Cleavage from solid support

Another example of solid phase DOS involves post-modification of the natural product macrolide antibiotic erythromycin (34) [77]. Erythromycin was first converted to analogue 32 which resembles a third generation macrolide antibiotic with high activity against resistant strains (ABT-773, 35), but is attached to solid phase-bound amino acids by reductive amination. Two further reductive amination steps and cleavage from solid support form a library of compounds of type 33 (Fig. 10). 

A promising approach to this topic is the development of biocompatible solid phase attachment systems for macrocycles that allow on-bead enzymatic and chemical modification [4]. While making use of recent developments in polymeric support for resins, we endeavored in constructing a new linker system, which allows easy attachment of macrocycles to the solid phase, simple organic or enzymatic reactions, and cleavage from solid support under mild conditions [98]. 

Cleavage from solid support and deprotection of amino acids side chain protecting groups by TFA and suitable scavenger... 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

SCHEME 8.4 Solid-phase synthesis methodology to attach a phosphoglycerate lipid unit to an elaborated disaccharide and cleavage from solid support. 

In the discovery of new antifungal compounds, Tsukuda and coworkers synthesized a nikkomycin analog library by Ugi condensation of uridine derivative 84, 59 carboxylic acids 85, 15 isocyanides 86, and an amino component attached to a Rink amide resin 87 (Figure 11.43). After cleavage from solid support, compounds 88 were tested for the enzyme inhibitory activity against Candida albicans chitin synthase 1. Among these derivatives, 246 samples exhibited more than 50% inhibition against this enzyme at a concentration of 10 tg/ml. 

The addition of nucleophiles to the cr-center of the selenium linker has been described by several groups among them Nicolaou et aL who investigated the formation of several spiro compounds 624 upon cleavage from solid supports [327] (Scheme 91). Crucial for these transformations are heteroatom-nucleophiles which can attack the released compoimds after sel-eniiun linker oxidation and elimination. Following the above-mentioned and similar routes, Nicolaou et aL synthesized diverse orthoesters and aUylic orthoesters [328]. 

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