Argyrin B, A-21459-B

Chemical Name: (4S,7S,13R,22R)-13-Ethyl-4-(1H-indol-3-ylmethyl)-7-(4-methoxy-1H-indol-3-ylmethyl)-18,22-dimethyl-16-methylene-24-thia-3,6,9,12,15,18,21,26-octaazabicyclo[21.2.1]hexacosa-1(25),23(26)-diene-2,5,8,11,14,17,20-heptone
CAS No. 406951-44-8 (undefined stereoch.)
项目整合开发状态: Biological Testing
项目研究机构: Aventis Pharma (Originator), GBF (Originator), Novartis (Originator)
合成路线:The racemic 4-methoxytryptophan amide (I) is resolved using immobilized Penicillin G acylase,to afford the desired L-aminoacid (III),while leaving unaltered the enantiomeric D-amide (II).After protection of aminoacid (III) as the N-benzyloxycarbonyl derivative (IV),coupling with glycine methyl ester (V) gives dipeptide (VI).Hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) yields amine (VII),which is then coupled with N-Cbz-L-tryptophan (VIII) to produce the protected tripeptide (IX).Hydrogenolysis of (IX) in the presence of Pd/C provides the tripeptide building block (X).

合成路线:N-Boc-D-Alanine (XI) is converted to the corresponding amide (XII) by reaction with ammonia in the presence of EDC and HOBt.Subsequent treatment of (XII) with Belleau's reagent (2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) furnishes thioamide (XIII).S-Alkylation of thioamide (XIII) with ethyl bromopyruvate (XIV) gives intermediate (XV),which is cyclized to thiazole (XVI) upon treatment with trifluoroacetic anhydride and 2,6-lutidine.After saponification of the ester group of (XVI) with LiOH,the resultant acid (XVII) is coupled with tripeptide (X) to provide precursor (XVIII).

合成路线:The tripeptide building block (XXVII) is prepared as follows.Cyclization of N-Boc-L-serine (XIX) to the beta-lactone (XX) is achieved by treatment with DEAD and PPh3.Subsequent ring opening with diphenyldiselenide in the presence of a reducing agent leads to selenide (XXI).Aminoacid (XXI) is then coupled to sarcosine ethyl ester (XXII) to afford dipeptide (XXIII).After acidic Boc group cleavage in (XXIII),the resultant carboxylic acid (XXIV) is coupled to N-Boc-D-aminobutyric acid (XXV) to give (XXVI).The N-Boc group of (XXVI) is then deprotected with trifluoroacetic acid,producing intermediate (XXVII).

合成路线:Basic hydrolysis of the precursor tetrapeptide ester (XVIII) provides acid (XXVIII).This is then coupled to the tripeptide ester (XXVII),leading to the linear peptide precursor (XXIX).Sequential hydrolysis in (XXIX) of the ethyl ester group with LiOH and the N-Boc group with trifluoroacetic acid produces aminoacid (XXX).

合成路线:Macrocyclization of aminoacid (XXX) in the presence of TBTU provides the cyclic peptide (XXXI).Conversion of the selenide group of (XXXI) to the target olefin is then accomplished by oxidation to selenoxide (XXXII) with sodium metaperiodate,followed by elimination in the presence of bicarbonate to produce the title compound.