The 2-Chloro-3-indenylmethyloxycarbonyl and Benzinden-3-ylmethyloxycarbonyl Base-Sensitive Amino-Protecting Groups. Application to an Inverse Merrifield Approach to Peptide Synthesis

Article abstract of DOI:10.1021/jo00288a042

Two new base-labile amino-protecting groups, which are more sensitive than the FMOC function, are described: the 2-chloro-3-indenylmethyloxycarbonyl (CLIMOC) and benzinden-3-ylmethyloxycarbonyl (BIMOC) groups.The former was determined to be usable in solvents such as methylene dichloride but not in DMF, the latter in any common solvent including DMF.Key intermediate alcohols 10 and 16 were synthesized from 2-chloroindene (9) and benzindene (14).Treatment of indene with chlorine gave 8, which upon dehydrochlorination with DMF gave 9, which was then converted to 10 by standard procedure involving formylation and reduction.Benzindene was converted to its anion by means of n-butyllithium and the anion hydroxymethylated by gaseous formaldehyde.The alcohols were converted to the corresponding chloroformates and thence to succinimido ester 12 and azidoformate 18 for clean, selective protection of amino acids.Model CLIMOC- and BIMOC-amino acids were synthesized and demonstrated to be useful in carrying out a continous peptide synthesis via a two-polymer (polymeric reagents) approach.The protected amino acids were first loaded onto a phenolic polymer such as 21, and the resulting polymeric active esters were used to acylate an amino acid ester or peptide ester.The resulting protected peptide esters were deblocked via silica-based reagents 6 or 23.The acylation step was then repeated with the next amino acid, and the synthesis continued in the same way until completed.Tetrapeptide 26 and pentapeptide 27 were synthesized in this way via CLIMOC (CH2Cl2) and BIMOC (DMF) protection, respectively.These represent the first examples of clean, continous two-polymer syntheses carried out in a single solvent without the release of any low molecular weight byproducts into the solution. the fi