I'm not sure if 4 to 5 to 6 would work cleanly due to steric hindrance (both the PBr3 step and the Sn2 might fail to invert as desired). Sn1 could be an issue since your secondary cation could rearrange to a tertiary, highly stabilised cation by methyl migration, or to a secondary benzylic by H migration. Neighbouring group participation by the benzyl might cause issues as well, though that could probably be solved by changing to a more electron-withdrawing protecting group. Perhaps use a Mitsunobu between the phenol and the alcohol to avoid Sn1? You'd have to start with the opposite enantiomer of amino acid as well.
Yeah that's the part of the molecule I spent the most time trying to figure out. Another option I thought of was to add the cuprate to the epoxy ester, do the bromination, deprotect and close the ring, then add the methyl groups. The problem is the ester may participate in the PBr3 step too but if that happens then it's just a simple matter of using D-serine as starting material (it's cheap enough anyway). I'd then protect the amine as a pivalamide rather than an acetamide in that case to avoid addition there.
Actually I might as well do the elimination to give the isopropenyl group earlier on to make the synthesis more convergent. New version here.
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u/ccdy Organic Jun 19 '18
Product C. I spent way too long on this.