Carboxylic acids hydroxy group activation

PBT has both hydroxy and carboxylic acid end groups, and it often contains active residual catalyst (usually titanium based). The resin is still capable of reacting, and molecular weight may be increased by solid-state polymerization. 

Esters from Carboxylic Acids and Alcohols via Hydroxy Group Activation (HGA)... 

The importance of the carboxylic acid moiety for activity is clearly illustrated by the next group of compounds. Removal of the carbethoxy substituent provided 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one (LIN) which is inactive at 3 mg/kg i.v. in the PCA procedure. Interestingly, the 2-methyl analog (LIV) exhibits excellent oral activity while displaying only weak intravenous activity. This may be rationalized on the basis of metabolic oxidation of this compound to the carboxylic acid (LX, Figure 10). The fact that the 2-ethyl (LV), 2-trifluoromethyl (LVI), and 2-acetyI (LVIl) analogs are considerably less active, and the 2-phenyl (LVI II) and 2-hydroxy (LIX) analogs are inactive, supports this explanation. 

The reagents containing hydroxy group have been developed for FL derivatization of carboxylic acid or other activated acids. 1-Pyrenemethanol (1-PM), 4-hydroxymethyl-7-methoxycoumarin (HMC), and 5-(4-pyridyl)-2-thiophenemethanol (PTM) have been applied to carboxylic acids with LC-FL detection. 

The effect of a carboxy group is illustrated by the reactivity of 2-bromopyridine-3- and 6-carboxylic acids (resonance and inductive activation, respectively) (cf. 166) to aqueous acid under conditions which do not give hydroxy-debromination of 2-bromopyridine and also by the hydroxy-dechlorination of 3-chloropyridine-4-car-boxylic acid. The intervention of intermolecular bifunctional autocatalysis by the carboxy group (cf. 237) is quite possible. In the amino-dechlorination (80°, 4 hr, petroleum ether) of 5-carbethoxy-4-chloropyrimidine there is opportunity for built-in solvation (167) in addition to electronic activation. This effect of the carboxylate ion, ester, and acid and its variation with charge on the nucleophile are discussed in Sections I,D,2,a, I,D,2,b, and II,B, 1. A 5-amidino group activates 2-methylsulfonylpyridine toward methanolic am-... 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

A second route (route B in Fig. 1) relies on an initiation process with an (meth)acryl hydroxyl compound and is adopted from the chemical ROP of lactones. The controlled character of these polymerizations ensures a virtually quantitative initiation and thus incorporation of hydroxy-functional initiator (e.g., acrylate) into the polymer chain. However, this is not automatically the case for lipase-catalyzed ROP due to the different mechanism. The latter follows an activated monomer mechanism in which the lipase activates any carbonyl group of a carboxylic acid derivative present in the system. It has recently been shown that acrylation using hydroxy-functional acrylate initiators like hydroxy ethyl(meth)acrylate (HEMA or... 

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