydrocinnamaldehyde (2a) and the bench-stable a-
amido sulfone 1a, catalyzed by the commercially available
TMS-diaryl prolinol-derived catalysts A and B (Table 1).[13]
The choice of the chiral amines was triggered by their
Scheme 1. Strategy for the aminocatalytic anti- and syn-Mannich reac-
tions of aldehydes with in situ generated N-carbamoyl imines.
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Chem. Eur. J. 2010, 16, 6069 – 6076

Aminocatalytic Enantioselective Mannich Reaction
Table 1. Optimization studies.[a]
FULL PAPER
Optimization studies highlighted the ability of a range of
bases, either solid or as an aqueous solution (Table 1, en-
tries 1–5), to generate the N-Boc imino ester in situ. Nota-
bly, catalyst A imparted very high stereocontrol, even at
room temperature, albeit the anti-adduct 3a was isolated
with moderate yield. The use of a,a-diphenyl prolinol silyl
ether B afforded slightly lower selectivity, although with im-
proved reactivity (Table 1, entry 3). This evidence prompted
us to select A as the catalyst of choice and further optimiza-
tion of the standard reaction parameters was carried out.
The nature and the amount of inorganic base and solvent[15]
was crucial to achieve high reaction efficiency. By using
5 equiv of KF in chloroform, the catalyst loading could be
reduced to 10 mol% and afforded 3a with high diastereo-
and enantiocontrol, in high yield (Table 1, entry 8). These
catalytic conditions were selected for further explorations
aimed at expanding the scope of this transformation.
Entry Catalyst Base
([equiv])
Solvent
t
Yield d.r.[c] ee
[h] [%][b] [%][d]
ACHTUNGTRENNUNG
1
2
3
4
5
6
A
A
B
A
A
A
A
A
K3PO4 (1)
K2CO3 (1)
K2CO3 (1)
toluene 36 32
toluene 36 53
toluene 24 65
13:1 92
13:1 92
5.3:1 85
8:1 91
19:1 95
16:1 96
16:1 95
16:1 96
K2CO3 (aq)[e] (1) toluene 36 24
KF (3)
KF (3)
KF (3)
KF (5)
toluene 36 31
CHCl3 24 95
CHCl3 24 65
CHCl3 24 87
7[f]
8[f]
[a] Reactions carried out on a 0.1 mmol scale using 2 equiv of 2a. [b] Iso-
lated yield after chromatography. [c] Diastereomeric ratio (d.r.), deter-
mined by 1H NMR analysis of the crude reaction mixture. [d] Enantio-
meric excess (ee) determined by HPLC analysis on chiral stationary
phases. [e] 0.1m solution of K2CO3. [f] Reaction carried out with
10 mol% of catalyst.
As shown in Table 2, different aliphatic aldehydes were
suitable substrates for the Mannich reaction. Products of
type 3 were isolated in high yields and with very high optical
known ability to impart high anti-selectivity in the direct ad-
dition of aldehydes to preformed N-PMP imines[6b] by ex-
ploitation of a “steric-control approach”.[13] As shown in
Scheme 2, the efficient shielding of the bulky chiral frag-
ment of the catalyst determines the selective engagement of
the imine Si face with the Re face of the enamine intermedi-
ate (Re when X is of highest priority), an unlike topicity
that forges an anti relative configuration in the b-aminoalde-
hyde product.
Table 2. Anti-Mannich reaction with in situ generated aromatic N-carba-
moyl a-imino ethyl glyoxylate.[a]
Entry
R
PG
3
Yield [%][b]
d.r.[c]
16:1
ee [%][d]
1
Bn
Bn
Me
iPr
Et
Boc
Boc
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
a
a
b
c
d
e
f
87
82
92
65
95
95
96
85
87
96
À96[e]
94[f]
95
2
3
13:1
10:1
>19:1
13:1
4[g]
5
96
6
7
8
9
Bn
nBu
iPr
iPr
10:1
11.5:1
13:1
92
98
g
g
95
13:1
À95[e]
[a] Reactions carried out on a 0.2 mmol scale using 2 equiv of aldehyde.
[b] Isolated yield after chromatography. [c] Determined by 1H NMR of
the crude mixture. [d] Determined by HPLC analysis on chiral stationary
phases. [e] Reaction carried out using the D-enantiomer of the catalyst
A, leading to the opposite antipode of anti products 3. [f] ee determined
by HPLC analysis of the corresponding oxime prepared with O-benzylhy-
droxylamine. [g] Reaction on a 1.2 mmol scale.
Scheme 2. Origin of the stereoselectivity in the anti-Mannich reaction,
catalyzed by TMS-diaryl prolinol-derived catalysts A and B; X is the
group of highest priority.
purity and anti diastereoselectivity. The catalyst A also
proved active with the more encumbered reagent isovaleral-
dehyde and furnished 3c in good yield, without affecting the
efficiency of the system (Table 2, entry 4). By using the
same conditions, the method was extended to the N-Cbz-
protected a-amido sulfone 1b, to afford the expected anti-b-
amino aldehydes 3d–g in good yields and with high stereo-
control. The extension of the anti-Mannich strategy to dif-
ferent carbamates represents an important feature from a
synthetic standpoint, providing a choice of easily removable
N-protecting groups.[16] As expected, it is possible to access
both of the enantiomers of the anti products 3 simply by se-
The a-amido sulfone 1a was selected as the precursor of
N-Boc-protected a-imino ethyl glyoxylate, a highly challeng-
ing substrate due to its synthetic importance and the intrin-
sic instability that has greatly hampered its use in the Man-
nich reaction. Despite the fact that N-carbamate-protected
a-imino esters would directly lead to synthetically useful
amino acid derivatives, they are known to be unstable, and
their use in organic synthesis has been rather limited be-
cause they must be used immediately after preparation.[14]
The in situ preparation method seems a suitable route to
overcome such a limitation.
Chem. Eur. J. 2010, 16, 6069 – 6076
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6071

P. Melchiorre et al.
lecting the appropriate catalyst enantiomer, and still main-
tain a very high level of selectivity (Table 2, entries 2 and 9).
The Mannich adducts 3 represent versatile intermediates
for accessing valuable chiral building blocks. In Scheme 3, a
concise preparation of trans-b-lactam 6 is reported, based on
ever, a general and highly efficient version for obtaining
anti-b-amino-b-aryl aldehydes still represents a difficult
target. Few and limited examples have been reported that
address the catalytic asymmetric anti-Mannich reactions
with N-Boc-protected aromatic imines. Very recently, during
our investigations, Maruoka and co-workers reported an
amino sulfonamide catalyzed anti-Mannich reaction of alde-
hydes and preformed aromatic N-Boc imines, a procedure
that afforded a wide range of adducts with high levels of ste-
reocontrol.[11]
Convinced of the synthetic utility of our approach, which
avoids the need to prepare and isolate unstable imines, we
turned our attention to the addition of aldehydes to N-car-
bamoyl aromatic imines generated in situ from stable a-
amido sulfones. Specifically, we investigated the reaction be-
tween propanal and aromatic sulfones, by using the same
catalytic conditions developed for the anti-Mannich reaction
of in situ generated N-Carbamoyl a-imino ethyl glyoxylate.
As reported in Scheme 4, catalyst A promotes the addition
Scheme 3. Assignment of the absolute configuration of anti-3c: Condi-
tions: a) i) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O;
ii) TMSCHN2; b) i) trifluoroacetic acid (TFA); ii) Et3N, TMSCl;
iii) tBuMgCl; c) i) NaOH; ii) TMSCHN2; iii) Boc2O, 4-dimethylaminopyri-
dine (DMAP), Et3N.
a simple oxidation–esterification step to afford the aspartic
acid derivative 4 and subsequent cyclization. Thus, treat-
ment of anti-3c with NaClO2, followed by the addition of
TMSCHN2 led to the formation of the corresponding
methyl ester 4 (83% yield over two steps). Subsequent Boc
deprotection and cyclization, based on a known proce-
dure,[17] gave b-lactam 5. Finally, a saponification-methyla-
tion-protection sequence afforded the N-Boc-protected
lactam 6. HPLC analysis on a chiral stationary phase con-
firmed that the whole synthetic sequence did not affect the
enantiopurity of compound 6. The absolute configuration
was determined to be (2S,3R) by comparison of the specific
optical rotation with the value reported in the literature,[18]
the trans configuration was confirmed by the observed
Scheme 4. Anti-Mannich addition of propanal to in situ generated N-Cbz
and N-Boc-protected phenyl imines, catalyzed by TMS-diaryl prolinol-de-
rived catalyst A.
1H NMR coupling constant (J
ACTHNUTRGNE(NUG H2,H3)=3.2 Hz).
Therefore, catalyst A promotes the asymmetric formation
of (2S,3R)-amino acid derivatives 3. The stereochemical out-
come of the Mannich reaction can be rationalized on the
basis of the proposed transition state depicted in Scheme 2.
The efficient coverage of the Si face of the chiral enamine
intermediate leaves the Re face available for the imine ap-
proach. The steric hindrance of the catalyst also determines
the enantiofacial selectivity of the electrophile and enforces
an unlike topicity for the Mannich reaction.
of propanal to in situ generated N-Cbz- and N-Boc-phenyl
imines with high levels of efficiency; the anti-adducts 7 were
obtained in good yield and with high stereoselectivity. How-
ever, the lower reactivity of aromatic imines relative to
imino glyoxylate derivatives requires longer and impractical
reaction times and thus, lowers the synthetic utility of the
method.
We considered these results quite encouraging for the de-
velopment of the catalytic system because they clearly dem-
onstrate that the N-carbamoyl aromatic imines can also be
formed in situ in the presence of KF, an inorganic base that
seems not to interfere with the catalytic efficiency of chiral
secondary amines. For this reason, we wondered whether
the less-encumbered catalyst B, which bears a simple phenyl
ring on the crucial bulky chiral fragment of the pyrrolidine
ring, may be useful to speed up the Mannich reaction of aro-
matic imines, but still maintain high levels of anti diastereo-
selectivity and good enantiocontrol. It is known that catalyst
A generally enforces a higher geometry control and better
facial discrimination relative to B, albeit at the expense of
reactivity. To our delight, however, we found that the use of
10 mol% of the less-encumbered catalyst B promoted the
addition of propanal to in situ generated N-Boc phenyl
imine in excellent yield and with useful levels of enantiose-
lectivity and anti diastereoselectivity (Table 3, entry 1).
Aminocatalytic anti-selective Mannich reaction of in situ
generated N-carbamoyl aromatic imines: The proline-cata-
lyzed asymmetric Mannich reaction is arguably one of the
most useful ways to synthesize chiral b-amino carbonyl com-
pounds. The recent discovery that this simple amino acid
can also enforce incredible levels of enantioselectivity and
syn-diastereoselectivity in the addition of aldehydes to N-
Boc-protected aromatic imines has broadly expanded the
applicability of this asymmetric system.[7] The facile and effi-
cient removal of the N-protecting group to yield the unfunc-
tionalized amine avoids drastic oxidative conditions involv-
ing harmful reagents, generally required for the removal of
the commonly used PMP group from nitrogen and thus, rep-
resents a crucial achievement to render the aminocatalytic
Mannich reaction more attractive as a synthetic tool. How-
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Chem. Eur. J. 2010, 16, 6069 – 6076

Aminocatalytic Enantioselective Mannich Reaction
FULL PAPER
Table 3. Scope of the anti-Mannich reaction with in situ generated N-
in the steric and electronic demand of the aromatic ring sub-
stituent can be accommodated without loss of stereochemi-
cal control. Both electron-releasing and -withdrawing groups
were tolerated and led to the formation of variously substi-
tuted aromatic N-Boc-protected anti-b-amino aldehydes 7g–
j (Table 3, entries 7–10). Heteroaromatic substituents also
proved to be suitable substrates for the Mannich reaction,
products 7k and 7l were afforded with good stereocontrol
(Table 3, entries 11 and 12). The corresponding in situ gener-
ated N-Cbz-protected aromatic imines were also tested. The
high reactivity and stereoselectivity observed further high-
light the generality of our approach; Mannich products with
orthogonal N-protecting groups can be easily accessed
(Table 3, entries 13 and 14).
carbACHTUNGTRENNUNG
amoyl aromatic imines.[a]
Entry
R
Ar
PG
7
Yield [%][b] d.r.[c]
ee [%][d]
5.2:1 94
5:1 96
1
2
Me Ph
Bu Ph
Bn Ph
iPr Ph
Boc
Boc
Boc
Boc
Boc
Boc
Boc
a
c
d
e
f
95
90
70
94
64
31
74
95
73
27
73
60
74
82
3
5.2:1 76
9.2:1 98
4[e]
5[f]
H
H
Ph
Ph
–
–
64[g]
77[g]
6[f,h]
7[e]
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
14[e]
f
6:1 84[g]
7:1 91
The stereochemical outcome of the anti-Mannich reaction
of aromatic imines is in agreement with that observed in the
anti-selective reaction of in situ generated N-carbamoyl a-
imino ethyl glyoxylate, further support for the plausible
transition state reported in Scheme 2.
iPr 4-MeC6H4
iPr 4-MeOC6H4 Boc
g
h
i
j
k
l
iPr 4-ClC6H4
iPr 4-NO2C6H4
iPr 2-thienyl
iPr 2-pyridyl
iPr 4-MeC6H4
Boc
Boc
Boc
Boc
Cbz
10:1 94
>19:1 99
8:1 96
9:1 87[g]
8:1 93[g]
9:1 99
m
n
iPr 4-MeOC6H4 Cbz
Aminocatalytic syn-selective Mannich reaction of in situ
generated N-carbamoyl aromatic imines: Achieving the full
matrix of all possible stereoisomeric products in the prepa-
ration of molecules with multiple stereocenters is a challeng-
ing synthetic target. This is particularly important for com-
pounds intended for biomedical applications because incom-
plete collections of stereoisomers impair efforts to extract
powerful stereochemistry-based structure–activity relation-
ships (SARs) from primary screening data.[21] Due to the
usefulness of the Mannich adducts as versatile building
blocks to access medicinally relevant chemical structures,
the development of highly efficient catalytic methodologies
that allow full control of the stereochemistry of the Mannich
reaction is exceedingly important. Prompted by these con-
siderations, we sought to apply our simple protocol to the
asymmetric, aminocatalytic syn-selective Mannich reaction.
The main issue lies in the identification of a suitable amine
catalyst that may coexist with the reaction conditions neces-
sary to generate the reactive imines in situ, but still impart
high syn-diastereo- and enantioselectivity to the Mannich
process.
We focused on the use of the commercially available pro-
line-derived tetrazole catalyst C. This catalyst had been orig-
inally designed and synthesized with the intention of over-
coming some of the drawbacks associated with the use of
proline, such as the solubility in conventional organic sol-
vents, yet preserving the dual-activation ability of the cata-
lyst.[12] Due to the similarity in pKa between the proline car-
boxylic acid and the tetrazole moiety, catalyst C can effec-
tively mimic the bifunctional activation mode of proline cat-
alysis.[22] Ley and co-workers have demonstrated the ability
of the tetrazole catalyst C to impart high syn diastereoselec-
tivity in the Mannich reaction between ketones and pre-
formed N-PMP-protected a-imino ethyl glyoxylate.[12] On
this basis, we decided to investigate the potential of C to
catalyze the syn-selective addition of aldehydes to in situ
generated imines. Using the same reaction protocol devel-
[a] Reactions carried out at room temperature on a 0.2 mmol scale using
2 equiv of aldehyde and 10 mol% of catalyst B. [b] Isolated yield after
chromatography. [c] Determined by 1H NMR of the crude mixture.
[d] Determined by HPLC analysis on chiral stationary phases. [e] Re-
action carried out with 20 mol% of catalyst B over 65 h. [f] Reaction car-
ried out using 5 equiv of acetaldehyde and 20 mol% of catalyst; the abso-
lute configuration of 7 f was determined to be (S) by comparison of the
specific optical rotation with the value reported in the literature, see
ref. [11a]. [g] Determined by HPLC analysis after reduction of the isolat-
ed aldehydic product. [h] Reaction carried out in the presence of
20 mol% of catalyst A.
More importantly, the reaction reaches completion after
24 h, hence the aim of identifying a simple, yet practical,
anti-Mannich protocol has been addressed.
As portrayed in Table 3, the catalytic system allows a
wide scope in terms of the nucleophilic component. Alde-
hydes with a long alkyl chain, a benzylic moiety, and a
more-encumbered chain all worked well in the anti-Mannich
protocol and gave products 7c–e in high yields, with good to
very high stereocontrol (Table 3, entries 2–4). Interestingly,
under the reported reaction conditions, acetaldehyde (the
simplest among the aldehydic donors, only recently intro-
duced in the aminocatalytic scenario)[19] proved to be a suit-
able nucleophilic partner. Reaction under the anti-Mannich
conditions delivered highly important synthetic intermediate
7 f[19a] in good yield, although with moderate enantioselectiv-
ity (Table 3, entry 5). The use of the catalyst A enforced
higher enantioselectivity in this transformation (77% ee,
Table 3, entry 6), but with poor chemical yield.
We performed a series of experiments to determine the
scope of the imine component in this aminocatalytic anti-
Mannich protocol.[20] Given the higher level of stereoinduc-
tion achieved when using isovaleraldehyde (R=iPr, Table 3,
entry 4), we further investigated its employment as a Man-
nich donor with several in situ generated aromatic imines in
the presence of catalyst B (20 mol%). Significant variation
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6073

P. Melchiorre et al.
oped for the anti-version, we found that the tetrazole cata-
lyst preserves its efficiency in the presence of KF and cata-
lyzes the highly stereoselective Mannich reaction to lead di-
rectly to highly enantioenriched syn-b-aminoaldehydes
(Table 4).
in situ formed N-carbamoyl imines and furnished excellent
results in terms of stereocontrol. The method proved to be
successful for a wide range of aliphatic aldehyde substituents
and led to b-amino aldehydes 8a–d in high yields, with high
diastereocontrol, and almost perfect enantioselectivity. In-
terestingly, the syn-Mannich products 8 can be easily isolat-
ed in good yields by simple trituration of the crude mixture
with cool hexane, thus avoiding time-consuming and costly
column chromatography. To prove that the remarkably high
stereoselectivity achieved did not arise from enantioenrich-
ment during the purification process and is only ascribable
to the catalyst efficiency, the enantiomeric purity of product
8b (Table 4, entry 2) has been measured after isolation by
column chromatography on silica gel (99% ee).
Table 4. Scope of the syn-Mannich reaction with in situ generated N-
carbACHTUNGTRENNUNG
amoyl imines.[a]
Notably, the employment of acetaldehyde in the presence
of C gave rise to the highly important synthetic intermediate
7 f with interesting enantioselectivity (84% ee, Table 4,
entry 5). Notably, both the TMS-diaryl prolinol and tetra-
zole catalysts catalyzed the Mannich reaction of acetalde-
hyde enforcing the same stereoinduction; the related b-
amino aldehyde 7 f was formed with the S absolute configu-
ration.[11,19a,b] This observation is in line with the proposed
transition states for the Mannich reactions shown in
Schemes 2 and 5, in which the electrophile facial selectivity
is common to both transformations. In fact, the opposite syn
or anti relative stereochemistry observed when using linear
aldehydes that lead to a,b-branched b-amino aldehydes
arises from an opposite enamine facial selectivity imparted
by the two catalyst types.
We examined the generality of the reaction by using iso-
valeraldehyde (R=iPr) as a nucleophilic donor and various
aromatic N-Boc- and N-Cbz-sulfones as imine precursors.[20]
Catalyst C afforded products 8e–l, which contain a range of
different aromatic substituents, with high levels of diastereo-
control and with almost total enantiopurity (Table 4, en-
tries 6–13).
Entry
R
Ar
PG
8
Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
Me Ph
Bu Ph
Bn Ph
iPr Ph
Boc
Boc
Boc
Boc
Boc 7 f 43
Boc
a
b
c
77
70
89
80
16:1
10:1
10:1 >99
99
99
4[e]
5[e,f]
6[e]
7[e]
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
d
11.2:1 >99
H
Ph
iPr 4-MeC6H4
iPr 4-MeOC6H4 Boc
–
84[g]
e
f
g
h
i
j
k
l
76
85
73
16
86
50
70
70
11:1 >99[g]
7:1
3:1 >99
2.5:1
9:1
2.5:1
3.2:1
99
iPr 4-ClC6H4
iPr 4-NO2C6H4
iPr 2-thienyl
iPr 2-pyridyl
iPr 4-MeC6H4
Boc
Boc
Boc
Boc
Cbz
94
99
90[g]
98[g]
iPr 4-MeOC6H4 Cbz
5:1 >99
[a] Reactions carried out at room temperature on a 0.2 mmol scale using
2 equiv of aldehyde and 10 mol% of catalyst C. [b] Isolated yield after
chromatography. [c] Determined by 1H NMR of the crude mixture.
[d] Determined by HPLC analysis on chiral stationary phases. [e] Re-
action carried out with 20 mol% of catalyst C over 65 h. [f] Reaction car-
ried out with 5 equiv of acetaldehyde for 36 h; the absolute configuration
of 7 f was determined to be (S) by comparison of the specific optical rota-
tion with the value reported in the literature, see ref. [11a]. [g] Deter-
mined by HPLC analysis after reduction of the isolated aldehydic prod-
uct.
The absolute configuration of the syn-Mannich product
8a was determined to be (1S,2S) by comparison of the spe-
cific optical rotation with the value reported in the literatur-
e.[7b] This supports a bifunctional mode of catalysis with C,
as depicted in Scheme 5, which is able to activate both the
reaction partners and leads to a well-organized transition
state, which mimics the accepted mechanism of the proline-
catalyzed Mannich reaction.[23]
The syn-stereochemical outcome of the reaction can be
rationalized on the basis of a transition state that resembles
the classical catalysis model of proline,[23] in which a specific
hydrogen-bonding interaction determines the stereoselectiv-
ity of the process by directing the electrophile approach
from the upper face of the enamine (hydrogen-bonding-di-
rected catalysis, Scheme 5).[24]
As shown in Table 4, tetrazole catalyst C proved to be
highly effective in the syn-Mannich addition of aldehydes to
Conclusion
We have developed a highly efficient system for the asym-
metric aminocatalytic Mannich reaction of unmodified alde-
hydes with in situ generated N-carbamoyl imines. The main
feature of this method lies in the operational simplicity: the
highly reactive N-carbamate-protected imines are generated
in situ from stable, easily handled a-amido sulfones. The ju-
dicious selection of commercially available chiral amine cat-
alysts A–C allows full control of the stereochemistry of the
Mannich process; either the syn- or anti-b-amino aldehydes
Scheme 5. Origin of the syn-stereoselectivity in the Mannich reaction,
catalyzed by C; X is the group of highest priority.
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Aminocatalytic Enantioselective Mannich Reaction
FULL PAPER
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are accessible with very high stereocontrol. From a synthetic
standpoint, the presented method is a rare example of a
highly anti-selective Mannich reaction with N-carbamoyl ar-
omatic imines. We believe that our approach provides a
simple and convenient protocol that may be useful to the
synthetic community.
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Experimental Section
General procedure for the anti-Mannich reaction of aldehydes with in
situ generated N-Cbz and N-Boc imines: The reactions were carried out
with no precautions to exclude air or moisture and by using the appropri-
ate TMS-diaryl prolinol-derived catalysts A or B for a-imino esters and
aromatic imines, respectively. Aldehyde (0.4 mmol, 2 equiv) was added to
a solution of catalyst (0.02 mmol, 0.1 equiv) in CHCl3 (1.0 mL) at room
temperature. After stirring for 5 min, a-amido sulfone
2 (0.2 mmol,
1 equiv) and KF (58.1 mg, 1.0 mmol, 5 equiv) were added successively.
Stirring was continued for 24 h, then the crude reaction mixture was di-
luted with CH2Cl2 (2 mL) and flushed through a short plug of silica (1:1
CH2Cl2/Et2O). The solvent was removed in vacuo and the residue was
purified by flash column chromatography with mixtures of ethyl acetate/
hexane as the eluent. Since the Mannich products are prone to epimeri-
zation during silica gel chromatography, which could affect the diastereo-
meric ratio of the isolated compounds 3 and 7, flash chromatography was
performed quickly.
General procedure for the syn-Mannich reaction of aldehydes with in
situ generated N-carbamoyl aromatic imines: The reactions were carried
out by using 10–20 mol% of the proline-derived tetrazole catalyst C, by
following the same experimental procedure described above. The only
difference concerns the isolation of the syn-adducts 8, which were ob-
tained in good yields after simple trituration of the crude mixture with
cool hexane.
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aldehydes, see: a) O. Penon, A. Carlone, A. Mazzanti, M. Locatelli,
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in synthesis, see: a) M. Petrini, Chem. Rev. 2005, 105, 3949; for
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Full compound characterization, further experimental details, and NMR
spectroscopy and HPLC traces can be found in the Supporting Informa-
tion.
Acknowledgements
This work was supported by Bologna University, MIUR National Project
“Stereoselezione in Sintesi Organica” and the Institute of Chemical Re-
search of Catalonia (ICIQ) Foundation.
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Chem. Eur. J. 2010, 16, 6069 – 6076
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6075

P. Melchiorre et al.
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has been evaluated. However, application of both the syn- or anti-
protocols resulted in sluggish processes together with negligible
levels of diastereoselectivity.
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and their use in organic synthesis has been rather limited. Generally,
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[15] Different solvents tested in the anti-Mannich reaction under the
conditions reported in Table 1, entry 2 (20 mol% of catalyst A and
1 equiv of K2CO3 as the inorganic base) gave worse results in terms
of both reactivity and stereoselectivity: for example, THF: 15%
conversion, 3.2:1 d.r.; Et2O: 25% conversion, 7:1 d.r.; CH3CN: 52%
conversion, 3:1 d.r..
[16] Aminocatalytic Mannich strategies are limited to N-Boc-protected
imines, see references [7] and [11]. Extension of our method to
Fmoc-protected aminosulfone failed under the reported reaction
condition.
[23] S. Bahmanyar, K. N. Houk, Org. Lett. 2003, 5, 1249.
[24] Under our reaction conditions, the use of proline for catalyzing the
syn-Mannich reaction of in situ generated imines gave worse results
in terms of catalytic efficiency, due to the detection of a large
amount of homo-aldol-elimination products. Just before the submis-
sion of this manuscript, a similar strategy catalyzed by proline has
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Received: November 24, 2009
Published online: April 15, 2010
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Chem. Eur. J. 2010, 16, 6069 – 6076