Aminocatalytic enantioselective anti-mannich reaction of aldehydes with in situ generated N-cbz and N-boc imines

Article abstract of DOI:10.1002/anie.200803819

(Chemical Equation Presented) The title reaction catalyzed by the commercially available chiral secondary amine 1 proceeds with high stereocontrol and allows the in situ generation of N-carbamate-protected imines from stable a-amido sulfones 2. This organocatalytic approach provides easy and convenient access to valuable compounds 3 in high yield, with very good anti selectivity,and in high enantiomeric purity.

Full text of DOI:10.1002/anie.200803819

Communications
DOI: 10.1002/anie.200803819
Asymmetric Organocatalysis (1)
Aminocatalytic Enantioselective anti-Mannich Reaction of Aldehydes
with In Situ Generated N-Cbz and N-Boc Imines**
Chiara Gianelli, Letizia Sambri, Armando Carlone, Giuseppe Bartoli, and Paolo Melchiorre*
The catalytic asymmetric Mannich reaction constitutes one of
the most powerful routes for accessing chiral b-amino
carbonyl compounds, and much effort has been devoted
toward the development of new and effective methodolo-
gies.[1] In this context, the discovery that chiral secondary
amines, such as proline and its derivatives, are able to catalyze
the direct, highly enantioselective addition of unmodified
carbonyl compounds to N-PMP (p-methoxyphenyl) imines[2]
has represented an important achievement from an atom-
Scheme 1. In situ generation of N-carbamoyl imines. TMS=trimethyl-
silyl.
economy standpoint. Accordingly, an impressive scientific
competition toward the identification of more efficient
aminocatalytic tactics started, and the Mannich reaction has
represented a benchmark for measuring the progress of
asymmetric aminocatalysis.[3] Although proline-catalyzed
addition of aldehydes to N-PMP imines affords syn-b-amino
aldehydes with high diastereo- and enantiocontrol,[2] the
development of an effective anti-Mannich protocol has
represented a challenging synthetic problem that was solved
by the rational design of new chiral amine catalysts.[4]
Recently, an important breakthrough was advanced by List
and co-workers,[5] who identified suitable reaction conditions
that account for the use of preformed aromatic N-Boc imine
(Boc = tert-butyloxycarbonyl) in proline-catalyzed syn-Man-
nich reactions of aldehydes. This study introduced important
synthetic advances owing to the easy removal of the N-
protecting group, which allows access to unfunctionalized
chiral amines.
Herein, we describe our contribution to the progress of
the aminocatalytic Mannich reaction and report the first anti-
selective addition of aldehydes to N-Cbz- and N-Boc-
protected imines (Cbz = benzyloxycarbonyl) catalyzed by
the commercially available chiral secondary amine 1. Besides
the high stereocontrol achieved, the main feature of this
research lies in the identification of a suitable procedure that
allows the in situ generation of carbamate-protected imines
from stable a-amido sulfones 2 (Scheme 1). We felt that our
approach provides a simple and convenient protocol that
significantly expands the synthetic potential and the scope of
the asymmetric aminocatalytic Mannich reaction of alde-
hydes.
Because of their inherent high reactivity, the N-carbamoyl
imines are rather sensitive to moisture, and their employment
introduces practical complications. Recently, the benefit of
using stable a-amido sulfones 2 as an imine surrogate[6] has
been exploited in phase-transfer-catalyzed Mannich-type
reactions[7a,b] and, later, extended to chiral base catalysis,[7c]
with important procedural simplification. Inspired by these
studies, and convinced of the compatibility between a chiral
secondary amine such as 1 and an inorganic base, necessary
for the in situ generation of N-carbamoyl imines from 2, we
sought to develop a simple protocol for the aminocatalytic
anti-Mannich reaction of aldehydes. For the exploratory
studies, we selected the reaction between hydrocinnamalde-
hyde and the bench-stable a-amido sulfone 2a catalyzed by 1
(Table 1). The choice of the chiral amine 1 was triggered by its
known ability to impart high anti selectivity in the direct
addition of aldehydes to preformed N-PMP imines,[4b,f]
Table 1: Optimization studies.[a]
Entry Base (equiv)
Solvent t [h] Yield [%][b] d.r.[c]
ee [%][d]
[*] C. Gianelli, Dr. L. Sambri, Dr. A. Carlone, Prof. G. Bartoli,
Dr. P. Melchiorre
1
2
3
K3PO4 (1)
K2CO3 (1)
toluene 36
toluene 36
32
53
24
31
95
65
87
93:7
93:7
92
92
Dipartimento di Chimica Organica “A. Mangini”, Alma Mater
Studiorum, Università di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax: (+39)051-209-3654
K2CO3(aq) (1)[e] toluene 36
89:11 91
4
5
KF (3)
KF (3)
KF (3)
KF (5)
toluene 36
95:5
94:6
94:6
94:6
95
96
95
96
CHCl3
CHCl3
CHCl3
24
24
24
6[f]
7[f]
E-mail: p.melchiorre@unibo.it
[**] The MIUR National Project “Stereoselezione in Sintesi Organica”
and Bologna University are gratefully acknowledged for financial
support. Cbz=benzyloxycarbonyl; Boc=tert-butyloxycarbonyl.
[a] Reactions carried out on a 0.1 mmol scale using 2 equiv of aldehydes.
[b] Yield of isolated product. [c] Determined by 1H NMR spectroscopy of
the crude mixture. [d] Determined by chiral HPLC analysis. [e] 0.1m
solution of K2CO3. [f] Reaction carried out with 10 mol% of the catalyst 1.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803819.
8700
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Angewandte
Chemie
whereas 2a might be the precursor of N-Boc-protected a-
imino ethyl glyoxylate, a highly challenging substrate owing to
its synthetic importance and the intrinsic instability that has
greatly hampered its use in the Mannich reaction.[8]
our approach allows the direct synthesis of aspartate deriv-
atives, which are valuable chiral compounds that can not be
prepared by the recently reported proline-catalyzed asym-
metric addition of acetaldehyde to aromatic and aliphatic N-
Boc imines.[11]
The Mannich adducts 3 represent versatile intermediates
for accessing valuable chiral building blocks. Scheme 2 shows
a concise preparation of trans-b-lactam 6 based on a simple
Initial results highlighted the ability of a range of bases,
either as a solid or as an aqueous solution (Table 1, entries 1–
4), to generate in situ the N-Boc imino ester. Under these
conditions, catalyst 1 imparted very high stereocontrol even at
room temperature, although the anti adduct 3a was isolated
with only moderate yield.[9] Further optimization of the
standard reaction parameters revealed that the nature of the
inorganic base and the solvent were crucial to obtain high
reaction efficiency. By using 5 equivalents of KF in chloro-
form, the catalyst loading could be reduced to 10 mol% while
affording 3a with high diastereo- and enantiocontrol and in
high yield (Table 1, entry 7). These catalytic conditions were
selected for further exploration aimed at expanding the scope
of this transformation.
Scheme 2. Preparation of trans-b-lactam 6. Conditions: a) 1) NaClO2,
NaH2PO4, 2-methyl-2-butene, tBuOH/H2O; 2) TMSCHN2; b) 1) tri-
fluoroacetic acid; 2) Et3N, TMSCl; 3) tBuMgCl; c) 1) NaOH;
2) TMSCHN2; 3) Boc2O, 4-dimethylaminopyridine, Et3N.
As highlighted in Table 2, the method proved to be
successful for a wide range of aliphatic aldehyde substituents.
More importantly, the N-Cbz-protected a-amido sulfones 2b
oxidation–esterification step to afford the aspartic acid
derivative 4 and subsequent cyclization. The absolute config-
uration of N-Boc-protected 6 was determined to be 3R,4S by
comparison of the specific optical rotation with the value
reported in the literature (see the Supporting Information for
details).
Table 2: Scope of the anti-Mannich reaction.[a]
The utility of a methodology is measured by its efficiency
as well as its applicability. As a proof-of-concept for
demonstrating the scope of the presented asymmetric,
catalytic Mannich approach, the addition of propanal to
in situ generated N-Cbzand N-Boc phenyl imines is reported
in Scheme 3. The anti adducts 7 are obtained in good yield and
high stereoselectivity.
Entry
R
PG
3
[%] yield[b]
d.r.[c]
[%] ee[d]
1
2
Bn
Me
iPr
Et
Bn
nBu
iPr
H
Boc
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
a
b
c
d
e
f
87
92
65
95
95
96
85
39
94:6
91:9
98:2
93:7
91:9
92:8
92:8
–
96
94[e]
95
3[f]
4
96
92
98
5
6
7
8
g
h
95
15[g]
[a] Reactions carried out on a 0.2 mmol scale, using 2 equiv of aldehydes.
Bn=PhCH2. [b] Yield of isolated product. [c] Determined by 1H NMR
spectroscopy of the crude mixture. [d] Determined by chiral HPLC
analysis. [e] Determined by HPLC analysis of the corresponding oxime
prepared with O-benzylhydroxylamine. [f] Reaction on a 1.2 mmol scale.
[g] The absolute configuration of 3h was determined to be S by
comparison of the specific optical rotation with the value reported in the
literature; ee value determined after oxidation to N-Cbz aspartic acid; see
the Supporting Information for details.
Scheme 3.
In summary, we have developed the first aminocatalyzed
anti-selective Mannich reaction of aldehydes with N-Cbz- and
N-Boc-protected imines generated in situ from stable a-
amido sulfones 2. Besides the high level of efficiency and
stereocontrol achieved, this approach introduces important
synthetic advantages, by avoiding the requirement to preform
the N-carbamoyl imines. The potential extension of this
method to the extremely challenging aliphatic imines would
further improve the utility of the aminocatalytic Mannich
reaction. Studies toward this aim are ongoing.[12]
can also be employed, leading to the formation of the
expected b-formyl-functionalized amino acids 3d–g (Table 2,
entries 4–7) in good yield and high stereocontrol.[10] The
extension of the anti-Mannich strategy to different carba-
mates represents an important feature from a synthetic
standpoint, as it provide orthogonal sets of easily removable
N-protecting groups.
Received: August 4, 2008
Published online: October 7, 2008
Interestingly, under the reported reaction conditions,
acetaldehyde proved to be a suitable nucleophilic partner
(Table 2, entry 8), and its addition to the in situ generated N-
Cbzimino ester provides easy access to the Mannich adduct
3h. Although the stereocontrol achieved was unsatisfactory,
Keywords: aldehydes · asymmetric catalysis · imines ·
.
Mannich reaction · organocatalysis
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Communications
ketone and N-Boc imines (two examples), see: c) D. Enders, C.
Grondal, M. Vrettou, Synthesis 2006, 3597.
[6] For a comprehensive review on the usefulness of a-amido
sulfones, see: M. Petrini, Chem.Rev. 2005, 105, 3949.
[7] For meaningful examples, see: a) F. Fini, V. Sgarzani, D.
Pettersen, R. P. Herrera, L. Bernardi, A. Ricci, Angew.Chem.
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5797; b) M. M. B. Marques, Angew.Chem. 2006, 118, 356;
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[8] N-carbamate-protected a-imino esters are known to be unstable,
and their use in organic synthesis has been rather limited.
Generally, they must be used immediately after their prepara-
tion; see, for example: a) Y. Nakamura, R. Matsubara, H.
Kiyohara, S. Kobayashi, Org.Lett. 2003, 5, 2481. For an
asymmetric organocatalytic Mannich reaction of Boc-imino
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Bella, K. A. Jørgensen, Angew.Chem. 2005, 117, 2956; Angew.
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[9] The use of a different a,a-diaryl prolinols silyl ether, with a
phenyl group as the aromatic moiety, in the aminocatalytic
Mannich reaction afforded lower selectivity, albeit with slightly
improved reactivity (toluene, 1 equiv of K2CO3, 24 h, 65% yield,
84:16 d.r. and 85% ee; compare with entry 2 in Table 1).
[10] Aminocatalytic Mannich strategies are limited to N-Boc-pro-
tected imines; see Ref. [5]. Extension of our method to Fmoc-
protected aminosulfone (Fmoc = 9-fluorenylmethyloxycar-
bonyl) failed under the reported reaction conditions.
[11] a) J. W. Yang, C. Chandler, M. Stadler, D. Kampen, B. List,
Nature 2008, 452, 453. For a review, see: b) B. Alcaide, P.
Almendros, Angew.Chem. 2008, 120, 4710; Angew.Chem.Int.
Ed. 2008, 47, 4632.
[12] Under the reported conditions, in situ generated cyclohexyl
imine reacts very slowly, albeit with high stereocontrol (1 week,
12% conversion, 95:5 d.r., 98% ee). Studies are focusing on the
identification of a more active catalytic system.
[3] For reviews on asymmetric aminocatalysis, see: a) C. F. Barba-
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47, 42; b) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
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Utsumi, M. Imai, N. Garcia-Delgado, M. Mifsud, K.
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Barbas III, J.Am.Chem.Soc. 2008, 130, 875. For an explanation
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[5] a) J. W. Yang, M. Stadler, B. List, Angew.Chem. 2007, 119, 615;
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For the first proline-catalyzed asymmetric Mannich reaction of a
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