Approaches to the Synthesis of Cytochalasans. Part 3. Synthesis of a substituted tetrahydroisoindolinone moiety possessing the same relative configuration as proxiphomin

✍ Scribed by Tibur Schmidlin; Werner Züurcher; Christoph Tamm

• Publisher: John Wiley and Sons
• Year: 1981
• Tongue: German
• Weight: 769 KB
• Volume: 64
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.19810640125

✦ Synopsis

Abstract

The total synthesis of the tetrahydroisoindolinone moiety corresponding to proxiphomin (1) is described, bearing functional groups for the attachment of the macrocyclic ring. Knoevenagel‐Cope condensation of racemic 2‐(benzyloxycarbonyl‐amino)‐3‐phenylpropanal (2) with methyl (4‐methyl‐2,4‐hexadienyl) malonate (3) yielded a mixture of the (E)‐ and (Z)‐olefins 4a and 4b, which upon heating underwent intramolecular Diels‐Alder cyclization (cf. Scheme 1). From the resulting products the tetrahydroisoindoline derivative 6 was isolated. X‐ray analysis of 6[5] revealed the same relative configurations at C(3), C(4), C(5) and C(8) as in 1, but not at C(9). Hydrolysis of 6 with KOH was accompanied by a change in configuration at C(9) yielding the hydroxy acid 14 which was converted into the hydroxy ester 11 (cf. Scheme 4). The presence of a cis‐anellated lactam ring in 11 has been confirmed by X‐ray analysis of its O‐acetyl derivative 16 [5]. Ring closure of the hydroxy acid 14 gave the lactone 17, corresponding to the natural product 1 as to the configuration. The presence of the N‐benzyloxycarbonyl group in lactone 6 has been shown to be essential for the above‐mentioned ‘inversion’ at C(9), because no configurational change occurred with the N‐unprotected lactone 8 when treated under the same conditions. The only product obtained was the hydroxy ester 10 possessing the same configuration at C(9) as 8. Along with stereochemical considerations, mechanistic aspects of the reactions are discussed.