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.