ORGANIC
LETTERS
2012
Vol. 14, No. 17
4354–4357
Rapid Construction of the Aza-Propellane
Core of Acutumine via a Photochemical
[2 þ 2] Cycloaddition Reaction
Raul Navarro and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California 91125, United States
Received June 29, 2012
ABSTRACT
Synthetic efforts toward the chlorinated aza-propellane alkaloid acutumine (1) are described. The key vicinal quaternary centers were constructed
by a photochemical [2 þ 2] cycloaddition reaction of a furanyl-tetrahydroindolone. Dihydroxylation of the [2 þ 2] product enabled a tandem retro-
aldol/intramolecular ketalization reaction, which revealed the aza-propellane core of 1 while generating an unusual, caged, pentacyclic hemiketal
product.
Acutumine (1, Scheme 1) is a chlorinated aza-propellane
alkaloid first isolated in 1929 by Goto and Sudzuki from
the medicinal herb Sinomenium acutum.1,2 This densely
functionalized small molecule exhibits promising biologi-
cal properties, including selective T-cell cytotoxicity3
and antiamnesic activity.4 The aza-propellane skeleton is
adorned with a spirocyclic cyclopentenone moiety and
contains a neopentyl chloride and two all-carbon quater-
nary centers embedded within five contiguous stereogenic
carbons. Although its structural and biological features
have attracted attention from the synthetic community,5
only a single enantioselective synthesis of the alkaloid has
been reported to date.6
As a part of our program aimed at developing a unified
synthetic strategy toward several structurally distinct aza-
propellane alkaloids, we recently reported the preparation
of N-tert-butanesulfinimine 9 (see Scheme 2), a compound
that undergoes highly diastereoselective 1,2-addition reac-
tions with a variety of organometallic reagents.7ꢀ9 Based
on these findings, we were able to complete concise total
syntheses of the hasubanan alkaloid 8-demethoxyruna-
nine, as well as the structurally related compounds cephar-
atines A, C, and D.7 Herein, we report that addition of
furanyl-based nucleophiles to N-tert-butanesulfinimine 9
enables the rapid construction of the aza-propellane core
of acutumine by a photochemical [2 þ 2] cycloaddition/
retro-aldol sequence.
(1) Original isolation paper: Goto, K.; Sudzuki, H. Bull. Chem. Soc.
Jpn. 1929, 4, 220.
(2) Structural assignment: (a) Tomita, M.; Okamoto, Y.; Kikuchi,
T.; Osaki, K.; Nishikawa, M.; Kamiya, K.; Sasaki, Y.; Matoba, K.;
Goto, K. Chem. Pharm. Bull. 1971, 19, 770. (b) Tomita, M.; Okamoto,
Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya, K.; Sasaki, Y.;
Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 2421. (c) Tomita, M.;
Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya, K.;
Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 2425.
(3) Yu, B.-W.; Chen, J.-Y.; Wang, Y.-P.; Cheng, K.-F.; Li, X.-Y.;
Qin, G.-W. Phytochemistry 2002, 61, 439.
(4) Qin, G.-W.; Tang, X.-C.; Lestage, P.; Caignard, D.-H.; Renard,
P. PCT Int. Appl. WO 2004000815, 2003.
(5) For synthetic studies toward acutumine, see: (a) Nguyen, T. X.,
Ph.D. Thesis, University of California, San Diego, 2009. (b) Moreau,
R. J.; Sorensen, E. J. Tetrahedron 2007, 63, 6446.
(6) (a) Li, F.; Tartakoff, S. S.; Castle, S. L. J. Am. Chem. Soc. 2009,
131, 6674. (b) Li, F.; Tartakoff, S. S.; Castle, S. L. J. Org. Chem. 2009, 74,
9082.
(7) Chuang, K. V.; Navarro, R.; Reisman, S. E. Angew. Chem., Int.
Ed. 2011, 50, 9447.
(8) Chuang, K. V.; Navarro, R.; Reisman, S. E. Chem. Sci. 2011, 2,
1086.
(9) For a seminal report regarding N-tert-butanesulfinimines:
Ellman, J. A.; Cogan, D. A. J. Am. Chem. Soc. 1999, 121, 268.
r
10.1021/ol3017963
Published on Web 08/14/2012
2012 American Chemical Society