Studies in solid-phase synthesis: The solid-phase synthesis and characterization of gamma-bicyclic thiazolidine lactams, the unexpected hydrolytic instability of N-acylated amino acid amides and peptides, and cyclopropenimine-promoted benzylations of the benzophenone imine of glycine on Wang resin

Jack Geno Samaritoni, Purdue University

Abstract

Section I: Novel bicyclic thiazolidine lactams were synthesized from Fmoc acetal Merrifield resins to demonstrate a new synthetic procedure permitting the use of a wide range of functionality and an expanded scope of traditional solid-phase organic and peptide chemistry. The Fmoc acetal resins, which play a pivotal role as versatile intermediates, were prepared, N-deprotected, and subsequently acylated with ozone-incompatible groups such as furanyl and alkenyl. Although the N-acylated acetal resins can be directly converted to bicyclic thiazolidine lactams by reaction with substituted cysteine dertivatives at elevated temperatures, it has been demonstrated that initial hydrolysis of the acetal resins to the aldehyde resins using 35:60:5 trifluoroacetic acid:dichloro-methane:water before treatment with amino thiols led to the subsequent use of considerably milder cyclitive cleavage conditions. In all cases cyclitive cleavage using cysteine derivatives afforded two major diastereomers which were separated by normal or reverse-phase (C₁₈) preparative HPLC. The stereoisomers were fully characterized spectroscopically (¹HNMR, ¹³CNMR, DEPT 90/135, HSQC, COSY, HMBC) and relative stereochemistry was determined using 1-D nOe difference spectroscopy and 2-D NOESY. ^ Section II: Trifluoroacetic acid-mediated cleavage of Rink resin-bound N-acylated amino acid amides afforded mixtures of primary amides and their carboxylic acid hydrolysis products. The majority of the hydrolysis occurred post-cleavage in solution. The rate of hydrolysis was sensitive to the electronic substituent effects of the acyl group and amide susceptibility to hydrolysis can be predicted from the substituent's Hammett sigma value. The rate-enhancing substituent effect of the p-methoxy group was nullified or retained by carbonyl group insulation or conjugation, respectively. The effect was also observed with acyl groups R²CO (R²= alkyl) and followed the trend whereby the rate of hydrolysis increased proceeding from primary to secondary to tertiary alkyl. Hydrolysis was completely suppressed by use of cleavage cocktails containing 65% TFA. A mechanism involving initial resin cleavage and subsequent hydrolysis via the intermediacy of an iminooxazoline (azlactone) is presented. N-Acylated dipeptide amides bound to Rink or Wang resins were also cleaved under the reaction conditions, which resulted in peptide truncation. ^ Section III: Cyclopropenimine bases were evaluated as substitutes for the phosphazene base BTPP in the solid-phase benzylation of the benzophenone imine of glycine on Wang resin. Using two equivalents of base and benzyl bromide each, the cyclopropenimine bases were all found to be inferior to BTPP resulting only in partial alkylation. When the alkylation was performed in NMP dried over 3Å molecular sieves, the ratio of alkylated to unalkylated product is dramatically increased (27:73 to 71:29). Use of four and six equivalents of cyclopropenimine base in dry NMP resulted in a ratio of 95:5 while four equivalents in anhydrous NMP afforded a slightly diminished ratio of 91:9 but the highest yield of alkylation product (60%) as determined by quantitative NMR (QNMR).^

Degree

Ph.D.

Advisors

Martin J. O'Donnell, Purdue University.

Subject Area

Chemistry|Organic chemistry

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