Mitsunobu reaction threonines

Ring closure of (3-hydroxy-a-amino acids with sulfuryl chloride/triethylamine 68 is accompanied by formation of (3-chloroalanine,16 1 whereas cyclization of urethane-protected serine and threonine by the Mitsunobu reaction 54 69 70 leads to oxazoline and dehydroalanine formation as side products. 47,71 Formation of dehydroalanine can be prevented by bulky carboxy protecting groups such as tert-butyl esters. 69 ... 

Employing the Mitsunobu reaction with diisopropyl azodicarboxylate and triphenyl-phosphine, aminoacylserine (in contrast to aminoacylthreonine) is converted into (ami-noacyl)oxazolidine-2-carboxylic acid. 54 By the same procedure a/Zo-threonine peptides are converted into the oxazoline derivatives, whilst the threonine peptides are apparently converted into the aziridines in good yields. 86 ... 

The strategy was chosen to (1) link the amino acid derivative to a polystyrene-supported hydroxylamine, (2) carry out the cyclization under Mitsunobu conditions, and (3) assemble a short peptide on the free amino group present in the ring. This approach has been shown to be suitable particularly for solid-phase synthesis, as the supported (3-lactam could be easily separated from the by-products of the Mitsunobu reaction. The linker employed was a polystyrene resin carrying 0-trityl-hydroxylamine linker, prepared according to the literature procedure [151]. After the deprotection of Fmoc group carried out with 20% piperidine in DMF, the L-cbz-serine (or L-cbz-threonine) was coupled using (4,6-Dimethoxy-[l, 3, 5]-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) [152] in M-methylpyrrolidone (NMP) in the presence of M,M-diisopropylethylamine (DIPEA) (Schemes 42 45). 

Mitsunobu reaction of p-hydroxy-a amino acid peptides. Reaction of the Cbz-prolyl-threonine N-methyl amide 1 with P(C6Hs)3 and DIAD provides the peptide aziridine 2 in 84% yield. 

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