Carboxylic from support-bound acids

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

The reaction of Tentagel-bound carboxylic esters with amidooximes has been used to prepare oxadiazoles (Entry 11, Table 15.20). Thiadiazoles have been prepared from support-bound iV-sulfonylhydrazones by treatment with thionyl chloride. Thiadiazole formation and cleavage from the support occurred simultaneously (Entry 12, Table 15.20). Perhydro-l-thia-2,5-diazole-2,2-dioxides (sulfahydantoins) have been prepared by aminosulfonylation of amino acids esterified with Wang resin, followed by ring-closure with simultaneous cleavage from the support [257]. 

Preparation of Esters from Support-Bound Carboxylic Acids 353... 

Nevertheless, the direct nucleophilic displacement of support-bound carboxylates to prepare hydroxamates presents some limitations. For example, O-tert-butyldimethylsilyl-protected hydroxylamine displaces common acids from oxime resin however, further treatment with trifluoroacetic acid (TFA) is necessary to remove completely the silyl... 

Another potential avenue for future development is extrapolation of these chemistries from benzofused to heteroanellated heterocycles. We have recently been able to show that thicno[2,3-/ ][ 1,4]thiazepine-5-ones (88)69 can be synthesized on solid support from resin-bound 5-chloro-4-nitrothio-phene-2-carboxylic acid (87) using essentially the same synthetic protocols developed in the carbocyclic series (Scheme 17 and Section 3.2.1).5 The starting material, 5-chloro-4-nitrothiophene-2-carboxylic acid, was synthesized in solution from commercially available 5-chlorothiophene-2-carbox-ylic acid. 

The main strategies for the release of aldehydes or ketones from insoluble supports are sketched in Figure 3.34. These include the hydrolysis of acetals and related derivatives, the treatment of support-bound carboxylic acid derivatives with carbon nucleophiles, and the ozonolysis of resin-bound alkenes. 

Polystyrene-bound benzhydryl- or trityl halides react much more rapidly with carboxylates than chloromethyl polystyrene, and the base used to form the carboxylate no longer plays a decisive role in these reactions (see Experimental Procedure 13.7). Support-bound phenyldiazomethanes have been used to prepare esters directly from carboxylic acids under mild reaction conditions. Unfortunately, the diazomethanes required are not easy to prepare, and have not yet found widespread application. 

Support-bound isocyanates can be conveniently prepared from carboxylic acids by Curtius degradation. Because the reaction of the intermediate acyl azides with alcohols to yield esters is slow, Curtius degradation can be conducted in the presence of alcohols to yield carbamates directly (Entries 4 and 5, Table 14.8). 

Thiazolidin-4-ones have been prepared by condensation of support-bound imines with a-mercapto carboxylic acids (Entry 11, Table 15.18). These thioaminals are quite stable and tolerate, for example, treatment with TFA [228,229]. Thiazolidines, which can be prepared from resin-bound cysteine and aldehydes (Entry 12, Table 15.18), are also remarkably stable towards acid-promoted hydrolysis. Libraries of thiazolidinones have been used to identify new cyclooxygenase-1 inhibitors [230]. 

A second advantage of preparing peptides by sequential acylation of support-bound amines arises from the fact that activated A -acyl amino acids readily form oxa-zolones, which quickly racemize under basic conditions, such as in the presence of excess amine. Hence, carboxyl group activation of support-bound peptides in the presence of an amine will readily lead to racemization (Figure 16.2). 

In addition to the aforementioned microwave-assisted reactions on solid supports, several publications describe microwave-assisted resin cleavage. A variety of cleavage procedures have been investigated, depending on the nature of the linker used. In this context it was shown that several resin-bound carboxylic acids (Scheme 16.1) were cleaved from traditionally non-acid-sensitive Merrifield resin by using 50% trifluoroacetic acid in dichloromethane (Scheme 16.37). Microwave irradiation enables these cleavages to be conducted at elevated pressure and/or temperature in sealed Teflon vessels [23]. Evaporation of the filtrate to dryness furnished the recovered benzoic acid in quantitative yield and excellent purity. 

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. 

C-Acylation with a polymer-bound ester in the presence of polymer-based trityllithium has been demonstrated as example of efficient multi-polymer reactions A novel degradation of peptides from the carboxyl end through the acid azide is performed on a controlled-pore glass support ... 

As a suitable model reaction, the coupling of various substituted carboxylic acids to polymer resins has been investigated by Stadler and Kappe (Scheme 7.8) [28]. The resulting polymer-bound esters served as useful building blocks in a variety of further solid-phase transformations. In a preliminary experiment, benzoic acid was attached to Merrifield resin under microwave conditions within 5 min (Scheme 7.8 a). This functionalization was additionally used to determine the effect of micro-wave irradiation on the cleavage of substrates from polymer supports (see Section 7.1.10). The benzoic acid was quantitatively coupled within 5 min via its cesium salt utilizing standard glassware under atmospheric reflux conditions at 200 °C. 

In addition to the aforementioned microwave-assisted reactions on solid supports, several publications also describe microwave-assisted resin cleavage. In this context it has been demonstrated that carboxylic acids could be cleaved from conventional Merrifield resin, using the standard TFA-DCM 1 1 mixture, by exposure of the polymer-bound ester and the cleavage reagent to microwave irradiation in a dedicated Teflon autoclave (multimode instrument). After 30 min at 120 °C, complete recovery of the carboxylic acid was achieved (Scheme 12.9) [26]. At room temperature, however, virtually no cleavage was detected after 2 h in 1 1 TFA-DCM. 

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

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