Ester enolates, polymer-bound

Additionally, it has been shown that novel benzylidene titanium complexes of type 74 react with polymer-bound carboxylic esters to form the corresponding enol ethers (Scheme 28).79... 

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

Various imines and imine precursors reacted with immobilized ester-enolate-derived triazene esters 481 to give polymer-bounded azetidin-2-ones 482 (Scheme 68). The esters were bound to a benzylamine resin by a triazene linker employing diazonium salts. Traceless cleavage from the triazene linker yielded the desired azetidin-2-ones 483 <2002JOC8034>. 

Polymer-bound P-lactams have been prepared via the ester enolate imine condensation route <02JOC8034>. On the other hand, an efficient asymmetric synthesis of 2-azetidinones was accomplished when chiral acid chlorides or chiral aldehydes were used in the polymer-supported Staudinger reaction <02TA905>. 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

The idea that a polymer support could help to isolate polymer-bound reactive species from one another was suggested and illustrated sh y after the flrst solid phase peptide syntheses. Cyclic tetrapeptides were obtained in higher yields from polymer-bound 2-nitrophenyl esters than from analogous micromolecular active esters (Scheme 1) (X). Polymer-bound ester enolates were formed at 0 °C and trapped with alkyl bromides and carboxylic acid chlorides with no competing selfcondensation (Scheme 2) (Z). Soluble analogs gave primarily self-condensation. 

The success of both peptide cyclizations and ester enolate tnqiping is due to the lesser mobility of polymer-bound species, which reduces the rates of die bimolecular reactions that lead to higher oligomeric peptides or to ester self-condensation. 

The activation of acids by oxidation or dehydration of their derivatives has been studied by a German school. Oxidation of an acid diphenylhydrazide by JV-bromosuccinimide yields the azonium ion (96), which functions as a highly activated acid derivative, azobenzene being eliminated on nucleophilic attack. A related activation by oxidation has been performed in the solid phase by production of the polymer-bound azo-compound (97), nitrogen being expelled on amide-bond formation. Dehydrative activation is exemplified by conversion of the ester (98), prepared from the acid and 1,1-diphenylethylene glycol, into the enol ester (99). The generation of azo-compounds by anodic oxidation of hydrazides has been reported. All of these procedures have been utilized successfully in peptide synthesis. 

In solution aliphatic esters are acylated or alkylated at the a position by treatment with a hindered organolithium base at dry ice temperature to generate an enolate, followed by addition of a carboxylic acid chloride or an alkyl bromide. At higher temperatures the ester self-condenses rapidly during the time of enolate generation. When the ester is bound to a slightly swellable 10-20% cross-linked PS, acylations and alkylations proceed at room temperature with 73-90% yields and little or no competing self-condensation of the ester as shown in Scheme 26. Self-condensation is retarded because it requires reaction of two polymer-bound species with each other. 

Two kinds of in situ-prepared diazonium salts from amino-esters (203, 206) have been immobilized on polymer-supported benzylamine (202), affording resins (204) and (207). liHMDS-mediated formation of the corresponding enolates and subsequent reactions with a variety of imines afforded the desired resin-bound p-lactams (205, 208). Use of a CH2CI2 solution of TEA allowed detachment of the diazonium salt from the resin, while the removal of the diazo group has been accomplished by means of a mixture of THE and DMF or THF and acetonitrile, both at r. t. for 12 h (Scheme 45). 

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