The polycyclic system was constructed using three classic cyclization reactions: the 1,3-dipolar addition of nitrones, the Pauson-Khand reaction, and the aza-Prins reaction.
Notably, the “strong thermodynamic driving force” of the nitrone [3+2] addition is used to create a bicyclic system containing cyclopentene with three consecutive quaternary centers. The latter two reactions were likely conceived based on structural features and presumed biosynthetic hypotheses; yet, they are skillfully combined.
The paper describes the synthesis of a racemic mixture. However, achieving enantioselective 1,4-addition of vinylmagnesium bromide during preparation of the [3+2] addition precursor could lead to optically active natural products.
Type IIのDA反応でビシクロ[3.3.1]系を構築するのが最大ポイントです。電子供与性のジエンと共役ケトンとの反応なので，電子論的には問題ないように見えますが，出発物のジエンは芳香環の一部であり，生成物は橋頭位アルケンを含むため，生成物が圧倒的に不安定となります。しかし，LiClO4を触媒とすると，出発物と目的物の平衡混合物が得られ，分離と再反応を３度おこない，目的物を実用的な収率で得ています。
DA反応前駆体は，非立体選択的な反応は含むものの，不斉アリル化＋脱炭酸，1,4付加＋アルドール，脱水の短工程３段階で，で光学活性体として合成しています。
DA反応後，D環はアルドール，エーテル環はオキシラジカルによる近い位置にあるアリル位水素の引き抜きを経るエーテル化で構築しています。
The key point is constructing the bicyclo[3.3.1] system via a Type II DA reaction. While the reaction between an electron-donating diene and a conjugated ketone seems straightforward from an electronic perspective, the starting diene is part of an aromatic ring and the resulting product is a bridged alkene, which makes it extremely unstable. Using LiClO₄ as a catalyst, however, yields an equilibrium mixture of the starting material and the target compound. After three rounds of separation and re-reaction, the target compound is obtained in a practical yield.
While the DA reaction precursor is synthesized as an optically active compound via a short, three-step process: asymmetric allylation + decarboxylation, non-stereoselective 1,4-addition + aldol, and dehydration.
After the DA reaction, the D ring is constructed through aldol condensation and the ether ring through etherification, which involves the abstraction of a nearby allylic hydrogen by an oxy-radical.
架橋構造と四級不斉中心を含む5/6環系（BC環）をPauson-Khand 反応で一挙につくります。六員環になる部分にシス二重結合を入れておく必要がありますが，後に1,6還元で不飽和化できます。残った共役結合のジアステレオ選択的水素化は，試薬制御（CBS還元）でケトンを立体選択的に還元した後，その水酸基の立体から誘導しています。
A環は向山アルドールと分子内1,2付加でつくりましたが，残念なことに生じたアルドールの水酸基の立体は望まない方が主成（1.4:1)し，種々検討したものの，逆転はできませんでした。その後は，水酸基の保護などで工夫が必要なケースもありましたが，収率よく最終物に誘導し，全収率3.4%は立派なものです。
中間体からPierisketolide Aへの誘導は難しくなさそうですが，発表してないところを見ると，何かの困難にぶつかっているのでしょう。水酸基の立体制御とともに検討中ということでしょうか。
The 5/6-membered ring system (BC ring), which contains a bridged structure and a quaternary chiral center, is synthesized in one step via the Pauson-Khand reaction. Although a cis double bond must be incorporated into the portion that forms the six-membered ring, it can subsequently be unsaturated by 1,6-reduction. Diastereoselective hydrogenation of the remaining conjugated bond was achieved through the stereoselective reduction of the ketone with reagent control (CBS reduction), followed by hydrogenation directed by the resulting hydroxyl group.
Ring A was constructed via a Mukaiyama aldol and intramolecular 1,2-addition reactions. Unfortunately, the the major diastereomer of the resulting aldol was undesired(1.4:1). Despite various attempts, inversion of the stereochemistry was unsuccessful. Subsequent steps required ingenuity, such as protection of the hydroxyl group. However these steps led to the final compound with a good yield. The overall yield of 3.4% is commendable.
The transformation of the intermediate to Pierisketolide A does not appear to be particularly difficult. However, the absence of the description here suggests that they encountered difficulty. Perhaps it is under investigation alongside controlling the stereochemistry of the hydroxyl group.
3つの連続するアミナールが大きな特徴でしたが，そのうち２つはジアミドをシュワルツ試薬で還元するだけで，脱水により生成し，もう一つは合成の最終段階でインドールのエナミン部分を既知の方法で酸化することにより生成しました。
鍵反応である置換ピリドンをジエンとする分子内DAでは，ジエノフィルがビニル基ではうまくいきませんでしたが，フェニルビニルスルフォンで好収率が得られました。続く反応はスルフォンの還元，二重結合への水素付加，ジアミドの還元で，順序を変えて実用的経路を検討しました。結局，HFIP／THF系で，転位を伴わない還元的スルフォン除去をおこない，MeOH中でのジアステレオ選択的水素付加，ジアミドの還元で実用的に目的物を得ています。
The three consecutive aminals were a major feature. However, two of them were generated by simply reducing the diamide with Schwarz reagent, followed by dehydration. The third was produced by oxidizing the enamine portion of the indole in the final stage using a known method.
In the key intramolecular DA reaction using substituted pyridone as a diene and a vinyl group as the dienophile, the latter did not work, but phenylvinyl sulfone produced a good yield. Subsequent reactions involved sulfone reduction, hydrogenation, and diamide reduction. They explored practical routes by varying the order of the reactions. Ultimately, the target compound was practically obtained by performing reductive sulfone removal without arrangement in HFIP/THF, followed by diastereoselective hydrogenation in methanol and diamide reduction.
The epoxyquinol moiety has multiple conjugated structures and one double bond that acts as a dienophile, reacting with the diene in the pyrone moiety. The pyrone moiety also has multiple conjugated structures. Although it is impossible to avoid forming homodimers, regioisomers, or stereoisomers, the desired product forms selectively alongside these byproducts. When the secondary alcohol in the diene is in the S configuration, hydrogen bonding with the hydroxyl group in the epoxyquinol moiety contributes to the selective formation of Herpotrichone C’s skeleton. When the secondary alcohol is in the R configuration, hydrogen bonding with the epoxy group enables the formation of Herpotrichone’s skeleton. In the latter case, diastereomers are formed in roughly equal amounts. However, using the pyrone moiety in which the hydroxyl group is either protected or absent yields lower yields, which clearly indicates the involvement of hydrogen bonding. This is also demonstrated by DFT calculations.
Many interesting reactions are employed in the asymmetric synthesis of the epoxyquinoline moiety. Using the chiral 6/4 ring system induces chirality in the six-membered ring. Breaking the original stereochemistry of the 6/4 system allows for a short route to the target structure.
Ten of the 21 stages (LLS) are catalytic reactions, including cross-metathesis.
The combination of asymmetric allylation and cross-metathesis is effective, yielding an average of 91.5% per stage.
Reactions involving C-C bond formation, such as asymmetric allylation, cross-metathesis, aldol reactions, and ring-opening addition to epoxides, account for approximately half of all reactions.
The lead players are asymmetric phosphoric acid derivatives with large molecular weights that exhibit high catalytic turnovers and can be efficiently recovered. Therefore, they may be suitable for the practical synthesis of building blocks containing chiral secondary alcohols.
They constructed complex polycyclic systems containing three bridged rings—[5.3.1], [3.3.1], and [2.2.1]—extremely efficiently through oxidative dearomatization and MHAT radical cyclization.
However, since numerous redox reactions were necessary to prepare the functional groups for these two key steps and subsequent modifications, 24 steps were required in total.
Nevertheless, forming the natural product skeleton required only 13 steps. Since an additional 11 steps were necessary to reach the final product, they had to synthesize 10 intermediates (a type of analogue) with the same skeleton as the natural product.
Upon investigating their biological activities, they identified analogues with activities not found in the natural product. As the saying goes, “Every cloud has a silver lining.”
The optical rotation of the final product was opposite to that reported. However, based on X-ray analysis and the consistency of CD direction, they estimate that the difference is due to impurities in the natural sample.
This is an extremely efficient cascade reaction that forms three C-C bonds at once, making the reaction mechanism of great interest.
Based on the Catellani reaction, NBE is used to activate the ortho-position C-H bond and performs sp2-sp3 coupling.
The release of NBE returns palladium (Pd) to its original position, and a double bond of the substituent introduced at the ortho position is inserted into the C(sp2)-Pd bond. This is formal sp2-sp3 coupling.
The resulting alkyl palladium then activates the C-H bond of the ortho-methyl group, performing intramolecular sp³-sp³ coupling and concluding the cascade.
This was likely a carefully planned cascade reaction based on a thorough understanding of the Catellani reaction and related reactions.
The acyl substitution reaction of the alkyl bromide competed with Pd transfer; however, through optimization, they obtained only the target product (42%) and the acyl substitution product (64%), which can be converted back to the original bromide.
The authors derived the title compound from a synthetic intermediate of a previously reported natural product synthesis.
The target compound was first isolated and structurally determined 40 years ago, and Baran and Shenvi reported the only total synthesis in 2006.
After much consideration and trial and error, the authors finally synthesized the target compound with a 21% yield in six steps.
They attempted to break the aromaticity of the indole ring to form a beta-lactam or distinguish between the two double bonds for chlorination.
However, since the starting material is a 12-membered amide with many functionalized carbon atoms, this was not straightforward.
Although the process is short, it involved extensive work, including DFT calculations, estimation of the reaction mechanism, screening of catalysts and reagents.
Paxdaphnine A and Daphlongamine B uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-27137.jpg
ニトロンの1,3双極子付加，ポーソン・カーン反応，アザープリンス反応という王道的環化反応を３つ使って多環系を構築しています。
特にニトロンの[3+2]付加の”強力な熱力学的駆動力”を使って３つの連続四級中心をもつシクロペンテンを含むビシクロ系を作るところが見事。後の２つの反応は構造式の特徴や推定されていた生合成仮説から思い至る反応でしょうが，それにしても，うまく組み合わせられています。
論文はラセミ体の合成ですが，ニトロンの反応前駆体の合成時におこなう臭化ビニルマグネシウムの1,4付加をエナンチオ選択的に行えば，形式的に光学活性体の合成になります。
The polycyclic system was constructed using three classic cyclization reactions: the 1,3-dipolar addition of nitrones, the Pauson-Khand reaction, and the aza-Prins reaction.
Notably, the “strong thermodynamic driving force” of the nitrone [3+2] addition is used to create a bicyclic system containing cyclopentene with three consecutive quaternary centers. The latter two reactions were likely conceived based on structural features and presumed biosynthetic hypotheses; yet, they are skillfully combined.
The paper describes the synthesis of a racemic mixture. However, achieving enantioselective 1,4-addition of vinylmagnesium bromide during preparation of the [3+2] addition precursor could lead to optically active natural products.
Bipolarolides A and B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-27219.pdf
Type IIのDA反応でビシクロ[3.3.1]系を構築するのが最大ポイントです。電子供与性のジエンと共役ケトンとの反応なので，電子論的には問題ないように見えますが，出発物のジエンは芳香環の一部であり，生成物は橋頭位アルケンを含むため，生成物が圧倒的に不安定となります。しかし，LiClO4を触媒とすると，出発物と目的物の平衡混合物が得られ，分離と再反応を３度おこない，目的物を実用的な収率で得ています。
DA反応前駆体は，非立体選択的な反応は含むものの，不斉アリル化＋脱炭酸，1,4付加＋アルドール，脱水の短工程３段階で，で光学活性体として合成しています。
DA反応後，D環はアルドール，エーテル環はオキシラジカルによる近い位置にあるアリル位水素の引き抜きを経るエーテル化で構築しています。
The key point is constructing the bicyclo[3.3.1] system via a Type II DA reaction. While the reaction between an electron-donating diene and a conjugated ketone seems straightforward from an electronic perspective, the starting diene is part of an aromatic ring and the resulting product is a bridged alkene, which makes it extremely unstable. Using LiClO₄ as a catalyst, however, yields an equilibrium mixture of the starting material and the target compound. After three rounds of separation and re-reaction, the target compound is obtained in a practical yield.
While the DA reaction precursor is synthesized as an optically active compound via a short, three-step process: asymmetric allylation + decarboxylation, non-stereoselective 1,4-addition + aldol, and dehydration.
After the DA reaction, the D ring is constructed through aldol condensation and the ether ring through etherification, which involves the abstraction of a nearby allylic hydrogen by an oxy-radical.
(+)-Pierisketone B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-29631.pdf
架橋構造と四級不斉中心を含む5/6環系（BC環）をPauson-Khand 反応で一挙につくります。六員環になる部分にシス二重結合を入れておく必要がありますが，後に1,6還元で不飽和化できます。残った共役結合のジアステレオ選択的水素化は，試薬制御（CBS還元）でケトンを立体選択的に還元した後，その水酸基の立体から誘導しています。
A環は向山アルドールと分子内1,2付加でつくりましたが，残念なことに生じたアルドールの水酸基の立体は望まない方が主成（1.4:1)し，種々検討したものの，逆転はできませんでした。その後は，水酸基の保護などで工夫が必要なケースもありましたが，収率よく最終物に誘導し，全収率3.4%は立派なものです。
中間体からPierisketolide Aへの誘導は難しくなさそうですが，発表してないところを見ると，何かの困難にぶつかっているのでしょう。水酸基の立体制御とともに検討中ということでしょうか。
The 5/6-membered ring system (BC ring), which contains a bridged structure and a quaternary chiral center, is synthesized in one step via the Pauson-Khand reaction. Although a cis double bond must be incorporated into the portion that forms the six-membered ring, it can subsequently be unsaturated by 1,6-reduction. Diastereoselective hydrogenation of the remaining conjugated bond was achieved through the stereoselective reduction of the ketone with reagent control (CBS reduction), followed by hydrogenation directed by the resulting hydroxyl group.
Ring A was constructed via a Mukaiyama aldol and intramolecular 1,2-addition reactions. Unfortunately, the the major diastereomer of the resulting aldol was undesired(1.4:1). Despite various attempts, inversion of the stereochemistry was unsuccessful. Subsequent steps required ingenuity, such as protection of the hydroxyl group. However these steps led to the final compound with a good yield. The overall yield of 3.4% is commendable.
The transformation of the intermediate to Pierisketolide A does not appear to be particularly difficult. However, the absence of the description here suggests that they encountered difficulty. Perhaps it is under investigation alongside controlling the stereochemistry of the hydroxyl group.
Erchinines A and B uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-26769.pdf
3つの連続するアミナールが大きな特徴でしたが，そのうち２つはジアミドをシュワルツ試薬で還元するだけで，脱水により生成し，もう一つは合成の最終段階でインドールのエナミン部分を既知の方法で酸化することにより生成しました。
鍵反応である置換ピリドンをジエンとする分子内DAでは，ジエノフィルがビニル基ではうまくいきませんでしたが，フェニルビニルスルフォンで好収率が得られました。続く反応はスルフォンの還元，二重結合への水素付加，ジアミドの還元で，順序を変えて実用的経路を検討しました。結局，HFIP／THF系で，転位を伴わない還元的スルフォン除去をおこない，MeOH中でのジアステレオ選択的水素付加，ジアミドの還元で実用的に目的物を得ています。
The three consecutive aminals were a major feature. However, two of them were generated by simply reducing the diamide with Schwarz reagent, followed by dehydration. The third was produced by oxidizing the enamine portion of the indole in the final stage using a known method.
In the key intramolecular DA reaction using substituted pyridone as a diene and a vinyl group as the dienophile, the latter did not work, but phenylvinyl sulfone produced a good yield. Subsequent reactions involved sulfone reduction, hydrogenation, and diamide reduction. They explored practical routes by varying the order of the reactions. Ultimately, the target compound was practically obtained by performing reductive sulfone removal without arrangement in HFIP/THF, followed by diastereoselective hydrogenation in methanol and diamide reduction.
(+)-Herpotrichones A-C uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/08/jacs25-26361.pdf
複数の共役構造をもつエポキシキノール部の中の一つの二重結合がジエノフィルとなり，複数の共役構造をもつピロン部の中のジエンが反応します。同種二量体や位置，立体異性体の生成を避けることはできませんが，その間を縫って，目的物を選択的に得ています。ジエンに含まれる二級アルコールがS配置の時は，エポキシキノール中の水酸基との水素結合により，Herpotrichone Cの骨格形成が選択的になり，R配置の時は，エポキシ基との水素結合により，Herpotrichone A/B の骨格形成が可能になります。後者の場合は同量程度のジアステレオマーも生成していますが，水酸基をTMS化したものや水酸基のないものを使うと，より低収率となりますので水素結合の関与は明らかです。DFT計算でも証明しています。
エポキシキノール部分の不斉合成中にも興味深い反応が多くあります。キラルな6/4環系を利用して６員環部分の不斉を誘導し，４員環部分の立体は壊して短工程で目的の構造へ導いています。
The epoxyquinol moiety has multiple conjugated structures and one double bond that acts as a dienophile, reacting with the diene in the pyrone moiety. The pyrone moiety also has multiple conjugated structures. Although it is impossible to avoid forming homodimers, regioisomers, or stereoisomers, the desired product forms selectively alongside these byproducts. When the secondary alcohol in the diene is in the S configuration, hydrogen bonding with the hydroxyl group in the epoxyquinol moiety contributes to the selective formation of Herpotrichone C’s skeleton. When the secondary alcohol is in the R configuration, hydrogen bonding with the epoxy group enables the formation of Herpotrichone’s skeleton. In the latter case, diastereomers are formed in roughly equal amounts. However, using the pyrone moiety in which the hydroxyl group is either protected or absent yields lower yields, which clearly indicates the involvement of hydrogen bonding. This is also demonstrated by DFT calculations.
Many interesting reactions are employed in the asymmetric synthesis of the epoxyquinoline moiety. Using the chiral 6/4 ring system induces chirality in the six-membered ring. Breaking the original stereochemistry of the 6/4 system allows for a short route to the target structure.
(-)-Neocucurbol C uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/08/jacs25-28589.pdf
3つの架橋環ビシクロ[5.3.1], [3.3.1],[2.2.1]を含む複雑な多環系を，酸化的脱芳香族環化とMHATラジカル環化によって，極めて効率的に構築しています。
この２つの鍵段階を行うための官能基調製と，その後の周辺の修飾に多くの酸化還元反応が必要だったので計24段階を要してしまいましたが，
天然物骨格の形成までは13段階です。つまり，最終物まであと11段階も必要ですが，天然物と同じ骨格の中間体（類縁体）を10個も合成することになるので，
これらの生理活性を調べて，天然物には無い活性をもつ類縁体を見出しています。「塞翁が馬」ですね。
最終物の旋光度が報告されたものと逆だったのですが，X線解析，CDの方向が一致したことなどから，報告された旋光度が異なるのは不純物によるものと推定しています。
They constructed complex polycyclic systems containing three bridged rings—[5.3.1], [3.3.1], and [2.2.1]—extremely efficiently through oxidative dearomatization and MHAT radical cyclization.
However, since numerous redox reactions were necessary to prepare the functional groups for these two key steps and subsequent modifications, 24 steps were required in total.
Nevertheless, forming the natural product skeleton required only 13 steps. Since an additional 11 steps were necessary to reach the final product, they had to synthesize 10 intermediates (a type of analogue) with the same skeleton as the natural product.
Upon investigating their biological activities, they identified analogues with activities not found in the natural product. As the saying goes, “Every cloud has a silver lining.”
The optical rotation of the final product was opposite to that reported. However, based on X-ray analysis and the consistency of CD direction, they estimate that the difference is due to impurities in the natural sample.
Benzenoid cephalotane-type diterpenoids uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/08/natcom25-4674.pdf
３つのC-C結合が一挙にできる，極めて効率的なカスケードなので，反応機構が注目されます。
カテラニ反応がベースで，まず，」NBEを利用してオルト位のC-Hを活性化してsp2-sp3カップリング。
NBE放出によりPdを元にもどし，オルト位に導入されたた置換基の中の二重結合を挿入（様式としてはsp2-sp3カップリング）。
生じたアルキルパラジウムがオルト位メチル基のC-Hを活性化し分子内でsp3-sp３カップリングを行いカスケード終了です。
カテラニ反応や関連反応の機構をよく勉強し，計画したカスケード反応だったのだろうと想像します。
オルト位と反応させるアルキル臭化物のアシル置換反応が競合しましたが，最適化を行って，目的物(42%)と元の臭化物に変換可能なアシル置換体(64%)のみが生成する条件を見出しています
This is an extremely efficient cascade reaction that forms three C-C bonds at once, making the reaction mechanism of great interest.
Based on the Catellani reaction, NBE is used to activate the ortho-position C-H bond and performs sp2-sp3 coupling.
The release of NBE returns palladium (Pd) to its original position, and a double bond of the substituent introduced at the ortho position is inserted into the C(sp2)-Pd bond. This is formal sp2-sp3 coupling.
The resulting alkyl palladium then activates the C-H bond of the ortho-methyl group, performing intramolecular sp³-sp³ coupling and concluding the cascade.
This was likely a carefully planned cascade reaction based on a thorough understanding of the Catellani reaction and related reactions.
The acyl substitution reaction of the alkyl bromide competed with Pd transfer; however, through optimization, they obtained only the target product (42%) and the acyl substitution product (64%), which can be converted back to the original bromide.
Chartelline C uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/08/jacs25-24921.pdf
著者らが先に報告した，別の天然物合成の合成中間体から，表題化合物を誘導しています。
40年前に単離構造決定された化合物で，全合成は2006年のBaran,Shenviによるものが唯一。
種々考察，試行錯誤し，最終的に６段階収率21%で目的物に行き着いています。
インドール環の芳香族性を壊してベータラクタムを作ったり，２つの二重結合を区別して塩素化したりしようとしますが，
出発物が12員環アミドですでに多くの炭素が官能基化されていますので，一筋縄ではいかない。
結果は6段階ですが，DFT計算，反応機構の推定，触媒，試薬のスクリーニングなど盛り沢山でした。
The authors derived the title compound from a synthetic intermediate of a previously reported natural product synthesis.
The target compound was first isolated and structurally determined 40 years ago, and Baran and Shenvi reported the only total synthesis in 2006.
After much consideration and trial and error, the authors finally synthesized the target compound with a 21% yield in six steps.
They attempted to break the aromaticity of the indole ring to form a beta-lactam or distinguish between the two double bonds for chlorination.
However, since the starting material is a 12-membered amide with many functionalized carbon atoms, this was not straightforward.
Although the process is short, it involved extensive work, including DFT calculations, estimation of the reaction mechanism, screening of catalysts and reagents.