Progress toward the total synthesis of bielschowskysin: A stereoselective [2 + 2] photocycloaddition

Article abstract of DOI:10.1021/ol0530225

The tetracyclic core of the diterpene bielschowskysin has been prepared as a single enantiomer via a stereoselective intramolecular [2 + 2] photocycloaddition of 5-alkylidene-2(5H)-furanone 3.

Full text of DOI:10.1021/ol0530225

ORGANIC
LETTERS
2006
Vol. 8, No. 5
903-906
Progress toward the Total Synthesis of
Bielschowskysin: A Stereoselective
[2
+ 2] Photocycloaddition
Brandon Doroh and Gary A. Sulikowski*
Department of Chemistry, Vanderbilt UniVersity, NashVille, Tennessee 37235
gary.a.sulikowski@Vanderbilt.edu
Received December 13, 2005
ABSTRACT
The tetracyclic core of the diterpene bielschowskysin has been prepared as a single enantiomer via a stereoselective intramolecular [2
photocycloaddition of 5-alkylidene-2(5H)-furanone 3.
+ 2]
Gorgonian octacorals are the most plentiful source of
octacorals in the West Indies. With over 190 documented
species in this family, these marine organisms have proven
to be an excellent source of biologically active metabolites.1
Recently, there has been interest in the reef-dwelling sea
plume Pseudopterogorgia kallos as it has been shown to
produce a wide range of structurally interesting diterpenes
displaying a broad spectrum of bioactivities.2
Rodriguez and co-workers have reported the isolation of
Figure 1. Structure of bielschowskysin.
the novel diterpene bielschowskysin (Figure 1) from P. kallos
collected near Old Providence Island off the coast of
Columbia.3 Bielschowskysin is a highly oxygenated hexacy-
While the relative configuration has been established via
X-ray crystal analysis, the absolute configuration has yet to
be assigned.
clic diterpene that incorporates 11 stereocenters (seven
contiguous) and a novel [9.3.0.02,10] tetradecane ring system.
Bielschowskysin demonstrated strong in vitro cytotoxicity
against small cell lung cancer and renal cancer cells.3
Furthermore, it exhibits antiplasmodial activity against
Plasmodium falciparum with an IC50 ) 10 µg/mL. Owing
to its intriguing architecture and our interest in the design
of synthetic strategies for the purpose of investigating
biological properties of natural products, we are currently
exploring a route toward the synthesis of this diterpene and
(1) Review: Rodriquez, A. D. Tetrahedron 1995, 51, 4571-4618.
(2) (a) Look, S. A.; Burch, M. T.; Fenical, W. J. Org. Chem. 1985, 50,
5741-5746. (b) Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis, R. G. J.
Org. Chem. 2003, 68, 4977-4979. (c) Marrero, J.; Rodriguez, A. D.; Baran,
P.; Raptis, R. G. Org. Lett. 2003, 5, 2551-2554. (d) Marrero, J.; Rodriguez,
A. D.; Baran, P.; Raptis, R. G. Eur. J. Org. Chem. 2004, 3909-3912.
(3) Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis, R. G.; Sa´nchez, J.
A.; Ortega-Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661-1664.
(4) (a) Brown, G. D.; Wong, H. F. Tetrahedron 2004, 60, 5439-5451.
(b) Gedge, D. R.; Pattenden, G.; Smith, A. G. J. Chem. Soc., Perkin Trans.
1 1986, 2127-2131.
(5) Saito, S.; Hasegawa, T.; Inaba, N.; Nishida, R.; Fujii, T.; Nomizu,
S.; Muriwake, T. Chem. Lett. 1984, 1389-1392.
(8) Duboudin, J. G.; Jousseaume, B.; Bonakdar, A. J. Organomet. Chem.
1979, 168, 227-238.
(9) (a) Kotora, M.; Negishi, E. Synthesis 1997, 121-128. (b) For a review
on the synthesis of γ-alkylidene butenolides, see: Negishi, E.; Kotora, M.
Tetrahedron 1997, 53, 6707.
(6) (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett.
1988, 29, 5419-5433. (b) Mori, Y.; Suzuki, M. J. Chem. Soc., Perkin Trans.
1 1990, 1809-1812.
(7) Meyers, A. J.; Lawson, J. P.; Walker, D. G.; Linderman, P. J. J.
Org. Chem. 1986, 51, 5111-5123.
(10) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
10.1021/ol0530225 CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/31/2006

herein report the preparation of the tetracyclic core (1) of
bielschowskysin employing a stereoselective intramolecular
[2 + 2] photocycloaddition.
Scheme 2
We reasoned that the congested tetracyclic intermediate
1 would be a good candidate for construction via an
intramolecular [2 + 2] photocycloaddition of the appropriate
5-alkylidene-2(5H)-furanone 2 (Scheme 1). Here, a key issue
Scheme 1
Silyl protection of the primary alcohol 9 was undertaken
in order to examine elaboration of the terminal acetylene to
the γ-alkylidene butenolide moiety. This was to be followed
by release of the primary alcohol and construction of the
second butenolide ring (cf. 3, Scheme 1). To this end,
Sonogashira coupling with Z-vinyl iodide 118 was followed
by a standard two-step oxidation leading to carboxylic acid
13 (Scheme 3). Silver-catalyzed cyclization yielded γ-alky-
Scheme 3
to be addressed was the stereoselectivity of the photocy-
cloaddition and its dependence on the starting double bond
geometry (vis a` vis 2 and 3). In the forward sense, the
Z-olefin 3 would be readily accessed by a silver-catalyzed
cycloisomerization of eneyne 4. Irradiation of 3 was antici-
pated to rapidly lead to a mixture of double bond isomers 2
and 3.4 The overall stereoselectivity of the cycloaddition,
particularly the configuration of the C6 quaternary carbon
(cf. 1), would need to be determined by experimentation.
The carboxylic acid 4 was anticipated to be generated from
alkynyl alcohol 5, which itself may be prepared from (-)-
malic acid.
The ester 6 has been prepared previously starting from
malic acid and served as the starting point for the synthesis.5
It was converted directly to the methyl ketone 7 via in situ
formation of the Weinreb amide and reaction with methyl-
magnesium bromide.6 Chelation-controlled addition of ethy-
nylmagnesium bromide to ketone 7 was achieved in good
yield and selectivity to provide a 4:1 mixture of alcohols 5
and 8 (Scheme 2).
As our synthetic strategy developed, we required protection
of the tertiary and secondary alcohols of 5 and unique
differentiation of the remaining primary alcohol. Meyers and
co-workers reported that treatment of an acetonide-protected
triol, related to 5, with mesitaldehyde dimethyl acetal under
acidic conditions led to exchange of the acetonide group for
a 1,3-dioxane leaving the primary alcohol uprotected.7
Indeed, treatment of 5 with camphorsulfonic acid and
mesitaldehyde dimethyl acetal affected exchange of the five-
membered acetonide ring for 1,3-dioxane acetal to give
alcohol 9 with the desired protecting group pattern.
lidene buteneolide 14 as a crystalline solid.9 X-ray analysis
of this product confirmed the assigned configuration of the
stereocenter resulting from the alkyne addition to ketone 7
as well as the double-bond geometry of the γ-alkylidene
butenolide produced from the cycloisomerization of 13.
Unfortunately, elaboration of alcohol 14 to butenolide 3
proved to be difficult, and this approach to 3 was abandoned.
904
Org. Lett., Vol. 8, No. 5, 2006

A second approach to bis-butenolide 3 that circumvents
difficulties encountered in our first reaction sequence is
shown in Scheme 4. Experience demonstrated that early
ene acetal 19 with aqueous acetic acid at room temperature
led to butenolide formation and completion of 3.
Irradiation of a chloroform solution of 3 with a sun lamp
for 2 h led to an approximately 3.6:1 mixture of geometric
isomers 3 and 2 as determined by 1H NMR analysis.
Continued irradiation of a chloroform solution of 3 and 2
resulted in consumption of both isomers and production of
a complex mixture of products. Upon replacing chloroform
with acetone, a similar equilibration-cyclization sequence
was observed on irradiation with a sun lamp; however, in
this case far fewer side products were observed. Moreover,
a 5:1 mixture of [2 + 2] photoadducts was isolated in 50%
yield with the major product assigned the structure of the
desired photoadduct 1. Initially, the stereochemical assign-
ment of 1, and most significantly the C6 sterecenter, rested
on an observed NOE between the â hydrogen of the
butenolide and the endo-oriented methyl group. The assign-
ment of 1 was later confirmed by single-crystal X-ray
analysis (Scheme 4).
Scheme 4
The intramolecular [2 + 2] photocycloaddition of buteno-
lides 2 and 3 likely follows the so-called rule of five leading
to intermediate 1,4-biradicals 2a and 3a (Figure 2), respec-
Figure 2. Model for observed diastereoselectivity of [2 + 2]
Still-Gennari olefination10 resulted in higher yields and
stereoselectivity when compared to olefination reactions after
construction of the γ-alkylidene butenolide (vide supra).
Also, delayed completion of the butenolide avoided undesired
Michael addition of the tertiary alcohol to the neighboring
butenolide. Therefore, Z-enoate 16 was directly subjected
to Sonogashira coupling conditions to yield allylic alcohol
17. Consecutive oxidations afforded the carboxylic acid 18
in acceptable overall yield. Silver nitrate catalyzed cyclization
under Negeshi’s conditions afforded alkylidene buteneolide
19 as a single geometric isomer. Finally, treatment of mesityl-
photocycloaddition.
tively.11 Weedon and Maradyn, who trapped triplet 1,4-
biradicals using hydrogen selenide, provided evidence for
the intermediacy of 1,4-biradicals and the appropriateness
of the rule of five in intramolecular photocycloadditions.12
Extending this model to substrates 2 and 3, triplet 1,4-
(11) (a) Liu, R. S.; Hammond, G. S. J. Am. Chem. Soc. 1967, 89, 4936-
4944. (b) Carlough, K. H.; Srinivasa, R. J. Am. Chem. Soc. 1967, 89, 4932-
4936.
Org. Lett., Vol. 8, No. 5, 2006
905

biradicals 2a and 3a could interchange by one of two
mechanisms. First, simple bond rotation could lead to rapid
interconversion of triplet biradicals 2a and 3a. A second
pathway involves simple reversion of 2a and 3a to starting
γ-alkylidene butenolides 2 and 3, respectively, which our
photochemical experiments showed interchange by simple
photoisomerization. By either of these two mechanisms the
favored production of photoadduct 1 by closure of 2a may
be explained by the development of unfavorable dipole and/
or electrostatic interactions in the alternative closure of 1,4-
biradical 3a to 20.13
diterpene bielschowskysin. Current efforts are directed
toward completion of the total synthesis of bielschowskysin
using the reported photocycloaddition as a key step.
Acknowledgment. We thank the National Institutes of
Health (GM067726-02) and the Vanderbilt Institute of
Chemical Biology for financial support. We also thank
Joseph Reibenspies (Center for Chemical Characterization
and Analysis, Texas A&M University) for determining the
X-ray crystal structures of 1 and 14.
In conclusion, we have described a concise and stereo-
controlled assembly of the tetracyclic core (1) of the marine
Supporting Information Available: Full characterization
data and experimental procedures for 1, 3, 5, 9, and 15-19.
X-ray data for compounds 1 and 14. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Maradyn, D. J.; Weedon, A. C. J. Am. Chem. Soc. 1995, 117, 5359-
5360.
(13) Crimmins, M. T.; King, B. W.; Watson, P. S.; Guise, L. E.
Tetrahedron 1997, 53, 8963-8974.
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Org. Lett., Vol. 8, No. 5, 2006