The construction of the skeleton uses reactions similar to those that the authors previously reported for synthesizing resiniferatoxin. However, due to the more complex oxidation patterns of all the ABC rings, the key lies in combining regio- and stereoselective reactions to arrange the functional groups. First, the C ring, which contains the same functional groups as the natural product, is synthesized from ribose. Then, the A and B rings are constructed via nucleophilic addition of a bridgehead radical, followed by intramolecular pi-allyl-Stille coupling for 7-end cyclization. One ketone of the A ring and one exomethylene of the B ring are used to introduce six oxygen functional groups (five of which are chiral centers) and two double bonds, including an exo-dichloromethylene group. Regio- and stereo-control are achieved using the trioxaadamantane structure of the C ring, along with five-membered carbonate and six-membered acetonide protecting groups, respectively. Despite the numerous functional groups that limit reaction conditions, the A ring is completed in eight steps, and the B ring is completed in six steps. Highly efficient functional group modifications are achieved by utilizing reactions that proceed beyond the intended products. This allows one to enjoy organic chemistry.
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.
Trigocherrins A and C uploaded
https://www.ohira-sum.com/wp-content/uploads/2026/01/jacs25-45670.pdf
骨格の構築は著者らが先に報告していたレシニフェラトキシンの合成と同様の反応を利用しますが，ABC環ともより複雑な酸化様式のため，いかに位置及び立体選択的な反応を組み合わせて，官能基を整えるかが鍵になります。まず，天然と同じ官能基をもつオルトエステル体のC環をリボースから合成し，橋頭位ラジカルの求核的付加反応と分子内パイアリル-スティルカップリングによる７−エンド環化でA環とB環を構築します。A環はケトン一つ，B環はエキソメチレンを頼りに六箇所（五箇所は不斉中心）の酸素官能基，エキソジクロロメチレンを含む二つの二重結合などを選択的に作っていきます。C環のトリオキサアダマンタン構造や，五員環炭酸エステル保護基，六員環アセトニドなどを利用した位置制御，立体制御が行われます。多くの官能基が存在するため，反応条件が限られてくる中で，A環は８段階，B環は６段階で仕上げています。予想した生成物より先に進んだ反応などを利用して，非常に効率的な官能基修飾が行われており，有機化学を楽しむことができます。
The construction of the skeleton uses reactions similar to those that the authors previously reported for synthesizing resiniferatoxin. However, due to the more complex oxidation patterns of all the ABC rings, the key lies in combining regio- and stereoselective reactions to arrange the functional groups. First, the C ring, which contains the same functional groups as the natural product, is synthesized from ribose. Then, the A and B rings are constructed via nucleophilic addition of a bridgehead radical, followed by intramolecular pi-allyl-Stille coupling for 7-end cyclization. One ketone of the A ring and one exomethylene of the B ring are used to introduce six oxygen functional groups (five of which are chiral centers) and two double bonds, including an exo-dichloromethylene group. Regio- and stereo-control are achieved using the trioxaadamantane structure of the C ring, along with five-membered carbonate and six-membered acetonide protecting groups, respectively. Despite the numerous functional groups that limit reaction conditions, the A ring is completed in eight steps, and the B ring is completed in six steps. Highly efficient functional group modifications are achieved by utilizing reactions that proceed beyond the intended products. This allows one to enjoy organic chemistry.
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.