Total Synthesis of Vilmoraconitine

Shimakawa T., Nakamura S., Asai H., Hagiwara K., Inoue M.

Li Y., Shang Y., Li X., Zhang Y., Xie J., Chen L., Gao F., Zhou X.

The C18-diterpenoid alkaloid lappaconitine (LA) is a non-addictive analgesic used in China. The toxicity (LD50 = 11.7 mg/kg) limits its application. Two series of LA derivatives, including amides and sulfonamides (1-93), were designed and synthesized by modification on their C4 acetamidobenzoate side chains in this work. In vivo analgesic activity and toxicity of all derivatives were evaluated, and the structure-activity relationship was summarized. Six lead compounds (35, 36, 39, 49, 70, and 89) exhibited approximate analgesic activity to LA but with significantly reduced toxicity. The therapeutic index of these compounds is 14-30 times that of LA. In vivo metabolism study of the lead compounds 39, 49, 70, and 89 were conducted by UPLC-MSE, indicating the reason for the low toxicity of the potential derivatives might be they are difficult to metabolize to toxic metabolite N-deacetyllappaconitine compared to LA. The effects of lead compounds on sodium channels and hERG channels were also studied by ion channel reader (ICR) which further revealed their analgesic and toxicity-attenuating mechanisms. Sodium channel assay revealed that the analgesic mechanism of these lead compounds was inhibiting the Nav 1.7 channels. Taken together, compound 39 was provided as a new analgesic lead compound with significantly low toxicity and comparable activity to LA.

Zhou B., Tian D., An J., Zhou Y., Yan R., Song H., Liu X., Qin Y.

The discovery of a new Co-catalyzed hydrogen atom transfer (HAT) C(sp3)-C(sp2) bond cleavage method to access ketones from alkenes is reported. This unprecedented transformation features mild reaction conditions and good...

Chen S., Zhu Q., Cao Y., Li C., Guo Y., Kong L., Che J., Guo Z., Chen H., Zhang N., Fang X., Lu J., Luo T.

A new and general method to functionalize the C(sp3)-C(sp2) bond of alkyl and alkene linkages has been developed, leading to the dealkenylative generation of carbon-centered radicals that can be intercepted to undergo Ni-catalyzed C(sp3)-C(sp2) cross-coupling. This one-pot protocol leverages the easily procured alkene feedstocks for organic synthesis with excellent functional group compatibility without the need for a photoredox catalyst.

Wong A.R., Fastuca N.J., Mak V.W., Kerkovius J.K., Stevenson S.M., Reisman S.E.

The C19 diterpenoid alkaloids (C19 DTAs) are a large family of natural products, many of which modulate the activity of ion channels in vivo and are therefore of interest for the study of neurological and cardiovascular diseases. The complex architectures of these molecules continue to challenge the state-of-the art in chemical synthesis, particularly with respect to efficient assembly of their polcyclic ring systems. Here, we report the total syntheses of (-)-talatisamine, (-)-liljestrandisine, and (-)-liljestrandinine, three aconitine-type C19 DTAs, using a fragment coupling strategy. Key to this approach is a 1,2-addition/semipinacol rearrangement sequence which efficiently joins two complex fragments and sets an all-carbon quaternary center.

Yu K., Yao F., Zeng Q., Xie H., Ding H.

The first and asymmetric total syntheses of two C11-oxygenated hetisine-type diterpenoid alkaloids, namely, (+)-davisinol and (+)-18-benzoyldavisinol, is described. The concise synthetic approach features a HAT-initiated transannular redox radical cyclization, an ODI-Diels-Alder cycloaddition, and an acylative kinetic resolution. By incorporating an efficient late-stage assembly of the azabicycle, our strategy would streamline the synthetic design of C20-diterpenoid alkaloids and pave the way for their modular syntheses.

Yang Z., Tan Q., Jiang Y., Yang J., Su X., Qiao Z., Zhou W., He L., Qiu H., Zhang M.

Liu X., Wang F., Qin Y.

Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic chemists need to address lies in how to efficiently construct the polycyclic frameworks as well as to install the requisite substituent groups. The diterpenoid alkaloids that biogenetically originate from amination of diterpenes and diversify through late-stage skeletal reorganization belong to such a natural product category. As the characteristic components of the Aconitum and Delphinium species, these molecules display a rich array of biological activities, some of which are used as clinical drugs. More strikingly, their intricate and beautiful architectures have rendered the diterpenoid alkaloids elusive targets in the synthetic community. The successful preparation of these intriguing compounds relies on the development of innovative synthetic strategies.Our laboratory has explored the total synthesis of a variety of diterpenoid alkaloids and their biogenetically related diterpenes over the past decade. In doing so, we have accessed 6 different types of skeletons (atisine-, denudatine-, arcutane-, arcutine-, napelline-, and hetidine-type) and achieved the total synthesis of 6 natural products (isoazitine, dihydroajaconine, gymnandine, atropurpuran, arcutinine, and liangshanone). Strategically, an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence was widely employed in our synthesis to form the ubiquitous [2.2.2]-bicyclic ring unit and its related ring-distorted derivatives in these complex target molecules. This protocol, in combination with additional bond-forming key steps, allowed us to prepare the corresponding polycyclic alkaloids and a biogenetically associated diterpene. For example, bioinspired C-H activation, aza-pinacol, and aza-Prins cyclizations were used toward a unified approach to the atisine-, denudatine-, and hetidine-type alkaloids via ajaconine intermediates in our first work. To pursue the synthesis of atropurpuran and related arcutine alkaloids, we harnessed a ketyl-olefin radical cyclization to assemble the carbocycle and an aza-Wacker cyclization to construct the unusual pyrrolidine ring. Furthermore, a one-pot alkene cleavage/Mannich cyclization tactic, sequential Robinson annulation, and intramolecular aldol addition were developed, which facilitated the formation of the napelline alkaloid scaffold and the first total synthesis of liangshanone. Finally, the utility of the Mannich cyclization and enyne cycloisomerization reactions allowed for access to the highly functionalized A/E and C/D ring fragments of aconitine (regarded as the Holy Grail of diterpenoid alkaloids). This Account provides insight into our synthetic designs and approaches used toward the synthesis of diterpenoid alkaloids and relevant diterpenes. These endeavors lay a foundation for uncovering the biological profiles of associated molecules and also serve as a reference for preparing other three-dimensionally fascinating natural products.

Huang H., Mi F., Li C., He H., Wang F., Liu X., Qin Y.

The first total synthesis of liangshanone, a hexacyclic ent-kaurane diterpenoid alkaloid, has been completed. Its intricate cagelike framework was assembled through several key transformations, including an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence, a tandem alkene cleavage/Mannich cyclization, a Robinson-type annulation, and an intramolecular aldol reaction. Notably, an organocatalytic enantioselective α-hydroxymethylation process allowed the preparation of an enantiomerically enriched tricyclic intermediate that should enable asymmetric access to the target natural product.

Wang F., Chao R.

This review summarizes the process of the discovery, research, and development of a cardioactive component, mesaconine, from the lateral roots of Aconitum carmichaelii (“Fu Zi”). To date, pre-clinical showed that mesaconine is a novel type of cardiotonic lead drug with relatively high potency, low toxicity, and a new mechanism.

Zhang X., Shang Y., Gao F., Fang D., Li X., Zhou X.

As a nonaddictive analgesic widely used in clinics, the LD50 of bulleyaconitine A is just only 0.92 mg/kg, which exhibits obvious toxicity. Therefore, 31 new non-natural C19-diterpenoid alkaloids (2a-w, 2'a-e, 3, 4a, and 4b) were designed and synthesized from bulleyaconitine A to develop nonaddictive analgesics with low toxicity. The chemical structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) spectra. The analgesic activities were evaluated by a hot plate test in mice. At the dosage of 10 mg/kg, six compounds (2d, 2j, 2k, 2m, 2t, 2w) exhibited good analgesic activities (increased pain threshold >100%) with a long duration. Among them, 2w showed the best analgesic activity and the longest duration. Its pain threshold reached 166.35% in 15 min, peaked at 30 min (182.35%), and remained 82.59% even at 60 min.

Matheau-Raven D., Gabriel P., Leitch J.A., Almehmadi Y.A., Yamazaki K., Dixon D.J.

The tertiary amide is a ubiquitous functional group and plays an irreplaceable role in medicinal chemistry. Its robust nature has meant—in the past—that selective manipulation of this motif remaine...

Meng Z., Mi F., Lu F., Tan W., Liu X., Qin Y.

A synthetic study toward the structurally complex rearranged-type C19-diterpenoid alkaloids leading to construction of the strained 6/3/5/6 tetracyclic core is presented. The synthesis features an intramolecular Diels–Alder cycloaddition reaction to assemble the highly substituted central cyclopropane motif, which may serve as a key strategy for the total synthesis of relevant natural product molecules.

Pang L., Liu C., Gong G., Quan Z.

Lappaconitine (LA), a natural compound with a novel C18-diterpenoid alkaloid skeleton, displayed extensive biological profile. Recent research on LA is focused mainly on its anti-tumor and analgesic effects, and therefore we aimed to investigate its anti-inflammatory potential. A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized. In the initial screening of LA derivatives against NO production, all the target compounds, except compound E2, exhibited excellent inhibitory ability relative to that of LA. Particularly, compound A4 exhibited the most potent inhibition with IC50 of 12.91 μmol/L. The elementary structure-activity relationships (SARs) of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy. Furthermore, compound A4 shows an anti-inflammatory mechanism by inhibiting NO, PGE2, and TNF-α generation via the suppression of NF-κB and MAPK signaling pathways. Notably, compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury (ALI) in vivo. Based on the above research, we further investigated the preliminary pharmacokinetic property of A4 in rats. Therefore, compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.

Wein L.A., Wurst K., Angyal P., Weisheit L., Magauer T.

We present a bioinspired late-stage C–H oxidation of the ent-trachylobane natural product mitrephorone B to mitrephorone A. The realization of this unprecedented transformation was accomplished by either an iron-catalyzed or electrochemical oxidation and enabled access to the densely substituted oxetane in one step. Formation of mitrephorone C, which is lacking the central oxetane unit but features a keto-function at C2, was not formed under these conditions.

Li X., Fang Y., Zhao Y., Luo S., Xue Y., Yong T., Wang B.

Metal-free radical cascade synthesis of substituted pyrazole derivatives was initiated by PhI(OAc)2 at 23 °C.

Li Q.-., Kang Y.-., Tang Y.

Gao Z., Wang H., Su A., Li Q., Liang Z., Zhang Y., Liu X., Zhu M., Zhang H., Hou Y., Li X., Sun L., Li J., Xu Z., Lou H.

Yu F., Xu L.

A Pd-catalyzed transannular alkenylation synthetic strategy for construction of the BCDF tetracyclic ring system of biologically active aconitine-type C19-diterpenoid alkaloids was successfully developed.

Narra R.R., Unnithan V.G., Liu Y., Guo Z.

AbstractDivergent nitrogen‐containing fused polycyclic ring systems are constructed from simple starting materials via a one‐pot aldehyde‐alkyne‐amine (A3) coupling and intramolecular Diels‐Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa‐bridged fused 5/5 bicycle and a 1,6‐enyne substructure. One‐step derivation of the oxa‐bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back‐to‐back to pyrroline or a 6/5 bicycle with the hexahydro‐1H‐isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5‐membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one‐pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity‐oriented synthetic approach thus allows rapid access to an under‐explored structural space for discovery of new biological or non‐biological activities or functions.

Yang Z., Rao H., Yin Y., Mu S., Jia Z., Ding H.

Lu F., Shao Y., Yan S., Yang D., Song H., Zhang D., Liu X., Qin Y.

Zhang Y., Shi S., Yang Z.

Asai H., Hagiwara K., Inoue M.

Talatisamine [(–)-1] is a C19-diterpenoid alkaloid with an intricately fused ABCDEF-ring system. In 2020, we reported a total synthesis of racemic talatisamine [(±)-1], in which AE-ring fragment (±)-5-α/5-β was utilized as the pivotal early-stage intermediate. Herein, we disclose the development of an enantioselective route to (–)-5-β for the total synthesis of (–)-1. Enantioselective intermolecular Mannich, Lewis acid-mediated intramolecular Mannich, and reductive N-ethylation reactions were employed as the three key transformations.

Li C., Lu F., Cai Y., Zhang C., Shao Y., Zhang Y., Liu X., Qin Y.

Tanaka F.

Mannich reactions are reactions of enolizable carbonyl compounds as nucleophiles with imines or iminium ions as electrophiles that afford β-amino carbonyl derivatives. Catalytic enantioselective Mannich reactions, including regioselective and/or diastereoselective versions of the reactions, have been achieved using various types of catalysts including metal-containing catalysts and organocatalysts. Depending on the reactant structures and the catalysts used, the Mannich reactions allow the stereocontrolled synthesis of β-amino carbonyl derivatives and related derivatives such as α,β-diamino acid derivatives, α-hydroxy-β-amino acid derivatives, and amino alcohols. This chapter reviews recent advances in these Mannich reactions.

Rocq C., Denis M., Canesi S.

Hypervalent iodine reagents are among the most fascinating reagents described in the last 30 years since they allow a plethora of different transformations and are environmentally friendly compounds that avoid...