Enantioselective synthesis of polysubstituted cyclopentanones by organocatalytic double Michael addition reactions

Article abstract of DOI:10.1021/ol101414b

The O-TMS-protected diphenylprolinol-catalyzed cascade double Michael addition reactions of α,β-unsaturated aldehydes with a β-keto ester bearing a highly electron-deficient olefin unit occur smoothly to afford polysubstituted cyclopentanones. This process allows formation of four contiguous stereocenters in the cyclopentanone ring in one-step with excellent enantioselectivity.

Full text of DOI:10.1021/ol101414b

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3634-3637
Enantioselective Synthesis of
Polysubstituted Cyclopentanones by
Organocatalytic Double Michael Addition
Reactions
Anqi Ma and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
Madw@mail.sioc.ac.cn
Received June 18, 2010
ABSTRACT
The O-TMS-protected diphenylprolinol-catalyzed cascade double Michael addition reactions of r,ꢀ-unsaturated aldehydes with a ꢀ-keto ester
bearing a highly electron-deficient olefin unit occur smoothly to afford polysubstituted cyclopentanones. This process allows formation of
four contiguous stereocenters in the cyclopentanone ring in one-step with excellent enantioselectivity.
Cyclopentane and cyclopentanone moieties have been fre-
quently found in bioactive natural products.1 This fact has
stimulated a large number of investigations exploring new
methodologies for asymmetric assembly of polysubstituted
cyclopentanes and cyclopentanones.1 In the field of orga-
nocatalysis, the Co´rdova group has found that 2,3,4-trisub-
stituted cyclopentanones could be assembled from 4-bromo
ꢀ-ketoesters and R,ꢀ-unsaturated aldehydes via domino Michael
addition/R-alkylation reactions,2 Wang et al. have reported the
synthesis of highly functionalized cyclopentanes via double
Michael additions,3 and Enders and co-workers have described
a cascade Michael addition/R-alkylation process to 1,1,2-
trisubstituted cyclo-pentanes.4 These achievements are additional
examples that demonstrate the powerful application spectrum
of organo-catalytic domino reactions in elaborating complex
synthetic intermediates from simple precursors.5,6
During the course of the development of organocatalytic
Michael reactions,7 we became interested in exploring the
possibility of assembling polysubstituted cyclopentanones via
a cascade double Michael addition process of ꢀ-keto ester 1
and R,ꢀ-unsaturated aldehydes. As outlined in Scheme 1,
we envisioned that after the Michael addition of an anion
generated from 1 to iminium 5 through the transition state
A, the newly formed enamine moiety in 6 would attack the
highly electron-deficient olefin part to afford the intramo-
(3) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W.
Angew. Chem., Int. Ed. 2007, 46, 3732.
(1) For reviews, see: (a) Hudlicky, T.; Price, J. D. Chem. ReV. 1989,
89, 1467. (b) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293. (c)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (d) Silva, L. F.
Tetrahedron 2002, 58, 9137. (e) Helmchen, G.; Ernst, M.; Paradies, G.
Pure Appl. Chem. 2004, 76, 495.
(4) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem., Int. Ed. 2008, 47,
7539.
(5) For reviews of organocatalytic cascade reactions, see: (a) Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (c) Alba, A.-N.;
(2) Rios, R.; Vesely, J.; Sunde´n, H.; Ibrahem, I.; Zhao, G.-L.; Co´rdova,
A. Tetrahedron Lett. 2007, 48, 5835.
Companyo´, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432
.
10.1021/ol101414b  2010 American Chemical Society
Published on Web 07/22/2010

satisfactory diastereoselectivity and enantioselectivity (Table
1, entry 1). Improved yields were observed by using some
Scheme 1. Catalytic Cycle for Double Michael Addition
Reactions of ꢀ-Keto Ester 1 and R,ꢀ-Unsaturated Aldehyde 2a
Table 1. Condition Screening for the Formation of
Cyclopentanone 4a via Organocatalytic Double Michael
Addition Reactions of 1 and 2aa
entry
solvent
t (h)
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7e
H2O
MeCN
THF
CH2Cl2
Cl(CH2)2Cl
toluene
toluene
2.5
4
8
3
1
62
66
71
71
77
77
82
19:1
21:1
16:1
20:1
18:1
21:1
20:1
99.4
97.1
99.6
99.1
99.9
>99.9
>99
1
1
a Reaction conditions: 1 (0.12 mmol), 2a (0.15 mmol), 2 mol % catalyst 3, 0.2
mL of solvent, 0 °C for 1 h, then rt if the reaction is not finished. b Isolated yield.
c Determined by 1H NMR measurements performed on the isolated product.
d Determined by chiral-phase HPLC analysis of the corresponding alcohol obtained
by reduction of the aldehyde moiety. e 2a (0.13 mmol) was used.
lecular Michael adduct 4a. Notably, this process would
provide a product with diverse functional groups and up to
four contiguous stereocenters in one step.
organic solvents (entries 2-6), and toluene was found to be
the best reaction media (entry 6). The highest yield could
be obtained by reducing the molar ratio of 2a and 1 from
1.25:1 to 1.08:1 (entry 7).
Having the optimized conditions in hand, the scope of the
cascade process was examined by varying R,ꢀ-unsaturated
aldehydes. The results are summarized in Table 2. In all
The ꢀ-keto ester 1 was prepared via Wittig olefination of
diethyl 2-oxomalonate with the ylide generated from ethyl
4-chloro-3-oxobutanoate and Ph3P (see Supporting Informa-
tion for detailed procedure). Its reaction with cinnamaldehyde
2a in the presence of 2 mol % O-TMS-protected diphenyl-
prolinol 3 as a catalyst was selected as a model for screening
suitable reaction conditions. It was found that the reaction
worked well in water to provide 4a in 62% yield and
Table 2. Asymmetric Double Michael Addition Reactions of 1
with ꢀ-Monosubstituted R,ꢀ-Unsaturated Aldehydesa
(6) For selected examples of organocatalytic cascade reactions, see: (a)
Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951. (b) Co´rdova,
A.; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67, 301. (c) Dudding,
T.; Hafez, A. M.; Taggi, A. E.; Wagerle, T. R.; Lectka, T. Org. Lett. 2002,
4, 387. (d) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2003, 42, 4233. (e) Yamamoto, Y.; Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962. (f) Yang, J. W.; Fonseca,
M. T. H.; List, B. J. Am. Chem. Soc. 2005, 127, 15036. (g) Huang, Y.;
Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 15051. (h) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am. Chem.
Soc. 2006, 128, 14986. (i) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe,
G. Nature 2006, 441, 861. (j) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng,
L. J. Am. Chem. Soc. 2007, 129, 768. (k) Zu, L.-S.; Wang, J.; Li, H.; Xie,
H.-X.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (l) Enders,
D. M. R.; Hu¨ttl, M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem., Int.
Ed. 2007, 46, 467. (m) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 1101. (n) Wang, J.; Li, H.; Xie,
H.; Zu, Li.; Shen, X.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 9050.
(o) Li, H.; Zu, L.; Xie, H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007,
9, 1833. (p) Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem., Int. Ed.
2008, 47, 3046. (q) Lu, L.-Q.; Cao, Y.-J.; Liu, X.-P.; An, J.; Yao, C.-J.;
Ming, Z.-H.; Xiao, W.-J. J. Am. Chem. Soc. 2008, 130, 6946. (r) Tan, B.;
Shi, Z.; Chua, P. J.; Zhong, G. Org. Lett. 2008, 10, 3425. (s) Bertelsen, S.;
Johansen, R. L.; Jørgensen, K. A. Chem. Commun. 2008, 3016. (t) Rueping,
M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48,
3699. (u) Schrader, W.; Handayani, P. P.; Zhou, J.; List, B. Angew. Chem.,
Int. Ed. 2009, 48, 1463. (v) Galzerano, P.; Pesciaioli, F.; Mazzanti, A.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892. (w)
McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11, 5654.
a Reaction conditions: 1 (0.12 mmol), 2 (0.13 mmol), 2 mol % catalyst
3, toluene (0.2 mL), 0 °C for 1 h, then rt for about 1 h. b Isolated yield.
(7) (a) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545.
(b) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10, 3075. (c)
Wang, J.; Ma, A.; Ma, D. Org. Lett. 2008, 10, 5425. (d) Ma, A.; Zhu, S.;
Ma, D. Tetrahedron Lett. 2008, 49, 3075. (e) Zhu, S.; Wang, Y.; Ma, D.
AdV. Syn. Catal. 2009, 351, 2563. (f) Xu, D.; Zhang, Y.; Ma, D. Tetrahedron
Lett. 2010, 51, 3827. (g) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem.,
Int. Ed. 2010, 49, 4656.
c
Determined by H NMR after purification. d Determined by chiral-phase
1
HPLC analysis of the corresponding alcohol obtained by reduction of the
aldehyde moiety. e Reaction was carried out at -20 °C for 1 h. f Reaction
was carried out with 5 mol % catalyst 3. g Determined by chiral-phase HPLC
analysis of the corresponding p-bromobenzoate derivative of the alcohol.
Org. Lett., Vol. 12, No. 16, 2010
3635

cases, only two diastereomers were determined by HPLC,
and their structures were established (see discussion below)
as 4 and 7. For aromatic R,ꢀ-unsaturated aldehydes, their
electronic nature seemed to have little influence on the
cascade reaction process, as is evident from the observation
that the substrates bearing both electron-rich and electron-
deficient aromatic groups all gave the corresponding cyclo-
pentanones in good yields and diastereoselectivity with
excellent enantioselectivity (entries 1-4, 6). In case of the
2-bromophenyl substituted R,ꢀ-unsaturated aldehyde, dias-
tereoselectivity dropped to 4:1 (entry 5), although the reason
for this phenomenon was not clear. When less-reactive
aliphatic R,ꢀ-unsaturated aldehydes were employed, increas-
ing the catalytic loading from 2 to 5 mol % was required to
ensure the complete conversion within 1-2 h (entries 7-9).
It seemed that steric hindrance of the R,ꢀ-unsaturated
aldehydes has a slight influence on enantioselectivity (com-
pare entries 7 with 8). The product 4h is a promising
intermediate for synthesizing brasoside and littoralisone,8
natural products with neuroprotection activity, while the
olefin part in the products 4i and 4j would allow further
transformations to elaborate more complex molecules.
proceeded quite slowly, but the desired product 4k was
isolated in 70% yield after 120 h (Table 3, entry 1). To
Table 3. Asymmetric Double Michael Addition Reactions of 1
with R,ꢀ- and ꢀ,ꢀ-Disubstituted R,ꢀ-Unsaturated Aldehydesa
Comparing with many Michael addition reactions of R,ꢀ-
unsaturated aldehydes catalyzed by secondary amines,9 this
double Michael addition process requires less catalyst and
proceeds significantly faster. The high efficiency may come
from the robust activity of the ꢀ-keto ester 1 and prompted
us to try the construction of quaternary carbon centers10-12
by using R,ꢀ- or ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated aldehydes.
This is a challenging task, because the additional alkyl group
makes R,ꢀ-unsaturated aldehydes much less reactive by
increasing both steric hindrance and electronic density of
the C-C double bond.11,13 To the best of our knowledge,
only one example using an R,ꢀ-disubstituted R,ꢀ-unsaturated
aldehyde as the Michael acceptor has been described.13
However, in this case, no quaternary carbon center was
formed.
a Reaction conditions: 1 (0.12 mmol), 2 (0.13 mmol), 2 mol % catalyst
3, toluene (0.2 mL), 0 °C for 1 h, then rt. b Isolated yield. c Determined by
1H NMR measurements after purification. e Determined by chiral-phase
HPLC analysis of the corresponding alcohol obtained by reduction of the
aldehyde moiety. The data in parentheses is the ee value for the minor
diastereoisomer. f Reaction was carried out at 45 °C for the indicated time.
g Reaction was carried out with 5 mol % catalyst 3. h Determined by chiral-
phase HPLC analysis of 4o.
With this idea in mind, the reaction of ꢀ-keto ester 1 with
(E)-2-methylbut-2-enal was conducted under our standard
conditions. It was found that at room temperature the reaction
(8) (a) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3696. (b) Li, Y.-S.; Matsunaga, K.; Ishibashi, M.; Ohizumi, Y. J. Org.
Chem. 2001, 66, 2165.
(9) For recent reviews, see: (a) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638. (b) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis
2007, 2065.
accelerate the reaction, we tried to heat the reaction mixture
and were pleased to find that the reaction was completed
after 20 h at 45 °C (entry 2). To our delight, enantioselectivity
only slightly dropped under these heating conditions, prob-
ably due to great asymmetric induction ability of the amine
catalyst.14 (E)-2-Methyl-3-phenyl-acrylaldehyde could also
be converted under these conditions giving cyclopentanone
4l in 67% yield (entry 3). Its reduced derivative 8 is
crystalline, thereby giving us the opportunity to establish the
relative configuration of the polysubstituted cyclopentanones
4 via X-ray analysis as indicated in Figure 1.
(10) For recent reviews on quaternary stereogenic centers, see: (a)
Douglas, C. J.; Overmann, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363. (b) Christroffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688.
(c) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (d)
Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (e) Trost,
B. M.; Jiang, C. Synthesis 2006, 369. (f) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2007, 5969
(11) For a review on the organocatalytic formation of quaternary
stereocenters, see: Bella, M.; Gasperi, T. Synthesis 2009, 1583
.
.
(12) For selected recent examples regarding the formation of an all-
carbon-substituted quaternary stereocenter in chiral amine-catalylzed domino
reactions, see: (a) Rios, R.; Sunden, H.; Vesely, J.; Zhao, G.-L.; Dziedzic,
P.; Cordova, A. AdV. Synth. Catal. 2007, 349, 1028. (b) Penon, O.; Carlone,
A.; Mazzanti, A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem.sEur. J. 2008, 14, 4788. (c) Tan, B.; Chua, P. J.; Li, Y.; Zhong, G.
The ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated aldehydes are more
reactive than R,ꢀ-disubstituted R,ꢀ-unsaturated aldehydes for
Org. Lett. 2008, 10, 2437
.
(13) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu,
(14) For a review, see: Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed.
2006, 45, 7876.
D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437
.
3636
Org. Lett., Vol. 12, No. 16, 2010

gave determinable ee values (>99% for major component,
98% for minor component).
The minor diastereomer in most cases was assumed to
be the 2-epimer of 4. To prove this hypothesis, a mixture of
the reduced derivative of 4n and its isomer was treated with
4-bromobenzoyl chloride and trimethylamine. Only one
isomer 9 (Figure 1) was isolated from this reaction, indicating
that the 2-position is the one most likely to isomerize in the
cascade reaction process.
In conclusion, we have developed a highly efficient
cascade double Michael addition process to assemble polysub-
stituted cyclopentanones, in which four contiguous stereo-
centers in the cyclopentanone ring were generated in one-
step with excellent enantioselectivity. The diverse functional
groups in the products will permit further manipulation to
synthesize bioactive natural products. Most importantly, our
result provides the first example for the creation of an all-
carbon-substituted quaternary stereogenic center by using
less-reactive R,ꢀ- or ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated alde-
hydes as Michael acceptors in organocatalytic reactions,
which will stimulate further investigations to extend the scope
of organocatalytic Michael addition reactions.
Figure 1. Structures of the alcohol 8 and the enol ether 9 and the
X-ray structure of 8.
this process, as is evident from the reaction of 1 with
3-methylbut-2-enal, which was completed at room temper-
ature in 2 h to give 4m in 90% yield (entry 4). In this case,
the diastereoselectivity was only moderate (5:2:1 for three
isomers), mainly because of the increased steric hindrance
at the ortho position of the 2-ester group. However, the major
diastereomer has over 99% ee. A similar phenomenon was
observed in the case of (E)-3-phenylbut-2-enal as a substrate
(entry 5). Next, we moved our attention to build fused and
spiro rings by employing cyclic R,ꢀ-unsaturated aldehydes.
Gratifyingly, starting from 1-cyclohexene-1-carbaldehyde, we
could isolated bicycle-[4.3.0]nonanone 4o in 81% yield with
a diastereoselectivity of 3:1 and an excellent ee (>99% major,
97% minor) (entry 6). When 2-cyclohexylideneacetaldehyde
was used, the reaction was finished in 2 h to afford
spiro[4.5]decanone 4p in 90% yield (entry 7). In this case,
four diastereomers were determined, presumably due to the
increased steric hindrance caused by the spiro ring. The ratio
for these isomers was about 11:3:1:1, and the two major ones
Acknowledgment. We are grateful to the Ministry of
Science and Technology (grant 2009ZX09501-00), Chinese
Academy of Sciences, and National Natural Science Founda-
tion of China (grant 20632050 & 20921091) for their
financial support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL101414B
Org. Lett., Vol. 12, No. 16, 2010
3637