Highly enantio- and diastereoselective organocatalytic cascade aza-Michael-Michael reactions: A direct method for the synthesis of trisubstituted chiral pyrrolidines

Article abstract of DOI:10.1039/b812464g

An unprecedented highly enantio- and diastereoselective cascade aza-Michael-Michael reaction of α,β-unsaturated aldehydes with trans-γ-Ts protected amino α,β-unsaturated ester has been developed; the simple and practical process, efficiently catalyzed by chiral diphenylprolinol TMS ether, serves as a powerful access to highly functionalized trisubstituted chiral pyrrolidines. The Royal Society of Chemistry.

Full text of DOI:10.1039/b812464g

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COMMUNICATION
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Highly enantio- and diastereoselective organocatalytic cascade
aza-Michael–Michael reactions: a direct method for the synthesis
of trisubstituted chiral pyrrolidinesw
Hao Li, Liansuo Zu, Hexin Xie, Jian Wang and Wei Wang*
Received (in College Park, MD, USA) 21st July 2008, Accepted 26th August 2008
First published as an Advance Article on the web 30th September 2008
DOI: 10.1039/b812464g
An unprecedented highly enantio- and diastereoselective cascade
aza-Michael–Michael reaction of a,b-unsaturated aldehydes
with trans-c-Ts protected amino a,b-unsaturated ester has been
developed; the simple and practical process, efficiently catalyzed
by chiral diphenylprolinol TMS ether, serves as a powerful
access to highly functionalized trisubstituted chiral pyrrolidines.
exploitable orthogonal functionality for further synthetic
elaboration.
Central to the implementation of new proposed cascade
aza-Michael–Michael reaction was the recognition of several
reactivity and selectivity issues that must be addressed
(Scheme 1). First, although ‘‘N’’-centered nucleophile has
been employed for conjugate addition reactions, the more
active specific species was required as a result of its weak
nucleophilicity.11 Second, the amine in 2 should not function
as catalyst for the formation of iminium (TS A), and must
serve as nucleophile for conjugate addition to the catalyst
activated iminium (e.g. TS B). Third, the substrate amine ester
2 should be stable during the reaction without undergoing
intramolecular lactamization. Consequently, in considering
these parameters, we designed a trans 4-amino protected a,b-
unsaturated ester 2. The protected amino group (e.g. amides,
carbamates or sulfonamides) inhibited forming an iminium
with enal 1, while the enhanced acidity rendered it to be readily
deprotonated under basic conditions to produce a more
nucleophilic nitrogen anion for the first Michael addition
reaction. Moreover, the trans-geometry could significantly
Substituted chiral pyrrolidines are ubiquitous structural
components of numeous naturally occurring alkaloids and
biologically active synthetic substances.1 For example, trisub-
stituted pyrrolidines are represented in natural products
neuroexcitatory amino acids (ꢀ)-kainic acid and (þ)-a-allo-
kainic acid,2 promising a new anti-cancer agent ABT-627,3
and influenza drug A-192558.4 In addition, the ‘‘privileged’’
structures are an important synthetic target in diversity
oriented synthesis.5 Despite their broad applications, synthetic
methods for the efficient preparation of chiral pyrrolidines are
highly limited. The state of the art in chiral pyrrolidine
synthesis prevalently relies on chiral auxiliary controlled
asymmetric synthesis and transition-metal-catalyzed asym-
metric dipolar addition reactions.6 In contrast, organocata-
lyzed asymmetric processes are largely undeveloped. Only
three related examples of employing organocatalyzed enantio-
selective [3þ2] cycloaddition strategy were disclosed recently
by Vicario, Cordova and Gong, respectively.7 Furthermore,
the asymmetric catalytic synthesis of trisubstituted densely
functionalized chiral pyrrolidines remains elusive and the
discovery of catalytic asymmetric reactions that yield such a
framework is an important challenge.
In this communication, we wish to report a new organo-
catalytic cascade aza-Michael–Michael process that directly
converts simple achiral substrates to highly fuctionalized
trisubstituted chiral pyrrolidines with high levels of enantio-
and diastereoselectivity.8–10 The reactions are accomplished
with remarkable efficiency by a simple chiral diphenylprolinol
silyl ether as promoter. This one-pot transformation produces
a complex molecular architecture formed with high stereo-
control of three new stereogenic centers and an array of
Department of Chemistry and Chemical Biology, University of New
Mexico, Albuquerque, NM 87131, USA. E-mail: wwang@unm.edu;
Fax: (þ1) 505 277 2609; Tel: (þ1) 505 277 0756
w Electronic supplementary information (ESI) available: Experimental
and NMR data. CCDC reference number 693305. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b812464g
Scheme 1 Proposed mechanism for the asymmetric aza-Michael–
Michael process promoted by an organocatalyst.
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Table
1
Optimization of organocatalytic enantioselective aza-
Table 2 Catalyst I promoted cascade aza-Michael–Michael reactions
for one-pot synthesis of chiral pyrrolidinesa
Michael–Michael addition reactionsa
Entry
R
3
t/d Yield (%)b ee (%)c drd
Entry
Cat
P1
Yield (%)b
ee (%)c
drd
1
2
3
4
5
6
7
8
9
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
Ph
3a
3b
3c
3d
4
3
4
3
4
4
4
3
3
4
4
92
91
90
94
88
92
85
80
89
85
90
499e
499e
96
430 : 1
30 : 1
7.5 : 1
21 : 1
27 : 1
12 : 1
10 : 1
7 : 1
1
2
3
4
5
6
7
I
I
I
I
II
III
IV
Ac
Boc
Cbz
Ts
Ts
Ts
0
0
0
83
78
75
o5
NDe
NDe
NDe
93
NDe
NDe
NDe
499
96e
15 : 1
13 : 1
14 : 1
NDe
3-MeO-4-AcC6H3 3e
91
87
4-CF3C6H4
4-NO2C6H4
3-NO2C6H4
4-CNC6H4
4-FC6H4
3f
3g
3h
3i
3j
3k
499
499
499
499
499e
499
Ts
NDe
430 : 1
14 : 1
18 : 1
a
Unless otherwise specified, to a solution of trans-4-methoxycinna-
maldehyde 1a (32 mg, 0.2 mmol) in the presence of catalyst (20 mol%)
and NaOAc (8.2 mg, 0.1 mmol) in CH2Cl2 (0.5 mL) was added 2
10
11
a
4-BrC6H4
b
Reaction conditions: unless specified, see footnote
a
in
(0.1 mmol) and the resulting solution was stirred for 3 d at rt. Isolated
c
yield. Determined by chiral HPLC analysis (Chiralcel OD-H).
b
Table 1. Isolated yields. Determined by chiral HPLC analysis
c
d
(Chiralpak AS-H, AD, OJ-H, or Chiralcel OD-H). Determined by
d
e
Determined by 1H NMR. Not determined.
1H NMR. Converted to enone via reacting product aldehyde with
e
Ph3PQCHCOPh for chiral HPLC analysis.
reduce intramolecular lactamization. With respect to the
catalysts, we reasoned that sterically bulky catalysts such as
chiral diarylprolinol ethers I–IV would be of choice due to
their established capacity to effectively participate in iminium
activation with enals and create high stereo-control.12
aldehydes can be tolerated. The electronic nature of the aryl rings
of a,b-unsaturated aldehydes 1 has apparently limited influence
on the stereochemical outcome. The reaction system is inert to
the electronic effect, as evidenced that in all cases, extremely high
enantioselectivity (96–499% ee) and high diastereoselectvity
(up to 430 : 1) are observed regardless of electron-donating
(entries 1–3), neutral (entry 4), combination of electron-donating
and withdrawing (entry 5) and withdrawing (entries 6–11)
substituents tested. Probing the steric effect on the enantio-
and diasteroselectivity of the cascade processes indicates that
such impact is also minimal (96% ee, 7.5 : 1 dr, entry 3). The
relative and absolute configuration of product 3c is determined
by the X-ray crystal structural analysis based on its derivative
4 (Fig. 1).13
Our orienting experiments were performed with trans-
cinnamaldehyde 1a with trans g-N-protected a,b-unsaturated
esters 2 in the presence of diphenylprolinol silyl ether catalyst I
and NaOAc as base (Table 1). The preliminary studies re-
vealed that the reaction efficiency highly depended on the
protection form of the nitrogen nucleophile (entries 1–4). No
reaction occurred with Ac, Boc and Cbz whereas a promising
result was obtained when Ts was used. This indicated that the
nucleophilicity of the nitrogen was critical for the cascade
process. The strong electron-withdrawing capacity of Ts group
rendered the NH more acidic and thus readily generating more
nucleophilic nitrogen anion under basic conditions. Further-
more, notably we did not observe the lactamization reaction in
2. The subsequent survey of different chiral organocatalysts
disclosed that similar results were achieved with catalysts II
and III (entries 5–6). However, the process proceeded very
poorly with IV (entry 7).
In further optimization of reaction conditions, we focused
on varying reaction parameters including base, solvent and
catalyst loading (see ESIw for detail). In these experiments, the
optimal results with respect to reaction time, yields, enantio-
and diastereoselectivity of the aza-Michael–Michael reaction
were obtained when the reaction cascade was performed with
10 mol% I in CHCl3 using 1.0 equiv. of NaOAc.
As revealed in Table 2, the cascade process serves as a general
approach to the preparation of highly functionalized trisubsti-
tuted chiral pyrrolidines. Significantly, three new stereogenic
centers are created in a one-pot transformation in high yields
(80–94%) and with excellent levels of enantioselectivities
(96–499% ee) and high diastereoselectivities (7 : 1 to
430 : 1 dr). Significant structural variation of a,b-unsaturated
Fig. 1 X-Ray crystallographic structure 4.
Chem. Commun., 2008, 5636–5638 | 5637
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In conclusion, driven by the lack of an efficient method for the
preparation of synthetically significant trisubstituted chiral pyrro-
lidines, we have uncovered an unprecedented organocatalytic,
highly enantioselective cascade aza-Michael–Michael reaction.
The process is efficiently catalyzed by readily available (S)
diphenylprolinol TMS ether to give trisubstituted synthetically
useful, highly functionalized chiral pyrrolidines.14 The scaffold
serves as an efficient starting point for further synthetic mani-
pulation in total synthesis of natural products, biologically
significant therapeutics and the diversity oriented library syn-
thesis. Moreover, in principle, the cascade strategy can be
exploited for the synthesis of synthetically and medicinally
important chiral piperidines. These represent our future endea-
vour aimed at demonstrating the synthetic utility and expanding
the scope of the powerful domino processes.
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Financial support for this work provided by the NSF
(CHE-0704015) and NIH-INBRE program (P20 RR016480)
is gratefully acknowledged. Thanks are expressed to Dr Elieen
N. Duesler for performing X-ray analysis. The Bruker X8
X-ray diffractometer was purchased via an NSF CRIF : MU
award to the University of New Mexico, CHE-0443580.
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13 CCDC-693305 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk and supporting informationw.
14 We carried out a 1 g scale of reaction of 1a with 2d in the presence
of I (10 mol%) and NaOAc (1.0 equiv.) in CHCl3 for 4 d to afford
3a in 93% yield, 499% ee and 430 : 1 dr.
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This journal is The Royal Society of Chemistry 2008
5638 | Chem. Commun., 2008, 5636–5638