Blakemore et al.
SCHEME 1
With the natural source of polycavernosides having
vanished, toxicological studies of 1 and its congeners
remain incomplete, and the precise cause of the human
fatalities in Guam is uncertain. This situation presents
an irresistible invitation to synthesis, and the challenge
has been met by two elegant syntheses of polycavernoside
A, the first by Murai5 and the second by Paquette.6,7 Our
own approach to 1 differs significantly from both of these
syntheses and has been disclosed in preliminary form.8
We now describe details of our approach which led to the
successful asymmetric synthesis of polycavernoside A and
which confirmed its absolute configuration as represented
by 1.
The synthesis plan for polycavernoside A as initially
conceived is shown in Scheme 1, but in the event, this
blueprint served only to guide us toward the major
subunits, i.e., 2, 3, and 4, and left the critical issue of
uniting them to improvisation. Attachment of the disac-
charide appendage to the aglycon core of polycavernoside
A appeared to be the most straightforward connection
and was envisioned by glycosidation at C-5 with an
activated form of a suitably protected fucopyranosylxy-
lopyranoside 2. A late-stage elaboration of the all-trans
triene side chain was projected via Stille coupling using
a metallodiene 3, and the aglycon itself would be as-
sembled by macrolactonization of seco acid 4 in a process
which we hoped could be carried out with much of the
polycavernoside functionality already in place. A key
question with 4 was how the bond between C-9 and C-10
would be forged since this was the locus at which we
planned to connect northern and southern fragments of
the seco acid. Two methods for this bond construction
were examined, only one of which was successful.
on the aglycon of polycavernoside A became focused on
the enantiomeric version of the structure now known to
be correct (Scheme 2). The two subunits initially pro-
grammed for assembling seco acid 5 were tetrahydropy-
ran 6 and dithiane 7, the key C-9,10 bond formation being
performed via nucleophilic attack at the aldehyde of 6
by the R-thianyl anion of 7. The latter was foreseen as
the product of two primary subunits, sulfone 8 and
aldehyde 9.
The Southern Subunit. Our first plan for creating
the tetrahydropyran of 6 was based on a reaction, the
intramolecular Pd(II)-mediated alkoxycarbonylation of a
6-hydroxy alkene,9 which had resulted in a favorable
outcome for us in another context10 and for this we
needed to prepare a protected 4,6,8-trihydroxy-3-methyl-
octene such as 10. The starting point for this objective
was isobutyl acetoacetate (11). Alkylation of the dianion
of 11 with chloromethyl benzyl ether afforded 12, which
was hydrogenated with Noyori’s Ru(II)-(S)-BINAP cata-
lyst11,12 to give (S)-hydroxy ester 13 in excellent yield and
very high enantiomeric excess (Scheme 3).After silylation
Results
First-Generation Approach. At the outset of this
study, the absolute configuration of the aglycon of poly-
cavernoside A was not known and even the configuration
of the disaccharide portion was not settled with certainty.
An early attempt to correlate the configuration of the
sugar with that of the aglycon through an NMR experi-
ment was less than conclusive and forced us to make an
arbitrary selection of aglycon absolute configuration for
the purpose of synthesis. In consequence, our first attack
(5) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J.
Am. Chem. Soc. 1998, 120, 10770.
(6) Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N.
J. Am. Chem. Soc. 2000, 122, 619.
(9) Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner,
M.; Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035.
(10) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001,
3, 4003.
(11) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856.
(7) Paquette, L. A. Chemtracts 2002, 15, 345.
(8) White, J. D.; Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln,
C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J. J. Am. Chem.
Soc. 2001, 123, 8593.
5450 J. Org. Chem., Vol. 70, No. 14, 2005