One-pot catalytic enantioselective domino nitro-michael/michael synthesis of cyclopentanes with four stereocenters

Article abstract of DOI:10.1002/chem.200801082

A highly enantioselective organocatalytic one-pot synthesis of nitro-, formyl-, and ester-functionalized cyclopentanes with four stereocenters is presented. The cyclopentanes were formed as a predominant diasteroisomer and isolated in high yields with 97-99% ee.

Full text of DOI:10.1002/chem.200801082

FULL PAPER
DOI: 10.1002/chem.200801082
One-Pot Catalytic Enantioselective Domino Nitro-Michael/Michael
Synthesis ofCyclopentanes with Four Stereocenters
Gui-Ling Zhao,[a] Ismail Ibrahem,[a, c] Pawel Dziedzic,[a, c] Junliang Sun,[b, c]
Charlotte Bonneau,[b, c] and Armando Córdova*[a, c]
Abstract: A highly enantioselective organocatalytic one-pot synthesis of nitro-,
Keywords: aldehydes · asymmetric
catalysis conjugate additions
cyclopentanes · domino reactions ·
formyl-, and ester-functionalized cyclopentanes with four stereocenters is present-
ed. The cyclopentanes were formed as a predominant diasteroisomer and isolated
in high yields with 97–99% ee.
·
·
organocatalysis
Introduction
tion of highly functionalized carbocycles, such as cyclohex-
anes by Enders,[6a,c] Jørgensen,[6b,d] and Hayashi,[6e] as well as
cyclopentanes by Wang[6f,g] and our group[6h] have recently
been achieved by the employment of enantioselective amine
catalysis.[6] Inspired by these elegant reports, and our recent-
ly developed nitrocyclopropanation of enals [Eq. (1)],[7] we
became intrigued as to whether it would be possible to as-
semble highly functionalized cyclopentanes by a catalytic
cascade nitro-Michael/Michael reaction by using a,b-unsatu-
rated aldehydes as acceptors [Eq. (2)]. Heteroatom func-
tionalized cyclopentanes are valuable synthetic building
blocks and are present in several natural products, such as
prostaglandins.[8] Herein, we present a highly diastereo- and
enantioselective one-pot synthesis of nitrogen-, formyl-, and
ester-functionalized cyclopentane derivatives with four ste-
reocenters (97–99% ee).
Domino, tandem, or cascade reactions, that involve the for-
mation of multiple carbon–carbon bonds and stereocenters
in one-pot, is a rapidly growing research field within the syn-
thesis of small molecules with complex molecular architec-
tures.[1] Domino reactions, a concept introduced by Tiet-
ze,[1a,b] have the advantages of including “green chemistry”
parameters, such as atom economy,[2] reduction of synthetic
steps, and reduction of waste and solvents.[3] In this context,
it is challenging and even more economic to develop catalyt-
ic asymmetric domino reactions. Therefore, there is intense
research into the development of new catalytic enantioselec-
tive domino and cascade transformations. The development
of organocatalytic asymmetric one-pot domino reactions is a
rapidly growing research area.[4–5] For example, the construc-
[a] Dr. G.-L. Zhao, Dr. I. Ibrahem, P. Dziedzic, Prof. Dr. A. Córdova
Department of Organic Chemistry
Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
Fax : (+46)8154908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
[b] J. Sun, Dr. C. Bonneau
Department of Structural Chemistry
Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
[c] Dr. I. Ibrahem, P. Dziedzic, J. Sun, Dr. C. Bonneau, Prof.
Dr. A. Córdova
Berzelii Center EXSELENT on Porous Materials
Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801082.
Chem. Eur. J. 2008, 14, 10007 – 10011
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10007

Table 1. Catalyst screening for the reaction between 1a and ester 2a.[a]
Entry
Cat.
Solvent
Additive
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
4
5
6
7
6
6
6
6
6
6
6
6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
toluene
CHCl3
CH2Cl2
CHCl3
CHCl3
none
none
none
none
benzoic acid
none
none
48
48
96
48
16
68
120
120
48
48
48
48
15
30
67
traces
89
82
86
67
70
4:1:2:0
3:0:1:0
3:1:1:1
nd
2:1:1:1
4:1:1:1
3:1:1:2
3:1:2:1
7:1:1:1
6:1:1:1
7:0:1:1
4:1:1:1
38:nd
70:nd
94:86:95:99
nd
68:94:91:99
99:84:91:99
92:61:86:97
92:61:86:97
99:nd
none
9
DABCO
DABCO
TEA
10
11
12
84
64
97
99:nd
97:nd
98:>10:86:93
NaOAc
[a] Experimental conditions: A mixture of 1a (0.25 mmol), 2a (0.30 mmol), and catalyst (20 mol%) in solvent (0.5 mL) was stirred at the temperature
1
and conditions displayed in the table. [b] Isolated yield of 3a and its diastereoisomers after silica-gel chromatography. [c] Determined by H NMR spec-
troscopic analysis of the crude reaction mixture. [d] Determined by chiral-phase HPLC analysis. nd=not determined; TMS=trimethylsilyl.
Table 2. Catalytic asymmetric domino reactions between crude 1 and ester 2.[a]
Entry
1
R1
R2
Product
t [h]
Yield [%][b]
70
d.r.[c]
ee [%][d]
Me
3a
48
7:1:1:1
99
2
3
4
5
Et
3b
3c
3d
3e
40
24
40
24
80
60
81
88
10:0:1:2
6:1:1:1
10:0:1:1
7:1:1:1
99
97
99
99
Me
Me
Me
6
7
Me
Me
3 f
3g
24
24
75
80
7:0:1:1
7:0:1:1
98
99
8
9
Me
Me
3h
3i
26
40
72
81
12:0:1:2
10:1:1:2
99
99
10
Me
3j
24
73
12:1:1:2
99
[a] Experimental conditions: A mixture of enal 1 (0.25 mmol), 2a (0.30 mmol), catalyst (20 mol%), and DABCO (20 mol%) in CHCl3 (0.5 mL) was
1
stirred at room temperature for the time displayed in the table. [b] Isolated yield of 3 after silica-gel chromatography. [c] Determined by H NMR spec-
troscopic analysis of the crude reaction mixture. [d] Determined by chiral-phase HPLC analysis on the major isomer.
10008
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Chem. Eur. J. 2008, 14, 10007 – 10011

Michael/Michael Synthesis of Cyclopentanes
FULL PAPER
Results and Discussion
In an initial catalyst screening, we found to our delight that
amines 4–7 catalyzed the asymmetric domino reaction be-
tween cinnamic aldehyde (1a) and methyl 5-nitro-pente-
noate (2a), which is simply derived by a Horner–Wads-
worth–Emmons reaction of 3-nitropropanal in CHCl3
(Table 1).
The transformation resulted in the assembly of the corre-
sponding cyclopentane derivative 3a with moderate diaste-
reoselectivity and 38–94% ee (entries 1–4). The protected
chiral diarylprolinol 6[9] exhibited the highest reactivity and
enantioselectivity. Thus, amine 6 was chosen as the catalyst
for further investigations. High enantioselectivity was also
achieved in other solvents (entries 6–8). The presence of an
acid additive increased the reactivity but decreased the dia-
stereoselectivity of the reaction (entry 5). Thus, we decided
to investigate the addition of a small amount of base (en-
tries 9–12). To our satisfaction, the rate and diastereo- and
enantioselectivity of the reaction increased. In particular,
the employment of organic bases 1,4-diazabicyclo-
versity-oriented synthesis,[11] we further modified the cyclo-
pentane derivatives 3 (Scheme 1). Consequently, reduction
and oxidation gave the corresponding alcohols and acids 8
and 12, respectively, in high yields. Both of these transfor-
mations can also be performed as one-pot operations. The
alcohol moiety of 8 can be esterified to give functional cy-
clopentanes 9 and a Wittig reaction of aldehyde 3 gave the
corresponding cyclopentane 11. Reduction of the nitro
group and Boc protection (Boc=tert-butoxycarbonyl) gave
access to amine-functionalized cyclopentane 10a. The rela-
tive stereochemistry of 3c was established by NOE NMR
spectroscopic experiments, which confirmed a trans relation-
ship between all the neighboring substituents. This was also
confirmed by X-ray analysis (Figure 1) of 12c
(1R,2R,3S,4S).[12]
A
for the formation of 3a with high diastereo- and enantiose-
lectivity (entries 9–11). The highest stereoselectivity (7:1 d.r.
and 99% ee; d.r.=diasteromeric ratio) was achieved when
DABCO was used as the additive (entry 9). Based on these
results, we decided to investigate the chiral amine 6-cata-
lyzed enantioselective domino reactions between enals 1
and 5-nitro-pentenoate esters 2
Based on these results and the chiral amine 6-catalyzed
reactions with enals,[9e] we propose the following domino re-
action mechanism to account for the observed stereochemis-
try of the reaction (Scheme 2).
in CHCl3 by using
a small
amount of DABCO as an addi-
tive (Table 2).
The organocatalytic asym-
metric domino reactions gave
the corresponding cyclopen-
tanes 3a–j in high yields (60–
88%) as a predominant diaste-
reoisomer, which was readily
separated from the other minor
diastereoisomers by silica-gel
column chromatography. The
enantioselectivity of the reac-
tion was excellent (97–99% ee).
Thus, the one-pot procedure
allows for the construction of
four stereocenters with very
high stereocontrol. Notably,
when 2-heptenal was employed
as the acceptor enal, the corre-
sponding chiral cyclohexane de-
rivative A with three stereocen-
ters was formed with >19:1 d.r.
and 91% ee by a formal [3+3]
cycloaddition.[10]
To show the synthetic utility
of the transformation and the
Scheme 1. a) NaBH4, MeOH, 0 8C; b) 2,4-Cl2C6H3COCl, TEA, CH2Cl2; c) Ph3P=CHCO2Et, CHCl3; d) cat. Pd/
possibility of employing it in di- C, H2, MeOH; e) NaClO2 KH2PO4, (CH3)2C=CHCH3, tBuOH/H2O 5:1; f) (Boc)2O, TEA.
Chem. Eur. J. 2008, 14, 10007 – 10011
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www.chemeurj.org
10009

A. Córdova et al.
corresponding cyclopentane product 3 and releases the
chiral amine catalyst. The role of the organic base additive
is possibly to enhance the deprotonation and proton-transfer
in the conjugate addition steps.
Conclusion
In summary, we have developed a highly diastereo- and
enantioselective one-pot cascade nitro-Michael/Michael re-
action for the synthesis of amino-, formyl-, and ester-func-
tionalized cyclopentanes with four stereocenters (97–
99% ee). These compounds can be used as scaffolds for fur-
ther diversification. The importance of the transformation is
additionally highlighted in that it correlates to the elegant
protocols for cyclohexene and cyclohexane synthesis report-
ed by the groups of Enders,[6a,c] Jørgensen,[6b,d] and Haya-
shi,[6e] as well as the cyclopentane synthesis developed by
Wangꢁs[6f,g] and our group[6h]
.
Figure 1. ORTEP picture of the crystalline compound 12c.
Acknowledgement
We gratefully acknowledge the Swedish National Research Council (VR)
and the Lars Hierta and Carl Trygger Foundations for financial support.
The Berzelii Center EXSELENT is financially supported by VR and the
Swedish Governmental Agency for Innovation Systems (VINNOVA).
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FULL PAPER
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Received: June 4, 2008
Published online: October 1, 2008
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