Aldehydes hemithioacetal formation

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]. 

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... 

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