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Post date: Nov 15, 2016 9:44:13 PM
Came across the Frater-Seebach alkylation in the first step of Mori's total synthesis of Cassiol (Tetrahedron, 1990 46 5563).
In sophomore ochem, you learn that esters generally have pKa of 25 while alcohols have pKa of 16. One would think therefore that the alcohol should deprotonate first and give you at minimum an O-alklyated product... Turns out if you add two equivalents of LDA (pKa of diisopropylamine is around 36), then you deprotonate both the alcohol AND the acidic proton of the ester (the Frater Seebach alkylation). The resulting six-membered ring is held together by two oxygens (alcohol oxygen and ester enolate oxygen) chelated to a Lithium counterion.
Frater Seebach alkylation:
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