ABSTRACT.The combined use of Fmoc (fluorenylmethoxycarbonyl) as N-protection and Tmse (trimethylsilylethyl) as 0-protection during demanding fragment condensation mediated by Bop-C1 (N,N'-bis(3-oxo-2-oxazolidinyl)phosphinyl chloride) has been explored in the preparation of useful synthons that are sensitive to acidic and even basic hydrolyBes. Stepwise deprotection by morfoline (Fmoc-deprotection) followed by F -mediated removal of Tmse results in a very effective peptide synthesis strategy, as exemplified by the preparation of i.a. Phg-MePhe-Thz. Similarly, combinations of N-B$c, 0-Tmse peptide esters are also possible that allow the preparation of H2-MePhe-Thz-OTmse (via Boc-MePhe-Thz-OTmse) without competitive DKP formation. I "Many bioactive (cyclic) peptides produced in nature possess a repetitive succession of N-alkylated aminoacid residues.We have demonstrated (1, 2) that such chain fragments are extremely sensitive to acid-catalyzed peptolysis (endopeptolysis), a fact which can be exploited for deliberate peptide chain rupture ( 3 ) . Although much slower, and therefore controlable, C'-terminal secondary aminoacids also can be splitt off from peptide acids in acidic conditions (4). These features are important in planning strategies for the preparation of N-alkylated peptides. In addition, the coupling of secondary aminoacids often demands strong activation. Mixed pivalic anhydrides ( 5 ) and phosphorous anhydrides (5-7) have been found superior in these cases. In our own laboratory we have gained experience in using N,N'-bis(Z0x0-3-oxazolidinyl)phosphinic chloride (Bop-C1) (6,9) although appreciable epimerization has been found ( 8 , 9) to occur in fragment condensations.We have recently reported on the synthesis of a linear precursor of Virginiamycin analog (10) (VS-analog) whereby 2 and BOC aminoprotection, combined with But ester protection was adapted in the strategy for the synthesis of the peptide material containing N-alkylated aminoacid residues. Other (orthogonal) protections would be wellcome and suitable groupings should meet following characteristics: (i) they should be cleavable by non-acidolytic methods and (ii) be removed by non-reductive procedures (this would allow concomittant use of a 2 group as a permanent blocking group); (iii) deprotection should leave an ester bond intact; and (iv) finally the protective groupings must be compatible with strong activation (11) e.g. mediated by BOP-C1.-505 -
Abstract. I 1A synthesis of Z-Thr -D-Abu'-Pro'-MePhe'-MeA bu(yPht) I-Phg'I (A2bu = a,y-diaminobutyric acid) is reported using the ver$ efficient coupling agent BOP-C1 (N,N'-bis(3-oxo-2-oxazolidinyl)phosphinic chloride) for imino acid peptide bond formation. The total yield is 11% for the 5 coupling steps and one lactonization. The final step was a cyclization between residues 5 and 6, after (i) first t-Boc acidic deprotection with 85% HCOOH o{ the linear precursor 2-Thr ( Na-Boc-Phg-0-) -D-Abu-Pro-MePhe-MeA2bu (yPht) -0Bu followed by (ii) acidic saponification (Tfa) of the t-Bu ester. This sequence was found to be a prerequisite, in view of the extreme lability .of the 4-5 peptide bond under acidic conditions. Jntroduction.Streptomyces virginiae, a bacteria isolated from Belgian soil (1) produces a mixture of two families (A and B) of cyclic lactone peptolides, one of which belongs to the streptogramin S-family.Among structurally related depsipeptidic compounds (11, Virginiamycin S (VS)(figure 1) is a typical representative of the B-family.
ChemInform Abstract The synthesis of (Ia) is reported using the very efficient coupling agent BOP-Cl (N,N'-bis(3-oxo-2-oxazolidinyl)phosphinic choride) for imino acid peptide bond formation. The total yield is 11% for 5-coupling steps and one lactonization.
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