Development of new preformed nitrogen sources for the osmium-catalysed aminohydroxylation reaction

Abstract

The aim of this project was to develop new preformed nitrogen sources for the osmium-catalysed aminohydroxylation reaction. Some limitations of the Sharpless asymmetric aminohydroxylation reaction such as the requirement for a number of reagents in excess to generate nitrogen sources, the remaining reagent not easily separated from the product, requires strong basic conditions to perform that in some substrates competes with Michael addition reaction, and chlorination of the substrates and products as a result of using chlorinating reagents to generate nitrogen sources.

Six tert-butyl carbamate-based preformed nitrogen sources have been synthesised. These first generation preformed nitrogen sources especially tert-butyl N-(methanesulfonyloxy)carbamate worked under mildly acidic reaction conditions, and do not undergo reaction above pH 6. The best yields are afforded under acidic conditions. No diol was observed, but low enantioselectivity was afforded in the presence of chiral cinchona alkaloid ligands typically employed for the Sharpless AA reaction. Five amino acid-based ligands were also synthesised. The aim was to prepare ligands that were able to work under mildly acidic conditions. Three ligands were derived from L-threonine with 4-toluenesulfonyl, 4-nitrophenylsulfonyl, and 4-methoxyphenylsulfonyl N-protection. One was derived from L-serine with 4-toluenesulfonyl N-protection, and one was derived from diamino acid (R)-2,3-bis(amino)propanoic acid with two-fold 4-toluenesulfonyl N-protection. These ligands gave moderate stereoselectivity under literature conditions, but they did not give similar induction in the osmium-catalysed aminohydroxylation reaction using preformed nitrogen sources.

A more base stable second generation of preformed nitrogen sources have also been synthesised including their substrate scope studies. These consisted of tert-butyl, ethyl, benzyl, 2,2,2-trichloroethyl, and 2-(trimethylsilyl)ethyl N-(4-toluenesulfonyloxy)carbamates. These preformed nitrogen sources worked under a wide range of pH conditions from pH 3 to 11, and gave excellent yields below pH 7 but decreased yields above pH 6. A high yields were generally afforded with 1.2 equiv of preformed nitrogen source and 0.01 equiv of osmium catalyst. Low enantioselectivity was observed in the presence of chiral ligands typically employed for the Sharpless AA reaction. In the scope study, these preformed nitrogen sources afforded a high yield and a high regioselectivity for monosubstituted and 1,1-disubstituted alkenes. With 1,2-disubstituted alkenes a high yield was afforded but for unsymmetrical 1,2-disubstituted alkenes poor regioselectivity resulted. Good regioselectivity was afforded with 1,1,2-trisubstituted alkenes, but low yields were afforded.

Reaction with tert-butyl, benzyl, and 2,2,2-trichloroethyl N-(4-toluenesulfonyloxy)carbamate consistently gave a high yields, while with ethyl and 2-(trimethylsilyl)ethyl N-(4-toluenesulfonyloxy)carbamate gave a lower yields. Benzyl N-(4-toluenesulfonyloxy)carbamate was selected as the preformed nitrogen source in a study of the diastereoselectivity of the aminohydroxylation reaction of allylic alcohols catalysed by osmium. First, reaction of monosubstituted allylic alcohols gave high yields, and the reaction was generally complete within 72 h. However these gave low diastereoselectivity. Protection of the allylic alcohol accelerated the reaction. Second, a moderate to high yield was afforded in terminal disubstituted allylic alcohols. The reaction gave higher diastereoselectivity but longer reaction times. Finally, trisubstituted allylic alcohols did not reliably undergo reaction. They gave a low yield of product with 1,2,2-trisubstituted allylic alcohols in two examples. - provided by Candidate.