Asymmetrie tandem michael addition-wittig reaction to cyclohexenone annulation

Article abstract of DOI:10.1021/ol9010568

A highly stereoselective tandem Michael addition-Wittig reaction of (3-carboxy-2-oxopropylidene)trlphenylphosphorane and α,β-unsaturated aldehydes has been developed by employing the combined catalysis of a newly designed bulky chiral secondary amine 1g,

Full text of DOI:10.1021/ol9010568

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2848-2851
Asymmetric Tandem Michael
Addition-Wittig Reaction to
Cyclohexenone Annulation
Yan-kai Liu,† Chao Ma,† Kun Jiang,† Tian-Yu Liu,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug DeliVery System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
UniVersity, Chengdu 610041, China, and State Key Laboratory of Biotherapy, West
China Hospital, Sichuan UniVersity, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received May 13, 2009
ABSTRACT
A highly stereoselective tandem Michael addition-Wittig reaction of (3-carboxy-2-oxopropylidene)triphenylphosphorane and r,ꢀ-unsaturated
aldehydes has been developed by employing the combined catalysis of a newly designed bulky chiral secondary amine 1g, LiClO4, and
DABCO. The multifunctional 6-carboxycyclohex-2-en-1-ones were generally obtained in excellent diastereo- and enantioselectivities (dr up to
>50:1, 86-99% ee).
Phosphorus ylides are versatile reagents for the construction
of carbon-carbon bonds in synthetic organic chemistry,
especially in the reaction with carbonyl compounds, well-
known as the Wittig reaction.1 However, the application of
phosphorus ylide-containing reagents in asymmetric synthesis
is limited.2 Phosphorus ylides adjacent to an electron-
withdrawing carbonyl group are stable materials and can be
easily handled without much caution. They have been
extensively applied to introduce further functional groups
into organic substrates. In 1983, Pietrusiewicz et al. designed
an elegant tandem Michael addition-Wittig reaction of (3-
carboxy-2-oxopropylidene)triphenylphosphorane and R,ꢀ-
unsaturated aldehydes to afford highly functionalized 6-car-
boxycyclohex-2-en-1-ones,3 which may find wide synthetic
utility for molecular complexity, in a formal [3 + 3]
annulation manner.4 A strong base, NaH, was used for the
enolate generation, which would facilitate the addition to
conjugated double bond of R,ꢀ-unsaturated aldehydes.
Nevertheless, only low to fair yields were attained. In our
† West China School of Pharmacy.
‡ West China Hospital.
(1) (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44. For
reviews, see: (b) Kolodiazhnyi, O. I. Phosphorus Ylides: Chemistry and
Application in Organic Synthesis; Wiley-VCH: Weinheim, 1999. (c) Cristau,
H.-J. Chem. ReV. 1994, 94, 1299. (d) Andrade, M. M.; Barros, M. T.;
Rodrigues, P. Eur. J. Org. Chem. 2007, 3655. (e) Sun, X.-L.; Tang, Y.
Acc. Chem. Res. 2008, 41, 937.
(2) For a few examples of chiral phosphorus ylides in asymmetric
synthesis, see: (a) Ye, L.-W.; Wang, S.-B.; Wang, Q.-G.; Sun, X.-L.; Tang,
Y.; Zhou, Y.-G. Chem. Commun. 2009, 3092. (b) Li, C.-Y.; Wang, X.-B.;
Sun, X.-L.; Tang, Y.; Zheng, J.-C.; Xu, Z.-H.; Zhou, Y.-G.; Dai, L.-X.
J. Am. Chem. Soc. 2007, 129, 1494. (c) Li, C.-Y.; Sun, X.-L.; Jing, Q.;
Tang, Y. Chem. Commun. 2006, 2980. (d) Zurawinski, R.; Donnadieu, B.;
Mikolajczyk, M.; Chauvin, R. Organometallics 2003, 22, 4810. (e) Pinho
e Melo, T. M. V. D.; Cardoso, A. L.; d’A. Rocha Gonsalves, A. M.; Pessoa,
J. C.; Paixa˜o, J. A.; Beja, A. M. Eur. J. Org. Chem. 2004, 4830. (f) Pinho
e Melo, T. M. V. D.; Cardoso, A. L.; d’A. Rocha Gonsalves, A. M.; Storr,
R. C.; Pessoa, J. C.; Paixa˜o, J. A.; Beja, A. M.; Silva, M. R. Tetrahedron
Lett. 2003, 44, 6409. (g) Denmark, S. E.; Kim, J.-H. J. Org. Chem. 1995,
60, 7535. (h) Iio, H.; Fujii, A.; Ishii, M.; Tokoroyama, T. Chem. Commun.
1991, 1390.
(3) (a) Pietrusiewicz, K. M.; Monkiewicz, J.; Bodalski, R. J. Org. Chem.
1983, 48, 788. For a review, see: (b) Feist, H.; Langer, P. Synthesis 2008,
3877.
(4) For the applications of phosphorus ylides in [3 + 3] type reactions,
see: (a) Dauben, W. G.; Ipaktschi, J. J. Am. Chem. Soc. 1973, 95, 5088. (b)
Padwa, A.; Brodsky, L. J. Org. Chem. 1974, 39, 1318. (c) Martin, S. F.;
Desai, S. R. J. Org. Chem. 1977, 42, 1664. (d) See ref 2a.
10.1021/ol9010568 CCC: $40.75
Published on Web 06/11/2009
 2009 American Chemical Society

continuing efforts to develop the catalytic asymmetric
reactions of phosphorus ylides,5 we envisaged that the
stereoselective version of the above reaction might be
realized via the iminium activation of the electrophilic R,ꢀ-
unsaturated aldehydes with a chiral secondary amine.6 A
following intramolecular Wittig reaction would deliver the
desired chiral cyclohex-2-en-1-one derivatives (Scheme 1).7,8
and BzOH in CHCl3 at room temperature.9 It was disap-
pointing that almost no reaction occurred after 24 h (Table
1, entry 1).10 Fortunately, the expected product 4a was
detected in the presence of a basic additive NaOAc, albeit
in very low yield (<10%) (entry 2).11 Moreover, a better yield
was obtained when DABCO (20 mol %) was used, while
the diastereo- and enantioselectivity was modest (entry 3).
To our gratification, the yield and enantioselectivity could
be significantly improved when LiClO4 (20 mol %) and
DABCO were employed together (entry 4). Probably, LiClO4
would coordinate with ꢀ-keto ester groups of 2a, which
would be helpful for its enolization process and thus enhance
the nucleophilic addition to cinnamaldehyde 3a. Other
lithium salts (LiOAc or LiBr) gave much inferior results in
the model reaction. A slightly higher yield was obtained
when the reaction time was extended to 48 h (entry 5), and
even an better yield was isolated when 40 mol % of DABCO
was applied (entry 6). Subsequently, more secondary amine
catalysts 1b-g were screened in order to improve the
enantioselectivity. O-TES ether 1b gave a higher ee value
but with much lower yield (entry 7). No reaction occurred
catalyzed by free prolinol 1c or O-TMS ether 1d with strong
electron-withdrawing aryl groups (entries 8 and 9, respec-
tively). On the contrary, O-TMS 1e and 1f with electron-
donating aryl groups afforded good yield and stereocontrol
(entries 10 and 11).12 Finally, we were pleased to find that
the newly designed bulky secondary amine 1g exhibited
excellent enantioselectivity without effects on the catalytic
efficacy (entry 12).13 In addition, more remarkable enantio-
and diastereoselectivities (98% ee, dr 41:1) were achieved
for the ylide 2b bearing a bulky tert-butyl ester motif (entry
13).
Scheme 1. Chiral Iminium Catalysis as the Key Step in the
Asymmetric Formal [3 + 3] Cyclohexenone Annulation
Based on such considerations, the possible tandem reaction
of stabilized phosphorus ylide 2a3 and cinnamaldehyde 3a
was initially investigated by the catalysis of a secondary
amine R,R-diphenylprolinol O-TMS ether 1a (see Table 1)
Table 1. Screening Studies of the Tandem Reaction of
Stabilized Ylides 2 and Cinnamaldehyde 3aa
With the optimal reaction conditions in hand, we then
examined the tandem reaction of a spectrum of R,ꢀ-
unsaturated aldehydes with phosphorus ylide 2b by the
combined catalysis of the secondary amine 1g (20 mol %),
LiClO4 (20 mol %), and DABCO (40 mol %). The reactions
were generally conducted in CHCl3 at room temperature for
48 h. The results were summarized in Table 2. R,ꢀ-
Unsaturated aldehydes bearing a diversity of electron-
withdrawing or -donating aryl groups could be well tolerated,
and excellent diastereo- and enantioselectivities were ob-
tained in good to high isolated yields (Table 2, entries 2-10).
It should be noted that R,ꢀ-unsaturated aldehyde with an
o-bromophenyl group exhibited lower reactivity, and 30 mol
% of 1g was employed for 72 h (entry 8). On the other hand,
outstanding ee values were obtained for R,ꢀ-unsaturated
.
entry
1
additive
2
yieldb (%) drc eed (%)
1e
1a BzOH
1a NaOAc
1a DBACO
2a
2a
2a
-
-
-
-
-
2e
4a, <10
4a, 21
4a, 53
4a, 62
4a, 71
4a, 46
-
3e
6:1
9:1
7:1
6:1
7:1
-
65
75
74
72
80
-
4e
1a DABCO + LiClO4 2a
1a DABCO + LiClO4 2a
1a DABCO + LiClO4 2a
1b DABCO + LiClO4 2a
1c DABCO + LiClO4 2a
1d DABCO + LiClO4 2a
1e DABCO + LiClO4 2a
5
(5) Zhang, Y.; Liu, Y.-K.; Kang, T.-R.; Hu, Z.-K.; Chen, Y.-C. J. Am.
Chem. Soc. 2008, 130, 2456.
6f
7f
(6) For reviews on iminium catalysis, see: (a) Erkkila, A.; Majander, I.;
Pihko, P. M. Chem. ReV. 2007, 107, 5416. (b) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(7) For selected examples for the construction of chiral cyclohexenones
by aminocatalysis, see: (a) Albrecht, L.; Richter, B.; Vila, C.; Krawczyk,
H.; Jørgensen, K. A. Chem.sEur. J. 2009, 15, 3093. (b) Hayashi, Y.;
Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett. 2009, 11, 45. (c) Zhou,
J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2008, 47,
7656. (d) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen,
Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389.
(8) For reviews on organocatalytic tandem reaction, 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.
8f
9f
-
-
-
10f
11f
12f
13f
4a, 75
4a, 79
4a, 82
4b, 85
8:1
8:1
8:1
41:1
80
79
97
98
1f
DABCO + LiClO4 2a
1g DABCO + LiClO4 2a
1g DABCO + LiClO4 2d
a Unless noted otherwise, reactions were performed with ylide 2 (0.1
mmol), cinnamaldehyde 3a (0.2 mmol), 20 mol % of 1, and 20 mol % of
additive in CHCl3 (0.8 mL) for 48 h. b Isolated yield. Determined by H
NMR analysis. d Determined by chiral HPLC analysis. e For 24 h. f With
40 mol % of DABCO.
c
1
Org. Lett., Vol. 11, No. 13, 2009
2849

Table 2. Asymmetric Tandem Reaction of Stabilized Ylide 2b
and R,ꢀ-Unsaturated Aldehydes 3a
.
entry
R
yieldb (%)
drc
eed (%)
1
2
3
4
5
6
Ph
4b, 85
4c, 67
4d, 85
4e, 81
4f, 74
4g, 78
4h, 81
4i, 56
4j, 82
4k, 76
4l, 80
4m, 82
4n, 82
4o, 65
4p, 62
4b, 60
41:1
17:1
36:1
21:1
>50:1
>50:1
>50:1
10:1
>50:1
>50:1
3:1
98
99
98
98
99e
99
98
99
98
98
96
98
96
86
93
99
p-NO2-C6H4
p-CF3-C6H4
m-CN-C6H4
p-Br-C6H4
p-Cl-C6H4
m-Cl-C6H4
o-Br-C6H4
p-MeO-C6H4
m-Me-C6H4
2-furyl
2-thienyl
1-naphthyl
Me
n-Pr
Ph
7
Figure 1. X-ray structure of enantiopure 4f.
8f
9
10
11
12
13
14f
15f
16g
8:1
Scheme 2
.
Synthetic Transformations of Cyclohexenone
Products
10:1
25:1
4:1
>50:1
a Unless noted otherwise, reactions were performed with ylide 2b (0.1
mmol), R,ꢀ-unsaturated aldehyde 3 (0.2 mmol), 20 mol % of 1g, 20 mol
% of LiClO4, and 40 mol % of DABCO in CHCl3 (0.8 mL) at rt for 48 h.
b Isolated yield. c Determined by 1H NMR analysis. d Determined by chiral
HPLC analysis. e The absolute configuration of enantiopure 4f was
determined by X-ray analysis; see Figure 1. The other products were
assigned by analogy. f With 30 mol % of 1g for 72 h. g At 0.6 mmol scale,
for 72 h.
aldehydes possessing heteroaryl groups, albeit moderate
diastereoselectivities were observed (entries 11 and 12). Good
results were also attained for 1-naphthyl-substituted enal
(entry 13). Importantly, R,ꢀ-unsaturated aldehydes with alkyl
substitutions could be successfully utilized, while higher
catalytic loadings and longer reaction time were required
(entries 14 and 15). Nevertheless, enals with ꢀ-branched alkyl
groups failed to give the desired products probably due to
steric reasons. A catalytic reaction has been conducted at a
larger scale, and good results were obtained after 72 h (entry
16).
formed to diastereo- and enantiomerically pure 5 with
adjacent quaternary and tertiary stereogenic centers. On the
other hand, the asymmetric Michael addition of nitromethane
to the allylation intermediate II from cyclohexenone 4b also
exhibited excellent diastereoselectivity; thus, another tertiary
chiral center was introduced in the highly substituted
cyclohexanone 6. Moreover, the asymmetric Michael addi-
tion of 4b to acrylonitrile gave intermediate III, which
underwent a tandem reductive ring closure process to afford
decahydroquinoline derivative 7 in excellent yield and
stereoselectivity.
In conclusion, we have developed the highly stereoselec-
tive formal [3 + 3] cycloaddition reaction of (3-carboxy-2-
oxo-propylidene)triphenylphosphorane and R,ꢀ-unsaturated
aldehydes by the combined catalysis of a newly designed
bulky chiral secondary amine, LiClO4 and DABCO. This
As an illustration of the utility of this method, the cyclic
product 4 could be readily converted to some interesting
compounds with more complexity (Scheme 2). The methy-
lation of 4a could be easily conducted under phase-transfer
catalysis to give intermediate I, which was further trans-
(9) For a review on R,R-diarylprolinol ethers catalysis, see: Palomo,
C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876.
(10) For Michael addition of 1,3-dicarbonyl compounds to enals via
iminium catalysis, see: (a) Brandau, S.; Landa, A.; Franze´n, J.; Marigo,
M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305. (b) Cabrera,
S.; Aleman, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2008, 47, 121. (c) Franze´n, J.; Fisher, A. Angew. Chem., Int. Ed.
2009, 48, 787. (d) See ref 7a,b.
(11) (a) Wang, Y.; Li, P.; Liang, X.; Ye, J. AdV. Synth. Catal. 2008,
350, 1383. (b) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.;
Wang, W. Org. Lett. 2007, 9, 965. (c) Li, H.; Zu, L.; Xie, H.; Wang, J.;
Wang, W. Chem. Commun. 2008, 5636.
(12) For solvent screenings with catalyst 1f: DCM, 64% yield, 65% ee;
THF, 50% yield, 73% ee; dioxane, 54% yield, 77% ee; MeCN, 61% yield,
74% ee (all dr ratios were less than 10:1).
2850
Org. Lett., Vol. 11, No. 13, 2009

tandem process, including an asymmetric Michael addition
and a following Wittig reaction in one pot, generally provided
synthetically important cyclohexenone derivatives in excel-
lent diastereo- and enantioselectivities for a broad spectrum
of R,ꢀ-unsaturated aldehyde substrates (dr up to >50:1,
86-99% ee). Currently, the further development of asym-
metric reactions of phosphorus ylide-containing reagents is
underway in our laboratory.
China (20772084) and Sichuan Province Government
(07ZQ026-027).
Supporting Information Available: Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC chro-
matograms of the products; CIF of enantiopure 4f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9010568
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
(13) For the synthesis of the bulky catalyst 1g, see the Supporting
Information.
Org. Lett., Vol. 11, No. 13, 2009
2851