C O M M U N I C A T I O N S
Table 2. Addition of Oxindoles to Nitroolefins
References
(1) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b) Rahman,
A. U.; Basha, A. Indole Alkaloids; Harwood Academic Publishers:
Amsterdam, 1997.
(2) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477. (b) Doumay, A. B.; Hatanaka, K.; Kodanko, J. J.;
Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem.
Soc. 2003, 125, 6261.
entry
R
R1
product
yield (%)a
drb
ee (%)c
(3) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308. (b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (c)
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
(4) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(5) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921.
(6) Kozlowski, M. C.; Linton, E. C. J. Am. Chem. Soc. 2008, 130, 16162.
(7) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872.
(8) (a) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131,
14. (b) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs,
E. J. Am. Chem. Soc. 2006, 128, 925.
(9) Reviews on organocatalysts, including urea and thiourea catalysts: (a)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (b)
Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (c) Connon,
S. J. Synlett 2009, 354. (d) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc.
Jpn. 2008, 81, 785.
(10) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(11) (a) Herrea, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576. (b) See ref 21.
1
2
3
4
5
6
7
8
Me
Et
allyl
cinamyl
4-Br-Bn
allyl
allyl
allyl
allyl
allyl
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
96
95
89
90
86
92
91
91
92
72
97
95
68
10:1
5:1
6:1
11:1
5:1
6:1
9:1
5:1
7:1
3:1
99
96
94
92
88
91
95
90
92
89
99
94
93
4-Br-C6H4
3-Br-C6H4
4-MeO-C6H4
4-OH-C6H4
3,4-Cl2-C6H3
2-furyl
9
10
11
12
13
4j
4k
4l
allyl
allyl
allyl
6:1
>20:1
>20:1
n-C7H15
(MeO)2CH
4m
a Isolated yield. b Determined by 1H NMR analysis of the crude
reaction mixture. c Determined by chiral-phase HPLC analysis.
Scheme 1
(12) (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
(b) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919.
(13) (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. (b) Tsogoeva,
S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.; Huthmacher, K.
Eur. J. Org. Chem. 2005, 4995. (c) Huang, H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2006, 128, 7170.
(14) (a) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185.
(b) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y. Tetrahedron
2006, 62, 365. (c) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006,
128, 6048.
(15) Aldol and Mannich reactions using oxindoles as nucleophiles: (a) Ogawa,
S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2007, 46, 8666. (b) Tian, X.; Jiang, K.; Peng, J.; Du, W.;
Chen, Y.-C. Org. Lett. 2008, 10, 3583.
(16) There is a single report on the use of oxindoles as nucleophiles in 1,4-
additions to R,ꢀ-unsaturated aldehydes with moderate ee: Galzerano, P.;
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem. Eur. J. [Online early access]. DOI:
10.1002/chem.200802466. Published Online: Jan 29, 2009.
(17) Related catalytic oxygenation and fluorination of oxindoles: (a) Ishimaru,
T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanesmasa, S. J. Am.
Chem. Soc. 2006, 128, 16488. (b) Ishimaru, T.; Shibata, N.; Horikawa, T.;
Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed.
2008, 47, 4157.
(18) Reviews of asymmetric conjugate additions to nitroolefins: (a) Berner,
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877. (b) Almasi,
D.; Alonso, A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(19) Pioneering work on the development of cinchona-derived thiourea catalysts: (a)
Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
(b) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
(20) The cinchona alkaloid catalysts hydroquinine, hydroquinidine, and (DHQD)2-
PHAL gave 0, 10, and 28% ee, respectively. These results imply that a chiral
tertiary amine alone is not sufficient for attaining high asymmetric induction.
(21) Catalyst 3c: Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558.
(22) The pyrrole nitrogen was not basic enough to affect this transformation.
(23) Thiourea-catalyzed additions of 1,3-carbonyl compounds to nitroolefins: (a)
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
(b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
most of these cases. Heteroaromatic nitroolefins were also viable
substrates (entry 11). More interestingly, the addition reaction of
aliphatic nitroolefins proceeded smoothly to afford products 4l and
4m in moderate to good yields with high dr and ee (entries 12-13).
Both relative and absolute configurations at the two newly created
centers were established by X-ray dispersion analysis of a sulfonamide
derived from product 4a.25 The configuration of the stereogenic center
at C3 was R and that at the remaining stereocenter was S. These data
indicated that compound 4n might be further elaborated to give (+)-
esermethole, which is a known intermediate in the synthesis of (+)-
physostigmine.26
To illustrate the synthetic utility of this methodology and further
confirm the absolute stereochemistry of this reaction, we undertook
the formal synthesis of (+)-physostigmine. The addition of oxindole
2f to nitroethylene in the presence of catalyst 3e (10 mol %)
afforded product 4n with 83% ee (Scheme 1).27-29 A single
recrystallization provided 4n with 96% ee. Raney nickel reduction
of this compound followed by methyl carbamate formation provided
the key intermediate 5n, which underwent reductive cyclization to
afford (+)-esermethole in 72% overall yield over three steps.30
In summary, we have demonstrated a novel organocatalytic
approach to the synthesis of pyrrolidinoindolines using 1,4-addition
of oxindole derivatives to nitroolefins as a key step. The addition
reaction was general with respect to oxindoles and nitroolefins and
provided the desired products bearing a chiral quaternary center at
C3 in good yield with good to excellent dr and ee. These features
make this method synthetically viable and attractive, as illustrated
in the formal synthesis of (+)-physostigmine. Further investigations
of the scope and synthetic utility of this chemistry are underway,
and the results will be reported in due course.
(24) Methylene chloride was an effective solvent for 3f-mediated catalysis, but
both the dr and ee were slightly lower than when chloroform was used as
solvent (entry 12 vs 11).
(25) See the Supporting Information.
(26) Selected previous syntheses of (-)-physostigmines: (a) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. (b)
Asakawa, K.; Noguchi, N; Takashima, S.; Nakada, M. Tetrahedron:
Asymmetry 2008, 19, 2304. (c) See refs 3b and 7.
(27) Use of nitroethylene as an acceptor in amine-catalyzed asymmetric Michael
reactions of aldehydes: Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am.
Chem. Soc. 2008, 130, 5608.
(28) With 3f, the reaction stalled, perhaps because of catalyst poisoning or the
polymerization of nitroethylene. 3e provided similar ee’s when the reaction
was performed between-15 and-20 °C; the former gave a slightly better yield.
THF was used instead of chloroform because of the solubility characteristics
of 2f.
Acknowledgment. This research was supported by The Skaggs
Institute for Chemical Biology.
(29) With the N-methyl protecting group, there was no reaction. We believe the
Boc protecting group enhanced the acidity of the methine proton, thereby
allowing the enolization of 2f to be more facile.
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, and a transition state
proposal. This material is available free of charge via the Internet at
(30) The absolute configuration of (+)-esermethole was determined by comparing
the optical rotation of the synthesized material with the literature value.
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