Total synthesis and structure elucidation of (+)-phorbasin C

Full text of DOI:10.1021/ja809491b

Published on Web 01/08/2009
Total Synthesis and Structure Elucidation of (+)-Phorbasin C
Todd K. Macklin† and Glenn C. Micalizio†,*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received December 4, 2008; E-mail: micalizio@scripps.edu
The phorbasins are a class of structurally novel diterpenes isolated
from a southern Australian marine sponge (Phorbas sp.) that are
structurally related to the terrestrial carvotacetone monoterpenes
and carvone (Figure 1).1 Initial isolation of the phorbasins was
prompted by an observed growth inhibitory activity of the crude
extracts against Gram positive bacteria Staphylococcus aureus and
Micrococcus luteus. More recently, studies have identified that
members of this class possess a range of selective cytotoxic
properties.1d The structures assigned for the phorbasins remain
stereochemically incomplete, with the relative stereochemistry of
C11 undefined. Recently, the absolute stereochemistry of the family
was assigned as depicted, based on an observed positive Cotton
effect in the CD spectra of members of the class and application
of the helicity rule for conjugated transoid ketones.1d,2 Here, we
describe the first total synthesis and complete structure elucidation
of a phorbasin by a pathway that explores the utility of allylic
alcohol-alkyne reductive cross-coupling3 in target-oriented
synthesis.
Figure 1. Representative phorbasins and related structures.
Our plan for the synthesis of phorbasin C is depicted in Figure 2.
Due to the stereochemical uncertainty of C11, we aimed to assemble
the skeleton by late-stage Suzuki cross-coupling4 between a suitably
functionalized vinyl iodide 1 and each enantiomer of a stereodefined
vinylboronic ester 2.
Anticipating that subtle spectroscopic differences might exist
between the diastereomeric products resulting from these Suzuki
coupling reactions, this plan would allow for the assignment of
the relative stereochemistry of phorbasin C. We then targeted the
synthesis of 1 by functionalization of the 1,4-diene 3, itself being
expected to derive from the commercially available diol 4 and TMS-
propyne (5).5
Figure 2. Retrosynthetic strategy for phorbasin C.
As depicted in Figure 3, protection and diastereoselective
dihydroxylation of the chiral diene 4, followed by Bu3SnH-
mediated dehalogenation furnished the stereodefined diol 6 in 65%
yield (dr g20:1).6 Titanium-mediated reductive cross-coupling of
this diol with TMS-propyne, via formal metallo-[3,3] rearrangement
(A), proceeded with exquisite selectivity and furnished the stereo-
defined 1,4-diene 3.3,7 Notably, this reductive cross-coupling process
proceeds with allylic transposition, in a suprafacial manner, with
high levels of site selectivity (C-C bond formation occurs distal
to the TMS substituent of 5). Interestingly, the initial coupling
process affords a new allylic alkoxide (B) that has the potential to
serve as a substrate for an additional reductive coupling reaction.
Fortunately, no product of additional coupling was observed, a
selectivity likely due to the steric impediment imposed by the
substitution of C6 in intermediate B.
Figure 3. Preparation of stereodefined 1,4-diene 3.
(Pd(PPh3)4), AcOH, THF)11 and acylation then delivered the
stereodefined carbocycle 8 in 90% yield. Finally, synthesis of the
functionalized coupling partner 1 was completed by (1) conversion
of the vinylsilane to the corresponding vinyl iodide,12 (2) removal
of the acetonide, (3) selective oxidation to the enone, and (4) site-
selective deacylation.13
Site- and stereoselective directed epoxidation (VO(acac)2, TB-
HP),8 followed by oxidation,9 and Wittig olefination,10 provided
the vinyl epoxide 7 (Figure 4). Palladium-catalyzed substitution
Synthesis of the stereodefined coupling partner 2 followed from
conventional functionalization of the known chiral alcohol 10
(Figure 5). Oxidation,9 followed by a stereoselective Julia-Kocienski
olefination14 provided 12 in 51% yield (E:Z g 20:1). Removal of
the THP ether, followed by oxidation to the aldehyde and Takai
olefination15 delivered the vinyl iodide 13 in 44% yield (E:Z g
† Current address: Department of Chemistry, The Scripps Research Institute,
Scripps Florida; 130 Scripps Way, #3A2, Jupiter, FL 33458.
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1392 J. AM. CHEM. SOC. 2009, 131, 1392–1393
10.1021/ja809491b CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
trivial. While, isomers 15 and 16 were virtually indistinguishable
1
by H NMR spectroscopy, subtle differences in their 13C spectra
were observed. On comparison of these spectra with the natural
product, it became clear that diastereomer 16 represents the correct
structure of phorbasin C.5 The absolute stereochemistry of the
natural product was then deduced by comparing the optical rotation
20
of 16 ([R]D +124 (c 0.18, MeOH)) with the value reported for
phorbasin C ([R]D22 -131 (c 0.18, MeOH)).1c On the basis of these
grounds, we conclude that the relative and absolute stereochemistry
of phorbasin C is that depicted as ent-16 (Figure 6).
In conclusion, our efforts in chemical synthesis have led to the
first total synthesis and complete structure elucidation of a phor-
basin, a marine-derived class of natural products that possesses
selective cytotoxic and antibiotic profiles. The success of this
endeavor demonstrates the utility of our site- and stereoselective
allylic alcohol-alkyne reductive cross-coupling reaction and further
supports the role that organic synthesis plays in the structure
elucidation of bioactive natural products.16
Figure 4. Conversion of 3 to coupling partner 1.
Acknowledgment. We gratefully acknowledge financial support
of this work by the American Cancer Society (RSG-06-117-01),
the Arnold and Mabel Beckman Foundation, Boehringer Ingelheim,
and Eli Lilly & Co. The authors also thank Professor Rob Capon
for sharing detailed spectra of natural phorbasin C and for helpful
discussions, as well as Professor Tomas Hudlicky for providing
chiral diol 4.
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 5. Synthesis of the coupling partners 2S and 2R.
References
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Figure 6. Synthesis and structure elucidation of phorbasin C.
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