U542745.pdf (12.18 MB)
Studies of alkylations of amino-acid derived anions.
thesisposted on 2015-11-19, 08:45 authored by Amanda Lisa. Guest
The area of enantioselective synthesis of a-amino-acids is of great current interest. This thesis describes three methods for the formation of a-alkylated amino-acids in a protected form ready for their incorporation into peptides. The methods discussed offer the possibility of forming a wide range of amino-acids in a mono- or di-protected form. The first method involves the formation of the ring system (3S) (5R)-N-benzyl-3-benzyl-5-phenyl-tetrahydro-l, 4-oxazin-2-one from phenylalanine and describes the stereoselective alkylation of this ring to give the a-alkylated product. The alkylated oxazinone then undergoes ring breakage to produce the mono-protected a-alkylated-a-benzyl amino-acid. The method also demonstrates the concept of self reproduction of chirality introduced by Seebach. The second method describes the formation of the glycine derivative (5S)-N-benzyloxycarbonyl-5-phenyl-tetrahydro-1,4-oxazin-2-one from the chiral auxiliary, phenyl glycinol. The ring is alkylated stereospecifically, via its enolate, to give the a-alkylated ring system, which undergoes hydrogenation to yield the a-alkylated mono-protected amino-acid. The final method to be discussed, produces the glycine derivative (5S)-N-BOC-5-phenyl-tetrahydro-l, 4-oxazin-2-one from the chiral auxiliary phenyl glycinol. Stereoselective electrophilic attack on the enolate of the oxazinone furnishes the a-alkylated ring system which may undergo ring breakage to produce the diprotected a-alkylated amino-acid. All three oxazinone ring systems demonstrate stereoselective alkylation, via their enolates to give C-3 substitution with the incoming group trans to the 5-phenyl group of the ring. The trans orientation is proved by X-ray crystal structure data which is provided for the products, (3S)(5R)-N-benzyl-3-methyl-3-benzyl-5-phenyl-tetrahydro -1,4-oxazin-2-one, (3S)(5R)-N-benzyl-3-dimethylallyl-3-benzyl-5-phenyl-tetrahydro-1,4-oxazin-2-one and (3S)(5S)-3-benzyl-5-phenyl-tetrahydro-1,4-oxazin-2-one. A reason is proposed for the formation of the trans product in preference to the cis.
Date of award1991-01-01
Awarding institutionUniversity of Leicester