Total Synthesis Highlights

49. The Crimmins Synthesis of (+)-SCH 351448
The symmetrical macrodiolide (+)-SCH 351448 (4) is the only known selective activator of
transcription from the low density lipoprotein receptor. The highly convergent synthesis of 4 from
1 and 2 reported (Org. Lett. 2006, 8, 2887. ) by Michael T. Crimmins of the University of North
Carolina illustrates the power of the chiral glycidyl anion approach for the preparation of α,α'-bis
chiral ethers.
The upper half of 1 was assembled by Sharpless resolution of the alcohol 5. Allylation of the
enolate derived from 6 then delivered, after reduction and methylenation, the triene 7. The lower
half of 1 was prepared by condensation of the anion derived from 8 with acrolein 9. Methylation
of product 10 led to 11, which was again allylated, to give, after homologation, the aldehyde 12.
Condensation with a chiral acetate equivalent gave 13. The corresponding aldehyde 14 was then
added to the enolate of 15, derived from 7, to arrive at 1.