Michael-type addition thiols

Thiols can be prepared by a variety of methods. The most-utilised of these synthetic methods for tertiary and secondary thiols is acid-catalysed synthesis for normal and secondary thiols, the most-utilised methods are free-radical-initiated, alcohol substitution, or halide substitution for mercaptoalcohols, the most-utilised method is oxhane addition and for mercaptoacids and mercaptonitnles, the most-utilised methods are Michael-type additions. 

The base-catalysed addition of thiols to Jt-electron-deficient alkenes is an important aspect of synthetic organic chemistry. Particular use of Triton-B, in place of inorganic bases, has been made in the reaction of both aryl and alkyl thiols with 1-acyloxy-l-cyanoethene, which behaves as a formyl anion equivalent in the reaction [1], Tetra-n-butylammonium and benzyltriethylammonium fluoride also catalyse the Michael-type addition of thiols to a,P-unsaturated carbonyl compounds [2], The reaction is usually conducted under homogeneous conditions in telrahydrofuran, 1,2-dimethoxyethane, acetone, or acetonitrile, to produce the thioethers in almost quantitative yields (Table 4.22). Use has also been made of polymer-supported qua-... 

The importance of chiral thiols and thioether linkages in biological systems has prompted intense investigation of the use of chiral amines [see e.g. 5-11] and ammonium salts [see e.g. 12] as agents for asymmetric induction in the Michael-type addition reaction. Considerable success has been achieved using chinchona alkaloids and their A-alkyl derivatives (see Chapter 12). 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

Michael-type addition of thiols to o-quinone and cr, j -unsaturated ketones... 

A Michael-type addition of secondary amines or thiols to 3-methylene-2-oxetanones (33) and subsequent pyrolysis of the adduct (34, X = NR22 or SR2) to yield allylic amines (35, X = NR22) or sulphides (35, X = SR2) has been proposed as a useful alternative to the Wittig olefination procedure (95JOC578). 

It is noteworthy that chiral organic bases such as pyrrolidines and cinchonines or cinchonidines were recently grafted onto a MCM-41 support.1183,1841 These materials catalyse enantioselective Michael-type addition between ethyl 2-oxocy-clopentanecarboxylate and methyl vinyl ketone[183] as well as thiol and 5-methoxy-2(5Z/)-furanone.[184] Although ee was only modest (maximum ee 35 %), these attempts are very promising. 

The unsaturated residues Dha and Dhb are formed by dehydration of serine and threonine residues, respectively, and the thioether linkages Lan and MeLan are generated by intramolecular Michael-type addition of cysteine thiols to the unsaturated sites (e.g., Fig. 3b). These modifications can be performed by either two separate enzymes (LanB and LanC) in class I lantibiotics or a single bifunctional enzyme (LanM) in class II lantibiotics. Typically, proteolysis of the leader sequence is performed by a dedicated protease, either a LanP serine protease (class I) or the cysteine protease domain of a LanT protein (class II). The lanB genes encode large ( 1000 residues) predominantly hydrophilic dehydratases that may be membrane associated. To date, the dehydratase activity of a LanB protein has not been reconstituted in vitro and little is known about the mechanism of catalysis of this group of enzymes. 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

During the first step, a one-electron oxidation yields a phenoxy radical (Ar-0 ). The presence of the radical was supported by fast flow ESR spectroscopy in the presence of horseradish peroxidase. In the second one-electron oxidation, the phenoxy radical is oxidized to NAPQl. As described in Figure 33.21, the highly electrophilic NAPQl may easily react with glutathione or protein thiol groups according to a Michael-type addition. The attack of liver protein thiol... 

Treatment of pristinamycin IIa with meta-chloroperbenzoic acid afforded a compound to which the structure (79) was initially assigned, resulting from epoxidation of the more substituted double bond (12,13-C). This material did not display chemical properties characteristic of an epoxide as the assumed epoxide moiety remaining after treatment with nucleophilic reagents. Michael-type addition products on the dehydroproline ring were observed after treatment with thiols or amines (see Sect. 5.4.5). 2D-NMR analysis of the product from reaction of pristinamycin IIa with mCPBA showed that a transannular oxidative cyclization had taken place leading to formation of (80). The reaction can be considered to involve initial epoxidation of the 12,13-double bond followed by an intramolecular nucleophilic attack by the 37-hydroxy of the enol ether (Scheme 19). A similar transannular oxidative cyclization reaction has been reported for the reaction of l,5-dimethylcyclooct-4-en-l-ol with meta-chloroperbenzoic acid [125]. 

Michael-type addition of thiols to the dehydroproline double bond of pristinamycin IIa was investigated. Attempted reaction with alkyl thiols, substituted phenyl thiols, ethyl mercaptoacetate or hydroxy-substituted alkyl thiols using standard conditions [128] (but at room temperature) was unsuccessful. Moderate yields (up to 50%) to conjugate addition products from reaction of pristinamycin 11 with these thiols (Scheme 22) were obtained when the reaction was carried out in the presence of N,N-dimethylethanolamine (see below for discussion of the stereochemistry associated with the conjugate addition products). With sterically hindered thiols, for example, 2-mercapto-pyran, no reaction was observed even under catalytic conditions. Similar results to those described above were obtained for reaction of either of the alcohols (60) or (61). 

In comparison to the above results, Michael-type addition of most dialkylaminoalkyl thiols to the dehydroproline double bond of pristinamycin 11, or either of the alcohols (60) or (61) [129, 130], occurred readily in the absence of catalysts. The length of the chain between the sulfur and the nitrogen atoms played an important role in the feasibility of this reaction. For example, the order of reactivity for diethylaminoalkyl thiols was Et2NCH2CH2SH > Et2NCH2CH2CH2SH > Et2NCH2CH2CH2CH2SH ... 

The Michael-type addition of thiols to a,p-unsaturated aldehydes has been reported to proceed very efficiently using O-TMS protected diarylprolinol 31c as catalyst (Scheme 3.32). The low configurational stability of the adducts at r.t. led the authors to modify the reaction conditions, which finally involved carrying out the reaction at -24 °C and reducing the adducts in situ, furnishing the corresponding y-thio alcohols in excellent yields and enantioselectivities. Both alkyl- and aryl-substituted enals could be used as suitable Michael... 

A thiol group reacts with a methacrylate group by Michael-type addition. 

Fig. 14 a Maleimides participate in DA reactions with diene-containing biomolecules, b maleimides also react with thiol-containing biomolecules in Michael type addition... 

Matsuno R, Takami K, Ishihara K. Simple synthesis of a library of zwitterionic surfactants via Michael-type addition of methacrylate and alkane thiol compounds. Langmuir 2010 26(16) 13028-32. 

Similar observations have been made with 6-a-halopenicillanic acids but in this case the thiol anion in the analogous enamine [71] displaces the halide at C(6) via the imine tautomer [72] (Gensmantel et aL, 1981). If the enamine [71] is produced in the transpeptidase-cataiysed reaction with penicillins, then inactivation of the enzyme could occur by a nucleophilic group on the enzyme attacking C(5) in a Michael-type addition reaction. 

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