Three building blocks are joined via 1,4-addition (Mukaiyama–Michael) and 1,2-addition to align all the carbon numbers (including the three chiral carbons).
Next, a seven-membered ring-bridged section is formed via an oxa-Michael/Aldol reaction, which introduces four chiral carbons. Finally, an SN2 etherification reaction creates the final five-membered ring section. Remarkably, the entire process consists of only six steps using the well-known building block TBS-oxi-cyclopentenone. Various trials and conditions were optimised to produce a brilliant cascade reaction that suppresses retro-aldol reactions while simultaneously introducing the halogen required for the next reaction. Although synthesising THF using 1,5-HAT to the alkoxy radical was unsuccessful, the resulting pathway more than compensates for this setback.
The synthesis begins with a compound containing a five-membered ring, which is biosynthetically formed in the final stage. Interestingly, they utilised the peculiar stereoselectivity of the Mukaiyama–Michael addition to TBS-oxi-cyclopentenone. In this reaction, a trisubstituted silyl enol ether mainly forms the cis adduct, an outcome that Danishefsky attributed to the Cieplak model, though this is still debated.
The key point is the formation of a seven-membered ring in the bicyclo[4.2.1] system through an intramolecular reaction involving a lactone enolate and a bromoalkene. Various ligands were tested with Ni(0), and the desired reaction was achieved using a nickel complex with an electron-deficient alkene as the ligand. This success can be attributed to the enhanced stability of the catalyst and the suppression of beta-hydrogen elimination side reactions, which makes this approach a viable option for enolate alkenylation catalysts.
Another bicyclic system [3,2,1] was synthesised via nickel-halogen exchange of bromoalkenes, followed by 1,2-addition to ketones. Although this competes with the Heck reaction for forming the six-membered ring, the team investigated ligands and additives to obtain the target compound in a high yield. The most common approach, halogen-lithium exchange, reportedly did not work well. Therefore, this intramolecular 1,2-addition using nickel appears to be generally applicable.
The key feature is “skeletal editing” via hydrodealkenation, which combines three classical reactions: ozonolysis, deacylation, and an intramolecular Mannich reaction. This process occurs efficiently in a one-pot system and results in an interesting skeletal transformation. Since the process yields a common substructure among numerous aconitine-related compounds, it may be applicable to the modular synthesis of the aconitine family.
Complex carbon skeletons can also be constructed using reactions described in textbooks, such as pinacol coupling, one-carbon ring expansion using TMS diazomethane, intramolecular DA reactions, Claisen rearrangements, and ring-closing metathesis.
The authors emphasize that introducing a nitrogen-containing quaternary chiral center at an early stage, via the addition of hydrogen cyanide to an allenic compound, made the synthesis efficient. The feasibility of asymmetric synthesis is an interesting point.
Proline and serine derivatives undergo radical coupling to form a carbon skeleton. This process leads to a key intermediate via C-H amination cyclization. Many of these reactions occur in a single pot, enabling a single researcher to synthesize over 9 g of the intermediate in three days. The ideality is 71%. This intermediate can be converted into numerous related natural products in just a few steps. This is truly impressive work by Professor Baran.
Additionally, the first synthesis of neo-STX has been achieved. Although the final route is short, it appears to be the result of considerable effort, such as timing the nitrogen oxidation and protecting the hydroxylamine.
The practical synthesis of the starting material, 4-hydroxyproline, is also significant. Genetically modifying a promising oxidase increased the yield from proline to 61%.
This is truly hybrid natural product synthesis, incorporating radical reactions, late-stage oxidation, and biological methods.
(+)-Punctaporonin U uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/11/jacs25-40106.pdf
三つのビルディングブロックを1,4付加（向山-マイケル）と1,2付加でくっつけて，全炭素数（３つの不斉炭素を含む）を揃えています。
続いてオキサーマイケル/アルドールで七員環渡環部をつくり，四つの不斉炭素も導入，最後はSN2エーテル化で五員環渡環部分を作って完成。有名なビルディングブロック，TBSオキシシクロペンテノンから，なんと全工程六段階です。いろいろな試行錯誤や条件最適化が行われ，見事なカスケード反応で，レトロアルドールを抑制し，同時に次の反応に必要とされるハロゲンの導入を行っています。アルコキシラジカルへの1,5-HATを使ったTHFの合成には失敗していますが，補って余りある経路になりました。
生合成的には最後にできる五員環から出発しています。TBSオキシシクロペンテノンへの向山-マイケルは三置換シリルエノールエーテルを用いると，シス付加物が主にできるという不思議な立体選択性（ダニシェフスキーはシープラック効果で説明しているが，議論はあるとのこと）を利用しているのも興味深いです。
Three building blocks are joined via 1,4-addition (Mukaiyama–Michael) and 1,2-addition to align all the carbon numbers (including the three chiral carbons).
Next, a seven-membered ring-bridged section is formed via an oxa-Michael/Aldol reaction, which introduces four chiral carbons. Finally, an SN2 etherification reaction creates the final five-membered ring section. Remarkably, the entire process consists of only six steps using the well-known building block TBS-oxi-cyclopentenone. Various trials and conditions were optimised to produce a brilliant cascade reaction that suppresses retro-aldol reactions while simultaneously introducing the halogen required for the next reaction. Although synthesising THF using 1,5-HAT to the alkoxy radical was unsuccessful, the resulting pathway more than compensates for this setback.
The synthesis begins with a compound containing a five-membered ring, which is biosynthetically formed in the final stage. Interestingly, they utilised the peculiar stereoselectivity of the Mukaiyama–Michael addition to TBS-oxi-cyclopentenone. In this reaction, a trisubstituted silyl enol ether mainly forms the cis adduct, an outcome that Danishefsky attributed to the Cieplak model, though this is still debated.
(+)-Auriculatol A uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/11/jacs25-42170.pdf
ラクトンエノラートと臭化アルケンの分子内カップリングでビシクロ[4,2,1]系の七員環をつくるところが最大ポイントです。Ni（０）で種々のリガンドを試し，電子不足のアルケンを配位子とするニッケル錯体で目的の反応を達成しました。触媒の安定性を上げ，副反応となるベータ水素脱離を抑制するためと考えられ，エノラートのアルケニル化触媒の一選択肢となりそうです。
もう一つの渡環系ビシクロ[3,2,1]は臭化アルケンをニッケル化し、ケトンへの1,2付加反応で合成しています。六員環を作るHeck反応と競合するのですが，リガンド，添加物を調べ，目的物を好収率を得ています。最も一般的なハロゲンーリチウム交換による反応がうまく行かなかったとのこと。このニッケルを使う分子内1,2付加も一般的に利用できそうです。
The key point is the formation of a seven-membered ring in the bicyclo[4.2.1] system through an intramolecular reaction involving a lactone enolate and a bromoalkene. Various ligands were tested with Ni(0), and the desired reaction was achieved using a nickel complex with an electron-deficient alkene as the ligand. This success can be attributed to the enhanced stability of the catalyst and the suppression of beta-hydrogen elimination side reactions, which makes this approach a viable option for enolate alkenylation catalysts.
Another bicyclic system [3,2,1] was synthesised via nickel-halogen exchange of bromoalkenes, followed by 1,2-addition to ketones. Although this competes with the Heck reaction for forming the six-membered ring, the team investigated ligands and additives to obtain the target compound in a high yield. The most common approach, halogen-lithium exchange, reportedly did not work well. Therefore, this intramolecular 1,2-addition using nickel appears to be generally applicable.
Giraldine I and Heterophyllisine uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/11/jacs25-37012.pdf
ヒドロデアルケニル化による”骨格編集”が最大の特徴です。古典的な反応（オゾン分解，デアシル化，分子内マンニッヒ反応）の組み合わせですが，ワンポットで収率よく進行し，面白い骨格変換になっています。数多くあるアコニチン関連化合物で共通の部分構造なので，モジュラー合成に利用できるかも。
他にもピナコールカップリング，TMSジアゾメタンによる一炭素環拡大反応，分子内DA反応，クライゼン転位，閉環メタセシスなど教科書に出てきそうな反応で複雑な炭素骨格を構築しています。
アレンへのシアン化水素付加で，初期の段階で窒素原子を含む四級不斉中心部分を作った事が効率的合成に繋がったことも，著者は強調しています。不斉合成が可能かが気になります。
The key feature is “skeletal editing” via hydrodealkenation, which combines three classical reactions: ozonolysis, deacylation, and an intramolecular Mannich reaction. This process occurs efficiently in a one-pot system and results in an interesting skeletal transformation. Since the process yields a common substructure among numerous aconitine-related compounds, it may be applicable to the modular synthesis of the aconitine family.
Complex carbon skeletons can also be constructed using reactions described in textbooks, such as pinacol coupling, one-carbon ring expansion using TMS diazomethane, intramolecular DA reactions, Claisen rearrangements, and ring-closing metathesis.
The authors emphasize that introducing a nitrogen-containing quaternary chiral center at an early stage, via the addition of hydrogen cyanide to an allenic compound, made the synthesis efficient. The feasibility of asymmetric synthesis is an interesting point.
Saxitoxin and related natural products uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/11/nat25-646-351.pdf
プロリンとセリンの誘導体をラジカルカップリングさせて炭素骨格をつくり，C-Hアミノ化環化で多くのSTXに変換できる重要中間体に導きます。多くの反応がワンポットで行われ，一人で３日間に９ｇ以上合成できたとのこと。アイデアリティ71% 。多くの関連天然物がここから数段階で合成できます。さすがBaran先生。
加えてネオSTXの初合成も達成しています。最終的には短工程ですが，窒素の酸化のタイミングとかヒドロキシルアミンの保護とか相当な苦労の結果のようです。
原料となる4-ヒドロキシルプロリンの実用的合成も重要で，有望な酸化酵素を改変して，プロリンからの収率を61％まで上げています。
ラジカル反応，後期酸化，生物的手法とまさにハイブリッド天然物合成です。
Proline and serine derivatives undergo radical coupling to form a carbon skeleton. This process leads to a key intermediate via C-H amination cyclization. Many of these reactions occur in a single pot, enabling a single researcher to synthesize over 9 g of the intermediate in three days. The ideality is 71%. This intermediate can be converted into numerous related natural products in just a few steps. This is truly impressive work by Professor Baran.
Additionally, the first synthesis of neo-STX has been achieved. Although the final route is short, it appears to be the result of considerable effort, such as timing the nitrogen oxidation and protecting the hydroxylamine.
The practical synthesis of the starting material, 4-hydroxyproline, is also significant. Genetically modifying a promising oxidase increased the yield from proline to 61%.
This is truly hybrid natural product synthesis, incorporating radical reactions, late-stage oxidation, and biological methods.