(-)-Aurafuron A

(-)-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!