Intramolecular cyclization debenzylative

Oda et al. have synthesized 5-azacarbapenems using the 1,2-diazetidine derivatives 123 (Scheme 13) as intermediates <1996H(42)577>. The diazetidines 123 can be easily prepared in good yield by an intramolecular cyclization of hydrazide followed by catalytic debenzylation using Pd(OH)2 on charcoal (Section 2.13.8.1). They developed a more practical and convenient synthetic route to 1,2-diazetidinones via hydrazones under very mild acidic conditions (Equation 23, Section 2.13.8.1). Michael cyclization of nitroalkenes 124a/b obtained from 123 gave the desired bicyclic 5-azacarbapenems 125. 

In the synthesis of these compounds, the 2-(l-chloro-2-fluoroethyl)thio compound 200 has been debenzylated and intramolecular cyclization was carried out to afford the 1,3-thiazetidine ring in compound 201 (Scheme 65). The alternative /3-elimination reaction is inhibited because the lone pair of electrons on the sulfur atom of the anion is delocalized on the quinolone ring and so cannot attack the cr-carbonatom of the chlorosulfenyl group <1999CPB1765>. 

The redox-sensitive linker 1.34 (91), obtained in several steps from Merrifield resin and a lactone precursor, was charged with a N-protected aminoacid, treated with NBS to debenzylate and oxidize the linker to quinone, and submitted to SPS. The quinone linker was reductively activated to dihydroquinone with NaBH4 in THF/MeOH for 30 min at rt, then cleaved by treatment with anhydrous TBAF in THF for 20 h at rt to provide the free acidic peptide via intramolecular cyclization of the linker moiety. 

The parallel, more convenient synthesis of KDO has been proposed by Schmidt and co-workers [94], Employing the ylide 92 and aldehyde 98 (protected with Bn group instead of TBS), the corresponding olefin was produced in 73% yield. Its transformation was simply achieved by hydrogenolytic debenzylation, proceeding with concomitant intramolecular cyclization, to furnish after treatment with diazomethane, the anomeric mixture a/p (2 1) of KDO methyl ester. 

E/Z = (2 1) isomers, easy transformed to the corresponding a-oxoester 123. The last one underwent an intramolecular cyclization under debenzylation conditions. In the same manner KDO was prepared in high yield. 

An intramolecular [3 + 2] dipolar cycloaddition reaction has also been exploited in the design of a concise, stereospecific synthesis of ( )-a-lycorane (57) (119). Thus, cyclization of the azomethine ylide 145, which was produced in situ by the reaction of 144 with IV-benzylglycine, in refluxing toluene furnished the cw-hydroindole 146 as the exclusive product (Scheme 14). The transformation of 146 to racemic a-lycorane (57) was then achieved by N-debenzylation via catalytic, transfer hydrogenation and subsequent Pictet-Spengler cyclization. 

A synthetic route to ( )-0,f>-dimethyltubocurarine iodide (CXXV), via the racemate of 0,0-dimethylbebeerine (CXXIII), was announced in 1959 by Tolkachev and his collaborators (94). It started by the condensation of 3-methoxy-4-hydroxyphenethylamine with 4-benzyloxy-phenylacetic acid to give the amide CXXVI. Reaction of the potassium salt of the latter with the methyl ester of 3-bromo-4-methoxyphenyl-acetic acid in the presence of copper powder gave compound CXXVII. This on condensation with 3-methoxy-4-hydroxy-5-bromophenethyl-amine afforded compound CXXVIII, which was methylated to CXXIX. The latter compound was cyclized with phosphorous oxychloride to the dihydroisoquinoline derivative CXXX. Debenzylation of CXXX followed by intramolecular Ullmann condensation yielded compound CXXXI. The latter was converted to racemic dimethylbebeerine (CXXIII) by reduction with zinc dust in acetic acid followed by methyla-tion. Finally, treatment of ( + )-CXXIII with methyl iodide furnished the dimethyl ether of ( + )-tubocurarine iodide, identified by comparison of its UV-spectrum with that of the dimethyl ether of natural tubo-curarine iodide and by melting-point determination of a mixture of the two specimens. 

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