Using podocarpic acid extracted directly from wood as the starting material, the C and D rings comprising the benzoquinone moiety are first constructed via a Diels–Alder reaction with in-situ-generated benzyne. The A and B rings of the terpenoid moiety are then elaborated through sequential oxidation and reduction steps modeled on the biosynthetic pathway, ultimately achieving the synthesis of seven related natural products. Reduction of the carboxylic acid to a methyl group affords the natural product that serves as the starting point for oxidative biosynthesis. Separately, oxidation at the benzylic position, followed by further oxidation at the α-position of the resulting ketone, constructs the “diosphenol” moiety in the B ring. Finally, decarboxylation followed by subsequent oxidation installs the structural element responsible for biological activity as a Michael acceptor. Helenaquinone, the most highly oxidized member of the series, is ultimately derived through seven consecutive oxidation reactions with high redox economy. It appears that as the oxidation state increases in the later stages, the intermediates become increasingly unstable, necessitating reordering of steps and optimization of reaction conditions.
1993年のKuehneらのラセミ体合成で使われた収束性のよいマンニッヒ- 電子環状反応カスケードをベースにして，それを進化させた経路になっています。その一つは光学活性トリプトファンを原料とし，そのキラリティーを環化反応に反映させて，エナンチオ選択的全合成にしていること。環化後，脱炭酸により，原料にあった不斉炭素は消滅します。もう一つはビルディングブロックの炭素数を増やして，収束性を上げている点。反応中に一部二重結合の異性化がおこるという問題が生じていますが，全体の段階数を減らすのに役立っています。２つのビルティングブロクの合成では，イリジウム触媒光反応条件下でのシアノメチル化，リガンドフリーのヘック反応などが効率的に使われています。なお，イリジウム-光で起きるラジカル反応はアミノ酸の脱炭酸時でも利用されています。
さらに，著者が強調しているのは，原料が「xylochemicals or other renewable resources, including the fermentation product」とのことで，それぞれのリソースも具体的に記述しています。イラン戦争以前の仕事ですが。
The route is based on and evolved from the convergent Mannich–electrocyclic reaction cascade used in Kuehne et al.’s racemic synthesis in 1993. One advancement is that optically active tryptophan is used as the starting material, and its chirality is reflected in the cyclization reaction, making it an enantioselective total synthesis. After cyclization, the asymmetric carbon present in the starting material is eliminated by decarboxylation. Another advancement is that the carbon count of the building blocks has been increased to improve convergence. Although a problem arises in that partial isomerization of double bonds occurs during the reaction, this proves useful in reducing the overall number of steps. In the synthesis of the two building blocks, cyanomethylation under iridium-catalyzed photochemical conditions and ligand-free Heck reaction are used efficiently. The iridium-photoredox-induced radical reaction is also utilized during decarboxylation of the amino acid.
Furthermore, what the authors emphasize is that the starting materials are described as “xylochemicals or other renewable resources, including the fermentation product,” and they specifically describe each resource as well. This work predates the Iran War, though.
近代的な３つの環化反応が効果的に利用されています。アルキンとヨードアレーンの還元的ヘック反応によるエキソメチレンを含む６員環の合成，アルデヒドから発生させたアゾメチンイリドのエキソメチレンに対する1,3双極子付加，ジェミナルジビニル基とアリル基とのRCMで， B環，C,D環，E環を順次構築しています。４級中心を３つ含んで，混み合っているC,D環系（ビシクロ[3.3.0]系）は，分子内1,3双極子付加によって一挙に構築されます。プリンス反応と競合して収率がよくなかったのですが，試薬のカルボン酸の半分をナトリウム塩にして反応系のpHを上げたり，MSを加えたりすることにより53%まで改良しています。
分子内ヘック反応については，反応が遅く，またヨウ化物の還元と競合するので，種々検討し，リガンドとしてdppfを用い，メタノール中８０℃で最適収率を得ています。
２つのカルボニル基に挟まれた活性メチレンのシクロプロペニルメチル化(ネオペンチル位のSN2反応)に続く，４級不中心を構築する活性メチンのアルキニル化(試薬：TMS-EBX)が特に印象的で，成功すれば天然物の不斉全合成になるような不斉触媒反応も試みられています。
Three modern cyclization reactions are effectively utilized. The B ring, C/D rings, and E ring are sequentially constructed via: a reductive Heck reaction of an alkyne and an iodoarene to form a six-membered ring containing an exo-methylene; a 1,3-dipolar cycloaddition of an azomethine ylide generated from an aldehyde onto the exo-methylene; and ring-closing metathesis (RCM) of a geminal divinyl group with an allyl group. The congested C/D ring system (bicyclo[3.3.0] system) bearing three quaternary centers is constructed in a single step by an intramolecular 1,3-dipolar cycloaddition. Although the yield was poor due to competition with the Prins reaction, it has been improved to 53% by raising the pH of the reaction system by converting half of the carboxylic acid reagent to its sodium salt, and by adding molecular sieves (MS).
Regarding the intramolecular Heck reaction, since the reaction is slow and competes with reduction of the iodide, various conditions were examined; the optimal yield was obtained using dppf as a ligand in methanol at 80°C.
Particularly impressive is the alkynylation of an active methine to construct a quaternary stereocenter (reagent: TMS-EBX), following cyclopropenylmethylation of an active methylene flanked by two carbonyl groups (an S~N~2 reaction at a neopentyl position). Asymmetric catalytic conditions for this reaction are also being attempted (thus far without success) with the goal of achieving an asymmetric total synthesis of the natural product.
Ussuriedineは７環性のアルカロイドで，キノリジジン環（4a-azabicyclo[4.4.0]decane）をE,F環にもつHeilonineのF環状の側鎖メチル基とE環の環上炭素が結合を作りG環を形成した構造をとっています。エピ化したメチル基末端とベンジル位の２箇所が酸化されて，生じたラジカルが結合を作り，ベンジル位が更に酸化されてアミナールを形成した形になり，生合成経路を暗示しています。そのジラジカルは４級アンモニウム塩のスティーブンス転位で生じると考えられるため，筆者らは４員環アゼチジウム塩を合成前駆体とする「生合成類似経路」を計画しました。そして，すでに発表していたHeilonineの合成と同じ[2+2+2]三量化を基本戦略として前駆体を合成し，転位反応を行って目的の骨格構築に成功しました。最後のアミナールへの酸化は中間体として反ブレット則二重結合を含むためか，条件検討が必要でしたが，最終的には，窒素付け根にアセトキシル基を導入する条件下で，目的を達成しています。
Ussuriedine is a heptacyclic alkaloid whose structure is related to that of the hexacyclic alkaloid Heilonine, which contains a quinolizidine ring (4a-azabicyclo[4.4.0]decane) in its E and F rings. In Ussuiriedine, the pendant methyl group on the F ring and a ring carbon on the E ring are bonded together to form the G ring. Two positions — the epimerized methyl terminus and the benzylic position — are oxidized, and the resulting diradical forms a bond; the benzylic position is then further oxidized to give an aminal, a structural feature that hints at the biosynthetic pathway. Since the diradical is thought to arise via a Stevens rearrangement of a quaternary ammonium salt, the authors devised a “biomimetic pathway” using a four-membered azetidinium salt as the synthetic precursor. Employing the same [2+2+2] trimerization strategy as in their previously reported synthesis of Heilonine, they synthesized the precursor and carried out the rearrangement, successfully constructing the target skeleton. The final oxidation to the aminal required optimization of the reaction conditions — likely because the intermediate contains an anti-Bredt double bond — but the goal was ultimately achieved under conditions that introduce an acetoxy group at the nitrogen α-position.
Helenaquinone and related compounds uploaded.
https://www.ohira-sum.com/wp-content/uploads/2026/06/jacs26-23316.pdf
実際に木材から抽出して得たポドカルピン酸を原料として，まず，発生させたベンザインへのDA反応で，ベンゾキノン部であるC,D環を構築します。次いで，テルペノイド部であるA,B環を，生合成に倣って，順次酸化還元反応を施すことにより，７種の関連天然物を合成しています。カルボン酸部分をメチル基に還元すると，酸化的生合成の出発点となる天然物となります。一方，ベンジル位を酸化し，さらにケトンα位を酸化して，B環の「ジオスフェノール」部分を構築します。最後に，脱炭酸と続く酸化で，マイケルアクセプターとして生理活性に寄与する構造部分が合成されます。最も酸化段階の高いヘレナキノンは，最終的に７つの連続する酸化反応によって，高いレドックス経済性で誘導されています。後の段階になって酸化段階が高くなると，物質が不安定になるため，反応の順番変更や条件検討が必要だったようです。
Using podocarpic acid extracted directly from wood as the starting material, the C and D rings comprising the benzoquinone moiety are first constructed via a Diels–Alder reaction with in-situ-generated benzyne. The A and B rings of the terpenoid moiety are then elaborated through sequential oxidation and reduction steps modeled on the biosynthetic pathway, ultimately achieving the synthesis of seven related natural products. Reduction of the carboxylic acid to a methyl group affords the natural product that serves as the starting point for oxidative biosynthesis. Separately, oxidation at the benzylic position, followed by further oxidation at the α-position of the resulting ketone, constructs the “diosphenol” moiety in the B ring. Finally, decarboxylation followed by subsequent oxidation installs the structural element responsible for biological activity as a Michael acceptor. Helenaquinone, the most highly oxidized member of the series, is ultimately derived through seven consecutive oxidation reactions with high redox economy. It appears that as the oxidation state increases in the later stages, the intermediates become increasingly unstable, necessitating reordering of steps and optimization of reaction conditions.
(−)-Strychnine uploaded
https://www.ohira-sum.com/wp-content/uploads/2026/06/jacsau26-1822.pdf
1993年のKuehneらのラセミ体合成で使われた収束性のよいマンニッヒ- 電子環状反応カスケードをベースにして，それを進化させた経路になっています。その一つは光学活性トリプトファンを原料とし，そのキラリティーを環化反応に反映させて，エナンチオ選択的全合成にしていること。環化後，脱炭酸により，原料にあった不斉炭素は消滅します。もう一つはビルディングブロックの炭素数を増やして，収束性を上げている点。反応中に一部二重結合の異性化がおこるという問題が生じていますが，全体の段階数を減らすのに役立っています。２つのビルティングブロクの合成では，イリジウム触媒光反応条件下でのシアノメチル化，リガンドフリーのヘック反応などが効率的に使われています。なお，イリジウム-光で起きるラジカル反応はアミノ酸の脱炭酸時でも利用されています。
さらに，著者が強調しているのは，原料が「xylochemicals or other renewable resources, including the fermentation product」とのことで，それぞれのリソースも具体的に記述しています。イラン戦争以前の仕事ですが。
The route is based on and evolved from the convergent Mannich–electrocyclic reaction cascade used in Kuehne et al.’s racemic synthesis in 1993. One advancement is that optically active tryptophan is used as the starting material, and its chirality is reflected in the cyclization reaction, making it an enantioselective total synthesis. After cyclization, the asymmetric carbon present in the starting material is eliminated by decarboxylation. Another advancement is that the carbon count of the building blocks has been increased to improve convergence. Although a problem arises in that partial isomerization of double bonds occurs during the reaction, this proves useful in reducing the overall number of steps. In the synthesis of the two building blocks, cyanomethylation under iridium-catalyzed photochemical conditions and ligand-free Heck reaction are used efficiently. The iridium-photoredox-induced radical reaction is also utilized during decarboxylation of the amino acid.
Furthermore, what the authors emphasize is that the starting materials are described as “xylochemicals or other renewable resources, including the fermentation product,” and they specifically describe each resource as well. This work predates the Iran War, though.
Scandine uploaded.
https://www.ohira-sum.com/wp-content/uploads/2026/06/jacsau26-2198.pdf
近代的な３つの環化反応が効果的に利用されています。アルキンとヨードアレーンの還元的ヘック反応によるエキソメチレンを含む６員環の合成，アルデヒドから発生させたアゾメチンイリドのエキソメチレンに対する1,3双極子付加，ジェミナルジビニル基とアリル基とのRCMで， B環，C,D環，E環を順次構築しています。４級中心を３つ含んで，混み合っているC,D環系（ビシクロ[3.3.0]系）は，分子内1,3双極子付加によって一挙に構築されます。プリンス反応と競合して収率がよくなかったのですが，試薬のカルボン酸の半分をナトリウム塩にして反応系のpHを上げたり，MSを加えたりすることにより53%まで改良しています。
分子内ヘック反応については，反応が遅く，またヨウ化物の還元と競合するので，種々検討し，リガンドとしてdppfを用い，メタノール中８０℃で最適収率を得ています。
２つのカルボニル基に挟まれた活性メチレンのシクロプロペニルメチル化(ネオペンチル位のSN2反応)に続く，４級不中心を構築する活性メチンのアルキニル化(試薬：TMS-EBX)が特に印象的で，成功すれば天然物の不斉全合成になるような不斉触媒反応も試みられています。
Three modern cyclization reactions are effectively utilized. The B ring, C/D rings, and E ring are sequentially constructed via: a reductive Heck reaction of an alkyne and an iodoarene to form a six-membered ring containing an exo-methylene; a 1,3-dipolar cycloaddition of an azomethine ylide generated from an aldehyde onto the exo-methylene; and ring-closing metathesis (RCM) of a geminal divinyl group with an allyl group. The congested C/D ring system (bicyclo[3.3.0] system) bearing three quaternary centers is constructed in a single step by an intramolecular 1,3-dipolar cycloaddition. Although the yield was poor due to competition with the Prins reaction, it has been improved to 53% by raising the pH of the reaction system by converting half of the carboxylic acid reagent to its sodium salt, and by adding molecular sieves (MS).
Regarding the intramolecular Heck reaction, since the reaction is slow and competes with reduction of the iodide, various conditions were examined; the optimal yield was obtained using dppf as a ligand in methanol at 80°C.
Particularly impressive is the alkynylation of an active methine to construct a quaternary stereocenter (reagent: TMS-EBX), following cyclopropenylmethylation of an active methylene flanked by two carbonyl groups (an S~N~2 reaction at a neopentyl position). Asymmetric catalytic conditions for this reaction are also being attempted (thus far without success) with the goal of achieving an asymmetric total synthesis of the natural product.
Ussuriedine uploaded.
https://www.ohira-sum.com/wp-content/uploads/2026/05/jacs26-151590.pdf
Ussuriedineは７環性のアルカロイドで，キノリジジン環（4a-azabicyclo[4.4.0]decane）をE,F環にもつHeilonineのF環状の側鎖メチル基とE環の環上炭素が結合を作りG環を形成した構造をとっています。エピ化したメチル基末端とベンジル位の２箇所が酸化されて，生じたラジカルが結合を作り，ベンジル位が更に酸化されてアミナールを形成した形になり，生合成経路を暗示しています。そのジラジカルは４級アンモニウム塩のスティーブンス転位で生じると考えられるため，筆者らは４員環アゼチジウム塩を合成前駆体とする「生合成類似経路」を計画しました。そして，すでに発表していたHeilonineの合成と同じ[2+2+2]三量化を基本戦略として前駆体を合成し，転位反応を行って目的の骨格構築に成功しました。最後のアミナールへの酸化は中間体として反ブレット則二重結合を含むためか，条件検討が必要でしたが，最終的には，窒素付け根にアセトキシル基を導入する条件下で，目的を達成しています。
Ussuriedine is a heptacyclic alkaloid whose structure is related to that of the hexacyclic alkaloid Heilonine, which contains a quinolizidine ring (4a-azabicyclo[4.4.0]decane) in its E and F rings. In Ussuiriedine, the pendant methyl group on the F ring and a ring carbon on the E ring are bonded together to form the G ring. Two positions — the epimerized methyl terminus and the benzylic position — are oxidized, and the resulting diradical forms a bond; the benzylic position is then further oxidized to give an aminal, a structural feature that hints at the biosynthetic pathway. Since the diradical is thought to arise via a Stevens rearrangement of a quaternary ammonium salt, the authors devised a “biomimetic pathway” using a four-membered azetidinium salt as the synthetic precursor. Employing the same [2+2+2] trimerization strategy as in their previously reported synthesis of Heilonine, they synthesized the precursor and carried out the rearrangement, successfully constructing the target skeleton. The final oxidation to the aminal required optimization of the reaction conditions — likely because the intermediate contains an anti-Bredt double bond — but the goal was ultimately achieved under conditions that introduce an acetoxy group at the nitrogen α-position.