Total synthesis of (+)-13-deoxytedanolide

Article abstract of DOI:10.1021/ja0289649

In this communication we describe the first total synthesis of (+)-13-deoxytedanolide, an architecturally complex marine macrolide possessing significant antitumor activity. The cornerstone of the synthesis comprises a highly convergent dithiane coupling

Full text of DOI:10.1021/ja0289649

Published on Web 12/18/2002
Total Synthesis of (+)-13-Deoxytedanolide
Amos B. Smith, III,* Christopher M. Adams, Stephanie A. Lodise Barbosa, and Andrew P. Degnan
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received October 15, 2002 ; E-mail: smithab@sas.upenn.edu
In 1984 Schmitz and co-workers reported the isolation and
complete structural elucidation of (+)-tedanolide (1) from Tedania
ignis, a Caribbean sponge.1 Seven years later Fusetani and co-
workers2 disclosed a similar metabolite, (+)-13-deoxytedanolide
(2), obtained from the Japanese sea sponge Mycale adhaerens.
Importantly, these intricate 18-membered macrocycles exhibit
significant antitumor activity.2 Not surprisingly, this combination
of architectural complexity and bioactivity has engendered wide
interest on the part of the synthetic community.3
The synthesis of (+)-13-deoxytedanolide (2) began with known
alcohol (-)-73e,f (Scheme 2). Conversion to acetate (-)-9 proved
straightforward and proceeded in high overall yield (51%; five steps,
Scheme 2).
Scheme 2
In 1995 we initiated a synthetic endeavor envisioned to exploit
a unified strategy to construct both tedanolide (1) and 13-deoxy-
tedanolide (2) from a common late-stage intermediate (Scheme 1).
The potential instability of the trisubstituted epoxide, in conjunction
with six epimerizable centers, and the fact that nearly every carbon
of the backbone of the tedanolides is functionalized, demanded
careful design of both the overall synthetic plan and an effective
protecting group scenario.
Scheme 1
Although the trisubstituted olefin in (-)-9 is certainly the more
electron-rich olefin, we envisioned that the sterically less encum-
bered monosubstituted terminal olefin would permit selective
oxidative cleavage to afford the aldehyde.6 This indeed proved to
be the case. Subsequent Brown crotylation7 however, resulted in
low yields due to difficulties experienced in the hydrolysis of the
intermediate boronate. This hurdle was overcome with the Roush
crotylation,8 known to generate more labile boronate intermediates;
exclusive formation of the desired alcohol (-)-10 was obtained in
excellent yield.9 After conversion to alcohol (+)-12, Dess-Martin
oxidation10 furnished a readily epimerizable aldehyde, which was
used without chromatographic purification in a highly Z selective
Wittig olefination (>20:1), followed by saponification, and iodi-
nation.11 No epimerization at C(20) was observed in the Wittig
olefination.
Toward this end, we selected a strategy calling for a late stage,
high-risk epoxidation of the C(18,19) trisubstituted olefin,4 in
conjunction with retention of the dithiane moiety until after
macrocyclization to prevent potential ketalizations with the C(15)
and C(29) hydroxyls. With this plan in mind, we envisioned 1 and
2 to arise from seco-acids 3a and 3b, which in turn would be
available via union of dithiane 45 respectively with epoxide 6 for
tedanolide (1) and iodide 5 for 13-deoxytedanolide (2).
With iodide (+)-5 in hand, we turned to the construction of SEM
ether (-)-13 from dithiane (-)-45 and assembly of the carbon
backbone of (+)-2 (Scheme 3). Use of (-)-13, possessing the free
hydroxyl would, upon successful union, afford (-)-14, comprising
the fully elaborated backbone ready for direct conversion to the
requisite carboxylic acid. This critical step was achieved by genera-
9
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C O M M U N I C A T I O N S
tion of the dianion of (-)-13 with 2.05 equiv of t-BuLi, followed
by addition of 1.1 equiv of iodide (+)-5; the yield was 75%.
isopropylsily (DEIPS) group.15 This event was not viewed as a
problem as we anticipated that Yamaguchi macrolactonization16
would prove highly selective for the C(29) primary hydroxyl, to
furnish macrolactone (+)-17. In the event, hydrolysis of the ester15
and macrocyclization afforded (+)-17. Silylation (TESCl) of the
less hindered allylic alcohol, removal of both the PMB ether and
dithiane, and Dess-Martin oxidation of the two free hydroxyls then
led to triketone (+)-18. Upon sequential deprotection of the TES
and SEM17 ethers, the stage was set for the critical epoxidation of
Scheme 3
diol (+)-19. To our delight, treatment of (+)-19 with mCPBA in
3f,18
the presence of NaHCO3
afforded the desired epoxide with
excellent stereoselectivity (>15:1, 48% yield). Deprotection (TBAF,
wet DMPU) completed the synthesis of (+)-13-deoxytedanolide
1
(2), identical in all respects to an authentic sample (500 MHz H
NMR, 125 MHz 13C NMR, HRMS, optical rotation, λmax, TLC in
three different solvent systems).
In summary the first total synthesis of the architecturally complex
marine natural product (+)-13-deoxytedanolide (2) has been
achieved via a highly convergent strategy.
Access to the seco-acid (3b, Scheme 1) next called for the
nontrivial conversion of the C(1) primary hydroxyl to the corre-
sponding carboxylic acid in the presence of the oxidatively labile
dithiane. Exhaustive screening of the standard arsenal of oxidants12
proved unrewarding. We therefore turned to a novel use of the SmI2-
promoted Evans-Tishchenko reduction,13 developed specifically
for this synthesis (Scheme 4).14 Pleasingly, Parikh-Doering oxida-
Acknowledgment. We thank Professor Fusetani for supplying
an authentic sample of (+)-2, and the National Institutes of Health
(Institute of General Medical Sciences) for support (GM-29028).
Supporting Information Available: Spectroscopic and analytical
data for compounds 2, 5, 8-14, 17-19 and selected experimental
procedures (PDF). This material is free of charge via the Internet at
http://pubs.acs.org.
Scheme 4
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