Final Activity Report Summary - AMINO HYDROXY ACIDS (A new approach to synthesis of b,a-amino hydroxy acids)
Our aim is to synthesise amino-hydroxy acids. We started our synthesis from ?-substituted furan bearing 1,3-dikarbonyl side chain. The prochiral keton functional group was reduced enantioselectively (97 % ee) to a secondary alcohol. Creating such enantiopure chiral centre was the most important achievement of this project. This centre will be used to create a second stereocenter. After achieving this very important crucial step in the synthesis of amino-hydroxy acid, we continued our work with rasemic alcohol which synthesised from ketoester by using NaBH4. NaBH4 was reduced both keton and ester funtional group to corresponding alcohols. The protection of primary hyhydroxyl group with silyl chloride, secondary hydroxyl group was converted to an azide followed by hydrogenation to yield an amine. The amine was protected with Boc2O and primary hydroxyl group was deprotected with TBAF. The oxidation of this primary alcohol gave an aldehyde which was subjected to the wittig reaction. After preparing of alkyl chain which is necessary for amino acid (AHDA), the furan ring was oxidised by photooxygenation to unsaturated 1,4-dicarbonyl compound.
Photooxygenation of mono Boc protected amine at -78 0 C resulted in the formation of six memebered piperidine ring. It was attributed that the nucleophilic character of mono boc protected amine. To reduce the nucleophilicity of mono Boc protected amine, we attempt to put second Boc group on to nitrogen. However, it did not work.
We went back and used a simple precursor, furan carrying the azide and the protected primary hyrdroxyl group. It was synthesised at the early stage of this project. The azide was used as a maseked amine. Photoxygenation of this yielded the unsaturated 1,4-dicarbonyl compound. But it was unsatable to purify on silicagel. So, it was freshly synthesized and used in next reaction without further purification. DibalH, LiAlH4 solution, NaBH4 were used in the reduction of keton functional group. None of them gave the desired reduction, a chiral centre adjacent to the azide. NaBH4-CeCl3, Luche condition, did not worked either in synthetically useful manner.
A model study showed that replacement of silyl group with an alkyl chain gave stable photooxygenation product, the unsaturated 1,4-dicarbonyl compound. This was reduced by employing the Luche condition to corresponding alcohol.
After this result, we prepared the furan derivative which bearing the alkyl group as AHDA has. AHDA is known amino acid in a rasemic and an enantiopure form. Photooxygenation of 1-azido-furyl octane gave the unsaturated 1,4-dicarbonyl compound. The keton functional group was reduced with NaBH4-CeCl3 to yield secondary alcohol adjacent to azide functional group. We observed 80% diastereoselectivity. We currently focused on increasing this diastereomeric ratio to higher than 95 %.
Photooxygenation of mono Boc protected amine at -78 0 C resulted in the formation of six memebered piperidine ring. It was attributed that the nucleophilic character of mono boc protected amine. To reduce the nucleophilicity of mono Boc protected amine, we attempt to put second Boc group on to nitrogen. However, it did not work.
We went back and used a simple precursor, furan carrying the azide and the protected primary hyrdroxyl group. It was synthesised at the early stage of this project. The azide was used as a maseked amine. Photoxygenation of this yielded the unsaturated 1,4-dicarbonyl compound. But it was unsatable to purify on silicagel. So, it was freshly synthesized and used in next reaction without further purification. DibalH, LiAlH4 solution, NaBH4 were used in the reduction of keton functional group. None of them gave the desired reduction, a chiral centre adjacent to the azide. NaBH4-CeCl3, Luche condition, did not worked either in synthetically useful manner.
A model study showed that replacement of silyl group with an alkyl chain gave stable photooxygenation product, the unsaturated 1,4-dicarbonyl compound. This was reduced by employing the Luche condition to corresponding alcohol.
After this result, we prepared the furan derivative which bearing the alkyl group as AHDA has. AHDA is known amino acid in a rasemic and an enantiopure form. Photooxygenation of 1-azido-furyl octane gave the unsaturated 1,4-dicarbonyl compound. The keton functional group was reduced with NaBH4-CeCl3 to yield secondary alcohol adjacent to azide functional group. We observed 80% diastereoselectivity. We currently focused on increasing this diastereomeric ratio to higher than 95 %.