Iminium-allenamine cascade catalysis: One-pot access to chiral 4Hchromenes by a highly enantioselective michael-michael sequence

Article abstract of DOI:10.1002/anie.200906050

Chemical Equation Presented Taking the Michael-Michael: A cascade Michael-Michael reaction of aryl or alkyl alkynals, involving an unprecedented iminium - allenamine sequence, is efficiently catalyzed by a chiral diphenylprolinol TBDMS ether, and affords highly functionalized 4H-chromenes in high yields. TBDMS = tert-butyldimethylsilyl.

Full text of DOI:10.1002/anie.200906050

Angewandte
Chemie
DOI: 10.1002/anie.200906050
Cascade Reactions
Iminium–Allenamine Cascade Catalysis: One-Pot Access to Chiral 4H-
Chromenes by a Highly Enantioselective Michael–Michael Sequence**
Xinshuai Zhang, Shilei Zhang, and Wei Wang*
Iminium catalysis has been utilized with great success in
highly efficient enantioselective cascade reactions for the
facile construction of complex molecular architectures.[1] The
chemistry relies on a combined iminium–enamine activation
strategy to control the enantioselectivity at the b-carbon atom
on the a,b-unsaturated aldehyde [Scheme 1, Eq. (1)].[1]
in situ would afford an unprecedented chiral allenamine
intermediate [Eq. (2)].[3–6] The allenamine formed would then
act as the nucleophile in a subsequent enantioselective
reaction with an electrophile to produce a new stereogenic
center.
This organocatalytic iminium–allenamine strategy faces
two important concerns. First, alkynals are known to be a
challenging class of electrophiles in asymmetric synthesis,[2]
and it is expected that they would behave differently to the
well-established enals in terms of reactivity and stereocontrol,
because they adopt different structures and geometry (linear
sp hybridized alkynes versus trans sp2 hybridized olefins).
Second, the stereochemistry is governed by a poorly under-
stood chiral allenamine[4–6] that is formed in situ in the second
step of the cascade reaction, whilst in the classic iminium–
enamine cascade processes, the enantioselectivity is generally
controlled by the initial conjugate addition step.
4H-Chromenes are a core structural feature of an array of
fascinating natural products that have intriguing biological
activities (Scheme 2). For example, rhodomyrtone and rho-
Scheme 1. Conventional (1) and iminium–allenamine (2) catalytic
enantioselective iminium-initiated cascade reactions.
Importantly, the geometry of the trans enals controls the
Michael-initiated cascade reactions to afford high enantio-
and/or diastereoselectivity. In contrast to these widely
reported iminium catalyzed systems, the organocatalytic
cascade transformation involving asymmetric conjugate addi-
tion to an alkynal has not yet been reported, presumably
owing to the fact that the alkynal substrates possess no
prochiral center at the b-carbon atom. This chemistry remains
largely unexplored, even in single-step conjugate addition
reactions.[2] Recently, MacMillan and co-workers reported the
use of propynal as the dienophile in an efficient iminium
activated [4+2] cycloaddition reaction.[2h]
Scheme 2. Examples of 4H-chromenes as substructures in biologically
interesting natural products.
To perform an enantioselective cascade reaction on an
alkynal substrate, we envision that their use instead of an enal
in the initial Michael addition to an iminium ion formed
domyrtosone B show potent antibiotic activities,[7] whereas
the dimeric 4H-chromene acylphloroglucinol, myrtucommu-
lone E, serves as a promising a-glucosidase inhibitor with
antibacterial activity.[8] These frameworks have become
attractive targets in organic synthesis,[9,10] and, despite sig-
nificant advances having been made, asymmetric methods for
their construction are still extremely rare.[11]
[*] X.-S. Zhang, Dr. S.-L. Zhang, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico
Motivated by the dearth of applications of alkynals in
organocatalysis (versus the widely explored enals), we
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax: (+1)505-277-2609
E-mail: wwang@unm.edu
recently developed
a highly enantioselective catalytic
double Michael addition reaction between 2-(E)-(2-nitro-
vinyl)-phenols and alkynals.[12] This one-pot process opens an
efficient route to the densely functionalized, biologically
interesting chiral 4H-chromenes. Herein, we wish to report a
[**] We gratefully acknowledge the National Science foundation (CHE-
0704015) for their financial support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906050.
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Table 2: Catalyst III promoted enantioselective cascade oxa-Michael–
Michael reactions of alkynals (1) with 2-(E)-(2-nitrovinyl)-phenols (2).[a]
Michael–Michael sequential approach to 4H-chromenes
using iminium–allenic enamine cascade catalysis.
To validate the feasibility of the iminium–allenamine
reaction, the reaction of 3-phenyl-2-propynal 1a with 2-(E)-
(2-nitrovinyl)-phenol 2a in dichloromethane was investigated
at room temperature in the presence of 20 mol% organo-
catalyst I (Table 1). Chiral secondary amines, and particularly
Entry
R, X, 3
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph, H, 3a
4
5
4
4
4
4
4
4
4
4
4
4
4
4
97
93
97
95
95
93
92
95
97
92
98
94
98
93
>99
99
99
99
99
99
99
98
99
99
99
99
99
98
Table 1: Optimization of reaction conditions.[a]
4-MeOC6H4, H, 3b
4-ClC6H4, H, 3c
4-BrC6H4, H, 3d
4-NO2C6H4, H, 3e
3-NO2C6H4, H, 3 f
Ph, 4-Cl, 3g
Ph, 6-OMe, 3h
Ph, 4-OMe, 3i
9
10
11
12
13
14
2-thienyl, H, 3j
4-BrC6H4, 4-OMe, 3k
4-MeC6H4, 4-Cl, 3l
4-MeOC6H4, 4-OMe, 3m
tBu, H, 3n
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
I
II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DCE
1
1
1
1
1
1
1
4
95
93
92
90
91
94
92
97
97
98
98
96
66
99
98
>99
[a] Unless specified, see the Experimental Section for reaction condi-
tions. [b] Yield of isolated product. [c] Determined by chiral HPLC
analysis (Chiralpak AS-H or IC column).
III
IV
V
III
III
III
7
8[d]
toluene
ration. Notably, in all cases, the reactions were completed in
4–5 hours, with excellent levels of enantioselectivity (98– >
99% ee) and in high yields (92–98%). Moreover, a broad
substrate scope was observed. Aromatic alkynals 1 that have
electron-donating (Table 2, entries 2, 12, and 13) or electron-
withdrawing substituents (Table 2, entries 3–6 and 11) were
investigated, and the effects of the substituent on the reaction
was found to be very limited. These reactions proceeded very
smoothly, affording excellent yields (92–98%) and excellent
[a] Unless specified, see the Experimental Section for reaction condi-
tions. [b] Yield of isolated product. [c] Determined by HPLC analysis
(Chiralpak AS-H column). [d] 08C; 15 mol% III. DCE=1,2-dichloro-
ethane, TBDMS=tert-butyldimethylsilyl, TES=triethylsilyl, TMS=tri-
methylsilyl.
diarylprolinol silyl ethers, are known to be capable of both
iminium and enamine catalysis in enal cascade reactions.[13]
Encouragingly, the reaction proceeded to completion within
1 h to yield the desired product (3a) in an excellent yield
(95%) and in an excellent ee (97%) (Table 1, entry 1). This
reaction shows that alkynals are more active than enals. A
screen of other diarylprolinol silyl ether analogues II–IV
revealed that the more bulky TBDMS catalyst III gave
slightly higher enantioselectivities (Table 1, entries 2–4),
although diamine V, reported by Barbas and Betancort,
showed poor enantiocontrol (Table 1, entry 5).[14] Accord-
ingly, catalyst III was chosen for further optimization of the
reaction conditions. A survey of different reaction solvents
revealed toluene to be the most suitable for this procedure
(Table 1, entries 6 and 7). Lowering the reaction temperature
to 08C and the catalyst loading to 15 mol% resulted in a
higher ee (> 99%) and higher yield (97%) without consid-
erably prolonging the reaction time (Table 1, entry 8).
enantioselectivities (99– > 99%).
observed with the structural variations of substrate
A similar trend was
2
(Table 2, entries 7–9 and 11–13). Heteroaromatic alkynal
thiophen-2-yl-propynal also effectively engaged in the cas-
cade process (Table 2, entry 10). Finally, the reaction of the
highly sterically hindered aliphatic alkynal also proceeded
successfully, in 93% yield and 98% ee (Table 2, entry 14). The
absolute configuration of product 3g was determined to be R
by using single crystal X-ray diffraction (Figure 1).[15]
In conclusion, we have developed a novel asymmetric
oxa-Michael–Michael reaction involving an unprecedented
Having established the optimal conditions for this cascade
oxa-Michael–Michael reaction, we then investigated the
scope of this process. As shown in Table 2, the one-pot
reaction promoted by III serves as a general and atom-
economical approach to “privileged” chiral 4H-chromenes,
À
with formation of two C C bonds, one new stereogenic
center, and the incorporation of two versatile nitro and
aldehyde functionalities that are available for further elabo-
Figure 1. ORTEP of compound 3g, with ellipsoids set at 20% proba-
bility.
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[4] Examples of catalytic asymmetric synthesis of chiral allenes are
chiral iminium–allenamine cascade. This process is a viable
one-pot approach to synthetically and biologically significant
chiral 4H-chromenes in high yields and with excellent
enantioselectivities. A broad substrate scope has been suc-
cessfully employed in this reaction, including aromatic and
aliphatic alkynals as Michael acceptors, and 2-(E)-(2-nitro-
vinyl)-phenols as Michael donors/acceptors with significant
structural variation. The proposed iminium–allenamine acti-
vation mode has potential applications in the development of
new organocatalytic enantioselective cascade reactions. This
work is currently underway within the group, including
mechanistic investigation and applications of the oxa-
Michael–Michael reaction in synthesis of 4H-chromene con-
taining natural products and bioactive molecules.
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Experimental Section
Representative procedure (see Table 2, entry 1): 2-(E)-(2-Nitro-
vinyl)-phenol 2a (0.10 mmol) and organocatalyst III (5.51 mg,
0.015 mmol) were added to a solution of alkynal 1a (0.11 mmol) in
toluene (0.8 mL) at 08C, and the solution was stirred for 4 h. The
crude reaction mixture was purified by column chromatography
(hexanes/ethyl acetate) to afford the desired product, which was
directly used for compound characterization and chiral HPLC
analysis.
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Received: October 28, 2009
Revised: November 9, 2009
Published online: January 18, 2010
Keywords: alkynal · cascade reactions · enantioselectivity ·
.
Michael addition · organocatalysis
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