Hemiester

In another signiflcant example published in the same period, Guanti and coworkers described the desymmetrization of the meso cydohexene diester (3) to give the hemiester (4), whose enantiomeric excess increased from 55 to 96% when moving from plain buffer to the same buffer containing 10% v/v t-BuOH (Scheme 1.2 and Table 1.2 [8]). 

Brown and Walker Electrosynthesis of hemiesters of dicarboxylic acids to obtain diesters having twice as many CH2 groups according to... 

Scheme 9.5 Attachment of the succinoyl linker (a) in one step as polymer-supported hemiester (b) in a two-step sequence (a) attaching to the acceptor succinoyl (using succinyl anhydride) first, followed by (b) the attachment of MPEG-OH to the free carboxyl of the succinoyl formed in step a.

Selected examples of carboxylic acid anhydrides and carbonic hemiester anhydrides... 

This example documents the difficulty of rationalizing the results of in vivo investigations when competitive metabolic reactions are seen. In such cases, simpler in vitro systems may be more informative, as exemplified by the hydrolysis of alkyl phenyl carbonates (phenyl-O-CO-O-alkyl) catalyzed by pig pancreatic elastase (EC 3.4.21.36) [15]. The rate of hydrolysis was monitored by following C02 production as with the carbamates discussed above. Indeed, the enzyme-catalyzed hydrolysis yields the phenyl hemiester of carbonic acid (phenyl-O-COOH), which decomposes rapidly to produce C02 and phenol. With these carbonates, the rate of hydrolysis decreased in the series Bu > i-Bu > Et hexyl, the /-Hu and cyclohexyl derivatives being... 

Our final example is that of cyclic anhydrides, namely prochiral 3-sub-stituted glutaric anhydrides (7.101, R = Me, Et, or Pr). When incubated with lipase in an inert solvent in the presence of an alcohol (methanol, butan-l-ol, etc.), these compounds underwent nucleophilic ring opening with formation of a hemiester (7.102) of (/ -configuration (60-90% ee) [180]. This product enantioselectivity and, of course, the lack of reactivity in the absence of lipase show the enzymatic nature of the reaction. 

It is also interesting to note that the three hemiesters of metronidazole are good substrates of pig liver esterases. The ty2 values for hydrolysis of the hemisuccinate, hemiglutarate, and hemimaleinate were 0.2, 2.3, and 2.0 h, respectively, in 5% pig liver homogenate at 37° and pH 7.4. 

In summary, the scattered data available indicate that hemiester prodrugs generally undergo negligible hydrolysis at neutral pH in buffered solutions and in human plasma. In contrast, hydrolysis appears relatively fast in the presence of hepatic hydrolases. This would suggest limited first-pass metabolism and activation mediated mainly by liver hydrolases. 

Activation by intramolecular cyclization is not restricted to nucleophilic attack by acidic and basic N-atoms, but can also be catalyzed by carboxylate groups. This has been demonstrated with hemiester prodrugs of phenol and paracetamol (8.136, R=H and MeCONH, respectively, Fig. 8.12) [174]. In... 

Most of the hemiesters 8.136 underwent no or little enzymatic degradation in human plasma, in agreement with the known inertness of hemiesters toward cholinesterase (see Chapt. 7). In contrast, very rapid hydrolysis was usually seen in pig and rat liver preparations, indicating the involvement of carboxylesterases. The only inert compound was the 3,3-dimethylglutarate hemiester of paracetamol (8.136, X = C(CH3)2CH2, Fig. 8.12). Data on the hydrolysis of such prodrugs by human hepatic enzymes will be welcome. 

Fig. 8.12. Activation of hemiester prodrugs of phenols by acid-catalyzed hydrolysis (Reaction a), base-catalyzed hydrolysis (Reaction b), and cyclization-elimination (Reaction c). Enzymatic hydrolysis not shown (adapted from [174]). 

C. Larsen, P. Kurtzhals, M. Johansen, Kinetics of Regeneration of Metronidazole from Hemiesters of Maleic Acid, Succinic Acid and Glutaric Acid in Aqueous Buffer, Human Plasma and Pig Liver Homogenate , Int. J. Pharm. 1988, 41, 121 - 129. 

K. Fredholt, N. Mprk, M. Begtrup, Hemiesters of Aliphatic Dicarboxylic Acids as Cyclization-Activated Prodrug Forms for Protecting Phenols against First-Pass Metabolism , Int. J. Pharm. 1995, 123, 209-216. 

The data presented here constitute part of the results attained in the development of a research project funded by the European Community (EC) and performed in cooperation with three independent European companies [6]. Hybrid polymeric materials based on intimate blends of human serum albumin (HSA), alkyl hemiesters of alternating copolymers of maleic anhydride (MAn), and vinyl ethers of monomethoxyoligoethylene glycols (PEGVE) were selected as biocompatible matrices for the formulation of the nanoparticles. 

The preparation and characterization of alternating copolymers of Maleic anhydride (MAn) and poly (ethylene glycol-vinyl ether) as well as their chemical conversions to provide various alkyl hemiesters (Scheme 1) have been described elsewhere [7]. The matrices are quoted as PAMm z, where m represent the number of oxyethylene units in R and n the number of carbon atoms in R. Human serum albumin (HSA) was provided by Isti-tuto Sierovaccinogeno Italiano SpA, Italy. 

Better results, as far as dispersion homogeneity and stability are concerned, were obtained when the fz-butyl hemiester (PAM 14) of the... 

Following the reaction, simple extraction provided access to both the hemiester prodnct and the alkaloid withont chromatography and the recovered cinchona alkaloid conld be reused with no deterioration in the ee or yield. This method has found use in the synthesis of P-amino alcohols and in natural product synthesis [198-201] and has recently been reported as an Organic Syntheses method [202],... 

Subsequently, Bolm developed a variant of this process which employed just a sub-stoichiometric quantity of cinchona alkaloid [203], In this method, 10 mol% of quinidine was nsed in conjunction with a stoichiometric amount of pempidine to prevent seqnestration of the cinchona alkaloid by the acidic hemiester product. The chiral hemiester products derived from various meio-anhydrides were obtained with >74% ee and >94% yields (Table 9) [203],... 

MeOH (0.122 mL, 3.0 mmol) was added dropwise to a stirred suspension of anhydride 57b (164 mg, 1.0 mmol) and quinidine (0.357 g, 1.1 mmol) in a mixture of toluene and tetra-chloromethane (1/1, 5 mL) at -55 °C under argon. The reaction mixture was stirred at this temperature for 60 h. During this period, the material gradually dissolved. Subsequently, the resulting clear solution was concentrated in vacuo to dryness, and the residue was dissolved in EtOAc. The solution was washed with 2N HCl and, after phase separation, followed by extraction of the aqueous phases with EtOAc the organic layer was dried (MgSO ), filtered and concentrated in vacuo to provide the corresponding hemiester (2//,35)-3-endo-methoxycarbonyl-bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid as a white solid (192 mg, 98%, 99% ee by chiral-HPLC on the methyl 4-bromophenol diester). 

Deng also showed that (DHQD)2AQN could catalyze the parallel KR (PKR) of a variety of monosubstituted succinic anhydrides via asymmetric alcoholysis [215]. The nature of the solvent was found to have a significant influence on the selectivity. Hence, increasing the size of the alcohol from methanol to ethanol resulted in increased levels of enantioselectivity, albeit with reduced reaction rates. In this context, 2,2,2-trifluoroethanol appeared to be the alcohol of choice as it allowed the ASD of 2-methyl succinic anhydride (58a) with a remarkable level of selectivity. Indeed, the use of (DHQD)2AQN (15 mol%) provided a mixture of two regioiso-meric hemiesters 59a and 60a in a 1 1 ratio with 93 and 80% ee respectively. 

Scheme 6.141 Mechanistic proposal for the 121-catalyzed asymmetric intramolecular Michael addition exemplified for the model substrates ( )-4-hydroxy-l-phenyl-2-buten-l-one (n = 0) and ( )-5-hydroxy-l-phenyl-2-buten-l-one (n = 1) 121 functions as push/pull-type bifunctional catalyst inducing the cyclization of boronic acid hemiester (1) to form intermediate (2) release ofdiol product (3) by oxidation.

Scheme 6.145 Chiral hemiesters obtained from the 121-catalyzed methanolic desymmetrization of cyclic meso-anhydrides.

Anderson, B. D., R. A. Conradi, and K. Johnson. 1983.ilBnce of premicellar and micellar association on the reactivity of methyl prednisolone 21-hemiesters in aqueous solutifRharm. Sci72 448-454. 

A hydrolase-type reaction is otherwise rare in homogeneous catalysis, but the opening of prochiral cyclic anhydrides mediated by cinchona alkaloid in the presence of methanol leads to optically active hemiesters (Bolm, 2000). Very structurally di-... 

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