Studies relating to the immunosuppressive activity of FK506

✍ Scribed by M. Furber; M.E. Cooper; D.K. Donald

• Publisher: Elsevier Science
• Year: 1993
• Tongue: French
• Weight: 187 KB
• Volume: 34
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)91793-3

✦ Synopsis

Beckmann rearrangement of FK506 E-oxime gave amide 2 and the fragmentation product 4. Compound 4 was atso prepared by total synthesis.

The immunosuppressant FK506 has been the subject of considerabie synthetic' and degradative2 studies. As part of our pmgramme in this area we investigated the stNdUral requirements for immunosuppressive activity through chemical manipulation of FK506, in the expectation that such information would support our synthetiiprogramme.

During the process of effecting modifications at C22 of FK506 we attempted to prepare the amides (1) and ( ) by Beckmann rearrangement of the respective C22 Z-and Eoximes . in the case of amide (1 ) this could be achieved, albeit in iow yieid, by treatment of FK506 with 0-mesityisulphonyihydroxyiamine foiiowed by basic alumina.3

Unfortunately amide (2) could not be isolated from this reaction and an aitematiie procedure was required (Scheme 1).

To this end FK606 was converted to a Separable mixture of C22 E / Z-oximes and the major E-isomer was proteded as its C-24 terf-butyktimethylsilyi ether through a silylation / selective desilylation sequence. Beckmann rearrangement was accomplished with 1,3dimethyl-2-fluoropyridinium 4-tosyiate in DME I Et3N to give, after deprotectfon with HF In acetonitrile, the amide (2). However, the yield of (2) was very low (6%) due to the fact that most of the oxime had