Totally Synthetic by Paul H. Docherty, 3 November 2006
Total Synthesis of Apoptolidinone A
J. Schuppan, H. Wehlan, S. Keiper, U. Koert, Chem. Eur. J. 2006, 12, 7364-7377.
Apoptolidinone A, completed by Ulrich Koert at Marburg, induces selectively cell apoptosis, and thus is particularly appealing. This unit is the aglycon, but they also published the total synthesis of Apoptolidin A, the parent natural product in an adjacent paper. Their disconnections for the macrocycle are somewhat standard, but the rest of the synthesis is quite impressive. The retroanalysis:
They first discuss the assembly of the tetrahydropyran, created from the acyclic precuror, which they made pretty short work of: selective asymmetric hydrogenation of the ketone in 94% and 97% ee, and reduction of the ester allowed them to complete an Evans aldol reaction with the known ketoimide, returning the product in 94% and 96:4 dr. Reduction of this with NaBH(OAc)3, again in excellent yield and dr left the polyol in a remarkably display of asymmetric control.
They then prepared a Weinreb amide:
Now that’s a great preparation, and one which seems really quite useful (published by Weinreb himself in the 70’s). They then coupled the Weinreb amide with a lithium compound generated from a vinyl halide, performed a substrate controlled dihydroxylation followed by tetrahydropyran formation, and achieved a 6:1 stereoselectivity.
Anyway, they were then set to complete the lower fragment, using Ardisson/Pancrazi modification of Kocienskis’s dihydrofuran operning procedure. This provided the stannane shown below in excellent yield. This is followed by displacement of the hydroxyl group by halogen after halogenation of the hydroxyl, and then grignard formation. Addition of this fragment into the aldehyde returned an excellent 96:4 dr!
The synthesis of the top fragment was also very nice, but used more routine chemistry (a lot of Wittig reactions!); noteable was the use of amber glassware to stop reaction of the triene before the Stille coupling. Great work!