Lactim ethers synthesis

Five-, six-, and seven-membered lactim ethers. Synthesis and chemical properties 05KGS645. 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Excellent reviews covering the enantioselective synthesis of non-proteinogenic amino acids via metallated his-lactim ethers of cyclic dipeptides (2,5-diketopiperazines) (187) have been compiled by Schollkopf188). 

A. Synthesis of Lactim Ethers from Piperazine-2,5-diones. 254... 

This section deals mainly with the metalation of lactim ethers and subsequent reaction with electrophiles to generate new C—C bonds at position 3 or 6. Hydrolysis of the products leads to new amino acid esters. The chief attraction of this synthetic route is the high degree of stereoselectivity in the carbon—carbon bond-forming step. It is known as the Schollkopf method for the chiral synthesis of amino acids. 

Subsequently, the asymmetric synthesis of stereospecifically monodeu-terated 1-aminocyclopropane-l-carboxylic acids (IS, 2R) and (IS, 2S) has also been achieved by a modification of the above route (89JOC270). The essential step involves an intramolecular alkylation on a lactim ether anion (Scheme 64). 

An enantioselective synthesis of CR)-amino acids has been developed which utilizes L-valine as the chiral auxiliary (81AG(E)798). The diketopiperazine cycZo-(L-Val-Gly) (780) was converted to its bis-lactim ether (781) by methylation with Meerwein s salt, and the ether metallated in the glycine portion by n-butyllithium. Alkylation of the delocalized... 

An alternative stereospecific synthesis of emetine has been accomplished from ethyl trans-5-ethyl-2-oxopiperidine-4-acetate by conversion into the lactim ether (107), which was allowed to react with 3,4-dimethoxyphenacyl bromide to give the ketone (108 R R2 = O). Reduction of this with sodium borohydride, followed by hydrogenolysis of the resulting alcohol, gave (108 R1 = R2 = H), which has previously been converted into emetine.135 The reaction of (107) with 3-benzyloxy-4-methoxyphenacyl bromide and with 4-benzyloxy-3-methoxyphenacyl bromide afforded analogues of (108 RJR2 = O), which were converted into 9-O-desmethylpsychotrine (109 R1 = H, R2 = Me) and 10-0-desmethylpsychotrine (109 R1=Me, R2 = H) respectively.136,137... 

The authors explored an ingenious synthesis involving the direct cyclocondensation of the lactim ethers of the corresponding diketopiperazine... 

Enantioseleetive Synthesis of a-Unsubstituted Amino Acids from the mixed Bis-lactim Ethers 20b of Cyclo(L-Val-Gly)... 

Enantioselective Synthesis of a-Methyl Amino Acids from the Bis-lactim Ether (6) of Cyclo(L-Ala-L-Ala) (5)... 

Synthesis of the Bis-lactim Ether (20 a) of Cyclo(L-VaI-Ala) and other Mixed 2 Bis-lactim Ethers (20)... 

Of course, the (3S)-compounds would also be formed if D-valine would be employed as chiral auxiliary. Hence, this method with valine as chiral auxiliary reagent solves the problem of enantioselective synthesis of a-methyl amino acids satisfactorily. Probably it can also be used — mutatis mutandis — for the asymmetric synthesis of a variety of a-alkyl amino acids, provided, the corresponding bis-lactim ether (type I) with valine as C-6 is regiospecifically metallated by butyl-lithium. This, for instance, is not be case with the mixed bis-lactim ether (20c) of cyclo(L-Leu-D,L-Ala)17). 

The application of lactams in heterocyclic synthesis depends on the activation of their amide function.5 Similar activation of other functional groups, e.g., the conversion of ketones to enamines6 and of carboxylic acid amides to imino ethers,7 presented new applications for these compounds. Similarly, the conversion of lactams into lactim ethers offers a greater scope for the use of lactams in organic synthesis. 

Lactim ethers are used in the synthesis of dyes10,11 and other important classes of organic compounds. They are also of interest because of their biological activity12 and use as accelerators for polymerization.13... 

---