Table 1. Optimization of the Vinylogous Michael Addition
Scheme 1. Proposed Approach to Enantioenriched γ-Buteno-
lides
entry
catalyst
solvent time (h) conva (%) drb eec (%)
costly transformations would represent an interesting
improvement in view of potential industrial applications.8
Given the fact that Angelica lactone possesses an acidic
hydrogen R to a double bond we postulated that it would
be possible to add to a sufficiently activated iminium
ion without any required additive. Herein, we disclose
the development of an operationally simple, additive-
free, and highly efficient direct vinylogous addition of
furanone to enals, constructing multiple stereocenters in
high stereocontrol. Furthermore, preliminary mecha-
nistic investigations have allowed for a better under-
standing of the process.
The application of our proposed direct vinylogous-
Michael addition was first evaluated with pentenal 1 in
toluene using a large range of different catalysts (Table 1).
As expected in our proposal, achiral pyrrolidine did
catalyze the given reaction furnishing the expected com-
pound with the tetrasubstituted carbon center in a 4,5:1
dr, indicating that the diastereoselectivity is mainly under
substrate control (entry 1). Surprisingly, MacMillan imi-
dazolidinone 4b, the catalyst used in the addition of
silyloxyfuran, did not lead to any reaction (entry 2). Using
5 mol % of diphenylprolinol silyl ether 4c, a promising
43% conversion together with a good 90% ee was ob-
served, while only traces of the adduct were obtained with
the fluorinated catalyst 4d (entry 4).9 We recently
1
2
2
3
4
5
6
7
4a (30 mol %) toluene
4b (5 mol %) toluene
4c (5 mol %) toluene
4d (5 mol %) toluene
5a (5 mol %) toluene
5b (5 mol %) toluene
5c (5 mol %) toluene
5d (5 mol %) toluene
1
18
17
14
17
14
14
17
18
13
18
>95
0
4,5:1
9,0:1
43
90
traces
51
6,6:1
6,1:1
9,2:1
7,3:1
5,5:1
70
70
93
81
88
94
94
28
48
23
10 5c (5 mol %) MeOH
11 5c (15 mol %) toluene
12 4c (15 mol %) toluene
>95
>95 (88) 7,6:1
>95 7,6:1
a Conversion determined by 1H NMR on the reaction mixture. Yield
of isolated product in parentheses. b Determined by 1H NMR analysis.
c Determined by chiral GC for the major diasteroisomer.
introduced Aminal-PYrrolidine (APY) catalysts as
powerful tools for enamine-catalyzed reactions.10 In ad-
dition to finding better conditions for the vinylogous
Michael addition, we were highly interested to check the
behavior of this catalyst backbone in this iminium pro-
cess. Gratifyingly, our first generation catalyst 5a and 5b
derived from proline did catalyze the reaction in a pro-
mising 70% ee (entries 4 and 5). As already observed for
enamine catalysis, phenoxy derivatives of hydroxyproline
5c and 5d gave a dramatic improvement in the enantios-
electivity (entries 6 and 7). The best catalyst 5c gave an
excellent 93% ee for the phenoxy derivative compared to
the 70% ee for the proline analogue 5a. This result is
crucial in terms of mode of action of aminal-pyrrolidine.
Indeed, given the distance of the phenoxy group from the
active site, it is probable that this phenoxy group is not
only encumbering the upper face (Re face) of the iminium
but also that it has a crucial role in slightly distorting the
(8) For pioneering direct vinylogous use of furanone in asymmetric
catalysis, see: (a) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2008, 10, 2319. (b) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009,
131, 4572. (c) Shepherd, N. E.; Tanabe, H.; Xu, Y.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 3666. For recent examples of
asymmetric organocatalytic vinylogous application of furanone for the
creation of enantioenriched γ-butenolide, see: (d) Cui, H.-L.; Huang,
J.-R.; Lei, J.; Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org. Lett.
2010, 12, 720. (e) Feng, X.; Cui, H.-L.; Xu, S.; Wu, L.; Chen, Y.-C.
Chem.;Eur. J. 2010, 16, 10309. (f) Pansare, S.; Paul, E. K. Chem.
Commun. 2010, 47, 1027. (g) Ube, H.; Shimada, N.; Terada, M. Angew.
Chem., Int. Ed. 2010, 49, 1858. (h) Zhang, Y.; Yu, C.; Ji, Y.; Wang, W.
Chem. Asian J. 2010, 5, 1303. (i) Wang, J.; Qi, C.; Ge, Z.; Cheng, T.; Li,
R. Chem. Commun. 2010, 46, 2124. (j) Yang, Y.; Zheng, K.; Zhao, J.; Shi,
J.; Lin, L.; Liu, X.; Feng, X. J. Org. Chem. 2010, 75, 5382.
(9) For leading references on the application of 4c and 4d as orga-
nocatalysts, see: (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212. For reviews, see:(c) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3,
922. (d) Xu, L. W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243.
(10) For the development and applications of Aminal-PYrrolidine
catalysts, see: (a) Quintard, A.; Bournaud, C.; Alexakis, A. Chem.;Eur.
J. 2008, 14, 7504. (b) Quintard, A.; Alexakis, A. Chem.;Eur. J. 2009, 15,
11109. (c) Belot, S.; Quintard, A.; Krause, N.; Alexakis, A. Adv. Synth.
Catal. 2010, 352, 667. (d) Quintard, A.; Alexakis, A. Adv. Synth. Catal.
2010, 352, 1856. (e) Quintard, A.; Belot, S.; Marchal, E.; Alexakis, A.
Eur. J. Org. Chem. 2010, 927. (f) Quintard, A.; Alexakis, A. Chem.
Commun. 2010, 46, 4085. (g) Quintard, A.; Alexakis, A. Org. Biomol.
Chem. DOI: 10.1039/C0OB00818D. Published Online: Jan 7, 2011. (h)
Quintard, A.; Alexakis, A.; Mazet, C. Angew. Chem., Int. Ed. DOI: 10.1002/
anie.201007001. Published Online: Feb 3, 2011.
Org. Lett., Vol. 13, No. 6, 2011
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