Scalable Total Syntheses and Structure–Activity Relationships of Haouamines A, B, and Their Derivatives as Stable Formate Salts

Hirokazu Tsukamoto, Saki Nakamura, Akito Tomida, Takayuki Doi

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Haouamines A, B, and their derivatives were synthesized via Suzuki–Miyaura coupling and three key cyclization reactions as follows: the newly developed palladium(0)-catalyzed arylative cyclization of phenylalanine-derived alkyne–aldehydes with 2-bromoarylboronic acid (an “anti-Wacker”-type cyclization); BF3⋅OEt2-promoted Friedel–Crafts-type cyclization of symmetrical electron-rich aromatic rings adjacent to a tertiary allylic alcohol leading to the indeno-tetrahydropyridine skeleton; and (cyanomethyl)trimethylphosphonium iodide-mediated macrocyclization of amino alcohols to afford aza-paracyclophane precursors. The palladium-catalyzed reduction of mono- and di-triflate intermediates in the later stages enabled the alteration of both the position and number of hydroxyl groups on the C-ring. The instability of haouamine B was dramatically improved by salt formation with formic acid. An unambiguous evaluation of the cytotoxicity of the prepared haouamine derivative formates with and without hydroxyl groups at different positions on the C-ring indicated that the catechol structure in haouamine B produced weak cytotoxicity.

Original languageEnglish
Pages (from-to)12528-12532
Number of pages5
JournalChemistry - A European Journal
Volume26
Issue number55
DOIs
Publication statusPublished - 2020 Oct 1

Keywords

  • Friedel–Crafts cyclization
  • haouamines
  • macrocyclization
  • structure–activity relationships
  • “anti-Wacker”-type cyclization

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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