Totally Synthetic by Paul H. Docherty, 21 January 2008
Total Synthesis of Erinacine E
H. Watanabe, M. Nakada, J. Am. Chem. Soc. 2008, 130, 1150-1151.
Focusing on relatively recent work, this ASAP by Nakada leapt out with the complexity of that molecule! The group has quite a bit of experience with this family of natural products, having previously completed a total synthesis of erinacine B, which allowed them to start with an advanced precursor from that synthesis. This precursor contained the entire 5,6,7-fragment (LHS); I’m not going to discuss that synthesis today, but focus on the amazing elaboration of this structure to the target.
The first step was installing the glycoside bond. Not an easy transformation, but the demostrated excellent control by using a thioglycoside starting material and MeOTf to give the desired anomer in 84% yield and 14:1 d.r. Protecting group manipulations generated the starting material for the scheme above, which after a double oxidation performed the first cyclisation in situ (probably promoted by triethylamine from the Swern oxidations).
Interestingly, they couldn’t get the key intramolecular aldol reaction to go at all using standard metal-cation bases (e.g. t-BuOK), but got a fantastic yield with an organic base. I guess the metal cation chelated the highly oxygenated RHS of the molecule in an unfavourable conformation, preventing reaction or even favouring decomposition. Also note that the benzoyl group has migrated; this prevents retro-aldol condensation, and is something they apparently planned. Completion of the synthesis required four further steps, including an inelegant but effective epimerisation of one of the secondary alchohols, finishing an amazingly complex molecule.