Journal of the American Chemical Society
ARTICLE
the N,O-aminal was observed by 1H NMR analysis of the crude
material prior to cyclization with silica gel.
supported by the NIH Division of Research Resources. We
thank Johnson Matthey for their generous gift of palladium
salts. J.D.S. thanks the American Cancer Society for a post-
doctoral fellowship.
With the successful reductive cyclization in hand, the pyrro-
lidinoinoline core of the gliocladins could be accessed from the
allene hydrocarbonation reaction in an efficient and highly
enantioselective manner. This methodology therefore represents
a convenient protocol to prepare this class of functional unit and
may be applied to other alkaloids possessing this structural motif.
Additionally, access to gliocladin C from advanced intermediate
39 can be envisioned to arise from global N-deprotection and
installation of the final trioxopiperazine ring with concomitant
dehydration according to the reaction sequence described by
Overman and co-workers.15b
’ REFERENCES
(1) Reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395. (b) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258. (c) Trost,
B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (d) Trost, B. M.;
Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427.
(2) Trost, B. M. Science 1991, 254, 1471.
(3) For reviews on atom-economic reactions, see: (a) Trost, B. M.;
Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067. (b) Trost,
B. M. Acc. Chem. Res. 2002, 35, 695. (c) Trost, B. M.; Frederiksen, M. R.;
Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630. (d) Li, C. Acc. Chem.
Res. 2010, 43, 581. (e) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem.
Rev. 2010, 110, 5447. (f) Aubert, C.; Fensterbank, L.; Garcia, P.;
Malacria, M.; Simmonneau, A. Chem. Rev. 2011, 111, 1954. (g) Corma,
A.; Leyva-Prez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (h) Yu,
D.-G.; Li, B.-J.; Shi, Z.-T. Acc. Chem. Res. 2010, 43, 1486. (i) You, S. ꢀL.;
Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190. (j) Abu, S.; Shariar, M.;
Liu, R.-S. Chem Soc. Rev. 2009, 38, 2269. (k) McGlacken, G. P.; Bateman,
L. M. Chem. Soc. Rev. 2009, 38, 2447. (l) Ganem, B. Acc. Chem. Res. 2009,
42, 463. (m) Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011,
50, 4760. (n) Yadav, J. S.; Antony, A.; Rao, T. S.; Reddy., B. V. S.
J. Organomet. Chem. 2011, 696, 16. (o) Alonso, F.; Foubelo, F.;
Gonzꢀalez-Gꢀomez, T. C; Martínez, R.; Ramꢀon, D. J.; Riente, P.; Yus,
M. Mol. Diversity 2010, 14, 411. (p) Fustero, S.; Sanchez-Rosello, M.; del
Pozo, C. Pure Appl. Chem. 2010, 82, 669. (q) Li, C.-J.; Trost, B. M. Proc.
Natl. Acad. Sci. U.S.A. 2008, 105, 13197. (r) Kondo, T. Synlett 2008,
5, 692. (s) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(4) (a) Trost, B. M.; Gerusz, V. J. J. Am. Chem. Soc. 1995, 117, 5156.
(b) Trost, B. M.; Simas, A. B. C.; Plietker, B.; J€akel, C.; Xie, J. Chem.
Eur.—J. 2005, 11, 7075. (c) Trost, B. M.; Xie, J. J. Am. Chem. Soc. 2006,
128, 6044. (d) Trost, B. M.; Xie, J. J. Am. Chem. Soc. 2008, 130, 6231.
(e) Trost, B. M.; J€akel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438.
(5) For nonenantioselective variants, see: (a) Yamamato, Y.; Al-
Masum, M.; Asao, N. J. Am. Chem. Soc. 1994, 116, 6019. (b) Yamamoto,
Y. Tetrahedron Lett. 1995, 36, 2811.
’ CONCLUSION
In conclusion, we have developed a useful atom economical
Pd-catalyzed allene hydrocarbonation reaction employing oxi-
ndoles as nucleophiles that allows for the formation of formal
AAA reaction products without the use of the typical allyl equiva-
lents bearing activated leaving groups required in AAA chemistry.
This methodology proceeds with high branched regioselectivity to
allow for the formation of valuable chiral oxindoles bearing two
vicinal stereocenters, with one being quaternary, in excellent yields,
diastereoselectivities, and enantioselectivities. The reaction condi-
tions are extremely mild, which allows for the use of oxindole nucleo-
philes bearing sensitive functional groups (i.e., thienyl-groups or
unprotected indoles), and sterically demanding oxindoles (i.e.,
ortho-substituted 3-aryloxindoles) can also be used. The choice of
acid cocatalyst in the reaction has a significant impact on reaction
selectivity, which we believe is the result of a Pd(II)+/conjugate base
ion pair intermediate, whereby the conjugate base is involved in
organizing the transition state. Additionally, the “wall-and-flap”24a,25
model for the Trost-family of chiral ligands can be used to rationalize
the observed stereochemical outcome in the reactions. We have
shown that this method can be extended to the less acidic 3-alkyl-
oxindoles as well by employing reaction conditions that favor ketoꢀ
enol tautomerization. Lastly, we have demonstrated the utility of this
methodology by conversion of the 3,3-disubstituted oxindole pro-
ducts from the hydrocarbonation reaction to the pyrrolidinoindo-
line core of the gliocladin natural products in a convenient and
efficient manner, and this may have application to other alkaloid
natural products bearing this structural motif. Overall, this metho-
dology adheres to the criteria of chemoselectivity, regioselectivity,
diastereoselectivity, enantioselectivity, and atom economy.
(6) Review: Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Kahn, F. A.
Chem. Rev. 2000, 100, 3067.
(7) (a) Diazonamide, A; Lindquist, N.; Fenical, W.; Van Duyne,
G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303. (b) Structural
revision: Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran, P. G.
Angew. Chem., Int. Ed. 2001, 40, 4770. (c) Gliocladin: Usami, Y.;
Yamaguchi, J.; Numata, A. Heterocycles 2004, 63, 1123. (d) Leptosin,
D; Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.; Araki, H.; Iwaki,
H.; Kushida, K. J. Chem. Soc., Perkin Trans. 1 1994, 1859. (e) Spiro-
tryprostatin: Cui, C. ꢀB.; Kakeya, H.; Okada, G.; Onose, R.; Osada, H.
J. Antibiot. 1996, 49, 527. (f) Javaniside: Ma, J.; Hecht, S. M. Chem.
Commun. 2004, 1190. (g) Gelsemine: Conroy, H.; Chakrabarti, J. K.
Tetrahedron Lett. 1959, No. 4, 6. (h) Communesin: Numata, A.;
Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura,
E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355.
(i) Physostigmine: Takano, S.; Ogasawara, K. Alkaloids 1989, 36, 225.
(j) Perophoramidine: Verbitski, S. M.; Mayne, C. L.; Davis, R. A.;
Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(8) For a review on catalytic asymmetric methods for the synthesis of
quaternary stereocenters, see: Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization data for all new compounds. This material is
’ AUTHOR INFORMATION
Corresponding Author
(9) (a) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org.
Chem. 1993, 58, 6949. (b) Matsuura, T.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6500. (c) Lebsack, A. D.; Link, J. T.;
Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124, 9008.
(d) Dounay, A.; Hatanaka, K.; Kodanko, J.; Oestreich, M.; Overman,
L. E.; Pfeifer, L.; Weiss, M. J. Am. Chem. Soc. 2003, 125, 6261. (e) For a
review on the of the asymmetric Heck reaction in the total synthesis of
’ ACKNOWLEDGMENT
We thank (GM-033049) National Science Foundation and
National Institutes of Health for their generous support of our
programs. Mass Spectra were provided by the Mass Spectro-
metry Regional Center of the University of California—San Francisco,
20621
dx.doi.org/10.1021/ja209244m |J. Am. Chem. Soc. 2011, 133, 20611–20622