Hemithioacetal formation

Although the reaction of dialkyl phosphites with orthoformic esters has been extended to triethyl trithioorthoformate," the preferred synthesis of formylphosphonate dithioacetals is usually the high-yield Michaelis-Arbuzov reaction of trivalent phosphorus compounds with the appropriate chlo-rodithioacetals.""" For the corresponding hemithioacetals, a Pummerer-type reaction of a-phos-phoryl sulfoxides with alcohols in the presence of iodine is usually the method of choice (Scheme 5.3). " ° However, hemithioacetal formation is solvent dependent and generally gives a moderate yield of product in a mixture with several other byproducts arising from transesterification reactions. 

M. R. Bendall, I. L. Cartwright, P. I. Clark, G. Lowe, and D. Nurse. Inhibition of papain by N-acyl-aminoacetaldehydes and N-acyl-aminopropanones. Evidence for hemithioacetal formation by a cross-saturation technique in NMR spectroscopy. Eur. J. Biochem. 79 201 (1977). 

Recently Kallen [183] has examined the mechanism of formation of thiazolidine-4-carboxylic acid and concludes that at high formaldehyde concentration and with most of the cysteine in the RSH form, the intermediate (56) is probably involved. When hemithioacetal formation is not favored on thermodynamic grounds [132, 133] thiazolidine likely results from (57). The rate determining steps are formation of the carbinolamine, in the acid region, and dehydration of the carbinolamine in the alkaline region the change in rate determining step occurs at pH 6-7. 

Racemization of some substrates can take place through reversible formation of the substrate via an addition/elimination process. The racemization can be acid or base catalyzed. In this section we vill discuss DKR of cyanohydrins and hemithioacetals. 

The electroreduction of disulfides R2S2 (R = Ar, Aik), in the presence of carbonyl compounds and MesSiCl, includes the formation of intermediate thiosilanes and results in trimethylsilyl ethers of hemithioacetals of ketones and aldehydes or in full thioacetals depending on whether a two-compartment (a) or an undivided (b) cell was used (Scheme 48) [218]. 

Addition of hydrogen sulfide and thiols is qualitatively similar to reaction with alcohols in that there are two stages, formation of hemithioacetal (or hemithio-ketal) followed by acid-catalyzed elimination of the hydroxy group and substitution of a second —SR (Equations 8.47 and 8.48). The transformation has been studied less extensively than hydration and acetal formation, and relatively little information on mechanism is available. The initial addition appears to be specific base-catalyzed, an observation that implies that RS is the species that adds. The situation is thus similar to cyanide addition. General acid catalysis has, however, been found at pH 1 to 2 for addition of weakly acidic alkyl thiols, and the reaction rate as a function of pH has a minimum and rises both on the... 

Peptide mimetics containing the a-ketoamide moiety are very important because they act as cysteine protease inhibitors. In fact, the a-ketoamide residue forms hemithioacetals with the -SH group of the cysteine residue of the enzyme [32], Nakamura et al. [26b] reported the preparation of a 100-member combinatorial library of a-ketoamides by means of a two-step one-pot synthesis. The first step consisted of the Ugi-4CR between (+/— )lactic acid, amines, isocyanides, and aldehydes leading to the formation of the lactamides 40 which were oxidized to the corresponding pyruvamides 41. This one-pot procedure was performed in THF since the PDC oxidation was incompatible with the presence of methanol. Five a-ketoamides showed an 80% average purity (Scheme 2.17). 

Fig. 8 (a) Reversible formation of cyclic and linear acetal oligomers from triethylene glycol and 4-nitrobenzaldehyde. (b) Reversible formation of hemithioacetal (HTA) from reaction between a thiol and an aldehyde derivative... 

In 2010, Ramstrom and coworkers showed that hemithioacetal (HTA) formation from reaction between a thiol derivative and a given aldehyde (or ketone) was a fast and reversible process in water, and therefore suitable for DCC-based systems (Fig. 8b) [65]. Because the thermodynamic equilibrium of the reaction of HTA formation is significantly displaced toward the two reactants, a virtual library of ten possible HTA was generated by mixing in water five aliphatic thiols and two aldehydes (one aromatic and one aliphatic). When carried out in the presence of an enzyme (i.e., (3-galactosidase) free of any cystein residues in its active site to avoid HTA formation between the library components and the enzyme itself, the formation of a specific HTA was highly favored as determined by saturation... 

Fig. 6.3 Interaction between phthalic dialdehyde, mercaptan group (OPA reagents) and primary amine (I) thioacetal formation (II) formation of fluorescent complex between hemithioacetal and primary amine (III).120 Reproduced with permission...

The aromatic ring of oestradiol or oestrone methyl ether readily forms a tricarbonyl chromium (0) complex in which the 13C signals from the aromatic ring are shifted strongly upheld (by ca. 14—34 p.p.m.). Smaller upheld shifts for other carbon atoms close to the aromatic ring (e.g. 2 p.p.m. for C-6) have been used to settle uncertainties in the earlier literature concerning the assignments of individual 18C resonances.69 13C N.m.r. spectra discriminate between A4- and A5-isomers of spiro-3-steroidal ketone derivatives thiazolidine formation results only in the (3i )-isomer (12), whereas hemithioacetals are mixtures of the (3R)- and (35)-forms.80... 

The 2-acetoxysulfides are obtained according reaction (11) by in situ formation of the configurationally unstable hemithioacetals and subsequent lipase-catalyzed acylation. Racemization of the hemithioacetals was achieved by silica gel. The 2-phenylthiocarboxylic acid was formed by hydrolysis of the corresponding thioester in the presence of trioctylamine [reaction (12)]. 

Above Steps (1) and (2) are peptide chain cleavage, Steps (3) and (4) are thiol formation by hydrolysis. Steps (5) and (6) are hemithioacetal regeneration via cyclization of the thiol. 

The major pathway for the formation of MVA in yeast and mammalian systems is shown in Fig. 2. Acetyl-CoA and acetoacetyl-CoA are condensed by the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) synthase (HMG-CoA acetoacetyl-CoA lyase, E.C. 4.1.3.5) to form 3-hydroxy-3-methylglu-taryl-CoA (HMG-CoA). In a two-step reduction, HMG-CoA is then reduced to MVA in a reaction catalyzed by the enzyme HMG-CoA reductase. In the first step of this reaction, the CoA hemithioacetal of mevaldic acid is formed. In the second step, this compound is reduced to MVA both steps require NADPH. Hydroxymethylglutaryl-CoA reductase is an important control point in the regulation of cholesterol biosynthesis in mammalian systems. The HMG-CoA reductase enzymes from yeast and mammalian liver have been purified to homogeneity, and some of their properties have been determined. This work is covered in detail in several reviews (Beytia and Porter, 1976 Rodwell et al., 1976 Kandutsch et al., 1978). 

The reduced reactivity of o(,j3-unsaturated ketones towards 3-mercapto-ethanol allows preferential formation of the hemithioacetal of an unconjugated carbonyl present in the molecule. One example of this general... 

The kinetics of the formation of the hemithioacetal in 50% ethanol-water have shown that the reaction is acid catalysed and does not involve a thiolate anion, probably proceeding via the formation of the protonated ketone , ... 

Other studies of rate and equilibrium constants of the formation and breakdown of hemithioacetals (MeCHO+PhSH, or AcSH, or p-NOaQ-H4SH) reveal a diffusion-controlled rate-determining step, with proton transfer in some sense concerted with cleavage and formation of the C—S bond. A general base-catalysed mechanism involves attack of the RS anion on the carbonyl group. ... 

The major pathways of metabolism of inhaled formaldehyde are oxidation to formate and incorporation into biological macromolecules via tetra-hydrofolate-dependent one-carbon biosynthetic pathways (Huennekens and Osborne 1959, Koi-VUSALO et al. 1982). The most important pathway for oxidation appears to be that catalysed by formaldehyde dehydrogenase (EC 1.2.1.1), an enzyme that requires both glutathione and NAD as cofactors. UOTiLA and Koivusalo (1974) showed that the true substrate is the hemithioacetal adduct of formaldehyde and glutathione and the product formed is the thiol ester of formic acid, S-formylglutathione. 

The reaction of the sulfonium intermediate with alcohols leads to their protection as hemithioacetals. Treatment of thioglyco-sides with MeOTf gives an efficient glycosylating agent, and p3TUvic acetal formation from a pyruvyl thioacetal has heen achieved in a reaction catalyzed by MeOTf (amongst other electrophiles). ... 

A-Tosyl-5-alkyl-5-aryl-sulphimides or the cycloalkyl-sulphimides (39 n = 2, 3, or 4) have been shown to react with hydroxide ion in methanol solution, affording either the corresponding sulphoxide, or the hemithioacetal (40), or a mixture of both products. Kinetic studies, including studies using the a-deuteriated compounds, have revealed that the formation of (40) proceeds via an lcB path that involves rate-determining cleavage of the S—N bond. ... 

FIGURE 14.18 Acid- and base-catalyzed formation of hemithioacetals. 

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