Design And Synthesis Of Callipeltin B Analog

Callipeltin B is a cyclic desipeptide isolated from marine sponge Callipelta sp.The structure of Callipeltin B contains natural amino acid L-leucine,D-arginine and non-natural(2R,3R)-?-methoxy-tyrosine,(3S,4R)-3,4-dimethyl-L-pyroglutamic,Dallo-threonine,N-methyl-L-alanine,N-methyl-L-Glutamine.The molecule was reported to exhibited broad-spectrum cytotoxicity against the tumor cell lines.The structure of Callipeltin B contains five non-natural amino acid units,which leads to great difficulty in the synthesis of Callipeltin B.In this paper,Callipeltin B molecular is designed which ?-MeO-Tyr is substituted of D-Tyr and pyroglutamic substitutes(3S,4R)-3,4-dimethyl-L-pyroglutamic and we hope this modification exhibiting antitumor activity.First,N-Me-Ala and N-Me-Glu were synthesized adopting the literature method.L/D-threonine was as a raw material,through acemization,N-acetylation and enzymatic resolution to give(2S,3S)and(2R,3R)-?-methoxy-tyrosine with high diastereomeric excess(100%de).The yield of O-tert-butyl-D-athreonine was greatly enhanced from 12% to 81.2% by changing the feeding way of isobutylene and optimizing the factors including ratio of solvent DCM and DMF,reaction temperature and reaction time.Finally,The chain peptide D-Tyr-N-Me-Glu-Leu-D-Arg-D-aThr-D-aThr(Pyroglu)-N-Me-Ala was synthesised by using 2-chlorine trityl chloride resin as the carrier,25% piperidine/DMF for deprotection,HATU/HOAt as coupling reagent and HFIP/DCM as cutting reagent in the microwave solid-phase synthesis instrument.Callipeltin B analog was synthesized by cyclization of the chain peptide in the liquid-phase.