This week’s choice is a catalytic one from the group of Fürstner at the Max-Plank (Catalytic) institute in Germany. The title is”Catalysis-Based Total Synthesis of Putative Mandelalide A” and can be read here. It should be noted at the outset that there is some doubt as to the actual structure of this compound so we will proceed with the one in this publication.

So by shaking his catalyst toolbox at the molecule it identified a number of useful disconnections for example the C14-C15 double bond magically transformed into a triple bond which then broke apart to give two new acetylenes, a terminal one and a methyl acetylene:

Now as everyone knows terminal acetylenes usually polymerise on meeting the Shrock alkylidine catalyst. Further rattling of the tool box provided further disconnections and the time had come to see it stitched back together.

A first catalytic application was a double allylation described by Kirsche and induced by iridium:

This produced the C2 symmetric diol A in  71% yield, with a d.r. of 26:1 and an %ee of 99%.  After desymmetrisation by iodoetherification, protection, and alkylation with the lithium enolate of N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpropionamide a couple more catalytic reactions, including a cross-metathesis, a Takai olefination with Cr(II) and a Suzuki propynylation delivered the key building block B

Several catalytic reactions later they arrived at the other coupling partner in good yield and of course excellent ee. Now because the coupling partner is an alcohol and fragment B an ester a “simple” transesterification (the transesterification was not so simple, but there wasn’t a catalyst in the box for that one!) gave the di-acetylene C.

Not surprisingly treatment of C with 10 mol% of molybdenum catalyst E

E

produced the target ring system in 72% yield. All that now remained was partial acetylene reduction with an activated Zn(Cu/Ag) couple under acidic conditions which produced the E,Z diene. Protecting group cleavage, and addition of the sugar unit completed the synthesis.

Once again it is impossible to convey this sort of synthesis and all the months and months of hard work and frustration with the sincerity it deserves in short posts, but I hope I have awakened your interest enough to go and read the actual paper. Especially the bits dealing with the structural assignment of the molecule. I’m sure some elements must be feeling left out here as I think only about 60% of the elements of the periodic table were used.

I thank Angewandte Chemie for the title picture.