C O M M U N I C A T I O N S
syn reduction of the aldol 21 is followed by formation of acetonide
22. The aliphatic fragment (3) is completed in three additional steps
and a total of 11 linear steps from the (S)-Roche ester.
Suzuki coupling9 unites the spiroketal and aliphatic fragments
yielding seco-acid 23 directly (Scheme 5). Yonemitsu’s modification
of the Yamaguchi esterification7 fails to give any product when
applied to seco-acid 23. Applying the Wasserman-Kita esterifi-
cation to macrolaconization27 affords the desired macrocycle 24
in ∼30% yield. However, the method of Shiina28 improves this
yield to 65%.
and alkynes as orthogonally reactive surrogates for hydroxyl and
carbonyl functionalities. Further novel features of this synthesis
include a new and highly regioselective gold catalyzed spiroket-
alization reaction, utilization of (S,S) ProPhenol in enantio- and
diastereoselective alkynylation and aldol reactions, and establish-
ment of the full structure of ushikulide A via total synthesis. Further
efforts to optimize this route and apply it to other members of the
family are underway and will be reported in due course.
Acknowledgment. We gratefully acknowledge K. Takahashi
for providing an authentic sample of ushikulide A and also S. Lynch
for his invaluable help in the acquisition of 2-D NMR data. We
thank the Stanford Graduate Fellowship Program and NIH (GM
13598) for their financial support of our program, Johnson Matthey
for their supply of precious metal salts, and Aldrich for ProPhenol.
Scheme 5. Completion of the Synthesisa
Supporting Information Available: Detailed experimental proce-
dures, full characterization of all products, and comparison NMR
spectra. This material is available free of charge via the Internet at
References
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a Conditions: (a) 3, 9-BBN, THF; then 2, DMF, H2O, 10 mol%
PdCl2(dppf), 10 mol% Ph3As, Cs2CO3, 67%; (b) 2-methyl-6-nitrobenzoic
anhydride, 4-DMAP, DCE, 65%; (c) HF·pyridine, pyridine, THF; (d)
Dess-Martin reagent, CH2Cl2; (e) DDQ, H2O, CH2Cl2 then dilute with
3:2 AcOH/H2O, 52% over 3 steps.
Deprotection of the C-17 TBS group of 24 is accomplished under
buffered HF ·pyridine conditions (Scheme 5). Dess-Martin oxida-
tion unveils the sensitive ꢀ, γ unsaturated ketone, which is cleanly
deprotected of its three p-methoxylbenzyl ethers upon exposure to
DDQ. The resulting triol (not shown) is dissolved in a 3:2 mixture
of acetic acid and water to remove the acetonide. As the reaction
progresses, TLC analysis shows the formation of a more polar spot
of indistinguishable Rf compared to an authentic sample of
ushikulide A. Upon isolation, this compound exhibits identical 1H,
13C, IR, HRMS, and HPLC properties when compared to the same
authentic sample. Measurement of the optical rotation {[R]24
)
D
-12° (c 0.28, MeOH)} confirms that the absolute stereochemistry
also matches that of natural ushikulide A1 {[R]25D ) -13° (c 0.50,
MeOH)}. In total, these data prove our tentative assignment to be
correct and lead us to assign the complete structure of (-)-
ushikulide A as depicted below.
In summary, we report the first synthesis of (-)-ushikulide A
which establishes its relative and absolute stereochemistry. Our route
requires 21 linear and 41 total steps (2.2% yield over the linear
sequence), which is gratifying given the complexity of our target
(40 carbon atoms and 14 stereogenic centers). The efficiency of
this strategy is in no small measure due to the utilization of alkenes
JA807127S
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16192 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008