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. DOI) 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.

Although the tandem ring closing metathesis - homologation of 1 with 2 proceeded spectacularly well, to give 3 in 88% yield, simple dimerization of 3 did not deliver the desired 4. As an alternative, 15 was cyclized with G1, then acylated with reduced 3 to give 16. Intramolecular acylation of 17 then worked well, leading to 4.

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