Synthesis of α‐amino‐3‐chloro‐4,5‐dihydro‐5‐methyl‐5‐isoxazoleacetic acid, a ring‐methylated analogue of the antitumor agent acivicin (AT‐125)

Abstract

a-Amino-3-chloro-4,5-dihydro-5-methyl-5-isoxazoleacetic involving the photoisomerization of N-phthaloylvaline acid (8), a ring-methylated analogue of the potent antitumor methyl ester (1). The stereochemical course of the 1,3-dipolar agent acivicin (AT-125), is synthesized in a 6-step procedure cycloaddition is proven by means of a X-ray structure analyin 63% overall yield from (S)-valine. Key step is the 1,3-dipo-sis of the major diastereoisomer ?a formed in the chloronitrile lar addition of bromonitrile oxide to the N,C-protected (S)-oxide cycloaddition. The absolute configuration of the major isodehydrovaline (6) available from (S)-valine in four steps ( u ) diastereomer ?a and the bromo derivative 7b is (aS,5R).

Free-Radical Reactions in the Synthesis of α-Amino Acids and Derivatives

“…The product diradicals then react by further hydrogen atom transfer to give the alkenes 182a − d , by rearrangement to give the bicyclic products 183a and 183b , or by coupling to give the tricyclic species 184 . It is interesting to note that the alanine and phenylalanine analogues 185 and 165a of the amino acid derivatives 157 and 181a − d did not react on photolysis, indicating that 1,5-hydrogen transfer to the excited state phthalimide does not occur. , The route outlined above for the preparation of the β,γ-dehydrovaline derivative 182b has been exploited in the asymmetric synthesis of the amino acid derivative 186

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“…199,200 The route outlined above for the preparation of the β,γ-dehydrovaline derivative 182b has been exploited in the asymmetric synthesis of the amino acid derivative 186. 201 For the photochemically initiated hydrogen transfer reactions of N-phthaloylamino acid derivatives, the carboxyl group must be protected, otherwise decarboxylation is the predominant reaction. 202,203 Alternatively, electron-transfer reactions sometimes compete effectively with the hydrogen abstraction and decarboxylation processes.…”

Recent Developments in the Use of N-Phthaloyl-Amino Acid Derivatives in Synthesis

“…Examples include the preparation of (2S,3S)-3-methylproline 49 via cyclisation of δchloroisoleucine 8, 14 and the asymmetric synthesis of the amino acid derivative 50 via nitrile oxide cycloaddition to the dehydrovaline derivative 34. 63 Side-chain bromination of N-phthaloyl-amino acids can be achieved without protection of the carboxy group and we found the product bromides to be suitable for the synthesis of amino lactone derivatives. For example, the bromoacids 51 and 52 reacted with silver carbonate to give the corresponding γ-lactones 54 and 55.…”