The key step is the construction of the congested four-membered ring via Baran’s reductive alkenyl coupling, also known as MHAT-induced alkenyl-enone radical cyclization. Remarkably, high yields are achieved under standard conditions without optimization. Since a congested three-membered ring of a natural product was previously constructed via this radical cyclization, this work demonstrates the expanded utility of the reaction.
Other major C-C bond-forming reactions include asymmetric Michael addition-enolate alkylation, the Conia-ene reaction, and Suzuki-Miyaura coupling. These reactions also appear to proceed smoothly under standard conditions.
Of the 19 steps in the total synthesis, nine are dedicated to “decorating” the A-ring region. However, since these are short and efficient reactions, the nine steps can be completed in just two days.
The author is a renowned professor of natural product synthesis, and the total synthesis appears to have been achieved without significant challenges. Nevertheless, there were challenges, such as the inability to synthesize the initially planned symmetric cyclohexadiene-one and the need to optimize conditions for conjugating the double bond.
Bis-tryptamine, formed by coupling at the 3-position, yields two aldehydes, two -NH₂, and two -NHMe when it undergoes hydrolysis. This compound forms intramolecular aminal structures while creating five- or six-membered rings and produces various isomers depending on the combination. These isomers, which likely include their oxidized forms, are called bis-cyclotryptamine alkaloids and have long been recognized as natural products.
One such member, (−)-psychotriaidine, is an isomer of bis-oxytryptamine. When the absolute configuration at the quaternary chiral centers (positions 3 and 3′) is R,S, the compound is meso, and when it is R,R or S,S, it is optically active. Synthesis has revealed that the natural product is the S,S isomer.
At the beginning of the synthesis, the quaternary chiral center at position 3 was introduced via a Meerwein-Eschenmoser-Claisen rearrangement. After transforming into a compound with a seven-membered cyclic amine via a Fischer indolization/Plancher rearrangement cascade, the compound was converted into the final product in one step (72% yield !) via dearomatization and ring contraction. Upon reviewing the Supporting Information (SI), it was found that, in the first-generation racemic synthesis, part of the substrate did not undergo the Plancher rearrangement during the Fischer indole synthesis. Instead, the NHTs groups formed an intramolecular aminal, yielding compounds with the same skeleton as the natural product, albeit with a low yield. In the second-generation enantioselective synthesis, the Plancher product was used, because it was obtained in good yield. The ring-contracting reaction restored the seven-membered ring to produce the natural product. I’m curious where the idea for this final reaction came from.
Dihydro-psychotriaidine, obtained by reducing the final product, isomerizes to (+)-calycanthine, probably the oldest bis-cyclotryptamine alkaloid, upon acid treatment. Interesting, isn’t it? The title could have been “Synthesis of (+)-Calycanthine via (−)-Psychotriadine.”
This compound brings to mind E. J. Corey’s groundbreaking first synthesis. One of the authors has postdoctoral experience in Corey’s laboratory.
In the previous [3]-ladderanol synthesis study, the alkyl side chain was attached to cyclohexane. The target compound was obtained by performing a formal C-H alkylation (Michael addition-elimination reaction) on the cyclohexenedione to desymmetrize the meso compound. Then, the cyclohexenedione was reduced to cyclohexane. However, since the alkyl side chain in [5]-ladderanoic acid is attached to cyclobutane, a new strategy was developed in which the cyclohexenedione used for desymmetrization decomposes and part of it is incorporated into the side chain. They applied this reaction sequence to synthesize [5]-ladderanoic acid and the unnatural isomer of [3]-ladderanol.
With both the natural and unnatural [3]-ladderanol now available, the authors conducted a “comparative proton permeability study” and a “comparative drug leakage study.” These studies demonstrated the superiority of the natural isomer. This suggests that the natural isomer was selected during the evolutionary process.
The starting materials are benzene and cyrene, a non-protonic polar solvent derived from cellulose. Both are used as solvents.
The key step is the rearrangement of the 1,3-diamine into a 1,4-diamine through a three-membered ring ammonium ion. This simultaneously introduces the methoxy group found in the natural product in a regio- and stereoselective manner.
Since 1,3-diamine derivatives are used in streptomycin antibiotic synthesis, this reaction increases the usefulness of asymmetric dearomative 1,2-hydroamination of benzene.
Differentiation between the two amine groups of the 1,4-diamine is achieved simultaneously with the introduction of oxygen at the desired position. Specifically, the reaction utilizes the fact that an amine reacts with carbon dioxide to produce carbamic acid in equilibrium. The presence of a bromine-substituted carbon atom adjacent to the amine leads to the formation of a cyclic carbamate.
The glycosyl donor was synthesized quickly from Cyrene, which already possesses the necessary carbon skeleton. The target compound was obtained via standard glycosylation and modified deprotection.
T The target compound is a DMOA-derived meroterpenoid. The DMOA moiety is highly oxidized to form a complex ring system containing an ortholactone-lactone acetal.
Retrosynthetic analysis begins with the hydrolysis of the DMOA moiety into a dicarboxylic acid. Retrosynthesis of this dicarboxylic acid to a cyclopentene double bond yields a realistic precursor. In the actual synthesis, stepwise cleavage of the double bond (dialdehyde → aldehyde carboxylic acid → dicarboxylic acid) was necessary.
The monoterpenoid portion was derived from (R)-(-)-carvone.
The 1,2-addition reaction between the DMOA portion and the monoterpenoid portion at both neopentyl positions was successful when performed in the presence of lanthanides.
A special approach was required to construct the final heterocyclic system. Despite applying acid treatment after preparing the necessary functional groups, various cationic intermediates formed, resulting in low yields of the target compound.
Inspired by glycosylation, the researchers succeeded in selectively generating the desired cation by activating the phenylthio group, achieving a practical yield.
The final step involves sensitive functional groups, so mild, chemoselective reactions were employed to provide valuable information.
The lead author is a professor who completed a postdoctoral fellowship with Professor Baran.
The C-C bond reactions forming the core are indeed:
1. Baran reductive olefin coupling (BROC) (Intermolecular)
2. 1,2-addition to ketones (intermolecular)
3. Photocatalytic deoxygenative alkylation (intermolecular)
4. Intramolecular aldol (four-membered enolate, diastereotopically selective)
5. Acyl radical cyclization (intramolecular)
Reactions 1 and 3 are radical reactions that form quaternary chiral centers. Stereocontrol on the five-membered ring is classical.
Through “merging local desymmetrization and radical retrosynthesis,” the skeleton of complex caged compounds was constructed in nine steps (12 steps total).
Optimization was required for these reactions, except for reaction 2, and yields were increased to over 50% for each reaction.
Unexpected difficulty arose during the final step of introducing a methyl group via 1,4-addition. One of the two ketones was first protected as an enolate. Then, a 1,3-dithiane anion underwent conjugate addition, and the resulting compound was converted to a methyl group via desulfurization.
(−)-Psathyrin A uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/10/jacs25-32365.pdf
混み合った４員環をバランの還元的アルケンカップリング（MHATに誘発されるアルケンーエノンラジカル環化）を使って構築するのが鍵ですが，標準的な条件で，最適化もなく，高収率が得られています。著者らの先の研究では，混み合った３員環をこのラジカル環化で構築する天然物合成を発表しているらしく，この反応の有用性が，拡張されたことになります。
その他の主なC-C結合反応は不斉マイケル付加-エノラートアルキル化，コニア-エン反応，鈴木-宮浦カップリングで，いずれも標準条件で問題なく進行しているようです。
全工程19段階のうち９段階はA環周辺の”デコレーション”に使われていますが，短時間で効率的な反応ばかりなので，その９段階は２日間で実行できるとのこと。
天然物合成ではおなじみの先生で，苦もなく全合成を達成している感じもしますが，当初計画していた対称シクロヘキサジエンが合成できなかったり，二重結合の共役化で，条件を最適化したり，それなりの苦労はあったようです。
The key step is the construction of the congested four-membered ring via Baran’s reductive alkenyl coupling, also known as MHAT-induced alkenyl-enone radical cyclization. Remarkably, high yields are achieved under standard conditions without optimization. Since a congested three-membered ring of a natural product was previously constructed via this radical cyclization, this work demonstrates the expanded utility of the reaction.
Other major C-C bond-forming reactions include asymmetric Michael addition-enolate alkylation, the Conia-ene reaction, and Suzuki-Miyaura coupling. These reactions also appear to proceed smoothly under standard conditions.
Of the 19 steps in the total synthesis, nine are dedicated to “decorating” the A-ring region. However, since these are short and efficient reactions, the nine steps can be completed in just two days.
The author is a renowned professor of natural product synthesis, and the total synthesis appears to have been achieved without significant challenges. Nevertheless, there were challenges, such as the inability to synthesize the initially planned symmetric cyclohexadiene-one and the need to optimize conditions for conjugating the double bond.
(−)-Psychotriadine uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/10/jacs25-32370.pdf
3位同士が結合したビス-トリプタミンを加水分解すると，２つのアルデヒド，２つのーNH2，２つの-NHMeが生じます。この化合物から５員環や６員環を形成しつつ，分子内アミナールを作ると，組み合わせによって色々な異性体ができますが，これらは（多分その酸化体も含め）ビスーシクロトリプタミンアルカロイドと呼ばれ，古くから天然に存在することが知られていました。
(-)-サイコトリアジンはその中の一つでビスーオキシトリプタミンの異性体です。４級不斉中心である３位，３‘位の絶対配置がR,Sの場合，その対称性からメソ体になり，R,RやS,Sなら光学活性体になります。今回筆者らの合成により天然物はS,S体であることが明らかになりました。
合成は，メアウイン・エッシェンモーザー・クライゼン転移で3位の４級不斉中心を導入し，フィッシャーインドール合成/プランチャー転移で７員環環状アミンを含む化合物とした後，脱芳香族的環縮小反応によって一気に（72% !）最終物に導きました。SIを見ると第一世代のラセミ体合成では，フィッシャーインドール合成の際，一部はプランチャー転移が起きず，-NHTsが分子内アミナールを作ることによって，低収率ながら，天然物と同じ骨格の化合物を得ています。第２世代の光学活性体合成では，好収率で得られるプランチャー転位体を用いて，脱芳香族的転位反応で７員環をもとに戻しつつ天然物に導いていますが，この最後の反応，どこから思いついたのか知りたいところです。
最終物を還元して，ジヒドロサイコトリアジンにすると，この化合物は酸処理により，最古の（多分）ビス-シクロトリプタミンアルカロイドである(+)-カリカンチンに異性化します。面白いですね。タイトルは「(-)-サイコトリアジンを経る(+)-カリカンチンの合成」でもよかったのでは。
Bis-tryptamine, formed by coupling at the 3-position, yields two aldehydes, two -NH₂, and two -NHMe when it undergoes hydrolysis. This compound forms intramolecular aminal structures while creating five- or six-membered rings and produces various isomers depending on the combination. These isomers, which likely include their oxidized forms, are called bis-cyclotryptamine alkaloids and have long been recognized as natural products.
One such member, (−)-psychotriaidine, is an isomer of bis-oxytryptamine. When the absolute configuration at the quaternary chiral centers (positions 3 and 3′) is R,S, the compound is meso, and when it is R,R or S,S, it is optically active. Synthesis has revealed that the natural product is the S,S isomer.
At the beginning of the synthesis, the quaternary chiral center at position 3 was introduced via a Meerwein-Eschenmoser-Claisen rearrangement. After transforming into a compound with a seven-membered cyclic amine via a Fischer indolization/Plancher rearrangement cascade, the compound was converted into the final product in one step (72% yield !) via dearomatization and ring contraction. Upon reviewing the Supporting Information (SI), it was found that, in the first-generation racemic synthesis, part of the substrate did not undergo the Plancher rearrangement during the Fischer indole synthesis. Instead, the NHTs groups formed an intramolecular aminal, yielding compounds with the same skeleton as the natural product, albeit with a low yield. In the second-generation enantioselective synthesis, the Plancher product was used, because it was obtained in good yield. The ring-contracting reaction restored the seven-membered ring to produce the natural product. I’m curious where the idea for this final reaction came from.
Dihydro-psychotriaidine, obtained by reducing the final product, isomerizes to (+)-calycanthine, probably the oldest bis-cyclotryptamine alkaloid, upon acid treatment. Interesting, isn’t it? The title could have been “Synthesis of (+)-Calycanthine via (−)-Psychotriadine.”
[5]-Ladderanoic Acid uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/10/jacs25-31829.pdf
この化合物を見ると，E.J.Coreyの衝撃的な初合成が思い起こされますが，著者はCorey研でポスドク経験の有る方です。
先の[3]-Ladderanol合成研究では，アルキル側鎖がシクロヘキサンについていたので，シクロヘキセンジオンへの形式的C-Hアルキル化（マイケル付加ー脱離反応）を利用して，メソ体の非対称化を行い，シクロヘキセンジオンをシクロヘキサンに還元する手法で目的物を得ていました。しかし，[5]-Ladderanoic acidではアルキル側鎖はシクロブタンについているので，非対称化に用いたシクロヘキセンジオンを分解して，その一部を側鎖に取り入れる手法を開発し，[5]-Ladderanoic acid と非天然型[3]-Ladderanolの合成に適用しました。
天然型と非天然型の[3]-Ladderanolが手に入ったので，”Comparative Proton Permeability Study”と”Comparative Drug Leakage Study”で比較し，天然型の優位性が示されています。進化の過程で天然型異性体が選ばれたと考えることができるということでしょう。
This compound brings to mind E. J. Corey’s groundbreaking first synthesis. One of the authors has postdoctoral experience in Corey’s laboratory.
In the previous [3]-ladderanol synthesis study, the alkyl side chain was attached to cyclohexane. The target compound was obtained by performing a formal C-H alkylation (Michael addition-elimination reaction) on the cyclohexenedione to desymmetrize the meso compound. Then, the cyclohexenedione was reduced to cyclohexane. However, since the alkyl side chain in [5]-ladderanoic acid is attached to cyclobutane, a new strategy was developed in which the cyclohexenedione used for desymmetrization decomposes and part of it is incorporated into the side chain. They applied this reaction sequence to synthesize [5]-ladderanoic acid and the unnatural isomer of [3]-ladderanol.
With both the natural and unnatural [3]-ladderanol now available, the authors conducted a “comparative proton permeability study” and a “comparative drug leakage study.” These studies demonstrated the superiority of the natural isomer. This suggests that the natural isomer was selected during the evolutionary process.
Sannamycins A and B uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-31476.pdf
原料は溶媒として用いられるベンゼンとシレン（セルロースから生産される非プロトン性極性溶媒）です。
鍵段階は1,3-ジアミンを３員環アンモニウムイオンを経て1.4-ジアミンに転位させるところ。天然物にあるメトキシ基を同時に位置および立体選択的に導入しています。
1,3-ジアミン誘導体はすでにストレプトマイシン系の抗生物質の合成に使われているので，ベンゼンの不斉脱芳香族1,2ヒドロアミノ化の有用性が広がったことになります。
1,4-ジアミンの２つのアミンの区別も必要な位置への酸素導入と同時に行います。即ち，アミンに二酸化炭素を反応させると，平衡的にカルバミン酸が生成し，隣に臭素を持つ炭素があると環状カルバメートが生成することを利用しています。
グリコシルドナーの方は，すでに必要な炭素骨格をもっているシレンから短工程で合成し，定番のグリコシル化，工夫した脱保護で目的物に誘導しました。
The starting materials are benzene and cyrene, a non-protonic polar solvent derived from cellulose. Both are used as solvents.
The key step is the rearrangement of the 1,3-diamine into a 1,4-diamine through a three-membered ring ammonium ion. This simultaneously introduces the methoxy group found in the natural product in a regio- and stereoselective manner.
Since 1,3-diamine derivatives are used in streptomycin antibiotic synthesis, this reaction increases the usefulness of asymmetric dearomative 1,2-hydroamination of benzene.
Differentiation between the two amine groups of the 1,4-diamine is achieved simultaneously with the introduction of oxygen at the desired position. Specifically, the reaction utilizes the fact that an amine reacts with carbon dioxide to produce carbamic acid in equilibrium. The presence of a bromine-substituted carbon atom adjacent to the amine leads to the formation of a cyclic carbamate.
The glycosyl donor was synthesized quickly from Cyrene, which already possesses the necessary carbon skeleton. The target compound was obtained via standard glycosylation and modified deprotection.
(-)-Novofumigatonin uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-31456.pdf
目的化合物はDMOA メロテルペノイドで，DMOA由来の部分が高度に酸化され，オルトラクトンーラクトンアセタールという複雑な環系を形成しています。
逆合成は，まずDMOA部を加水分解して解きほぐし，ジカルボン酸にします。これを一つのシクロペンテンの二重結合へ逆合成すると，具体的な前駆体が見えてきます。実際の合成では二重結合を段階的に切断(ジアルデヒド→カルボン酸アルデヒド→ジカルボン酸)することが必要でした。
モノテルペノイド部分はR-(-)カルボンから誘導，DMOA部分とネオペンチル位同士での1,2付加反応は，ランタノイド存在下で行うと，問題なく成功しました。
最後のヘテロ環系の合成に一工夫が必要でした。必要な官能基を揃えて，酸処理しましたが，種々のカチオン中間体が生成するため，目的物は低収率でした。
そこで，グリコシル化をヒントに，フェニルチオ基を活性化して脱離させる方法で，目的のカチオンを選択的に発生させ，実用的収率を得ました。
最終工程では，敏感な官能基を含むため，温和な官能基選択的反応が多用されており，いろいろ参考になります。
T The target compound is a DMOA-derived meroterpenoid. The DMOA moiety is highly oxidized to form a complex ring system containing an ortholactone-lactone acetal.
Retrosynthetic analysis begins with the hydrolysis of the DMOA moiety into a dicarboxylic acid. Retrosynthesis of this dicarboxylic acid to a cyclopentene double bond yields a realistic precursor. In the actual synthesis, stepwise cleavage of the double bond (dialdehyde → aldehyde carboxylic acid → dicarboxylic acid) was necessary.
The monoterpenoid portion was derived from (R)-(-)-carvone.
The 1,2-addition reaction between the DMOA portion and the monoterpenoid portion at both neopentyl positions was successful when performed in the presence of lanthanides.
A special approach was required to construct the final heterocyclic system. Despite applying acid treatment after preparing the necessary functional groups, various cationic intermediates formed, resulting in low yields of the target compound.
Inspired by glycosylation, the researchers succeeded in selectively generating the desired cation by activating the phenylthio group, achieving a practical yield.
The final step involves sensitive functional groups, so mild, chemoselective reactions were employed to provide valuable information.
Harziane Diterpenoids uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/09/jacs25-30599.pdf
主著者はバランのところでポスドクをやってたことのある先生です。
さすがにコアをつくるC-C結合反応は
１．Baran reductive olefin coupling (BROC)，分子間
２．ケトンへの1,2付加，分子間
３. photocatalytic deoxygenative alkylation，分子間
4. 分子内アルドール（４員環エノラート，ジアステレオトポ選択的）
5. acyl radical cyclization，分子内
で，1と3のラジカル反応は四級不斉中心をができる反応。５員環上での立体制御は古典的です。
「局地的非対称化とラジカル逆合成の合流」によって，複雑なケージ化合物の骨格が短工程(９段階，全工程は１２段階）で合成されています。
２の反応以外は最適化が必要でしたが，いずれも50%以上の収率まで上げています。
予想外に苦労したのが，最終工程の1,4付加によるメチル基導入。一方のケトンをエノール化により保護し，1,3-ジチアン陰イオンの共役付加後，脱硫によりメチル基に変換しています。
The lead author is a professor who completed a postdoctoral fellowship with Professor Baran.
The C-C bond reactions forming the core are indeed:
1. Baran reductive olefin coupling (BROC) (Intermolecular)
2. 1,2-addition to ketones (intermolecular)
3. Photocatalytic deoxygenative alkylation (intermolecular)
4. Intramolecular aldol (four-membered enolate, diastereotopically selective)
5. Acyl radical cyclization (intramolecular)
Reactions 1 and 3 are radical reactions that form quaternary chiral centers. Stereocontrol on the five-membered ring is classical.
Through “merging local desymmetrization and radical retrosynthesis,” the skeleton of complex caged compounds was constructed in nine steps (12 steps total).
Optimization was required for these reactions, except for reaction 2, and yields were increased to over 50% for each reaction.
Unexpected difficulty arose during the final step of introducing a methyl group via 1,4-addition. One of the two ketones was first protected as an enolate. Then, a 1,3-dithiane anion underwent conjugate addition, and the resulting compound was converted to a methyl group via desulfurization.