Ibuprofen nucleophiles

Figure 3.4 The synthesis of ibuprofen is initiated by a Friedel-Crafts acylation of an aUcyl-substituted benzene ring. The resulting ketone is then reduced to an alcohol with sodium boro-hydride. The alcohol functionality then undergoes a functional group interchange by conversion to a bromide. In turn, this permits the introduction of an additional carbon atom in the form of a nitrile introduced via an 8, 2 nucleophilic displacement. This is then hydrolyzed to give the target molecule.

Henke et al78 reported the resolution of 2(4-isobutylphenyl)propanoic acid 59 (ibuprofen) by transesterification of its corresponding vinylester 61 using lipase from Candida antarctica. Depending on the nucleophile, the vinylester 61 was recovered with 8-99% ee while the alkyl ester 62 or the free acid 59 is recovered with 16-75 % ee. 

In addition, although most abiotic processes are nonenantioselective, not aU are indeed the case. Nucleophilic 5 jv2-substitution reactions at a chiral center will result in chiral inversion to the antipodal enantiomer. While such processes are often biologically mediated, as for the nonsteroidal anti-inflammatory drugs [328], they can also be abiotic. Appropriate sterile controls should be used for experiments with such compounds, as was done in the demonstration of microbial chiral inversion of ibuprofen in Swiss lake water [329]. Photolysis of a-HCH [114], /3-PCCH [114], and chlordane compounds [116] was demonstrated not to be enantioselective, as expected for an abiotic process. However, this may not be the case for some pyrethroids, known to isomerize photolytically. 

Ibuprofen is the generic name for the pain reliever known by the trade names of Motrin and Advil. Like aspirin, ibuprofen acts as an anti-inflammatory agent by blocking the synthesis of prostaglandins from ara-chidonic acid. One step in a commercial synthesis of ibuprofen involves the reaction of a nucleophilic eno-late with an electrophilic carbonyl group. In Chapter 24, we learn about the carbon-carbon bond-forming reactions of enolates with carbonyl electrophiles. 

UGT-catalyzed glucuronidation of the carboxylic acid group in drugs results in the formation of acyl glucuronides, which are intrinsically electrophilic in nature. Protein modification can occur via a simple transacylation reaction with a protein nucleophile(s) or by acyl migration within the f3-0-glucuronide unit to a reactive aldehyde intermediate. Detailed mechanistic discussion on this issue is provided with the NSAIDs ibufenac and ibuprofen in the following section. 

CHAPTER 17 CARBOXYLIC ACIDS AND THEIR DERIVATIVES Nucleophilic Addition-Elimination at the Acyl Carbon 17.53 An alternative synthesis of ibuprofen is given below. Supply the structural formulas for compounds A-D ... 

As shown in Table 31.12, hydroxide cleanly provides the carboxylic acids ibufenac (entry a), ibuprofen (entry b), and felbinac (entry i), whereas nucleophilic amines such as benzylamine and piperidine provide high yields of the amide derivatives. 

After fine-tuning the nucleophile and the BTM catalyst, this method was eventually used in the KR of ibuprofen (s = 34), ketoprofen (s = 14), fenoprofen (s = 17), flurbiprofen (s = 15), and naproxen (s = 61), five chiral non-steroidal antiinflammatory drugs (Figure 41.5). 

Another approach for the enzymatic preparation of 5-ibuprofen has been demonstrated by de Zoete et al. [229]. The enantioselective ammonolysis of ibuprofen 2-chlo-roethyl ester by Candida antarctica lipase (lipase SP435) gave the remaining ester 5-(+) enantiomer in 44% yield and 96% e.e. The enantioselective enzymatic esterification of racemic ibuprofan has also been demonstrated using lipase from Candida cylindraceae [230]. The reaction was carried out in a water-in-oil microemulsion [bis(2-ethyl-hexyl)sulfosuccinate (AOT)/isooctane). The lipase showed high preference for the S-(+) enantiomers of ibuprofen which was esterified and R-(—) enantiomer remained unreacted. The reaction yield of 35% was obtained using n-propanol in the reaction mixture as nucleophile. 

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