(-)-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!

Aldingenin

 

Aldingenin

Organic Letters 2012, 14, 2168

M. T. Crimmings*, C. O. Hughes

The retrosynthesis of aldingenin begins with the deprotection of the benzyl ether and the bromoetherification of compound 13.  The bromoetherification step using 2,4,4,6-tetrabromocyclohexa-2,5-dienone (TBCO) also gave the 5-exo product (i.e. produced bromotetrahydrofuran ring) which reduced the overall yield.  The tertiary hydroxyl group in 13 was prepared by the addition of “Me^-” to ketone 12 by using MeLi along with CeCl₃.LiCl.  Here the attacking reagent is presumably the less nucleophilic “MeCeCl₂” with additional coordination with LiCl.   When isopropylidiene phosphorane was used on aldehyde 10, the prenyl product 12 could not be prepared. So, the prenyl group in 12 was prepared by a cross-metathesis reaction between alkene 11 and 2-methyl-2-butene (also served as the solvent!).  This is a really neat trick because alkene 11 was prepared from aldehyde 10 by using a variation of “Wittig-reaction” – Nysted conditions (Zn₃Br₂(CH₂)₂, BF₃.OEt₂, THF).  Again, this was necessitated by the failure of traditional Wittig and Tebbe reagents in this step, which I suspect might be due to the presence of a keto group in addition to the aldehyde.  Keto-aldehyde 10 was prepared by a double Swern oxidation step of alcohol 9, which, in turn was prepared from compound 8.  In this step, the cyclopentadienyl ketal got hydrolyzed to reveal the diol which immediately cyclized with the internal ketone group.  Compound 8 is an alpha-hydroxy ketone, and is formed by the nucleophilic attack of dithiane 7’ on aldehyde 7.  This is the classic “umpulong” chemistry and it required the presence of CeCl₃.LiCl along with the base (nBuLi).  The Crimmins group also came up with a method to dry CeCl₃ – which was crucial in this step.  The aldehyde group in 7 came by the Ley oxidation of alcohol 6, which was prepared from diol 5.  syn-Diol 5 was prepared by a hydroxyl-directed stereoselective dihydroxylation step employing OsO₄ along with TMEDA – which is quite noteworthy.  Alkene 4 is ripe for a RCM disconnection to reveal bis-alkene 3, which came from the removal of the chiral auxiliary from 2. Compound 2 was prepared by a “anti-selective-aldol” reaction between dibenzyl acetal 1’ and the chiral thiazolidinone 1.

Unfortunately, at the end of the synthesis the spectra of the natural and the synthetic material did not match! That’s not what you want to see at the end of the synthesis – but a great job by the synthetic chemist nevertheless – after all this was the structure they proposed!  So, the structure of the naturally isolated material needs to be elucidated correctly.