Acylations site-selective

Histidine residues are efficient nucleophiles in aqueous solution at pH 7, much more so than lysines, and this is the basis for the site-selective functionalization of lysine residues in folded polypeptides and proteins [24, 25]. p-Nitrophenyl esters react with His residues in a two-step reaction to form an acyl intermediate under the release of p-nitrophenol followed by the reaction of the intermediate with the most potent nucleophile in solution to form the reaction product. In aqueous solution the reaction product is the carboxylic acid since the hydroxide ion is the most efficient nucleophile at pH 7. If there is an alcohol present the reaction product will be an ester and the overall reaction is a transesterification reaction. 

Hence, a reaction of Type I will involve a racemic or achiral/me,t(9 nncleophile which will react enantioselectively with an achiral acyl donor in the presence of a chiral catalyst, while on the other hand, a reaction of Type II will associate an achiral nncleophile and a racemic or udm lmeso acyl donor in the presence of a chiral catalyst. In both cases, when a racemic component is implicated the process constitntes a KR and the maximum theoretical yield of enantiomerically pure product, given perfect enantioselectivity, is 50%. When an achiral/mera component is involved, then the process constitutes either a site-selective asymmetric desymmetrisation (ASD) or, in the case of tt-nucleophiles and reactions involving ketenes, a face-selective addition process, and the maximum theoretical yield of enantiomerically pure product, given perfect enantioselectivity, is 100%. 

Miller also explored the ASD of glycerol derivatives through an enantioselective acylation process which relies on the use of a pentapeptide-catalyst which incorporates an A-terminal nucleophilic 3-(l-imidazolyl)-(5)-alanine residue [171], Most recently, Miller has probed in detail the role of dihedral angle restriction within a peptide-based catalyst for ferf-alcohol KR [172], site selective acylation of erythromycin A [173], and site selective catalysis of phenyl thionoformate transfer in polyols to allow regioselective Barton-McCombie deoxygenation [174],... 

Other authors have attempted to rationalize the enzyme selectivity toward sugar derivatives by simulating the interaction of the substrates with the enzyme by molecular modeling [100], although this is not an easy task [101]. The first published example related to the regioselective acylation of sucrose [102]. However, the two observed acylation sites of sucrose were not on the same monosaccharide unit, and therefore a possible explanation of subtilisin selectivity could reside in the different steric hindrances. 

The effects of cationic head groups on the alkaline hydrolysis of the quinoxaline (192) to give (193) have been looked at using the surfactants (194 R = Me, Et, n-Pr, n-Bu X = Cl, OH).164 The reactivity increases with increasing head-group size and is related to the disruption of the hydration of the HO ion. An earlier paper from the same group describes the synthesis of (192) and some micellar effects on its basic hydrolysis.165 A novel site-selection functionalization reaction is facilitated by histidine side-chains in helical structures which can catalyse the acylation by mono-p-nitrophenyl... 

This concept has been applied for the synthesis of the structurally complex and highly oxyfunctionalized triquinane (—)-coriolin (Sch. 31) [61]. Two carbonyl groups, both in the right position for 1,2-acyl shift were present in the trimethyl-functionalized bicyclo[2.2.2]octenone 58. With a site-selectivity of 85% the expected regioisomeric tricyclic dione 59 was formed as a mixture of epimers (Sch. 31). Subsequent transformations involving the annulations of the third five-membered ring as well as epoxidation and hydroxylation steps led to the desired natural product... 

Carbonylation at a C-H bond fi to the sp2 ring nitrogen can also be achieved by a Ru3(CO)12 catalyst. The Ru3(CO)12-catalyzed reaction of 1,2-dimethyl-benzimidazole with an alkene and CO provides the corresponding /J-acylated product in high yield with complete site-selectivity [42] (Eq. 25). A tri-nuclear ruthenium cluster 19 is proposed as the key catalytic species. A similar basicity-dependent reactivity of substrates as described in the a-carbony-lation was observed in the case of the carbonylation at C-H bond to the sp2 nitrogen. 

For nonsymmetrical bicyclic imidazoles, direct TV-alkylation (arylation or acylation) is problematic since site-selectivity is influenced by many subtle electronic effects. Thus, Curtius rearrangement-based syntheses have been used widely for the synthesis of differentiated TV-substituted thienoimidazoles (104), (106) from (acylamido)thiophene carbonyl azides (103), (105) (Equations (30) and (31)) <79JCR(S)96>. These intermediates are useful for the synthesis of angiotensin II antagonists (Equation (32)) <91EUP483683,92EUP520423>. 

Relative to acylation strategies, modification via reductive alkylation preserves the overall charge state (and thus the solubility) of the protein. In general, this technique also suffers from poor site selectivity. 

The power of this methodology has been demonstrated by the facile synthesis of a thia-zolo[4,5-c]quinolinone, a class of molecule which was anticipated to have high affinity for the GABA receptor [97]. In a single reaction flask, beginning with 186, consecutive, site-selective Suzuki couplings were followed by acyl substitution to provide 190. 

Figure 5.3. Intramolecular acyl transfer between residues four positions apart in the sequence in a helical conformation, the key step in the site-selective functionalization reaction [13].

Although the silyl group confers a site selectivity on the acylation reaction, other structural factors may be sufficient to override the -effect. This is demonstrated by comparison of acylations of the alkenylsilanes (4) and (5) (Scheme 8). In the former, both the aromatic and silyl substituents direct the electrophile to the same carbon site, and acylation proceeds in high yield. However, in the latter substrate, where the substituents are in opposition, the aromatic group dominates the site of acylation, and the... 

The y-isoenzyme lacks the C2 domain, is prenylated at the C-terminus, and lacks the regulatory phosphorylation sites of cPLAja. The enzyme demonstrates high lysophospho-lipase activity and lacks the acyl chain selectivity of the a-isoenzyme suggesting a role in phospholipid remodeling [23]. The 6, e, and -isoezymes have been identified more recently (H. Chiba, 2004 T. Ohto, 2005) and are discussed [23]. The group IV isoenzymes (a- ) have also been designated A-F [15]. 

Azabuta-l,3-dienes have been prepared in which the imino group is conjugated with an enol ester acylation of carbanions derived from N-(diphenylmethyl)arylmethanimines affords a wide range of the 2-azadienes (Scheme 197). The site selectivity for the attack of the electrophile on the aza-allyl anion depends upon the substituents on the carbanion, and on the hardness of the... 

In conclusion, the technology of attaching tailor-made fatty acids through site-selective acylation of insulin and GLP-1 has proven to provide new and long-acting pharmacotherapies with superior properties. 

In carbohydrate synthesis, multistep procedures involving protection/ deprotection sequences are usually employed, because of the lack of a direct method for site-selective manipulation of one specific hydroiq l group out of the multiple hydroiqrl groups in carbohydrates. If such site-selective transformation becomes feasible and available as a practical process, it will be a great advance in sustainable and green chemistry because it enables a reduction in the number of synthetic steps. Recently, chiral DMAP- and PPY-derivatives have been developed for site-selective acylation of carbohydrates. ... 

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