Thiol aminolysis

Benesch, R., and Benesch, R.E. (1956) Formation of peptide bonds by aminolysis of homocysteine thiol-actones./. Am. Chem. Soc. 78, 1597. 

Other authors have described the lipase-catalyzed chemoselective acylation of alcohols in the presence of phenolic moities [14], the protease-catalyzed acylation of the 17-amino moiety of an estradiol derivative [15], the chemoselectivity in the aminolysis reaction of methyl acrylate (amide formation vs the favored Michael addition) catalyzed by Candida antarctica lipase (Novozym 435) [16], and the lipase preference for the O-esterification in the presence of thiol moieties, as, for instance, in 2-mercaptoethanol and dithiotreitol [17]. This last finding was recently exploited for the synthesis of thiol end-functionalized polyesters by enzymatic polymerization of e-caprolactone initiated by 2-mercaptoethanol (Figure 6.2)... 

As has been pointed out, halogen in the 3-position in 1,2,4-thiadia-zoles is inert towards most nucleophilic reagents. Thus, under the usual conditions, 3-chloro-5-phenyl-1,2,4-thiadiazole cannot be hydrogenated catalytically to the parent base, and resists aminolysis, hydrazinolysis, and replacement of the halogen by cyano or thiol groups.178 It is unaffected by concentrated sulfuric acid at 100°, which converts the 5-analogs into the hydroxy compounds.178... 

Qo R C-CNRa OR Aminolysis of thiol esters HB=general acid or specific acid. 

The occurrence of general acid-catalyzed hydroxylaminolysis or methoxylaminolysis of thiol esters or amides has been described in Section IIB in terms of kinetically important tetrahedral intermediates. Two kinetically indistinguishable mechanisms for general acid-catalyzed aminolysis reactions are represented by transition states 42 and 43. Mechanism 42 involves a prior protonation of the ester followed by a general base-catalyzed aminolysis mechanism 43 is a general acid-assisted nucleophilic reaction of the amine. Mechanism 42 can be ruled out in the hydrazinolysis of phenyl acetates (Bruice and Benkovic, 1964) and in the hydrazinolysis of S-thiolvalerolactone (Bruice et al., 1963) on the basis of a calculated rate constant which is greater than the diffusion-controlled limit. Mechanism 43 is therefore correct. 

Applying results from low-molecular-weight thiolesters and esters to the corresponding polymers should give slightly slower acid hydrolysis, equally fast alkaline hydrolysis, and a much faster aminolysis of poly-(thiol esters) compared with polyesters (24, 35, 36). 

Lima et al. [190-192] performed the RAFT of MM A in the presence of (4-cyano-l-hydroxylpenl-4-yl) dithiobenzoate CTA (entry E in Table 16). Monohydroxy oligomethylmethacrylates were obtained. To get the telechelic structure, aminolysis of monofunctional PMMA with 1-hexylamine was undertaken, leading to a o -OH,cw-SH-PMMA. A hydroxyl group can replace the thiol terminal by Michael addition with hydroxyethyl acrylate [192] (Scheme 33). 

The value of thiourea for the preparation of thiols is that on reaction with alkyl halides,271 mixtures of hydrogen bromide and alcohols,272 or suitable aromatic273 or heterocyclic halides274 it readily yields S-alkyl- or S-aryl-thiouronium salts, from which the thiols are usually obtained in good yield by alkaline hydrolysis or by aminolysis with high-boiling, strongly nucleophilic... 

Noting the fairly pronounced reactivity of phenyl esters in aminolysis Bodanszky concluded [21] that the enhanced aminolysis rates observed with thiophenyl esters [4] are due only in part to their thiol ester character and perhaps to a major extent to the fact that they are aryl esters. This conclusion was based on the fundamental studies of Gordon, Miller and Day [22] who found extremely high rates in the ammonolysis of phenyl and vinyl esters. To further increase the electronic effect operative in phenyl esters, their nitro-derivatives were prepared and examined. For practical application p-nitrophenyl esters were... 

Alternatively, Whittaker et al. utilized the reversible oxidation/reduction of a thiol-terminated linear polymer as a homocoupling reaction to access macrocycles that could be reversibly cyclized and cleaved (Scheme 12.5) [29]. The linear precursors were prepared using reversible addition-fragmentation chain transfer (RAFT) polymerization of styrene from a bifunctional initiator (16). The desired polystyrene with thiol end groups could be isolated in near-quantitative yields by aminolysis of the polymer with terminal dithioester groups (17). The linear dithiols... 

Thiol-ene coupling was also used for the end-functionaHzation of PNIPAM in an analogous study conducted by the groups of Lowe and Hoyle [55]. In this case, PNIPAM was prepared by RAFT polymerization, followed by the aminolysis of the thiocarbonylthio end group to produce a terminal thiol simultaneous Michael addition with aUyl methacrylate yielded the alkene mono end-functional PNIPAM. The polymer terminus was then modified via a radical thiol-ene dick reaction with three different mercaptans to afford a series of PNIPAM polymers with varied LCSTs (Scheme 30.5). 

Scheme 30.5 The post-polymerization modification of PNIPAM prepared by RAFT polymerization by sequential aminolysis/Michael addition and thiol-ene click coupling. Adapted from Ref. [55].

Interestingly, lipase-catalyzed acyl transfer onto SH-groups (corresponding to ester thiolysis in analogy to aminolysis) does not take place [289]. As a result, the resolution of sec-thiols is not feasible by this method and has to be performed via hydrolysis or alcoholysis of the corresponding thioesters [290-292]. 

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