J. Am. Chem. Soc. 1999, 121, 9875-9876
Scheme 1
9875
Tandem Radical Cyclizations Initiated with
r-Carbonyl Radicals: First Total Synthesis of
(+)-Paniculatine
Chin-Kang Sha,* Fang-Kun Lee, and Ching-Jung Chang
Department of Chemistry, National Tsing Hua UniVersity
Hsinchu 300, Taiwan, R.O.C.
ReceiVed July 6, 1999
Paniculatine (1), magellanine (2), and magellaninone (3),
isolated from club mosses paniculatum and magellanicum, belong
to a subclass of Lycopodium alkaloids.1-3 These compounds,
possessing unique tetracyclic frameworks with 5-7 stereogenic
centers, have been challenging targets for total synthesis since
their isolation. Several promising synthetic approaches toward
construction of the tetracyclic skeleton have been reported.4 In
1994, total syntheses of magellanine (2) and magellaninone (3)
were accomplished independently by Overman via a Prins pinacol
rearrangement5 and by Paquette via a tandem Michael-Michael
addition.6 However, to date, the total synthesis of paniculatine
(1) has not been reported.
Scheme 2
In our previous work, we have demonstated that R-carbonyl
radical cyclization reactions can serve efficiently as key steps in
total syntheses of several natural products, including (()-
modhephene, (-)-dendrobine and (-)-5-oxosilphiperfol-6-ene.7
As an extension of our work in this area, we herein report the
tandem radical cyclizations8 initiated with R-carbonyl radicals as
well as their application to the first total synthesis of (+)-
paniculatine (1). The retrosynthetic analysis is shown in Scheme
1. R-Iodo ketone 6 could be prepared from enone 79 by the
conjugate addition and iodination method developed in our
laboratories.7 Grignard reagent 8 would add to enone 7 from the
R-face with stereoelectronic control.10 This conjugate addition
would establish the desired stereochemistry at C(3) in 6. Radical
generated from iodo ketone 6 would undergo a tandem radical
cyclization reaction to produce the angularly fused tricyclic ketone
5. Subsequent modification of 5, including allylic oxidation and
desilylation, should furnish enone 4. Furthermore, we anticipate
that 1,4-addition of an acetate unit to the enone moiety in 4 would
occur from the less hindered convex R-face of the BC ring and
would thus provide a handle to control the stereochemistry of
the center at the CD ring juncture. Introduction of a methylamine
unit followed by functional group modification would then afford
(+)-paniculatine (1).
Our work began with a systematic investigation on the
feasibility of the R-carbonyl radical-initiated tandem cyclization.
CuI-mediated conjugate addition of 4-(trimethylsilyl)-3-butynyl-
magnesium chloride (8) to chiral enone 9,9 followed by trapping
the resulting enolate with cholorotrimethylsilane (TMSCl), gave
trimethylsilyl enol ether 14. Without purification, crude 14 was
treated with a mixture of NaI and m-CPBA to afford the unstable
iodo ketone 19. Treatment of crude 19 with a benzene solution
of tributyltin hydride and AIBN, introduced with a syringe pump
at reflux, failed to give the expected tandem radical cyclization
product. Instead, 24 was produced exclusively (Scheme 2). The
radical cyclization apparently proceeded only to the first stage.
The expected ensuing radical cyclization failed to occur, presum-
ably because of two bulky trimethylsilyl groups on both side
chains in 19. To minimize this steric hindrance, we decided to
(1) Castillo, M.; Morales, G.; Loyola, L. A.; Singh, I.; Calvo, C.; Holland,
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10.1021/ja992315o CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/08/1999