128684-89-9Relevant academic research and scientific papers
Application of stereocontrolled aldol coupling to synthesis of segments of immunosuppressants FK-506 and rapamycin
White, James D.,Deerberg, J?rg,Toske, Steven G.,Yakura, Takayuki
supporting information; experimental part, p. 6635 - 6641 (2011/02/26)
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.
A practical synthesis of the cyclohexyl part of the immunosuppressant FK506
Haller, Bernd-Uwe,Kruber, Susanne,Maier, Martin E.
experimental part, p. 656 - 661 (2011/10/09)
Starting from the benzylidene lactone 3 of D-(-)-quinic acid the cyclohexyl fragment 15 (C-28-C-34 part) of the immunosuppressant FK506 was synthesized. Key steps include homolytic deoxygenation reactions on compounds 4 and 6 as well as a regioselective opening of the benzylidene acetal 5. Opening of the lactone 7 to provide the methyl ester 8 was followed by methylation of the hydroxy group to give 9. Further steps provided the aldehyde 12 which was elongated to the alkyne 15. This sequence provides 15 in gram quantities.
Synthesis of a C22-34 subunit of the immunosuppressant FK-506
Marshall,Xie
, p. 7230 - 7237 (2007/10/03)
A new route to the C22-34 subunit of FK-506 was developed. A highly diastereoselective Diels-Alder reaction of 1,3-butadiene with the bis-acrylate of (R,R)-hydrobenzoin and subsequent saponification provided the cyclohexenecarboxylic acid 6.4 of 95% ee. Elaboration to the enal 9.2 was effected by known transformations. Enal 9.2 underwent diastereoselective and enantiospecific S(E)2' addition of allenyl stannane (S)-3.9 affording the homopropargylic alcohol 9.3 as an 85:15 syn/anti mixture. The PMB ether 9.5 was converted to the known benzylidene derivative 10.4 by sequential treatment with Red-Al, epoxidation, a second reduction with Red-Al, and oxidative benzylidene formation with DDQ.
Practical, asymmetric synthesis of the cyclohexyl C28-C34 fragment of the immunosuppressant FK-506 via (S)-(-)-3-cyclohexenecarboxylic acid
Chini,Crotti,Macchia,Pineschi,Flippin
, p. 539 - 544 (2007/10/02)
The asymmetric synthesis of the cyclohexyl fragment of FK-506 is reported. This new synthesis (five steps, 30% overall yield) starts, for the first time, from (S)-(-)-3-cyclohexenecarboxylic acid (S-2) instead of the commonly used R form (acid R-2) and utilizes an epimerization reaction. The overall yield is improved to 35% by recycling recovered starting product (hydroxy ester 7c) from the epimerization step.
Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506
Nakatsuka, Masashi,Ragan, John A.,Sammakia, Tarek,Smith, David B.,Uehling, David E.,Schreiber, Stuart L.
, p. 5583 - 5601 (2007/10/02)
Asymmetric syntheses of FK506 and (C8,C9-13C2)-FK506 are reported. The latter compound was designed to facilitate an investigation of the interactions between FK506 and its receptor, the recently discovered immunophilin, FKBP. The syntheses involved the preparation of intermediates 7-9 in nonracemic form; the key coupling reactions included a Cram-selective addition of the vinyl Grignard reagent derived from bromide 9 to aldehyde 8 and the addition of the lithioanion of phosphonamide 7 to aldehyde 51, followed by thermal elimination. Dithiane 65 was then hydrolyzed, and glycolic ester 6 (or 6*) was added via an aldol reaction that allowed the introduction of 13C labels at C8 and C9. Elaboration to FK506 proceeded via a Mukaiyama lactamization reaction and a selective deprotection/oxidation sequence, the efficiency of which was critically dependent upon the order of protecting group removal.
Synthesis of the C10-C34 segment of the immunosuppressant FK506
Gu,Sih
, p. 3287 - 3290 (2007/10/02)
The biocatalytic strategy used in the synthesis of the C20-C34 fragment, 2, and the methodology for its attachment to 1 to generate the C10-C34 moiety of FK506 is disclosed.
