A Scalable, Nonenzymatic Synthesis of Highly Stereopure Difunctional C₄ Secondary Methyl Linchpin Synthons

In response to the continuing widespread use of heterodifunctional C₄ secondary methyl building blocks in asymmetric synthesis, we have developed a mole-scale, two-step synthesis of a 1:1 mixture of the diastereomers of 3-bromo-2-methyl-1-propyl camphorsulfonate (casylate). One isomer (<b>2</b><i><b>S</b></i>) has been crystallized to >99:1 dr in ∼25% yield. Equilibration of the mother liquor (enriched in <b>2</b><i><b>R</b></i>) to a 1:1 mixture and recrystallization significantly raises the overall yield of <b>2</b><i><b>S</b></i>. Applications of <b>2</b><i><b>S</b></i> include chemoselective Grignard coupling, enabling the very short synthesis of highly stereopure long-chain natural products containing remote, methyl-bearing stereogenic centers [e.g., (<i>R</i>)-tuberculostearic acid], with complete control of configuration. Also, Ag-mediated, completely chemoselective Br displacement from <b>2</b><i><b>S</b></i> leads to a range of >99:1 er difunctional synthons. Both applications incorporate concurrent recovery of CasO. The <i>enantiomer</i> of <b>2</b><i><b>S</b></i> can be made from commercial (1<i>R</i>)-10-CasOH