Application of stereocontrolled aldol coupling to synthesis of segments of immunosuppressants FK-506 and rapamycin |
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Authors: | James D White Jörg Deerberg Steven G Toske Takayuki Yakura |
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Institution: | Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331-4003, USA |
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Abstract: | 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. |
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