Many works are described. First is the construction of the common synthetic intermediate skeleton. Oxidative dearomatization, followed by 5+2 cycloaddition and acyl transfer, constructs a bicyclo[3.2.1] skeleton that fuses with a six-membered ring. Then, epoxidation followed by pinacol coupling with samarium(II) iodide and Grob fragmentation converts the bicyclo[3.2.1] skeleton to the required bicyclo[3.3.0] system. Next, the substituents on the C ring are aligned to produce aberrarone and elisabanolide. For elisabanolide, a biosynthesis-inspired route is employed: first, the D-ring portion of the elisapterosins is constructed, followed by cleavage of that ring. Oxidation of this intermediate’s D-ring portion leads to the synthesis of elisapterosins A, B, C, D, E, and F, where B and C match the natural product structures and A and F differ from previous report. Therefore, the NMR spectra of A, D, E, and F were re-examined, and an “in silico” structural assignment was performed to infer the correct structures. E was found to have the correct structure. A and D were found to be stereoisomers, and F was found to have a peroxy ring instead of an ether ring. Each compound was synthesized and matched the natural products. Unfamiliar oxidation reactions were used throughout the process, resulting from extensive trial and error. Computational science played a major role in explaining the stereoselectivity of the oxidation after DFT calculations.
The key step is forming 1,4-benzodioxane through the [4+2] formal addition of a styrene derivative’s double bond to an orthoquinone. They initially planned to synthesize the orthoquinone from 1,3-benzodioxole to achieve a unified synthesis of phrymarolin and haedoxan; however, the desired orthoquinone could not be obtained. Therefore, they attempted to synthesize the orthoquinone by first deprotecting a benzyloxy group lacking an adjacent oxygen atom, and then oxidizing it. This method was successful, so they reduced the orthoquinone to convert it into 1,3-benzodioxazole, which is part of phrymarolin. Using a benzyloxy styrene derivative lacking an oxygen atom in the para position also improved the yield of the formal [3+2] addition necessary for forming the furofuran moiety. Both the [4+2] and [3+2] reactions are stepwise processes. Regioselectivity, stereoselectivity, and yield vary depending on the structure of the styrene derivative (i.e., the number and position of oxygen functional groups) and the reaction conditions. The reasons for these variations are unclear. Although the overall yields are not high, they synthesized analogues of haedoxan and conducted SAR studies. Since the racemic compound showed significantly lower activity than the natural product, the next challenge will likely be the synthesis of an optically active compound. How will this be approached? Note that the synthesis of an optically active haedoxan was reported in 1998 by a group led by Professor Taniguchi at the Faculty of Agriculture at Kyushu University.
Caprolactam is synthesized via the nucleophilic addition of an allyl radical. Meanwhile, the 6/7/5 complex system and the bicyclo[3.3.1]nonane portion are constructed using classical reactions, including the Mannich reaction, the vinylogous Mukaiyama-Michael cascade, and the Dieckmann reaction. Ultimately, a smart 19-step synthetic route was achieved without significantly altering the initial design. However, as the authors frequently mention, many reactions with limiting conditions were discovered only after extensive experimentation. It’s clear that many aspects of the process were not straightforward, such as the one-step conversion of TBS enol ether to its benzoyl ester or the use of amides in the Dieckmann reaction. I imagine that one student worked hard to complete this route and the student must have experienced great accomplishment.
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.
Elisapterane and Relevant Diterpenoids uploaded
https://www.ohira-sum.com/wp-content/uploads/2026/02/jacs25-33136.pdf
大作です。まず共通合成中間体の骨格構築。酸化的脱芳香化→5+2環化付加→アシル転移で六員環と縮環するビシクロ[3.2.1]骨格を作り，エポキシ化の後，ヨウ化サマリウムによるピナコールカップリング→グロブ開裂で，必要なビシクロ[3.3.0]系に変換しています。ここからC環上の置換基を揃え，アベラロンとエリサバノリドに導きますが，エリサバノリドの方はエリサプテロシン類のD環部分構築した後，その環を切断するという，生合成を参考にした経路で選択的に合成しています。この中間体のD環部分を酸化してエリサプテロシンA,B,C,D,E,Fの合成を進め，B，Cは天然物の構造と一致しましたが，A,Fは報告された構造が異なることがわかりました。そこで，A,D,E,FについてNMRを見直し，”インシリコ”構造帰属を行って正しい構造を推測しました。Eは正しい構造で，A,Dは立体異性体，Fはエーテル環ではなくペルオキシ環を持つことがわかり，それぞれを合成し，天然物と一致させました。見慣れない酸化反応も多く，色んな試行錯誤があったようです。DFT計算で酸化の立体選択性を説明するなど計算科学大活躍です。
Many works are described. First is the construction of the common synthetic intermediate skeleton. Oxidative dearomatization, followed by 5+2 cycloaddition and acyl transfer, constructs a bicyclo[3.2.1] skeleton that fuses with a six-membered ring. Then, epoxidation followed by pinacol coupling with samarium(II) iodide and Grob fragmentation converts the bicyclo[3.2.1] skeleton to the required bicyclo[3.3.0] system. Next, the substituents on the C ring are aligned to produce aberrarone and elisabanolide. For elisabanolide, a biosynthesis-inspired route is employed: first, the D-ring portion of the elisapterosins is constructed, followed by cleavage of that ring. Oxidation of this intermediate’s D-ring portion leads to the synthesis of elisapterosins A, B, C, D, E, and F, where B and C match the natural product structures and A and F differ from previous report. Therefore, the NMR spectra of A, D, E, and F were re-examined, and an “in silico” structural assignment was performed to infer the correct structures. E was found to have the correct structure. A and D were found to be stereoisomers, and F was found to have a peroxy ring instead of an ether ring. Each compound was synthesized and matched the natural products. Unfamiliar oxidation reactions were used throughout the process, resulting from extensive trial and error. Computational science played a major role in explaining the stereoselectivity of the oxidation after DFT calculations.
Phrymarolin and Haedoxan uploaded.
https://www.ohira-sum.com/wp-content/uploads/2026/01/jacs25-46461.pdf
スチレン誘導体の二重結合とオルトキノンの形式的[4+2]付加で1,4 ベンゾジオキサンをつくるところが鍵で，当初，1,3 ベンゾジオキソールからオルトキノンを誘導し，フリマロリンとハエドキサンの統合的合成とする計画でしたが，目的のオルトキノンが得られませんでした。そこで隣に酸素のないベンジルオキシ基の脱保護とそれに次ぐ酸化でオルトキノンを合成すると，うまくいったのでこのオルトキノンを還元し1,3ベンゾジオキサゾールに変換してフリマロリンに誘導しました。パラ位に酸素のないベンジルオキシ体を使うとフロフラン部分を作るための形式的[3+2]付加の収率も上がりました。[4+2]も[3+2]も段階的反応で，スチレン誘導体の構造（酸素官能基の数や位置）や反応条件により位置選択性や立体選択性，収率が変わり，その理由も明らかではありません。好収率ではないものの，ハエドキサンの類縁体を合成しSARをやっています。天然物と比較してラセミ体は大きく活性が落ちることが示されたので，次の課題は光学活性体の合成と考えられますが，どのように展開するのでしょう。なお，すでに九州大学農学部の谷口先生達のグループにより光学活性ハエドキサンの合成が1998年発表されています。
The key step is forming 1,4-benzodioxane through the [4+2] formal addition of a styrene derivative’s double bond to an orthoquinone. They initially planned to synthesize the orthoquinone from 1,3-benzodioxole to achieve a unified synthesis of phrymarolin and haedoxan; however, the desired orthoquinone could not be obtained. Therefore, they attempted to synthesize the orthoquinone by first deprotecting a benzyloxy group lacking an adjacent oxygen atom, and then oxidizing it. This method was successful, so they reduced the orthoquinone to convert it into 1,3-benzodioxazole, which is part of phrymarolin. Using a benzyloxy styrene derivative lacking an oxygen atom in the para position also improved the yield of the formal [3+2] addition necessary for forming the furofuran moiety. Both the [4+2] and [3+2] reactions are stepwise processes. Regioselectivity, stereoselectivity, and yield vary depending on the structure of the styrene derivative (i.e., the number and position of oxygen functional groups) and the reaction conditions. The reasons for these variations are unclear. Although the overall yields are not high, they synthesized analogues of haedoxan and conducted SAR studies. Since the racemic compound showed significantly lower activity than the natural product, the next challenge will likely be the synthesis of an optically active compound. How will this be approached? Note that the synthesis of an optically active haedoxan was reported in 1998 by a group led by Professor Taniguchi at the Faculty of Agriculture at Kyushu University.
Aconicarmisulfonine A uploaded.
https://www.ohira-sum.com/wp-content/uploads/2026/01/jacs25-46800.pdf
カプロラクタムはアリルラジカルの求核的付加環化で作りますが，下部の複雑な6/7/5系はマンニッヒ反応，ビシクロ[3.3.1]ノナン部分はビニログ的向山-マイケルカスケード反応とディークマン反応という古典的な反応を利用して構築しています。最終的には，最初の合成デザインを大きく変更することなく，全19段階のスマートな合成経路に仕上がっていますが，著者が論文中で度々述べているように，大量の実験の後に見つけた条件の厳しい反応も多く含まれているようです。TBSエノールエーテルのベンゾイルエステルへのワンステップ変換とか，アミドを使ったディークマン反応とか，あちこちで，一筋縄ではいかなかったことが想像できます。１名の学生さんが頑張って完成したものと想像しますが，良い達成感を得たことでしょう。
Caprolactam is synthesized via the nucleophilic addition of an allyl radical. Meanwhile, the 6/7/5 complex system and the bicyclo[3.3.1]nonane portion are constructed using classical reactions, including the Mannich reaction, the vinylogous Mukaiyama-Michael cascade, and the Dieckmann reaction. Ultimately, a smart 19-step synthetic route was achieved without significantly altering the initial design. However, as the authors frequently mention, many reactions with limiting conditions were discovered only after extensive experimentation. It’s clear that many aspects of the process were not straightforward, such as the one-step conversion of TBS enol ether to its benzoyl ester or the use of amides in the Dieckmann reaction. I imagine that one student worked hard to complete this route and the student must have experienced great accomplishment.
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.