The key step was efficiently constructing the unusual heterocyclic system, cis-oxazadecalin. A Troc-protected hydroxylamine, synthesized in four steps from a tyrosine t-butyl ester, was used to oxidatively de-aromatize the phenol via a [4+2] addition of singlet oxygen, forming a p-hydroxy-dienyl ketone. The target compound is then obtained in one pot via an intramolecular Michael reaction. However, this reaction is carried out under a liquid-gas two-phase system and requires sufficient light irradiation, so it cannot be performed under normal batch conditions. A particular flow reactor was devised, which led to the divergent synthesis of six natural products. A by-product with undesired stereochemistry in the fused portion was generated, but it could be isomerized to the thermodynamically stable desired product through the elimination and addition of water.
Derivatization of the six natural products was efficiently achieved through functional group modifications on the oxazadecalin ring using stereoselective 1,2-oxidation, SN2 substitutions, and 1,3-sigmatropic rearrangements.
Trichodermamides A-F uploaded
https://www.ohira-sum.com/wp-content/uploads/2026/01/jacs25-43342.pdf
シス−オキサザデカリンという変わったヘテロ環骨格をもつ化合物の合成で，この環系をいかに効率よく構築するかが鍵となります。チロシンt-ブチルエステルから4段階で収率良く合成できるTroc保護されたヒドロキシルアミンを用い，一重項酸素の[4+2]付加でフェノールを酸化的に脱芳香化し，p-ヒドロキシルジエニルケトンとすると，分子内マイケル反応によって一挙に目的物が得られます。ただし，液-気の二層反応で，さらに十分な光の照射が必要なため，通常の条件では実用的収率は得られません。フロー合成の装置を工夫することが必要で，これが成功し，6個の天然物の発散的合成に繋がりました。縮環部分の立体が異なる副生成物が生じるのですが，幸運にも，水の脱離，付加を経て（多分），熱力学的に安定な目的物への異性化が可能でした。
6個の天然物への誘導は，オキサザデカリン環状の官能基修飾で，立体選択的な1,2酸化，SN２置換反応，1,3シグマトロピーなどを用いて，効率よく行っています。
The key step was efficiently constructing the unusual heterocyclic system, cis-oxazadecalin. A Troc-protected hydroxylamine, synthesized in four steps from a tyrosine t-butyl ester, was used to oxidatively de-aromatize the phenol via a [4+2] addition of singlet oxygen, forming a p-hydroxy-dienyl ketone. The target compound is then obtained in one pot via an intramolecular Michael reaction. However, this reaction is carried out under a liquid-gas two-phase system and requires sufficient light irradiation, so it cannot be performed under normal batch conditions. A particular flow reactor was devised, which led to the divergent synthesis of six natural products. A by-product with undesired stereochemistry in the fused portion was generated, but it could be isomerized to the thermodynamically stable desired product through the elimination and addition of water.
Derivatization of the six natural products was efficiently achieved through functional group modifications on the oxazadecalin ring using stereoselective 1,2-oxidation, SN2 substitutions, and 1,3-sigmatropic rearrangements.