Exploiting the geminal acylation reaction to produce a β-turn peptidomimetic

Abstract

The focus of this research was to develop a route to 5,6-fused 1-aza-2-oxobicycloalkane amino acids, beta-turn peptidomimetics, with carbon-based bridgehead substituents. The route that was developed proceeded as follows: Geminal acylation of the acetal derived from hex-5-en-2-one gave 2-(3-butenyl)-2-methyl-1,3-cyclopentanedione in 76% yield. Experiments with baker's yeast showed that desymmetricization of this 1,3-diketone could be carried out with very high enantioselectivity. Beckman rearrangement of (2S, 3S) 2-(3-butenyl)-3-[(tert-butyldimethylsilyl)oxy]-2-methylcyclopentanone using O-mesitylenesulfonyl hydroxylamine provided the corresponding lactam, (3S, 4S)-1-Aza-6-(3-butenyl)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-2-cyciohexanone. Cyclization of the lactam nitrogen onto the double bond was carried out with trimethylsilyl triflate and iodine in the presence of triethylamine which yielded the iodolactam (6S,5S,9S)-1-aza-5-[(tert-butyldimethylsilyl)oxy]-9-(hydroxymethyl)-6-methyl- bicyclo[4.3.0]nonan-2-one. This iodolactam was then converted into the propyl ester of (6S,5S,9S)-1-aza-5-[(tert-butyldimethylsilyl)oxy]-9-(hydroxymethyl)-6-methylbicyclo[4.3.0]nonan-2-one. The development of this route, including the elucidation of the structures of side-products, is discussed in detail.