Lactim benzyl ethers

Lactim benzyl ethers. Cyclodipeptides are converted to the bislactim ethers, which are valuable intermediates for stereoselective a-amino acid synthesis. 

The anions derived from mixed bis-lactim ethers of type II with R=benzyl seem to adopt a folded conformation of type 43 — stabilized possibly by an (HOMO)-anion-(LUMO)aryl attraction —, in which one of the diastereotopic faces is most effectively shielded. Consequently, electrophiles enter predominantely from the bottom side and show a much stronger face differentiation than they would do if the more size of the benzyl group would be the decisive factor. With (S)-a-methyl-(3,4-dimethoxy)-phenylalanine 44 — the precursor of a-methyldopa (2) — a suitable commercial chiral auxiliary is available. 

The lithiated bis-lactim ether (52) in which benzyl at the inducing center is replaced by phenyl, reacts with electrophiles considerably less stereospecifically (Table 8)20. Since phenyl is commonly regarded as bigger than benzyl — although the apparent size of a group depends very much on the reacting system — this finding seems to be consistent with the folded conformation 43 of the anion and the transition state of it s reactions with electrophiles. 

Common synthetic methods for the preparation of cyclic 8-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed by hydrogenolytic decarboxylation, or the imino ester carbon-carbon condensation with tert-butyl cyanoacetate followed by a trifluoroacetic acid treatment. The use of a thiolactam condensed with ethyl bromoacetate gives, after sulfur extrusion by triphenylphosphine, cyclic 8-enamino esters. Compared with these methods, the Meldrum s acid condensation followed by the monodecarboxylating transesterification described here is more convenient and practical. An extension of this procedure permits preparation of smaller... 

O-Alkylation gives the bis-lactim ether shown at the top right of Scheme 3.11. After deprotonation, alkylation occurs stereoselectively such that the electrophile approaches the anion anti to the isopropyl. Typical selectivities for this process are listed in Table 3.2. Advantages of this process are that selectivities are high and that it makes chiral quaternary carbons. Disadvantages are that the electrophiles must often be activated (Le., allylic, benzylic), and that the alkylated amino ester and the amino ester chiral auxiliary must be separated at the end. 

A Schollkopf-type synthesis, used by Subramanian and Woodard (342) to prepare (lS)-[2,2- H2]-ACPC, is shown in Scheme 88. Initial alkylation of the anion of the bis(lactim ether) 351 occurred cis to the bulky benzyl group, in violation of observations by Schollkopf. Both addition of BrCHjC Hj-O-trifyl and the subsequent cyclization 352 - 353 were stereoselective reactions. The (2R)-isomer was obtained using BrC HjCHj-O-triflyl in the synthesis, and both isomers were obtained in enantiomeric excesses of ca. 44%. 

Common synthetic methods for the preparation of cyclic B-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed... 

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