Hernani L. S. Maia

Deprotection by electrolysis: Part I. The application of homogeneous redox catalysis to the study of the reduction of tosyl esters and amides

Abstract The mechanism of the cathodic cleavage of tosylate protecting groups from alcohols, amines and phenols in dimethylformamide has been probed using the technique of homogeneous redox catalysis. Some nine tosyl esters and six tosyl amides have been investigated and it is confirmed that these deprotection reactions occur by cleavage of the anion radicals. The formal electrode potentials for the couples, neutral molecule/anion radical, are reported and it is shown that the rate constants for the cleavage of the anion radicals lie in the range 104 s−1 to >108 s−1. Indeed for aromatic amines and phenols, the homogeneous charge transfer between the catalyst and the substrate becomes the rate determining step.

Reductive cleavage of N-substituted aromatic amides as tert-butyl acylcarbamates

Synthetic and spectroscopic details relating to a set of heteroaromatic N-benzyl carboxamides and in particular the corresponding tert-butyl acylcarbamates are reported. These compounds were required to study the postulated effect of various heterocycles (pyridine and pyrazine with and without condensed benzene rings) on the cleavage of acyl–N bonds by reduction. All compounds were initially characterized by cyclic voltammetry (CV) which indicated various degrees of facilitated reduction, reflecting a direct influence of the heterocyclic component. Selected acylcarbamates were studied with respect to acyl–N bond cleavage by mild reducing agents, and selectively deacylated by activated aluminium and sodium borohydride. Conversion to acylcarbamates followed by reduction might therefore be a mild, efficient two-step procedure to effect cleavage of amides, allowing isolation of carbamates and with sodium borohydride also the corresponding alcohols.

Synthesis of novel β-substituted α,β-dehydroamino acid derivatives

Abstract β-Substituted α,β-dehydroamino acids are synthesised in high yields by a Michael addition of heterocyclic nucleophiles to the methyl esters of N-tert -butyloxycarbonyl, N -(4-toluenesulfonyl)dehydroamino acids, followed by a base-induced elimination of the 4-toluenesulfonyl group with regeneration of the α,β-double bond.

Synthesis of non-proteinogenic amino acids from N-(4-toluenesulfonyl)dehydroamino acid derivatives

By treating N-(4-toluenesulfonyl)-N-(tert-butyloxycarbonyl)-dehydroamino acid derivatives with different reactants under different conditions, a variety of new amino acids are obtained, viz. (i) α-alcoxy-α-amino acids, (ii) α,α-diamino acids and (iii) novel β-substituted dehydroamino acids.

Structural versatility of peptides from Cα,α-disubstituted glycines. Preferred conformation of the Cα,α-dibenzylglycine residue

The preferred conformation of the Cα,α-dibenzylglycine residue has been assessed in selected derivatives and small peptides by conformational energy computations, 1H NMR spectroscopy, and X-ray diffraction. Conformational energy computations on the Cα,α-dibenzylglycine monopeptide, Ac-Dbz-NHMe, strongly support the view that this Cα,α-symmetrically disubstituted residue is conformationally restricted and that its minimum energy conformation falls in the fully-extended (C5) region. The results of the theoretical analysis are in agreement with the solution and crystal-state structural propensity of Tfa-Dbz-Gly-DBH, Tfa-Dbz-L-Phe-OMe and its benzyl ester analogue, m-ClAc-Dbz-OH, Z-Gly-Dbz-Gly-OH and its t-butyl ester derivative. The implications for the use of the Dbz residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.

Mild Reductive Cleavage of Tryptophan and Histidine Side-Chain Protecting Groups

The activation potentials of the p-toluenesulfonyl and benzoyl groups as determined by cyclic voltammetry when they are linked to indole or imidazole are less negative than when these groups are linked to aliphatic amines. This makes them most suitable for side-chain protection of tryptophan and histidine, as it allows mild selective cleavage not only by controlled-potential electrolysis but also by chemical reduction using either magnesium in anhydrous methanol or mercury-activated aluminum.

Synthesis and cathodic cleavage of a set of substituted benzenesulfonamides including the corresponding tert-butyl sulfonylcarbamates: pKa of sulfonamides

From a series of substituted benzenesulfonic acids, most of which have previously been employed for the protection of amino functions and including a few such known to facilitate cleavage by acid, benzylamides 1a–k have been derived and studied. Initially their electrochemical cleavage potentials were determined by cyclic voltammetry in order to further explore selective deprotection within this substance group. In parallel, the corresponding tert-butyl sulfonylcarbamates 2a–k have also been prepared and studied. Among the sulfonamides investigated S–N bond cleavage was found to take place over a wide range of potentials from –1.67 to –2.64 V (excluding the nitro derivative), the most acid-labile groups requiring more negative potentials, whereas this cleavage was facilitated by 0.19–0.30 V for the sulfonylcarbamates. Small scale electrolyses of 2 at controlled potential with determination of the cleavage products formed were subsequently performed. For the N-benzylbenzenesulfonamides 1, the pKas in DMSO and in some cases also in water have been determined and found to be in the range 14.0–16.4 and 10.07–11.53, respectively.

The cathodic cleavage of the benzyloxycarbonyl group from aliphatic amines in dimethylformamide

Abstract It is shown that the reduction of the benzyloxycarbonyl derivatives of n-butylamine, cyclohexylamine, piperidine and morpholine at vitreous carbon cathodes in DMF only occurs at very negative potentials, approx. −2.8 V vs. SCE, but the reaction leads to cleavage and hence to toluene and free amines in good yields ( > 80%). Cyclic voltammetry and controlled potential electrolysis have been used to probe the mechanism of these reductions both in the aprotic medium and in the presence of low concentrations of proton donor. The behaviour of protected primary and secondary amines is shown to differ slightly and the conclusions of the study are used to comment on the mechanism of deprotection of amino acids and peptides.

Selective cathodic cleavage of unsymmetrical imidodicarbonates, acylcarbamates and diacylamides

A study of the selective cathodic cleavage of one of the alkoxycarbonyl or acyl groups from various imidodicarbonates, acylamides, and diacylamides is reported. The compounds investigated include all 15 possible combinations of the following groups in unsymmetrical N,N-diprotected derivatives, of benzylamine: p-nitrobenzyloxycarbonyl, trichloroethyloxycarbonyl, toluene-p-sulfonyl, benzoyl, benzyloxycarbonyl, and tert-butyloxycarbonyl which can all be electrochemically cleavaged, except the last one. Initially the compounds were examined by cyclic voltammetry in order to measure the potentials associated with the cleavage of each group and afterwards they were electrolysed at constant potential in the presence of a proton donor. The following ranges in negative potential were recorded: 1.03–1.13 V [Z(NO2)], 1.8–2.14 V (Troc), 1.75–2.41 V (Tos), 1.88–2.52 V (Bz), and 2.83–2.9 V (Z), thus occasionally revealing a drastic effect of the auxiliary group. In the electrolytic experiments competitive attack by base occasionally led to mixtures of monoacylamides. However, all compounds apart from some of the trichloroethyloxycarbonyl derivatives could be selectively cleaved in 89–100% yields when an appropriate proton donor was used. Tentative explanations are given for the behaviour of the compounds studied and some conclusions are drawn.

Cyclic voltammetry studies on substituted arenesulfonhydrazides

Additional Z and Boc groups on the vicinal nitrogen of sulfonyl hydrazines have no significant effect on the cathodic potential of the sulfonyl functions as measured by cyclic voltammetry, whereas a Boc group on the geminal nitrogen invariably gives rise to shifts of about 0.2 V to less negative potential similar to those previously observed for derivatives of amines.