Highlights.
The acyloin rearrangement related to the biosynthesis, allowed simultaneous synthesis of two types of limonoids.
The Nazarov reaction using Lewis acids didn’t work, so the milder photochemical alternative was used. Since iPrCOOH is added from the beginning, it seems that the interrupted Nazarov reaction, which intermolecularly traps the cation after cyclization, was assumed.
Although the 6π-electron cyclization occurred with the compound containing a conjugated diene, its synthetic precursor containing the hydroxyl group underwent the desired reaction. Unfortunately, the stereoselectivity was not in the desired direction. Light Nazarov is disrotatory, so the selectivity is a matter of inward or outward rotation. This is called “torque selectivity”.
They proved by calculation that if the hydroxyl group is methylated to prevent intramolecular hydrogen bonding in the transition state, the selectivity is reversed and the desired compound is obtained (inward rotation → outward rotation). Excellent.
The NHC-catalysed reactions were used in two places, and the benzoin (acyloin?) condensation via the Breslow intermediate is impressive.
There are interesting reactions in various places, e.g. the semipinacol rearrangement via cyclic phosphorane, ozone decomposition in the presence of Et3N and NMO, intramolecular Reformatsky using tellurium, practical acylative kinetic resolution, functional group transformation by redox reaction in the final step.
RCM was used to construct the 7/5 system stereoselectively and efficiently from MJA. For the 6/6 system, the precursor for an intramolecular DA could not be obtained, and cascade radical cyclization was impractical, including stereoselectivity, so they ended up achieving their goal by intramolecular PK + C1 ring expansion. From the resulting cage-like compound, they extended the side chain stereoselectively to reach the final product.
The alkylation of the ester α-position of MJA produces an quaternary chiral center via acyclic stereoselection. This finding makes MJA a useful starting material for natural product syntheses.
There are two basic skeletons in related compounds. The general construction of the 5/6/7-membered ring system was already reported in 2023 by the same author, and now the synthesis of the 5/7/6-membered ring has been established.
Although the synthetic method for each fragment is different, it is similar to the route of Furstner et al. (including the difficulty in the final oxidation). It is interesting to compare the two papers, including the failures leading to the pathway, to see the differences and similarities.
The 7-membered ring part was constructed with the royal aldol reaction. The only one that succeeded after trying various catalysts was Bu2BOTf, which is unprecedented. Good job.
The conversion of ineleganolide to hororide that Furstner et al. found were not reported here, but since various ene-dione compounds did not undergo C12 isomerization, it was proposed that the isomerization may occur through retro-Michael-Michael after oxa-MIchael.
You can enjoy the first stage, which focuses on skeletal construction, and the second stage, which focuses on functional group transformation, in a variety of ways.
I wish I had listened to it at the lecture.
The protecting group assumes multiple roles. Acetonide is also a protecting group for acetylene and has a conformational fixing role to make a 5/7 system. Epoxide is a precursor of diol, but it contributes to selective introduction of hydroxyl and acyl groups through hydrogen bonding. This is in contrast to the three membeed gem-dimethyl ring, which serves as a steric hindrance in the same upward side.
The multifunctional groups are crowded together, so orchestrating operations would be inevitable .
As an old-timer, I feel nostalgic as there are quotations in the old standard reactions.
uploaded Phragmalin and Khayanolide-Type Limonoids
https://www.ohira-sum.com/wp-content/uploads/2025/02/jacs25-3003.pdf
見どころ満載です。
acyloin rearrangementは生合成とも関わっており、2つのタイプの関連化合物の同時合成を可能にしています。
ルイス酸をつかうナザロフはうまくいかなかったので milder photochemical alternativeを検討します。最初からiPrCOOHを入れているので、環化後のカチオンを分子間でトラップするInterrupted Nazarovを想定していたようです。
共役ジエンを含む化合物では6π電子環化が起きたので、その合成前駆体の水酸基を含む化合物を使うと、目的の反応が起こりますが、立体選択性は望まない方向。光ナザロフは逆旋性なので、内向きにまわるか外向きにまわるかの選択性が問題になります。“Torquoselectivity”と言うらしい。
遷移状態で分子内水素結合が生じないよう水酸基をメチル化すると、選択性が逆転し，（内旋→外旋）望む化合物が得られる事を計算で証明しています。すばらしい。
NHCを触媒とする反応を二箇所で使っていますが、Breslow中間体を経るベンゾイン（アシロイン？）縮合が印象的。
環状ホスホランを経由するセミピナコール転位とか、Et3NとNMO共存下のオゾン分解、テルルを使う分子内Reformatsky, 実用的なacylative kinetic resolution、最終段階での酸化還元反応による官能基変換などなど、各所でおもしろい反応を見ることができます。
Highlights.
The acyloin rearrangement related to the biosynthesis, allowed simultaneous synthesis of two types of limonoids.
The Nazarov reaction using Lewis acids didn’t work, so the milder photochemical alternative was used. Since iPrCOOH is added from the beginning, it seems that the interrupted Nazarov reaction, which intermolecularly traps the cation after cyclization, was assumed.
Although the 6π-electron cyclization occurred with the compound containing a conjugated diene, its synthetic precursor containing the hydroxyl group underwent the desired reaction. Unfortunately, the stereoselectivity was not in the desired direction. Light Nazarov is disrotatory, so the selectivity is a matter of inward or outward rotation. This is called “torque selectivity”.
They proved by calculation that if the hydroxyl group is methylated to prevent intramolecular hydrogen bonding in the transition state, the selectivity is reversed and the desired compound is obtained (inward rotation → outward rotation). Excellent.
The NHC-catalysed reactions were used in two places, and the benzoin (acyloin?) condensation via the Breslow intermediate is impressive.
There are interesting reactions in various places, e.g. the semipinacol rearrangement via cyclic phosphorane, ozone decomposition in the presence of Et3N and NMO, intramolecular Reformatsky using tellurium, practical acylative kinetic resolution, functional group transformation by redox reaction in the final step.
Uploaded (+)-Mannolide B
https://www.ohira-sum.com/wp-content/uploads/2025/02/jacs25-0636.pdf
7/5系は，RCMを使い，MJAから立体選択的，効率的に構築できました。しかし，6/6系では，分子内DAの前駆体ができず， カスケードラジカル環化では立体選択性も含めて非実用的ということで，結局，分子内PK＋C1環拡大で目的を達成しました。できた籠状化合物から立体選択的に側鎖を伸ばし，最終物まで誘導しています。
MJAのエステルα位をアルキル化すると，非環状立体選択的に４級不斉中心ができるという知見は,MJAの出発原料としての一つの有用性となっています。
RCM was used to construct the 7/5 system stereoselectively and efficiently from MJA. For the 6/6 system, the precursor for an intramolecular DA could not be obtained, and cascade radical cyclization was impractical, including stereoselectivity, so they ended up achieving their goal by intramolecular PK + C1 ring expansion. From the resulting cage-like compound, they extended the side chain stereoselectively to reach the final product.
The alkylation of the ester α-position of MJA produces an quaternary chiral center via acyclic stereoselection. This finding makes MJA a useful starting material for natural product syntheses.
uploaded Scabrolide B, Ineleganolide
https://www.ohira-sum.com/wp-content/uploads/2025/01/jacs25-0130.pdf
関連化合物として２つの基本骨格がありますが，５/6/7員環系の一般構築法はすでに2023年に報告しており，今回5/7/6員環の合成を確立しました。
各フラグメントの合成法は異なるものの，先に発表されたFurstnerらの経路と似たものになっています。（最後の酸化で苦労するあたりも）
その経路に至るまでの失敗なども含めて，２つの論文を比較すると，違う所や同じ所が見えて，面白いです。
https://www.ohira-sum.com/?cpage=7
https://www.ohira-sum.com/wp-content/uploads/2024/10/jacs24-24250.pdf
７員環部分を王道のアルドール反応でやってます。種々触媒を試して唯一成功したのが，例のないBu2BOTf。よかったー。
Furstnerらが見つけたIneleganolideからHororideへの変換については報告してませんが，種々のエン-ジオン化合物がC12異性化をおこさなかったことから，異性化はoxa-MIchael の後，retro-Michael-Michaelで起こるのではないかと提案しています。
There are two basic skeletons in related compounds. The general construction of the 5/6/7-membered ring system was already reported in 2023 by the same author, and now the synthesis of the 5/7/6-membered ring has been established.
Although the synthetic method for each fragment is different, it is similar to the route of Furstner et al. (including the difficulty in the final oxidation). It is interesting to compare the two papers, including the failures leading to the pathway, to see the differences and similarities.
https://www.ohira-sum.com/?cpage=7
https://www.ohira-sum.com/wp-content/uploads/2024/10/jacs24-24250.pdf
The 7-membered ring part was constructed with the royal aldol reaction. The only one that succeeded after trying various catalysts was Bu2BOTf, which is unprecedented. Good job.
The conversion of ineleganolide to hororide that Furstner et al. found were not reported here, but since various ene-dione compounds did not undergo C12 isomerization, it was proposed that the isomerization may occur through retro-Michael-Michael after oxa-MIchael.
Uploaded Euphorbialoid A
https://www.ohira-sum.com/wp-content/uploads/2024/12/jacs24-34221.pdf
骨格構築が中心の第一ステージも，官能基変換が中心の第二ステージもいろいろと楽しむことができます。
講演会でで聞いてみたかった。
保護基が複数の役目を負っています。アセトニドはアセチレンの保護基でもあったり，5/7系をつくるためのコンフォーメーション固定の役割を持ちます。エポキシドはジオールの前駆体ですが，水素結合を通して選択的な水酸基やアシル基導入に寄与します。同じ上向き三員環でもgem-dimethyl環が立体障害として役立っているのと対照的。
多官能基で混み合っているから，必然的にorchestrating operationになるのでしょう。
古い定番の反応にちゃんと引用があるので，古い人間としてはなつかしく，心地よいです。
You can enjoy the first stage, which focuses on skeletal construction, and the second stage, which focuses on functional group transformation, in a variety of ways.
I wish I had listened to it at the lecture.
The protecting group assumes multiple roles. Acetonide is also a protecting group for acetylene and has a conformational fixing role to make a 5/7 system. Epoxide is a precursor of diol, but it contributes to selective introduction of hydroxyl and acyl groups through hydrogen bonding. This is in contrast to the three membeed gem-dimethyl ring, which serves as a steric hindrance in the same upward side.
The multifunctional groups are crowded together, so orchestrating operations would be inevitable .
As an old-timer, I feel nostalgic as there are quotations in the old standard reactions.