The First Total Synthesis of — -FK

The FK-506 synthesis is based on constructing the C19-C20 olefin by addition of a phosphine oxide anion (296 CiQ-Cxg) to an aldehyde (298 C20-C34), and cyclization by Mukaiyama s condition. 

The C10-C18 fragment 295, prepared from the optically pure monoepoxy alcohol, was functionalized to the dithiane phosphine oxide 296. The other fragment 297 prepared from quinic acid was treated with LiOOH to remove the chiral auxiliary, and the resulting acid was transformed into the aldehyde 298 

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FK-506 (146) is a clinically important immunosuppressive agent (O Fig. 14). The first total synthesis of FK-506 (146) was achieved by the Merck group [88,89] using the Evans aldol technology. Danishefsky and coworkers also synthesized FK-506 (146) (formal total synthesis) from four segments, 147,148,149, and 150 [90,91,92,93]. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

The Mukaiyama reagent, l-methyl-2-chloropyridinium iodide (28), is also suitable for macrolactamization [85]. Jones et al. [86] achieved the first total synthesis of the important immunosupressant (-)-FK-506 (151) using the Mukaiyama method as a key cyclization step. As shown in Scheme 50, the unstable amino acid 149 was treated with 28 under high dilution to give the macrocycle 150 in... 

C5 H,9N0,3, Mr914.19, cryst., mp. 183-185°C, [aJu -58.2° (CH3OH), a 31-membered peptide lactone in which a long-chain carboxylic acid is cyclized with l- pipecolic acid as a bridge and produced by Strepto-myces hygroscopicus. R. has antifungal, antineoplastic, and immunosuppressive activities, it is structurally related to FK-506 and exhibits a similar mechanism of action in the development of the immune response. R. was first marketed in 1999 in combination with cyclosporin and tacrolimus for use in transplantation medicine. The first total synthesis of R. was realized in 1993. 

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