Application of stereocontrolled aldol coupling to synthesis of segments of immunosuppressants FK-506 and rapamycin

The sector comprising C24–C34 of FK-506 containing five of the stereogenic centers in this macrolide was synthesized from (−)-quinic acid. Aldol coupling of the C24–C34 unit with a methyl ketone representing C20–C23 of FK-506 proceeded with complete Felkin stereoselectivity to afford the C20–C34 portion of the immunosuppressant. A chelate transition state invoking coordination of a lithium enolate with a trityl ether is proposed to explain this stereoselectivity. The strategy adopted for construction of the C26–C34 moiety of FK-506 was extended to the C34–C42 subunit of rapamycin. A Mukaiyama asymmetric anti-aldol coupling was used to set in place the vicinal diol functionality at C27,28 in the C26–C33 segment of this macrolide.