Asymmetric Total Synthesis of Hinckdentine A

• Douki Kazuya

  名大院創薬

• Ono Hiroyuki

  東大院薬

• Shimokawa Jun

  名大院創薬

• Fukuyama Tohru

  名大院創薬

• Kitamura Masato

  名大院創薬

Bibliographic Information

Other Title

• ヒンクデンチンAの不斉全合成

Abstract

Hinckdentine A (1) was isolated from marine bryozoan Hincksinoflustra denticulatain 1987. The structure of 1 was unambiguously determined by single crystal X-ray crystallographic analysis. Biological activities of 1 have not been reported presumably because the material is scarcely available. It is, therefore, important to supply the material by total synthesis for studying the biological activity of 1 and its derivatives. Unprecedented structural features of 1 include the highly brominated indolo[1,2-c]quinazoline core structure connected to azepanone moiety through the tetrasubstituted carbon center, as well as the characteristic cyclic amidine moiety. These features make this molecule a fascinating synthetic target that has stimulated numerous synthetic studies of natural product itself and its substructures. By examininig the synthetic effort by Kawasaki and McWhorter, we identified two crucial issues to address: regioselective tribromination and construction of tetrasubstituted carbon center. Our retrosynthetic analysis involves the intermediate 2 that was expected to facilitate o,p-dibromination on the left hand indoline and single p-bromination on the right hand anilide prior to the introduction of the amidine unit (Scheme 1). The intermediate 2 could be deemed the dearomatized indole with an aromatic moiety wedging into the indole 2-position. Thus, 2 was retrosynthetically disconnected to two planar synthons (i.e., indole core and latent aniline moiety via asymmetric dearomatizing coupling transform). Retrosynthetic excision of the nitrogen functionality in the latent azepanone moiety and anilide led to N-acyl tetrahydrocarbazole 4 as the ideal starting material for this synthesis. The crucial dearomatization transformation was realized with the newly developed asymmetric cyclization reaction of 2,3-disubstituted N-2’-iodobenzoylindole 4under the conditions catalyzed by palladium/phosphoramidite (Table 1). The cyclization reaction successfully implemented a rapid construction of the polycyclic indoline with the chiral tetrasubstituted carbon center. Remaining transformations to the total synthesis of 1 was the construction of azepanone moiety, the formation of cyclic amidine moiety, and the regioselective introduction of three bromides. Seven-membered lactam 11 was constructed by Beckmann fragmentation-mediated ring expansion of cyclohexenone 5 (Scheme 2). Nitrogen functionality was introduced as isothiocyanate by cycloaddition/rearrangement sequence between nitrile oxide and thiourea 14 (Scheme 3). Regioselective tribromination on the aromatic moieties was realized by bromination of the free aniline ring and acetanilide 16 (Scheme 4). Finally, the amidine moiety was constructed to afford hinckdentine A (1). The concise synthesis is amenable to scale up, and 300 mg of the natural product has been synthesized in our laboratory.

Journal

• Symposium on the Chemistry of Natural Products, symposium papers

  Symposium on the Chemistry of Natural Products, symposium papers 58 (0), Oral2-, 2016

  Symposium on the Chemistry of Natural Products Steering Committee

Details

• CRID: 1390001277364253696
• NII Article ID: 130007722964
• DOI: 10.24496/tennenyuki.58.0_oral2
• ISSN: 24331856
• Text Lang: ja
• Data Source:
  • JaLC
  • CiNii Articles
• Abstract License Flag: Disallowed