This is an application of trideoxy glycosylation of an alcohol using enantioselective hydroalkoxylation of alkoxy arenes under mild conditions.
Since the five-membered ring of the sugar is formed through RCM, the precursor is an acyclic compound. The asymmetric center of the anomeric carbon is derived from the asymmetric catalyst; therefore, the α- or β-form of the glycosyl bond is determined at this point.
When this method was applied to the tertiary alcohol of Fridamycin B, which is unstable under acidic conditions, regioselective acetalization occurred due to the involvement of the neighboring phenolic hydroxyl group.
Based on these findings, the natural product could be synthesized efficiently. Scince the three hydroxyl group of Fridamycin B can be regioselectively glycosylated, other analogues were synthesized as well.
The general route is similar to that described in the previous paper. First, an intermolecular reaction occurs between the decalin moiety and the alcohol in the eastern part, forming an ether bond. This is followed by an intramolecular radical cyclization that creates a tetrahydrofuran ring.
The decalin moiety is synthesized via borylative Heck cyclization (intramolecular cross-coupling) to create quaternary asymmetric centers stereoselectively. Although this cyclization reaction is not widely used yet, it is expected to be applied in many cases.
The most difficult step was cleaving the epoxide and adding the alcohol to form the ether bond. A practical yield was obtained under conditions of no catalyst or solvent with heating in a plastic container. Decomposition occurred in glass, borate glass, and siliconized glass containers. Interesting.
Lactonization, the final step, was difficult due to the substrate’s acid-base instability. They achieved it by modifying the conditions Woodward used half a century ago.
This is a story about the development of CASP (Computer-Assisted Synthetic Planning) based on previous work (JACS 2020; Nature Communications 2023) to synthesize 25 picrotoxanes, which are natural products.
A key step is a reaction in which an oxyradical is generated, a neighboring methyl group’s hydrogen is abstracted, and a five-membered ring ether is formed by radical cyclization. Since beta cleavage depends on the mode of substitution of the five-membered ring near the oxyradical, the basic idea is to predict this selectivity through calculation. Because DFT calculations are time-consuming, the researchers used a simpler parameterization to select a substitution mode of the five-membered ring that favors cyclization. They then performed cyclization in a key reaction and synthesized various picrotoxanes through a series of functional group transformations.
As the paper describes, the trial-and-error process of actual synthesis takes far more time than synthetic design. Therefore, when building a library of particular compounds, enhancing the synthetic design part with CASP will be advantageous in terms of time and economy.
Both natural products are cage compounds with a tetracyclo[5.3.1.1.0]dodecane skeleton. This skeleton is derived from the well-known sesquiterpene guaiane skeleton via an intramolecular DA (double Michael reaction).
The guaiane skeleton was formed through the photoreaction of santonin. Selenization of the α-position of ketones and lactones and oxidative elimination simultaneously created two double bonds for 4+2.
However, when the double bond was generated by dehydration in the seven-membered ring to synthesize artatrovirenol B, the steric strain became too high, preventing the 4+2 reaction from proceeding. Therefore, they performed the 4+2 reaction before dehydration. Using a not-too-strong base catalyst led to the target product, Artatrovirenols B, via two dehydrations (one of which is Chugaev elimination). Regioselective epoxidation of artatrovirenol B produced artatrovirenol A in one step.
Two diterpenes (derivatives of ozic acid and abeo-abietane) were synthesized in optically active forms and subjected to the intermolecular DA reaction, resulting in endo-addition from sterically unconstrained directions to give two diastereomers (the precursors of Taiwaniadducts I and L). Upon exposure of one of the diastereomers to light, intramolecular 2+2 cyclization occurred and the most complex Taiwaniadduct J was obtained in good yield.
The two diterpenes were synthesized without major problems via Lewis acid catalyzed polyene cyclization of epoxides prepared by Sharpless asymmetric epoxidation, based on previous work.
Although some optimization was needed in the intermolecular DA, they finally found a good catalyst that gave a good yield.
メルク社発の高コレステロール血症治療薬（PCSK9阻害剤）の合成法開発物語です。
北部分は第３世代合成，南部分は第２世代合成までで最適化し，それらを結合させる順序も改良しています。
多くの非天然型アミノ酸の合成法，保護脱保護，脱水縮合の効率化，メタセシスによるC-C結合生成のタイミング，
さらに大量合成のため，終盤の中間体を結晶化させる努力などが述べられています。
最後には100KgのL-プロリンから100Kgのエンリシチドが合成できる経路になったとのこと。
”developed over many years by a large and diverse team of fearless scientists”と書かれています。
確かにそうでしょう。
This is Merck’s story about the development of a synthesis method of the new drug for the treatment of hypercholesterolemia (PCSK9 inhibitor).
The northern part was optimized by third-generation synthesis, the southern part by second-generation synthesis, and the way each part is combined was also improved.
It describes the synthesis of many unnatural amino acids, protection-deprotection, efficient dehydrative condensation, timing of C-C bond formation by metathesis, and efforts to crystallize the later stage intermediates for mass synthesis.
In the end, they say, the pathway was able to synthesize 100 kg of enlicitide from 100 kg of L-proline.
They wrote “developed over many years by a large and diverse team of fearless scientists.”
That is certainly true.
Himalomycin B uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/05/jacs25-14432.pdf
トリデオキシ糖の配糖化を，アルコキシアレンへのエナンチオ選択的ヒドロアルコキシル化を使って，温和な条件で行うという変換法の応用です。
RCMで糖の五員環をつくるので前駆体は鎖状化合物となり，アノメリック炭素の不斉は不斉触媒からの誘導となって，その時点でアルファ体かベータ体かが決まります。
酸性条件に不安定な三級アルコールに適用しようとしたところ，近隣のフェノール性水酸基の関与によって，位置選択的アセタール化が起きることがわかり，
天然物の合成が効率的にできることを証明しました。三箇所のアルコールが位置選択的にグリコシル化できるということなので，他の類縁体も合成してみせています。
This is an application of trideoxy glycosylation of an alcohol using enantioselective hydroalkoxylation of alkoxy arenes under mild conditions.
Since the five-membered ring of the sugar is formed through RCM, the precursor is an acyclic compound. The asymmetric center of the anomeric carbon is derived from the asymmetric catalyst; therefore, the α- or β-form of the glycosyl bond is determined at this point.
When this method was applied to the tertiary alcohol of Fridamycin B, which is unstable under acidic conditions, regioselective acetalization occurred due to the involvement of the neighboring phenolic hydroxyl group.
Based on these findings, the natural product could be synthesized efficiently. Scince the three hydroxyl group of Fridamycin B can be regioselectively glycosylated, other analogues were synthesized as well.
Nimbolide uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/05/jacs25-14083.pdf
デカリン骨格部分と東半分のアルコールを分子間反応させ，エーテル結合を作った後，分子内ラジカル環化でテトラヒドロフラン環をつくるという，おおまかなルートは，先行論文と同じなのですが，異なる基質や反応を利用することにより，立体選択性を飛躍的に改善しています。
デカリン部分の合成はborylative Heckというあまり使われていない環化反応（分子内クロスカップリング）で高立体選択的に四級不斉中心を作っています。いろいろ応用可能な環化反応になりそうです。
最も苦労したのがエポキシドを開裂しながらアルコールを付加させてエーテル結合を作るところで，なんと無触媒無溶媒，プラスチック容器中（ガラス容器，ホウ酸ガラス容器，ケイ素化処理したガラス容器では分解）で加熱するという条件で実用的な収率を達成しました。こんなことがあるんですね。
最後のラクトン化も簡単ではなく，気質が酸塩基に不安定なため，半世紀前にWoodwardらによって使われた条件を改良して，達成しています。
The general route is similar to that described in the previous paper. First, an intermolecular reaction occurs between the decalin moiety and the alcohol in the eastern part, forming an ether bond. This is followed by an intramolecular radical cyclization that creates a tetrahydrofuran ring.
The decalin moiety is synthesized via borylative Heck cyclization (intramolecular cross-coupling) to create quaternary asymmetric centers stereoselectively. Although this cyclization reaction is not widely used yet, it is expected to be applied in many cases.
The most difficult step was cleaving the epoxide and adding the alcohol to form the ether bond. A practical yield was obtained under conditions of no catalyst or solvent with heating in a plastic container. Decomposition occurred in glass, borate glass, and siliconized glass containers. Interesting.
Lactonization, the final step, was difficult due to the substrate’s acid-base instability. They achieved it by modifying the conditions Woodward used half a century ago.
picrotoxanes uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/05/nat25-980.pdf
これまでの仕事（JACS2020, Nature Comm.2023)をCASP(computer-assisted synthetic planning)に展開して25種のピクロトキサン類（天然物）を作ったという話です。
オキシラジカルを発生させ近隣のメチル基の水素を引き抜き，ラジカル環化で五員環エーテルを作る反応を鍵段階としています。オキシラジカルの近くにある五員環の置換様式によっては環化よりベータ切断の方が優先するため，この選択性を計算で予見するというのが基本です。DFT計算は時間がかかかかるためより簡便なパラメータ化により，環化が有利になる五員環の置換様式を選び出して，鍵反応で環化をおこない，一連の官能基変換により種々のピクロトキサンを合成しています。
論文に書かれているように，合成デザインの時間より，実際の合成の試行錯誤の方が圧倒的に時間を要しますから，化合物のライブラリーを作りたい時，CASPによって合成デザインの部分を充実できれば，時間的にも経済的にも有利になるでしょう。
This is a story about the development of CASP (Computer-Assisted Synthetic Planning) based on previous work (JACS 2020; Nature Communications 2023) to synthesize 25 picrotoxanes, which are natural products.
A key step is a reaction in which an oxyradical is generated, a neighboring methyl group’s hydrogen is abstracted, and a five-membered ring ether is formed by radical cyclization. Since beta cleavage depends on the mode of substitution of the five-membered ring near the oxyradical, the basic idea is to predict this selectivity through calculation. Because DFT calculations are time-consuming, the researchers used a simpler parameterization to select a substitution mode of the five-membered ring that favors cyclization. They then performed cyclization in a key reaction and synthesized various picrotoxanes through a series of functional group transformations.
As the paper describes, the trial-and-error process of actual synthesis takes far more time than synthetic design. Therefore, when building a library of particular compounds, enhancing the synthetic design part with CASP will be advantageous in terms of time and economy.
Artatrovirenols A and B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/05/jacsau25-1376.pdf
天然物はtetracyclo[5.3.1.1.0]dodecane という骨格を持つcage compound ですが，よく知られたセスキテルペンguaiane骨格から分子内DA（ダブルマイケルで構築しています。
guaiane 骨格はサントニンの光反応でつくり，ケトン，ラクトンのアルファ位をセレン化，酸化脱離により，４＋２のための２重結合を同時につくります。Artatrovirenols Bを目指して，先に脱水により二重結合を七員環側に入れるとひずみが大きくなりすぎて４＋２が全く進みませんでした。そこで脱水前に4+2を行ったところ，強過ぎない塩基触媒で目的物が得られたので，２つの脱水（一方はチュガエフ)によりArtatrovirenols Bに導きました。これを位置選択的にエポキシ化すると，一挙にArtatrovirenols Aが得られます。
Both natural products are cage compounds with a tetracyclo[5.3.1.1.0]dodecane skeleton. This skeleton is derived from the well-known sesquiterpene guaiane skeleton via an intramolecular DA (double Michael reaction).
The guaiane skeleton was formed through the photoreaction of santonin. Selenization of the α-position of ketones and lactones and oxidative elimination simultaneously created two double bonds for 4+2.
However, when the double bond was generated by dehydration in the seven-membered ring to synthesize artatrovirenol B, the steric strain became too high, preventing the 4+2 reaction from proceeding. Therefore, they performed the 4+2 reaction before dehydration. Using a not-too-strong base catalyst led to the target product, Artatrovirenols B, via two dehydrations (one of which is Chugaev elimination). Regioselective epoxidation of artatrovirenol B produced artatrovirenol A in one step.
Taiwaniadducts I, J, L uploaded.
https://www.ohira-sum.com/wp-content/uploads/2025/05/jacsau25-1376.pdf
2つのジテルペン（ozic acid と abeo-abietane の誘導体）を光学活性体として合成し，
分子間DAで付加反応をさせると，立体的に混み合わない方向からendo-付加が起こり，2種ジアステレオマーが生成します。（Taiwaniaddudts I, Lの前駆体）その一方に光を照射すると分子内2+2環化がおこり，好収率で最も複雑なTaiwaniadduct J が合成できました。
２つのジテルペンは過去の論文を参考にして，シャープレス酸化でつくったエポキシドをルイス酸触媒でポリエン環化して，大きな問題もなく合成しています。
分子間DAで最適化が必要だったようですが，最終的には好収率で目的を達成しました。
Two diterpenes (derivatives of ozic acid and abeo-abietane) were synthesized in optically active forms and subjected to the intermolecular DA reaction, resulting in endo-addition from sterically unconstrained directions to give two diastereomers (the precursors of Taiwaniadducts I and L). Upon exposure of one of the diastereomers to light, intramolecular 2+2 cyclization occurred and the most complex Taiwaniadduct J was obtained in good yield.
The two diterpenes were synthesized without major problems via Lewis acid catalyzed polyene cyclization of epoxides prepared by Sharpless asymmetric epoxidation, based on previous work.
Although some optimization was needed in the intermolecular DA, they finally found a good catalyst that gave a good yield.
Enlicitide Decanoate uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/05/jacs25-11036.pdf
メルク社発の高コレステロール血症治療薬（PCSK9阻害剤）の合成法開発物語です。
北部分は第３世代合成，南部分は第２世代合成までで最適化し，それらを結合させる順序も改良しています。
多くの非天然型アミノ酸の合成法，保護脱保護，脱水縮合の効率化，メタセシスによるC-C結合生成のタイミング，
さらに大量合成のため，終盤の中間体を結晶化させる努力などが述べられています。
最後には100KgのL-プロリンから100Kgのエンリシチドが合成できる経路になったとのこと。
”developed over many years by a large and diverse team of fearless scientists”と書かれています。
確かにそうでしょう。
This is Merck’s story about the development of a synthesis method of the new drug for the treatment of hypercholesterolemia (PCSK9 inhibitor).
The northern part was optimized by third-generation synthesis, the southern part by second-generation synthesis, and the way each part is combined was also improved.
It describes the synthesis of many unnatural amino acids, protection-deprotection, efficient dehydrative condensation, timing of C-C bond formation by metathesis, and efforts to crystallize the later stage intermediates for mass synthesis.
In the end, they say, the pathway was able to synthesize 100 kg of enlicitide from 100 kg of L-proline.
They wrote “developed over many years by a large and diverse team of fearless scientists.”
That is certainly true.