Marcel Patek

Solid-Phase Synthesis of "Small" Organic Molecules Based on Thiazolidine Scaffold

Abstract 2-Substituted thiazolidine-4-carboxylic acids were obtained by reaction of aldehydes with unprotected (R)-cysteine attached to the polymeric support via an ester bond. Subsequent transformation into N-acyl derivatives followed by alkaline hydrolysis provided almost exclusively the corresponding (2R,4R)-stereoisomer. A convenient solid phase synthesis of substituted thiazolidines, including an evaluation of aldehydes, conditions for N-acylation and S-oxidation as well as the stability of thiazolidines to reagents used in solid phase synthesis are described.

Safety-catch anchoring linkage for synthesis of peptide amides by Boc/Fmoc strategy

Summary: 2-Methoxy-4,4’-bis(methylthio)benzhydrylamine (10) and the corresponding disulfoxide were prepared and tested as a model amide protecting groups for their stability toward acidic conditions. Subsequently, the novel 4-[4,4’-bis(methylsulfinyl)-2-o~-(9-fluorenylmethylo~c~bonyl) benzhydrylami- nolbutanoic acid (SCAL) handle (9) has been prepared and applied to solid-phase peptide synthesis of C-terminal peptide amide using both 9-fluorenylmethyloxycarbonyl (Fmoc) and tert-butyloxycarbonyl (Boc) groups for Na-amino protection. A range of naturally occurring peptides, especially hormones such as oxytocin, secretin, LHRH, and calcitonin, contain a C-terminal amide function. Synthesis of peptide amides is best carried out by application of appropriate handles, which are quantitatively coupled in a single step onto amino-functionalized supports to provide ageneral starting point for peptide chain assembly. Surprisingly, the development of amide-anchor groups which can be cleaved by relatively mild procedures (e.g., TFA), were established only recently.’ Considerable attention has been focused on preparation of benzylamine1’2 and benzhydrylamine1’3 deriva- tives substituted with electron-donating alkoxy groups. Earlier we have examined some benzhydrylamines containingp-methylsulfinyl orp-methylthio groups as a model amrde protecting groups4 We have found that 4,4’-bis(methylsulfinyl)benzhydryl protecting group for amides is fully compatible with Fmoc and/or Boc protecting groups. We now describe the synthesis and application of anew type of safety-catch acid labile5 (SCAL) handle9 derived from 2-alkoxy-4,4’-bis(methyl- thio)benzhydrylamine, which extends the orthogonalit

SAFETY-CATCH AND MULTIPLY CLEAVABLE LINKERS IN SOLID-PHASE SYNTHESIS

of currently

All-cis cyclopentane scaffolding for combinatorial solid phase synthesis of small non-peptide compounds

This review article focuses on concepts that incorporate safety‐catch and multiply cleavable linkers in solid‐phase synthesis. Discussed are specific applications of such linkers in the synthesis of peptides, peptide mimetics, and “small” organic molecules, as well as their limitations for particular chemistries and reaction conditions.

A safety-catch type of amide protecting group

Abstract A convenient synthesis of all-cis cyclopentane template 6 from commercially available anhydride 1 is described. Regioselective conversion of the anhydride 6 to functionalized cyclopentanes 7 with a range of nucleophiles, as well as the regiochemical assignment of the major regioisomer are also discussed.

Monitoring solid phase reactions with ion-selective electrode

Abstract A p-substituted benzhydrylamine derivatives 1 – 4 were synthesized and evaluated for their lability toward various acids. The pair 2 & 4 seems to be suitable for peptide synthesis using the base labile Fmoc- and/or acid labile Boc- strategy,

Unusual KF/Al2O3 promoted tandem electrophilic-nucleophilic aromatic substitution leading to the xanthone formation

Abstract A noninvasive method for monitoring and quantitative determination of basic functionalities (pK hb +>7) on solid support is described and its usefulness is demonstrated with practical examples. The method is based on quantitative protonation of the basic moieties on solid support with perchloric acid, followed by release of perchlorate anions by base and their concomitant potentiometric determination using an ion-selective electrode.

Synthetic Combinatorial Libraries: A New Tool for Drug Design

Formation of xanthone (III) by the KF/Al2O3 mediated O-alkylation of 2-hydroxybenzophenone (I) is described and mechanistic rationalization is proposed for this unexpected side-reaction.

A Convenient Preparation of Monosubstituted N,N′-di(Boc)-Protected Guanidines

Development of new leads for drug design and structure/function relationship studies were revolutionized by the introduction of combinatorial or “library” techniques (for review see e.g. (Moos et al., 1993; Gallop et al., 1994; Gordon et al., 1994)). These techniques allow for the generation and screening of millions of potentially active structures. Due to the well developed and finely tuned synthetic methodology, peptides were the first group of compounds evaluated by this new approach. However, the next logical challenge is to synthesize libraries of nonpeptidic structures. The combinatorial library approach applied at Selectide consists of three basic steps: (i) chemical synthesis based on the split synthesis method yielding a library with one test compound structure per one bead; (ii) screening of the library either using an on-bead binding assay or a multiple step release assay; and (iii) recovery of positive beads and determination of the structure of the test compound (Lam et al., 1991).