(-)-Aurafuron A
Organic Letters 2012, 14, 3064
O. Hartmann & M. Kalesse*
The retrosynthesis of (-)-aurafuron
A begins with the disconnection of the furanone ring into
mono-dithane-β-diketone moiety followed by deprotections of the TBS
ethers. The formation of the furanone
ring proved to be troublesome as several reagents failed to give the desired
product. The goal is to enolize the
carbonyl group in 14 and then make
it attack at the dithiane carbon (after hydrolysis or with simultaneous
hydrolysis). Synthetically, methyl
iodide with CaCO3 in acetone gave the desired product, which was then followed
by the removal of the TBS ethers by using HF.pyridine in THF/pyridine*. Compound 14
was prepared by an aldol reaction between diethiane ketone 13 and the aldehyde 12
with lithium bistrimethylsilylamide employed as the base. Compound 12
was prepared by a Suzuki reaction between vinly iodide 5 and boronate ester 11. Boronate ester 11 was formed by a cross-metathesis reaction between vinyl boronate
ester 10 and alkene 9.
The original strategy of the authors was to perform a Heck reaction
between alkene 9 and vinyl iodide 5 to prepare 12. When it failed, the
present route was used instead. This
sort of thing happens quite frequently and it is really crucial to be able to
make adjustments to the original plan.
In this regard, the terminal alkene is quite versatile intermediate as
it can be easily transformed into a vinyl iodide or a boronate ester. Moving further back, compound 9 was formed by the reaction of “butane
anion” on aldehyde 7 by using a
chiral borate. This reaction gave the
trans product exclusively. Aldehyde 7 was prepared by another aldol
condensation between propanal and 3-methylbutanal. Vinyl iodide 5 was prepared by the selective deprotection of the primary TBS
ether in 4 while keeping the
secondary TBS ether intact. This was
achieved by using PPTS in methanol and was then followed by the syn reduction of the alkyne. Compound 4
was prepared by TBS protection of the secondary alcohol in 3 followed by changing TMS group to the iodide. Alcohol 3
came by (a) attack of TMS-acetylene on aldehyde; (b) oxidation of the racemic
alcohol to the ketone; (c) stereoselective reduction of the ketone by using
Noyori’s catalyst. Aldehyde 2 was derived from butenol by
protection and ozonolysis.
Overall, a neat
synthesis from the Kalesse group with several noteworthy steps including tricky
aldol condensations, an interesting cross-metathesis step (which incidentally
has been used before in their labs), and a stereoselective establishment of the
butene group.
*: Back in the year
2000, I was a postdoc with Prof. Kalesse and used HF.pyridine in THF/pyridine
to deprotect two TBS ether in the final step of making ratjadone. Ratjadone was very sensitive to even trace
amounts of acids and we used extra pyridine during the TBS deprotection
step. It works really well!
