Synthesis of highly functionalized chiral cyclopentanes by catalytic enantio- and diastereoselective double Michael addition reactions

Article abstract of DOI:10.1002/anie.200700485

(Chemical Equation Presented) Do a double take: A novel highly enantio-and diastereoselective cascade double Michael reaction, in which two C-C bonds and three contiguous stereogenic centers are formed, has been developed. The one-pot process, which was e

Full text of DOI:10.1002/anie.200700485

Communications
DOI: 10.1002/anie.200700485
Organocatalysis
Synthesis of Highly Functionalized Chiral Cyclopentanes by Catalytic
Enantio- and Diastereoselective Double Michael Addition Reactions**
Liansuo Zu, Hao Li, Hexin Xie, Jian Wang, Wei Jiang, Yun Tang,* and Wei Wang*
À
Reactions that involve the formation of C C bonds are
considered the most important processes in organic synthesis.
Cascade reactions that involve the production of multiple
À
C C bonds and multiple stereogenic centers in a single
manipulation are a particularly appealing strategy in the rapid
construction of complex molecular architectures because of
their operational simplicity, atom economy, low use of energy,
and minimization of chemical waste.[1] While significant
progress has been made in the use of chiral precursors for
stereocontrol, the development of catalytic enantio-and
diastereoselective cascade reactions has proven to be a
challenging task.[1] Notably the recent development of
organocatalytic asymmetric domino reactions based on
chiral small molecules has been hotly pursued.[2–5]
Recently, we and the research group of Córdova simulta-
neously described enantioselective cascade sulfa-, oxa-, and
aza-Michael/aldol/dehydration reactions promoted by chiral
secondary amines (Scheme 1a).[6,7] We envisioned that the
employment of a nucleophilic carbon atom instead of
heteroatoms S, O, and N for the initial Michael addition
À
could enable the generation of two new C C bonds.
Furthermore, change of the aldehyde group to an a,b-
unsaturated ester 2 as the electrophile, which allows for a
second conjugate addition reaction, would produce a new
cascade double conjugate addition process (Scheme 1b).[8,9]
To the best of our knowledge, such a process has not been
described to date.[10] Significantly, the cascade process would
afford a product with the formation of three stereogenic
centers rather than one, which was observed in the Michael/
aldol/dehydration sequence (Scheme 1a). Herein we wish to
report the results of an investigation that has led to a novel
organocatalytic diastereo-and enantioselective cascade
À
double Michael reaction, in which two C C bonds and
Scheme 1. Organocatalytic, enantioselective Michael initiated cascade
reactions: a) the cascade Michael/aldol/dehydration reaction, and
b) the cascade double Michael reaction. X=S, O, or NPG, PG=pro-
tecting group, TMS=trimethylsilyl, sphere=chiral side chain.
[*] L. Zu, H. Li, H. Xie, J. Wang, W. Jiang, Prof. Dr. Y. Tang,
Prof. Dr. W. Wang
Department of Chemistry, University of New Mexico
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax: (+1)505-277-2609
E-mail: ytang234@yahoo.com.cn
wwang@unm.edu
three contiguous stereogenic centers are efficiently created in
a one-pot transformation with a high control of relative and
absolute stereochemistry. This new catalytic methodology
Prof. Dr. W. Wang
Department of Medicinal Chemistry, School of Pharmacy
East China University of Science & Technology
serves as a facile approach to synthetically useful, highly
Shanghai 200237 (P. R. China)
Fax: (+86)21-6425-3651
functionalized chiral cyclopentanes.[11]
The design of a catalytic cascade double Michael addition
[**] Financial support of this research by the University of New Mexico,
reaction required the consideration of several factors. The
reactivity of the a,b-unsaturated system in 2 that participates
in the second conjugate addition reaction must be high
enough to allow for the intramolecular Michael reaction, but
ACS-PRF, and NIH-INBRE program (P20 RR016480) is gratefully
acknowledged. We thank Dr. E. N. Duesler for X-ray analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3732
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Angewandte
Chemie
Table 2: Cascade double Michael addition reactions promoted by
catalyst IV for the one-pot formation of chiral cyclopentanes.[a]
lower than that of the a,b-unsaturated iminium A, which was
derived from an a,b-unsaturated aldehyde 1 (Scheme 1b).
Recognition of this reactivity profile should allow the design
of systems capable of undergoing efficient double Michael
addition sequences. Generally, an a,b-unsaturated ester 2
undergoes a conjugate addition at a lower rate than an a,b-
unsaturated aldehyde 1 and will not interfere with the
secondary amine catalyst. Furthermore, a carbon nucleophile
should be active enough to only engage in the first Michael
addition reaction. To address this concern, we used an
enolizable malonic ester in the a,b-unsaturated ester 2
(Scheme 1).
Entry
R
R’
t [h]
Yield [%][b]
ee [%][c]
d.r.[d]
1
2
3
4
5
6
7
8
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-MeOC6H4
Ph
4-NO2C6H4
4-CNC6H4
4-FC6H4
Me
Et
iPr
18
18
24
18
18
16
12
15
12
16
24
20
92
92
87
90
91
92
90
87
95
93
86
85
99
99
99
99
99
84
98
99
97
99
98
94
10:1
11:1
11:1
>20:1
19:1
16:1
17:1
Bn
Me
Me
Me
Me
Me
Me
Me
Bn
Initial efforts focused on the establishment of the optimal
conditions for the catalytic asymmetric double Michael
addition process. Gratifyingly, upon an initial screen of a set
of chiral secondary amine organocatalysts I–IV, (S)-di-
phenylprolinyl TMS ether (IV) was found to be the best
9:1
9
15:1
>20:1
>20:1
9:1
10
11
12
2-ClC6H4
2-naphthyl
n-C3H7
promoter (Table 1, entry 4).[12,13]
A survey of solvents
[a] For reaction conditions unless specified, see the Experimental
Section. Bn=benzyl. [b] Yield of isolated product. [c] Determined by
HPLC analysis on a chiral stationary phase (Chiralpak AS-H, or Chiralcel
Table 1: Optimization of the organocatalytic enantioselective double
Michael addition reaction.[a]
1
OD-H). [d] Determined by H NMR spectroscopy; major isomer: trans.
tuted with a b-alkyl group (for example, R = nC3H7; Table 2,
entry 12) and a similar good result was also obtained (84%
yield, 94% ee, and 9:1 d.r.). The absolute configuration of the
products 3 from the double Michael addition process was
determined by comparison with a derivative from compound
3j (Table 2,entry 10, and see the Supporting Information for
details).[14]
Motivated by the paucity of catalytic asymmetric methods
for the powerful double Michael addition reactions, we have
developed an unprecedented organocatalytic asymmetric
version of the cascade process. This transformation, which
Entry
Cat.
Solvent
t [h]
Yield [%][b]
ee [%][c]
d.r.[d]
1
2
3
4
I
II
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
toluene
THF
12
10
24
12
18
15
15
15
15
90
96
0
95
92
32
30
17
12
11
10:1
4:1
24
III
IV
IV
IV
IV
IV
IV
nd[e]
99
nd[e]
10:1
10:1
5:2
5[f]
6
99
99
7
8
9
93
14:1
10:1
10:1
nd[e]
nd[e]
DMSO
À
results in the formation of two C C bonds and three
[a] For reaction conditions unless specified, see the Experimental
Section. DMSO=dimethylsulfoxide. [b] Yield of isolated product.
[c] Determined by HPLC analysis on a chiral stationary phase (Chiralcel
OD-H). [d] Determined by H NMR spectroscopy; major isomer: trans.
[e] Not determined. [f] 10 mol% catalyst was used.
contiguous stereogenic centers, enables the facile assembly
of tetrasubstituted, highly functionalized cyclopentanes from
simple achiral molecules with high levels of enantio-and
diastereocontrol in a single operation. Through variation of
both the nucleophiles and the electrophiles, it is our
anticipation that this general organocatalytic methodology
will stimulate further contributions to the rapidly growing
family of catalytic cascade reactions with a significantly
expanded scope.
1
revealed that EtOH was optimal for the cascade process; in
this case, the reaction proceeded efficiently to give the adduct
3a in an excellent yield (95%) and with an excellent ee value
(99%) and a good d.r. value (10:1). Similar results were
obtained when the catalyst loading was lowered to 10 mol%
(Table 1, entry 5).
Using these optimized reaction conditions, the scope of
the asymmetric double Michael addition reactions catalyzed
by IV was investigated next. The new methodology provided
a facile approach to a range of tetrasubstituted, highly
functionalized chiral cyclopentanes 3 with the generation of
3 new stereogenic centers in high enantiomeric excess (84 to
99% ee) and high diastereoselectivity (9:1 to > 20:1 d.r.;
Table 2). It appears that the size of the R’ group of the
malonate ester moiety in 2 has a limited effect on the
processes (Table 2, entries 1–4). Moreover, it seems that large
substituents (Table 2, entries 5, 10, and 11) can also be
tolerated. Finally, we used an unsaturated aldehyde substi-
Experimental Section
General Procedure (Table 2, entry 1): A mixture of 1a (0.12 mmol),
2a (0.1 mmol), and the catalyst IV (0.01 mmol) in EtOH (0.2 mL) was
stirred at room temperature for 18 h. The mixture was purified by
column chromatography on silica gel, eluted by hexane/EtOAc (10:1
to 3:1) to give the desired product in 92% yield, 99% ee (HPLC on a
Chiralcel OD-H column, hexane/EtOH 4:1 at 0.5 mLminÀ1, l =
254 nm); tminor = not observed, tmajor = 23.38 min; 10:1 d.r. (determined
by 1H NMR); [a]D23(major) = À19.4 (c = 1.0, CHCl3).
Received: February 2, 2007
Published online: April 12, 2007
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www.angewandte.org
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Communications
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Chem. 1993, 105, 1059; Angew. Chem. Int. Ed. Engl. 1993, 32,
1010.
Keywords: aldehydes · cyclopentanes · domino reactions ·
Michael addition · organocatalysis
.
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[14] The structure of the compound derived from 3j was determined
by X-ray analysis. CCDC-635261 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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