Study Organic Chemistry with Lluís: Total Synthesis of Vilmoraconitine

[00:00:00]Hello, everyone. In this video, I’m going to talk  about the synthesis of Vilmoraconitine, a natural product that features a heptacyclic core. The synthesis begins with the addition of the aryl lithium species, generated  in situ from aryl bromide and nBuLi, to the aldehyde. This produces a mixture of  diastereomers in 91% yield. The alcohol is then treated with iodobenzene diacetate in methanol,  leading to an oxidative dearomatization. This step provides the substrate required for the desired  intramolecular Diels-Alder reaction, which occurs between the diene and the dienophile to give  exclusively the endo-cycloadduct. This product arises from the alkene approaching the diene with  the substituent oriented towards the π system.

[00:00:54]After separation of the desired isomer,  methylation of the hydroxyl group is achieved using sodium hydride and methyl iodide.  Next, desilylation occurs after exposing the substrate to TBAF. Subsequent oxidation  with IBX provides the aldehyde. Treating the aldehyde with potassium tert-butoxide generates  an enolate intermediate, which is quenched with methyl iodide to produce the aldehyde in 89%  yield as the only isomer. This occurs as the methyl iodide approaches the in situ-generated  enolate from the sterically less hindered face, installing a quaternary stereogenic center. Reductive amination of the aldehyde with ethylamine hydrochloride and sodium  cyanoborohydride yields the secondary amine, which is protected with a Boc group by adding  sodium hydroxide and Boc anhydride directly to the reaction mixture. The product is obtained in  90% yield. After that, the ketone is first reduced to an alcohol with lithium aluminum hydride. Then,  the acetal is removed under acidic conditions, and finally, reductive removal of the hydroxyl  group with samarium iodide provides the ketone in 62% yield over three steps. The ketone is  then subjected to these conditions to effect a hydrodealkenylative fragmentation. This  generates the aldehyde in 77% yield. For more information about this interesting  transformation, check out this paper.

[00:02:38]Addition of TFA to the substrate promotes the Boc  cleavage and the Mannich cyclization to give the tetracycle. The Mannich reaction involves the  condensation of an aldehyde or ketone with a primary or secondary amine and a non-enolizable  aldehyde or ketone to prepare aminoalkylated derivatives. Treatment with LDA generates the  enolate by deprotonating the alpha-carbon of the ketone. The enolate is then quenched with  methyl cyanoformate (also known as Mander’s reagent) to install the methoxycarbonyl group  at the alpha-position of the carbonyl group.

[00:03:20]The Robinson annulation takes places in  two steps. First, a Michael addition with methyl vinyl ketone and cesium carbonate, which  attaches the methyl vinyl ketone from the less hindered convex face of the substrate,  producing a single diastereomer. Next, intramolecular aldol addition of the diketone  proceeds with potassium HMDS, generating an additional ring in 85% yield. The ketone of the  pentacyclic product is then protected as the corresponding dimethyl acetal using a Lewis acid  and methanol. This allows for the reduction of the ester to the aldehyde in two steps: first,  reduction to the alcohol with lithium aluminum hydride, followed by oxidation. Although DIBAL  can reduce esters to aldehydes in a single step, the reduction is sometimes difficult to control.  Therefore, it is often more convenient to reduce the ester fully to the alcohol and  subsequently oxidize it to the aldehyde.

[00:04:24]The aldehyde undergoes Horner-Wadsworth-Emmons  olefination with LDA and a phosphonate to give the corresponding E-alkene. The alkene is then  treated with TMS triflate to provide the alpha, beta-unsaturated ketone in 86% yield. By the  way, if you are interested in name reactions, you will love “The Chemists’ Cookbook.”  It contains 201 named reactions with real examples from the total synthesis of natural  products, along with experimental procedures.

[00:04:56]Check the description for more details. Since the tertiary amine within the enone interferes with subsequent steps, it is oxidized  to the corresponding amide, and the lactam is obtained in very good yield using iodine and  sodium bicarbonate. Do you know the mechanism for this transformation? Let me know in the  comments! The enone gives rise to the enol silane with TMP and TBS triflate. Heating the reaction  to 150 ºC promotes the intramolecular Diels-Alder reaction to deliver the heptacyclic product upon  acidic workup. Interestingly, the regioselectivity in this transformation is opposite to what would  typically be expected. In Diels-Alder reactions, the regioselectivity usually follows the  ortho-para rule: the regioisomers obtained are predominantly the 1,2- and the 1,4-products  rather than the 1,3-product seen here.

[00:05:59]Reduction of the ketone with sodium  borohydride gives the alcohol with excellent diastereoselectivity. Methylation  of the secondary alcohol is accomplished using potassium tert-butoxide and methyl iodide. The  next step involves an oxidative decyanation of the secondary nitrile. This transformation  is achieved using LDA and oxygen, followed by quenching with tin dichloride and workup with  aqueous sodium carbonate. Finally, the lactam is converted back to the tertiary amine in two steps:  first, reduction of the amide and the ketone groups with lithium aluminum hydride, followed  by oxidation of the resulting secondary alcohol.

[00:06:45]Thank you for watching! I hope you  enjoyed the video. Please subscribe, like, and leave me a comment below.  I’ll see you in the next video. Bye!