Scheme 1. 1,3-Dioxolan-4-ones as Potential Pro-nucleophiles
in Enantioselective Organocatalytic Additions to Electrophiles
Figure 1. DABCO and cinchonine derived organocatalysts.
encouraging; heterocycle 2a, derived from mandelic acid and
acetone,5 reacted with trans-â-nitrostyrene with DABCO
(10%) as catalyst in THF at 30 °C but the conversion was
<5% after 14 days (Table 1, entry 1). Ascribing this to an
(X ) Y). Additionally, the use of such pro-nucleophiles
would provide adducts with an activated ester moiety, which
could undergo hydrolysis, aminolysis, and alcoholysis reac-
tions to yield a range of useful chiral building blocks
containing up to two adjacent, and possibly fully substituted,
stereocenters.4
Table 1. Catalyst Screen and Reaction Condition
Optimizationa
Here, we present our findings on the use of 5-aryl-1,3-
dioxolan-4-ones as pro-nucleophiles in the enantioselective
organocatalytic Michael addition to nitro olefins. The
subsequent manipulation of the adducts, exploiting the natural
reactivity of the carbonyl group, is also reported.
Proof of reactivity studies were required to assess whether
the acidity/nucleophilicity profile of selected 1,3-dioxolan-
4-ones was sufficient for the direct organocatalyzed Michael
addition to nitro olefins. A preliminary study was partially
temp
(°C)
de
ee
entry cat.
R
solvent
convn (%)b (%)b (%)c
1
2
1ad Me
1ad CF3
THF
THF
30
30
0
0
0
0
0
0
0
<5e
>98f
>60g
>98h
>98g
>80g
>98g
>40g
>40g
>85g
>98
>80
>98
>85
>98
>95
>90
>90
>80
3
4
5
6
7
8
9
1c
1c
1c
1b
1d
1e
1f
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
DCM
PhMe
TBME
DCM
DCM
DCM
DCM
DCM
65
76
57
43
70
51
26
56
(3) For recent applications of epi-9-amino-9-deoxy cinchona alkaloid
derivatives as bifunctional organocatalysts, see: (a) Li, B.; Jiang, L.; Liu,
M.; Chen, Y.; Ding, L.; Wu, Y. Synlett 2005, 603. (b) Vakulya, B.; Varga,
S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967. (c) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (d) Lou, S.; Taoka,
B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256. (e)
To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.;
Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086. (f) Ye,
J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. (g) Tillman, A.
L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (h) Song, J.; Wang,
Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (i) Wang, Y. Q.; Song,
J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156. (j) Wang,
J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem.
Soc. 2006, 128, 12652. (k) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli,
A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew.
Chem., Int. Ed. 2006, 45, 4966. (l) Bode, C. M.; Ting, A.; Schaus, S. E.
Tetrahedron 2006, 62, 11499. (m) Liu, T.; Cui, H.; Long, J.; Li, B.; Wu,
Y.; Ding, L.; Chen, Y. J. Am. Chem. Soc. 2007, 129, 1878. (n) Song, J.;
Shih, H.; Deng, L. Org. Lett. 2007, 9, 603. (o) McCooey, S. H.; Connon,
S. J. Org. Lett. 2007, 4, 599. (p) Wang, B.; Wu, F.; Wang, F.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (q) Chen, W.; Du, W.; Yue,
L.; Li, R.; Wu, Y.; Ding, L.; Chen, Y. Org. Biomol. Chem. 2007, 5, 816.
(r) Xie, J.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.; Wu,
Y.; Zhu, J.; Deng, J. Angew. Chem., Int. Ed. 2007, 46, 389. (s) Xie, J.;
Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.; Chen, Y. Org. Lett. 2007, 3,
413. (t) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J.
Am. Chem. Soc. 2006, 128, 3830. (u) Biddle, M. M.; Lin, M.; Scheidt, K.
A. J. Am. Chem. Soc. 2007, 129, 3830. For mechanistic studies utilizing
the cinchona alkaloids, see: (v) Kumar, A.; Salunkhe, R. V.; Rane, R. A.;
Dike, S. Y. Chem. Commun. 1991, 485. (w) Li, H.; Wang, Y.; Tang, L.;
Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed.
2005, 44, 105. (x) Hamza, A.; Schubert, G.; Soo´s, T.; Pa´pai, I. J. Am. Chem.
Soc. 2006, 128, 13151.
10
1g
0
a Reaction was carried out with 2 (1.0 equiv), 3a (0.5 equiv), and 1b-g
(0.05 equiv) in solvent (1.0 M in 3). b Determined by 1H NMR. c Determined
by HPLC analysis with a chiral column. d 0.1 equiv used. e After 14 days.
f After 96 h. g After 72 h. h After 48 h.
insufficiently low pKa of 2a, we then investigated the
analogous heterocycle 2b where the methyl groups had been
substituted by trifluoromethyl groups.6 This switch was
necessary to lower the pKa sufficiently to allow enolization
and hence activation by the amine base; Michael adduct 4b
was formed smoothly and efficiently with DABCO in THF
at 30 °C for 96 h. In addition, the diastereoselectivity of
this tertiary amine catalyzed process was excellent (>98%;
Table 1, entry 2).
Having established a good reactivity profile with 2b and
trans-â-nitrostyrene, a screen of a small library of cincho-
(4) For examples of the use of chiral dioxolan-4-ones in stereoselective
Michael reactions, see: (a) Blay, G.; Ferna´ndez, I.; Monje, B.; Pedro, J.
R.; Ruiz, R. Tetrahedron Lett. 2002, 43, 8463. (b) Blay, G.; Ferna´ndez, I.;
Monje, B.; Pedro, J. R. Tetrahedron 2004, 60, 165. (c) Aitken, R. A.;
McGill, S. D.; Power, L. A. ARKIVOC 2006, 7, 292.
(5) Coote, S. J.; Davies, S. G.; Middlemass, D.; Naylor, A. J. Chem.
Soc., Perkin Trans. 1 1989, 2223.
(6) Radics, G.; Koksch, B.; El-Kousy, S. M.; Spengler, J.; Burger, K.
Synlett 2003, 1826.
2108
Org. Lett., Vol. 9, No. 11, 2007