amide 11, whereas the acid 8 could be built from geraniol.
The other epoxy alkyne 4 was planned from the epoxy
alcohol 9 through the intermediate 6. This retrosynthetic
planning was designed keeping in mind that the analogue
synthesis becomes easier. Thus, most of the key steps were
planned in such a way that a simple change of a reagent
would allow us to synthesize the other chiral variants as
well as the side chain and other key functionalities.
The synthetic endeavor began from commercially
available geraniol which was subjected to Sharpless asym-
metric epoxidation13 followed by benzyl protection of
alcohol with NaH and BnBr providing the epoxy benzyl
ether 12 in 79% yield (two steps). Perchloric acid mediated
hydrolysis14 of the epoxy functionality to the diol and
ketalization of vicinal diol to 13 in 78% yield (two steps)
were very smoothly executed. The ozonolysis of the trisub-
stituted olefinic functionality in 13 generated the aldehyde
which allowed homologation of R,β-unsaturated ester
14 using (carbethoxymethylene)triphenylphosphorane in
benzene. The DIBAL-H reduction of 14 gave allylic
alcohol which set the stage for yet another Sharpless
asymmetric epoxidation to provide chiral epoxy alcohol
15 (64% yield, two steps). The reductive opening of
epoxide 15 to 1,3-diol 16 was achieved with Red-Al15 in
THF at ꢀ40 °C in 84% yield (1,2-diol was removed by
treating the crude reaction mixture with NaIO4 in THF/
H2O). The disilylation of 1,3-diol 16 and subsequent
debenzylation with Raney-Ni16 produced primary alcohol
17 (87%, two steps). This primary alcohol 17 was oxidized
with DessꢀMartin periodinane and subsequent Wittig
methylenation affording 18 in 78% yield (for two steps).
The selective cleavage of primary silyl ether in 18 using
Figure 1. Pladienolide B, D, and E7107.
of Kotake10a and Ghosh10b have reported the total synthe-
sis of potent macrolide pladienolide B. Burkart et al.10c
reported their synthetic efforts toward the construction
of side chains, whereas the group of Jensen11 published
the macrocyclic core of the (ꢀ)-pladienolide B. Maier12a
and Webb12b have accomplished progress in the synthesis
of pladienolide B based analogues.
Scheme 1. Retrosynthetic Analysis of Pladienolide B, 1
HF py followed by one-step oxidation of the correspond-
ing alcohol with BAIB/TEMPO furnished acid 8 in a
straightforward manner (Scheme 2).
3
As shown in Scheme 3, the hydroxy vinyl iodide 7 was
prepared starting from aldehyde 1017 which upon syn
aldol18 condensation with Evan’s amide 11 provided the
adduct 19 with good diastereoselectivity (25:1). This, upon
silylation with TBSOTf, followed by auxiliary removal
with LiBH4 furnished the primary alcohol 20 (68%, two
steps). Thedeoxygenation19 oftheprimaryhydroxyl group
(13) (a) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2010, 49, 3517–3519. (b) Mohapatra, D. K.; Pramanik, C.;
Chorghade, M. S.; Gurjar, M. K. Eur. J. Org. Chem. 2007, 5059–5063.
(c) Hashimoto, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. Org.
Chem. 1991, 56, 2299–2311.
As depicted in Scheme 1, the typical dissection of
pladienolide B would provide two synthons, the side chain
4 (C14ꢀC23 unit) and the macrolactone 5 (C1ꢀC13 unit).
We anticipated that a Stille typecouplingwouldallow usto
stitch these fragments with ease. The macrolactone 5 in
turn could be built from hydroxy vinyl iodide 7 and
carboxylic acid 8. The hydroxy vinyl iodide 7 could be
constructed by coupling vinyl iodo aldehyde 10 and Evan’s
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€
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B
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