These terpenoids are based on a 6/6/5 tricyclic structure. Depending on the condensation pattern of the C ring, four types of diastereomers are possible. All of these types exist in nature.
The most efficient method of constructing such a ring system is the cyclization of polyene, which mimics biosynthesis; however, only stable diastereomers can be produced.
Therefore, they adjusted the reaction conditions of the metal-catalyzed Rautenstrauch rearrangement to selectively produce two diastereomers containing double bonds. After the selective hydrogenation of these double bonds, all diastereomers could be synthesized. In the rearrangement reaction, Au and Pd exhibited different selectivities. They provided a detailed explanation of the reasons using DFT calculations.
Furthermore, they demonstrated the usefulness of their reaction by converting the obtained cyclized compounds into three types of natural products that are typically difficult to synthesize.
I mistakenly believed that constructing the trans 5/5 ring system was impossible due to high strain. However, this natural product contains both trans and cis 5/5 systems, which have adjacent quaternary centers at their junctions.
Does the existence of the 5/5 system depend on the release of strain by forming five-membered rings above and below, or by introducing double bonds?
Using the unique [6+2] cyclization and alkylation reactions of fulvene, researchers successfully synthesized the crowded cis-5/5 system, as well as the bicyclo[2.2.1] system, which could support a trans-5/5 system.
The asymmetric [6+2] reaction has been attempted with over 30 chiral amines, but no practical yields have been obtained. Since this reaction is highly efficient for forming the skeletal structure, it may be the subject of further research.
Regarding the subsequent oxidation reaction, the O-O bond introduced by singlet oxygen was cleaved due to strain in the trans-5/5 system and did not lead to the final product. However, this issue was resolved using nitroso-DA.
RuO₄ oxidation of the hydroxyl and exomethylene groups induced dihydroxylation, dehydrative etherification, and oxidation of the methylene group. This led to the formation of a hydroxy lactone in one step.
I am personally familiar with this natural product.
Although creating adjacent chiral quaternary centers in three steps using a Michael reaction and a Claisen condensation (three-component coupling) sounds simple, these were the only conditions that worked successfully after trying various methods. The ketone was converted to an enol triflate. After reducing the aldehyde, optical resolution was performed using chiral high-performance liquid chromatography (HPLC) to obtain 30 g of pure enantiomer from 60 g of racemic product. Separation technology supports this research process.
Adding an allenyl carbon chain to the aldehyde of this intermediate with “orthogonal reactivity” via enantioselective 1,2-addition of an organochromium reagent then allowed for the construction of a hydrindane skeleton with a unique diene structure by an intramolecular Heck-type reaction. No new chiral centers are formed here, but chiral ligands are used to optimize the conditions.
Thus, the basic skeleton with the desired functional groups was quickly obtained. The remaining steps involve introducing the appendage based on previous examples and performing standard functional group transformations.
I expect that a review titled Natural Product Synthesis Using Heck-Type Intramolecular Reactions will be published soon.
It is a cascade reaction of dehydrative condensation, halo-Prins, halo-Nazarov, and Friedel-Crafts.
The authors apparently studied the reaction in detail and used it effectively in the total synthesis. Although it is racemic, three adjacent chiral centers (two of which are quaternary) are constructed diastereoselectively. The strategy of using the carbonyl group as two cation sources, where the addition of two carbanion equivalents creates a quaternary center, is emphasized.
After completing the key reaction, mundane reactions appeared to lead to the natural product. However, classical transformations, such as intramolecular aldol reactions, ketone reduction to methylene, and introducing an isopropylidene group from an aldehyde, required investigation and optimization.
The byproducts of the cascade reactions prompted a more in-depth discussion of the reaction mechanism and led to the proposal of interesting chemical equilibria, including the retro-Friedel-Crafts reaction.
The diacetal moiety, a complex ring system, is constructed alongside the generation of axial dialdehyde, so the precursor alkene has a relatively simple structure. The cyclopentene moiety is formed through ketyl radical cyclization with SmI₂. Since this process involves substituent adjustment around a solid trans-decalin ring, an alternative route could be considered.
I came up with an diaxial divinyl precursor for cyclopentene, but it could be used without RCM.
The Pd-catalyzed reduction and carbonylation of enol triflate were used effectively.
２つの６員環は超古典Wieland-Miescher ketoneを用い，残りの５員環はtandem Negishi/Heck cross-coupling (NHCC) で，また７員環はBaran reductive olefin coupling (BROC) で作っています。NHCCは生成物が反応系で不安定なため，また，BROCは３つの立体を制御する必要もあることから，様々な考察を含む工夫，最適化を行っており，読み応えがあります。
古典的な反応も使われており，Wieland-Miescher，Mukaiyama, Corey-Seebach, Mioskowski, Comins, Ley-Griffith, Grieco-Sharplessなど，著名な有機化学者の名前が出ていました。
The two six-membered rings were made using the classic starting material, the Wieland-Miescher ketone. The remaining five-membered ring was constructed using tandem Negishi/Heck cross-coupling (NHCC). The seven-membered ring was made using Baran reductive olefin coupling (BROC). NHCC posed a challenge because the products were unstable in the reaction system. BROC required controlling three contiguous stereocenters. Various considerations and optimizations were discussed, which I enjoyed.
Classic reactions are also employed, bearing the names of renowned organic chemists, such as Wieland-Miescher, Mukaiyama, Corey-Seebach, Mioskowski, Comins, Ley-Griffith, and Grieco-Sharpless.
The central pyrrolidine ring’s precursor is pyrrole. Introduction of a side chain via radical addition to its double bond causes dearomatization, resulting in an enamine. A cascade reaction of 5-endo-dig cyclization and aza-Prins occurred between the multiple bonds of the introduced side chain and the enamine (enamide) to construct the two rings at once. After adjusting the oxidation state, the final aldol reaction completes the synthesis of lycojapomine B and lycojapomine A through kinetic and thermodynamic control, respectively. The only difference in the reaction conditions is the temperature (34 degrees) and reaction time.
This demonstrates that radical-mediated dearomatization effectively shortens reaction steps. It appears that synthesizing optically active compounds may also be possible with the use of a chiral auxiliary.
Several reactions were optimized from 0% yield to practical yields, and I can imagine the student’s hard work. (Probably one of the two authors.)
最も複雑なbisdehydrostemoninineの合成は全１１段階で，そのうち６つは光化学反応です。もっとも，その中には，通常の”polar chemistry”でも問題なく実現できる反応もあります。
２つの五員環AB環を，ビニルアレンからタイプの異なるPRCCを連ねて，立体選択的に合成してしまうところがキモです。
linchpin化合物はラセミ体なのですが，これに対して試薬制御（光反応）で側鎖に不斉中心を導入し，ジアステレオマーを分離し，最大50%に対して15%の収率で，光学活性体を取り出しています。
筆者らの専門分野である9-メシチルアクリジニウム塩の機能とか，用いた光化学反応についてまとめて反応機構が示されており，いい勉強になります。
Bisdehydrostemoninine, the most complex molecule in this paper, was synthesized in 11 steps, six of which are photochemical reactions. However, some of these reactions can be easily achieved using conventional “polar chemistry.”
The key point is the stereoselective synthesis of two five-membered AB rings by linking PRCCs of different types from the vinyl allene.
The linchpin compound is a racemic mixture. However, after introducing an asymmetric center into the side chain via reagent control (a photochemical reaction), the diastereomers were separated and the optically active compound was isolated with a 15% yield relative to a maximum yield of 50%.
The reaction mechanism is summarized, including the functionality of 9-mesitylacridinium salts, which is the authors’ specialty, and the photochemical reactions employed there, making it a valuable learning resource.
All four chiral centers on the right half were introduced by reagent control, while the three on the left half were introduced by substrate control from chiral centers obtained by optical resolution.
The chiral sources used for the reagent control were three chiral phosphine ligands and an amine derived from proline. The metals were iridium and platinum.
Reactions such as the Carreira arylation, which diastereoselectively and enantioselectively constructs two chiral centers, or the Catellani reaction, which simultaneously forms two adjacent C-C bonds,
, are not widely used, but can be highly effective for specific skeletal constructions.
Optically active γ-butenoides of this type are frequently encountered. Since they cannot be synthesized via diastereoselective reactions, the Krische reaction may become the standard method.
It’s a five-step synthesis! The “ideality” is probably 100%.
Substituted decalin is constructed in one step using a Cope/Prins/Friedel-Crafts cascade based on biosynthesis.
To evolve it into an asymmetric synthesis, the initial Cope rearrangement must be made an asymmetric reaction. However, this has not yet been attempted.
The racemic synthetic intermediate was separated by liquid chromatography, and each enantiomer was converted into an optically active natural product.
Professor Lie has previously synthesized many related compounds, and this knowledge is fully utilized here.
perhydrobenz[e]indene terpenoids uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/08/jacs25-24847.pdf
6/6/5系の三環を基本とするテルペノイドですが，C環の縮合様式で４種類のジアステレオマーがあり，すべて天然物が存在します。
このような環系の最も効率的な構築法は生合成を模したポリエンの環化なのですが，安定なジアステレオマーしかできないという制限があります。
そこで金属を触媒とするRautenstrauch rearrangementの反応条件を調整して二重結合を含む２種のジアステレオマーを作り分け，さらに二重結合の２種のジアステレオ選択的水素化によって全てのジアステレオマーの合成を可能にしました。転位反応ではAuとPdが逆の選択性を示しましたが，DFT計算でその理由を詳しく説明しています。
さらに，得られた環化体を，通常合成しにくい立体様式の天然物（３種類）に誘導して，開発した反応の有用性を示しています。
These terpenoids are based on a 6/6/5 tricyclic structure. Depending on the condensation pattern of the C ring, four types of diastereomers are possible. All of these types exist in nature.
The most efficient method of constructing such a ring system is the cyclization of polyene, which mimics biosynthesis; however, only stable diastereomers can be produced.
Therefore, they adjusted the reaction conditions of the metal-catalyzed Rautenstrauch rearrangement to selectively produce two diastereomers containing double bonds. After the selective hydrogenation of these double bonds, all diastereomers could be synthesized. In the rearrangement reaction, Au and Pd exhibited different selectivities. They provided a detailed explanation of the reasons using DFT calculations.
Furthermore, they demonstrated the usefulness of their reaction by converting the obtained cyclized compounds into three types of natural products that are typically difficult to synthesize.
Illisimonin A uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-23417.pdf
トランス5/5環系は高ひずみのため，構築不可能と思っていたのですが，この天然物，接合部に隣り合った４級中心をもつトランス5/5系とシス5/5系を含んでます。
シス5/5系はともかく，トランス5/5系は上下に５員環を作ったり２重結合が入ることによってひずみを分散してるのでしょうか。
フルベンの独特な反応である[6+2]環化とアルキル化を使って，混み合ったシス5/5系，さらに将来トランス5/5系をささえるビシクロ[2.2.1]系を，さほど難なく作っています。
[6+2]は30種以上のキラルアミンを用いて不斉反応を試み，実用的な収率には至っていません。反応は非常に効率的な骨格形成反応ですので，別の研究テーマになりそうです。
続く酸化反応ついては，一重項酸素では（多分トランス5/5系のひずみのため）O-O結合が切れて，最後まで届きませんでしたが，ニトロソ-DAを使って解決しました。
エキソメチレンと平行に立つ水酸基から，RuO４酸化で，ジヒドロキシル化，脱水エーテル化，メチレンの酸化を経て，一挙にヒドロキシラクトンに誘導しています。
I mistakenly believed that constructing the trans 5/5 ring system was impossible due to high strain. However, this natural product contains both trans and cis 5/5 systems, which have adjacent quaternary centers at their junctions.
Does the existence of the 5/5 system depend on the release of strain by forming five-membered rings above and below, or by introducing double bonds?
Using the unique [6+2] cyclization and alkylation reactions of fulvene, researchers successfully synthesized the crowded cis-5/5 system, as well as the bicyclo[2.2.1] system, which could support a trans-5/5 system.
The asymmetric [6+2] reaction has been attempted with over 30 chiral amines, but no practical yields have been obtained. Since this reaction is highly efficient for forming the skeletal structure, it may be the subject of further research.
Regarding the subsequent oxidation reaction, the O-O bond introduced by singlet oxygen was cleaved due to strain in the trans-5/5 system and did not lead to the final product. However, this issue was resolved using nitroso-DA.
RuO₄ oxidation of the hydroxyl and exomethylene groups induced dihydroxylation, dehydrative etherification, and oxidation of the methylene group. This led to the formation of a hydroxy lactone in one step.
Glycinoeclepin A uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-23411.pdf
個人的に馴染深い天然物です。
隣り合った不斉四級中心を，マイケル反応とクライゼン縮合で一挙に（３段階）つくる（3成分連結）というと，簡単そうですが，どちらも，色々試した中で，唯一うまくいった条件です。ケトンをエノールトリフラートにして，（アルデヒドを還元した後）キラルHPLCで光学分割を行い，60gのラセミ体から30gの光学純品を調整。分離技術が研究をささえます。
官能基に対して「直交的な反応性」をもつこの中間体のアルデヒドへの有機クロム化合物のエナンチオ選択的1,2付加でアレンを含む炭素鎖を加え，分子内ヘック型反応で，特殊なジエン構造をもつヒドロインダン骨格を構築します。ここでは新たな不斉中心生成は起こらないにもかかわらず，キラル配位子を使用して，条件を最適化してます。
あっという間に必要な官能基をもつ基本骨格ができました。後は先行例を参考にした付属物の導入と通常の官能基変換です。
そのうち「ヘック型分子内反応を使う天然物合成」というレビューが現れそうですね。
I am personally familiar with this natural product.
Although creating adjacent chiral quaternary centers in three steps using a Michael reaction and a Claisen condensation (three-component coupling) sounds simple, these were the only conditions that worked successfully after trying various methods. The ketone was converted to an enol triflate. After reducing the aldehyde, optical resolution was performed using chiral high-performance liquid chromatography (HPLC) to obtain 30 g of pure enantiomer from 60 g of racemic product. Separation technology supports this research process.
Adding an allenyl carbon chain to the aldehyde of this intermediate with “orthogonal reactivity” via enantioselective 1,2-addition of an organochromium reagent then allowed for the construction of a hydrindane skeleton with a unique diene structure by an intramolecular Heck-type reaction. No new chiral centers are formed here, but chiral ligands are used to optimize the conditions.
Thus, the basic skeleton with the desired functional groups was quickly obtained. The remaining steps involve introducing the appendage based on previous examples and performing standard functional group transformations.
I expect that a review titled Natural Product Synthesis Using Heck-Type Intramolecular Reactions will be published soon.
(±)-Tubingensin A uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-23120.pdf
脱水縮合/halo-Prins/halo-Nazarov/Friedel-Crafts のカスケード反応です。
著者らが詳しく研究してきたらしい反応を有効に利用した全合成で，ラセミ体ですが，三つの隣り合った不斉中心（二つは四級）がジアステレオ選択的に構築されます。カルボニル基を二つのカチオンソースとして，二つのカルバニオン等価体を付加させて四級中心をつくるという戦略が強調されて述べられています。
キー反応終了後は，平凡な変換反応で，天然物へ誘導できそうでしたが，分子内アルドール反応，ケトンからメチレンへの還元，，アルデヒドからイソプロピリデン基の導入など，古典的な変換で最適化が必要でした。
カスケード反応で生じる副生成物から反応機構を深く検討し，レトローフリーデル・クラフツ反応を含む，興味深い化学平衡を提案しています。
It is a cascade reaction of dehydrative condensation, halo-Prins, halo-Nazarov, and Friedel-Crafts.
The authors apparently studied the reaction in detail and used it effectively in the total synthesis. Although it is racemic, three adjacent chiral centers (two of which are quaternary) are constructed diastereoselectively. The strategy of using the carbonyl group as two cation sources, where the addition of two carbanion equivalents creates a quaternary center, is emphasized.
After completing the key reaction, mundane reactions appeared to lead to the natural product. However, classical transformations, such as intramolecular aldol reactions, ketone reduction to methylene, and introducing an isopropylidene group from an aldehyde, required investigation and optimization.
The byproducts of the cascade reactions prompted a more in-depth discussion of the reaction mechanism and led to the proposal of interesting chemical equilibria, including the retro-Friedel-Crafts reaction.
(-)-Crotonine G and (-)-Crotonolide uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-2238.p
複雑な環系になっているジアセタール部分は，アキシアルのジアルデヒドが発生すれば自動的に生成するので，その前駆体のアルケンは比較的シンプルな構造になります。このシクロペンテン部分はSmI2によるケチルラジカル環化を使って構築しています。堅固なトランスデカリン環の周りの置換基調整なので，別経路を提案する人が出るかもしれません。
シクロペンテンの前駆体としてアキシアルジビニル体を思いつきましたが，これ，RCMなしでも使えそう。
Pd触媒をつかうエノールトリフレートの還元，カルボニル化が有効に使われています。
The diacetal moiety, a complex ring system, is constructed alongside the generation of axial dialdehyde, so the precursor alkene has a relatively simple structure. The cyclopentene moiety is formed through ketyl radical cyclization with SmI₂. Since this process involves substituent adjustment around a solid trans-decalin ring, an alternative route could be considered.
I came up with an diaxial divinyl precursor for cyclopentene, but it could be used without RCM.
The Pd-catalyzed reduction and carbonylation of enol triflate were used effectively.
Swinhoeisterols A−C uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-20239.pdf
２つの６員環は超古典Wieland-Miescher ketoneを用い，残りの５員環はtandem Negishi/Heck cross-coupling (NHCC) で，また７員環はBaran reductive olefin coupling (BROC) で作っています。NHCCは生成物が反応系で不安定なため，また，BROCは３つの立体を制御する必要もあることから，様々な考察を含む工夫，最適化を行っており，読み応えがあります。
古典的な反応も使われており，Wieland-Miescher，Mukaiyama, Corey-Seebach, Mioskowski, Comins, Ley-Griffith, Grieco-Sharplessなど，著名な有機化学者の名前が出ていました。
The two six-membered rings were made using the classic starting material, the Wieland-Miescher ketone. The remaining five-membered ring was constructed using tandem Negishi/Heck cross-coupling (NHCC). The seven-membered ring was made using Baran reductive olefin coupling (BROC). NHCC posed a challenge because the products were unstable in the reaction system. BROC required controlling three contiguous stereocenters. Various considerations and optimizations were discussed, which I enjoyed.
Classic reactions are also employed, bearing the names of renowned organic chemists, such as Wieland-Miescher, Mukaiyama, Corey-Seebach, Mioskowski, Comins, Ley-Griffith, and Grieco-Sharpless.
Lycojapomine A and B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-20200.pd
中央のピロリジン環の前駆体をピロールとし，その二重結合へのラジカル付加で側鎖を導入すると脱芳香化し，エナミンが残る。導入した側鎖の多重結合とエナミン(エンアミド）の５-endo-dig とアザプリンスのカスケード反応で２つの環を一挙に構築します。酸化状態を整えて，最後のアルドール反応では速度論制御でLycojapomine B，熱力学制御で Aの合成が完了です。(反応条件の違いは温度差（34度差）と反応時間のみ）
ラジカル反応による脱芳香化は短工程化に有効な手法になることを示しました。補助剤を使えば光学活性体の合成も可能なように思えます。
収率0%から初めて実用的収率まで最適化した反応がいくつかあり，一人の学生さん（多分）の苦労が思いやられました。
The central pyrrolidine ring’s precursor is pyrrole. Introduction of a side chain via radical addition to its double bond causes dearomatization, resulting in an enamine. A cascade reaction of 5-endo-dig cyclization and aza-Prins occurred between the multiple bonds of the introduced side chain and the enamine (enamide) to construct the two rings at once. After adjusting the oxidation state, the final aldol reaction completes the synthesis of lycojapomine B and lycojapomine A through kinetic and thermodynamic control, respectively. The only difference in the reaction conditions is the temperature (34 degrees) and reaction time.
This demonstrates that radical-mediated dearomatization effectively shortens reaction steps. It appears that synthesizing optically active compounds may also be possible with the use of a chiral auxiliary.
Several reactions were optimized from 0% yield to practical yields, and I can imagine the student’s hard work. (Probably one of the two authors.)
Stemoamide Alkaloids uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/07/jacs25-15482.pdf
最も複雑なbisdehydrostemoninineの合成は全１１段階で，そのうち６つは光化学反応です。もっとも，その中には，通常の”polar chemistry”でも問題なく実現できる反応もあります。
２つの五員環AB環を，ビニルアレンからタイプの異なるPRCCを連ねて，立体選択的に合成してしまうところがキモです。
linchpin化合物はラセミ体なのですが，これに対して試薬制御（光反応）で側鎖に不斉中心を導入し，ジアステレオマーを分離し，最大50%に対して15%の収率で，光学活性体を取り出しています。
筆者らの専門分野である9-メシチルアクリジニウム塩の機能とか，用いた光化学反応についてまとめて反応機構が示されており，いい勉強になります。
Bisdehydrostemoninine, the most complex molecule in this paper, was synthesized in 11 steps, six of which are photochemical reactions. However, some of these reactions can be easily achieved using conventional “polar chemistry.”
The key point is the stereoselective synthesis of two five-membered AB rings by linking PRCCs of different types from the vinyl allene.
The linchpin compound is a racemic mixture. However, after introducing an asymmetric center into the side chain via reagent control (a photochemical reaction), the diastereomers were separated and the optically active compound was isolated with a 15% yield relative to a maximum yield of 50%.
The reaction mechanism is summarized, including the functionality of 9-mesitylacridinium salts, which is the authors’ specialty, and the photochemical reactions employed there, making it a valuable learning resource.
(+)-Rubriflordilactone A uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/06/jacs25-16792.pdf
右半分の４つの不斉中心はすべて試薬制御で導入，左半分の３つは，光学分割で得た不斉中心から基質制御で導入しています。
試薬制御に使われた不斉源は３つのキラルホスフィンリガンドとプロリン由来のアミンです。金属はイリジウムと白金。
２つの不斉中心をジアステレオ選択的かつエナンチオ選択的に構築するカレイラのアリル化とか，隣り合った２つのC-C結合を同時に作るカテラーニ反応とか，
広範に使われる反応ではないでしょうが，特定の骨格については強力に有効な骨格構築法となることがわかります。
この手の光学活性γ-ブテノライドはちょくちょく見かけますが，ジアステレオ選択的反応では合成できそうにないので，Krische反応は定番になるかもしれません。
All four chiral centers on the right half were introduced by reagent control, while the three on the left half were introduced by substrate control from chiral centers obtained by optical resolution.
The chiral sources used for the reagent control were three chiral phosphine ligands and an amine derived from proline. The metals were iridium and platinum.
Reactions such as the Carreira arylation, which diastereoselectively and enantioselectively constructs two chiral centers, or the Catellani reaction, which simultaneously forms two adjacent C-C bonds,
, are not widely used, but can be highly effective for specific skeletal constructions.
Optically active γ-butenoides of this type are frequently encountered. Since they cannot be synthesized via diastereoselective reactions, the Krische reaction may become the standard method.
Ambiguine P uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/06/jacs25-18391.pdf
５段階合成です。多分idealityは100%.
生合成に準じたCope/Prins/Friedel-Crafts cascadeで置換デカリンを一挙に作ります。
不斉合成に進化させるにはするには，最初のCope転位を不斉反応にする必要がありますが，さすがに試みられておらず
ラセミの合成中間体を液クロ分離して光学活性天然物に導いています。
Lie先生は過去に多くの関連化合物の合成を達成しており，そこで得られた知識が生かされてます。
It’s a five-step synthesis! The “ideality” is probably 100%.
Substituted decalin is constructed in one step using a Cope/Prins/Friedel-Crafts cascade based on biosynthesis.
To evolve it into an asymmetric synthesis, the initial Cope rearrangement must be made an asymmetric reaction. However, this has not yet been attempted.
The racemic synthetic intermediate was separated by liquid chromatography, and each enantiomer was converted into an optically active natural product.
Professor Lie has previously synthesized many related compounds, and this knowledge is fully utilized here.