Synthesis and reactivity of alpha-trialkylsilyl alpha-amino acids
This work deals with the synthesis and reactivity of alpha-trialkylsilyl alpha-amino acids. They were synthesised using an established protocol involving rhodium(II)-catalysed insertion reactions of alpha-trialkylsilyl alpha-diazo esters into N-H bonds of carbamates. As an extension to this procedure, it was accounted that a diastereoselective approach to N-protected alpha-trialkylsilyl alpha-amino acids precursors may lead, after deprotection, to the formation of enantiomerically-pure alpha-trialkylsilyl alpha-amino acids. A variety of diastereoselective synthetic strategies were examinated. These investigations involved the use of alpha-trialkylsilyl alpha-keto-acetates as substrates, as well as various reactants such as chiral amines, ureas, or carbamates as sources of the chiral information. Carbamates were confirmed as the mostly efficient N-H sources for rhodium(II)-catalysed reaction. A diastereoselective N-H insertion reaction was attempted between a alpha-triethylsilyl alpha-diazo benzyl acetate and L-menthyl carbamate. The reaction proceeded in a diastereoselective formation of the N-H inserted product in a diastereomeric ratio of 75 to 25. A part of this project was then devoted to the synthesis of the racemic N-Cbz-protected 2-trimethylsilyl glycine. The possibility to obtain the free carboxylic functional group of the named compound from selective deprotection of a corresponding ester moiety was investigated. Various ester protecting groups were considered, the removal of which could give access to the free carboxylic acids and thus to enantiopure alpha-silyl alpha-amino acids through resolution by chemical methods. The most promising result was obtained when the 2-triethylsilyl-2-diazo-(4-methoxybenzyl) acetate underwent reaction with aluminum thrichloride/ethanthiol to yield to the mono-deprotected compound in a 1H NMR ratio 1.6 to 1 respect to the substrate. Attempts to selective removal of the benzyl ester moiety of N-Cbz-protected alpha-silyl alpha-amino benzyl acetate through selective hydrogenation remained unsuccessful. Hydrogenation over palladium(0) allowed exclusively the formation of the bi-deprotected alpha-silyl alpha-amino acetic acid. The alpha-silyl alpha-amino acid core could become a substructure of a more complicated structure, as for example of a modified Matrix metalloproteinase (MMP) inhibitor. Various synthetic strategies were considered and attempted towards the synthesis of the two building blocks of a silyl modified succinyl hydroxamic acid based MMPs inhibitor. The coupling of a iso-butyl succinyl hydroxamic acid (or the corresponding iso-propyl analogue) and the trifluoroacetic salt of 2-triethylsilyl-2-amino benzyl acetate using various coupling reagents, between them, PyBOP(R) combined with ethyldiisopropylamine, appeared the most promising. Finally, studies on microwave assisted synthesis of N-protected alpha-trialkylsilyl alpha-amino esters were described. A final summary of the several examples reported indicated a shortening of the reaction times under microwave irradiation in comparison to the same transformations performed under standard conditions and conventional heating. To these results, although, did not correspond a sensible enhancement of the chemo- and the stereoselectivity of the discussed reactions.
info:eu-repo/classification/ddc/540, Chemie, Aminosäuren, Carbene, Rhodium-katalyse, NH Insertion, Amino Acids, Rhodium-catalysis
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