leiodelide A would hopefully help resolve the “leiodelide B
puzzle”.2
diastereomers in the event of discrepancies between the
synthetic and natural products.
The synthesis of bromide 5 commenced with the forma-
tion of olefin 14 (Scheme 1). Starting from known alcohol
11,5 methylation provided lactone 12, which was then
opened to the corresponding Weinreb amide. Since the
chromatographic purification of the amide on silica gel
resulted in recyclization to 12, immediate conversion to the
triethylsilyl ether 13 was performed.
Scheme 1. Synthesis of the Northern Subunit Precursor 14
Reduction of amide 13 to the corresponding aldehyde
using DIBAL set the stage for the Wittig olefination. The
coupling partner, phosphonium bromide 8, was prepared
in two steps: bromination of 2-(benzyloxy)ethanol6 fol-
lowed by treatment with ethyltriphenylphosphonium bro-
mide in the presence of n-BuLi.7 The Wittig reaction
resulted in an inconsequential 1:1 mixture of E- and Z-
olefins 14, which were separated for analytical purposes.
The reduction/deprotection sequence proved to be more
difficult than expected and required some optimization.
Treatment of unsaturated benzyl ether 14 with various
sources of palladium all led to hydrogenolysis of the benzyl
ether to alkane 15 (Scheme 2). This product is presumably
formed via an olefin migration/palladium π-allyl forma-
tion/elimination mechanism. Palladium is known to have
a high isomerization activity,8 and this type of reaction
has been previously reported with both homoallylic
Figure 2. Retrosynthetic analysis of leiodelide A (1).
As outlined in Figure 2, our retrosynthetic strategy
started by disconnection at C22 to reveal macrolide 4
and side chain 3. Macrolide 4 could be accessed from
simplified fragments5, 6, and 7. First, the northern subunit
5, with its three contiguous oxygenated chiral centers, was
envisioned to originate from the opening of chiral lactone
12 (derived from D-xylose) followed by Wittig olefination
with phosphonium bromide 8. Second, the R,β-unsatu-
rated ester 7 could be generated from an Evans aldol
reaction between acylated oxazolidinone 9 and aldehyde
10 followed by a HornerÀWadsworthÀEmmons olefina-
tion reaction to install the ester moiety. Finally, oxazole 6
can be obtained in three steps from known 2-thiooxazole.4
The key steps of the synthesis would be the appending of
the northern and southern fragments onto the oxazole via
metal-catalyzed cross-coupling reactions.4 This highly
convergent strategy would provide a great deal of flex-
ibility when it comes to derivatization and SAR studies.
It would also provide us with easy access to multiple
ꢀ
(5) Han, S.-Y.; Joullie, M. M.; Fokin, V. V.; Petasis, N. A. Tetra-
hedron: Asymmetry 1994, 5, 2535.
(6) Hammerschmidt, F.; Kaehlig, H. J. Org. Chem. 1991, 56, 2364.
(7) Marinier, A.; Deslongchamps, P. Can. J. Chem. 1992, 70, 2350.
(8) Rylander, P. N. Hydrogenation Methods; Academic Press: London;
Orlando, FL, 1985; pp 31À36.
(9) Cocker, W.; Shannon, P. V. R.; Staniland, P. A. J. Chem. Soc. C
1966, 41.
(10) Nishimura, S.; Uramoto, M.; Watanabe, T. Bull. Chem. Soc.
(4) Counceller, C. M.; Eichman, C. C.; Proust, N.; Stambuli, J. P.
Adv. Synth. Catal. 2011, 353, 79.
Jpn. 1972, 45, 216.
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