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.
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.