Strategies for the Construction of Benzobicyclo[3.2.1]octane in Natural Product Synthesis.

Benzobicyclo[3.2.1]octane is a cage-like unique motif containing a bicyclo[3.2.1]octane structure fused with at least one benzene ring. It is found in various natural products that exhibit structural complexities and important biological activities. The total synthesis of natural products possessing this challenging structure has received considerable attention, and great advances have been made in this field during the past 15 years. This review summarizes thus far achieved chemical syntheses and synthetic studies of natural compounds featuring the benzobicyclo[3.2.1]octane core. It focuses on strategic approaches constructing the bridged structure, aiming to provide a useful reference for inspiring further advancements in strategies and total syntheses of natural products with such a framework.

Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine.

Pynegabine, an antiepileptic drug candidate in phase I clinical trials, is a structural analog of the marketed drug retigabine with improved chemical stability, strong efficacy, and a better safety margin. The reported shortest synthetic route for pynegabine contains six steps and involves the manipulation of highly toxic methyl chloroformate and dangerous hydrogen gas. To improve the feasibility of drug production, we developed a concise, three-step process using unconventional methoxycarbonylation and highly efficient Buchwald-Hartwig cross coupling. The new synthetic route generated pynegabine at the decagram scale without column chromatographic purification and avoided the dangerous manipulation of hazardous reagents.

Asymmetric Total Synthesis of Naphthospironone A.

Naphthospironone A, a polyhydroxy cagelike bioactive natural product, was synthesised for the first time in this study. The spiro[bicyclo[3.2.1]octane-pyran] core was constructed by an acid-promoted epoxide-opening lactonisation and a base-induced intramolecular aldol-type cyclisation.

Strategies and Efforts towards the Total Synthesis of Palhinine Alkaloids.

The palhinine family of Lycopodium alkaloids were first reported in 2010, which feature an intriguing isotwistane carbon cage and a nine-membered azonane ring. It is noteworthy that the tetracyclic 5/6/6/9 skeleton was unprecedented in Lycopodium alkaloids before their seminal discovery. Over the past decade, extensive synthetic efforts stemming from seven research groups have resulted in two racemic total syntheses to date. This review article takes the opportunity to survey these efforts and achievements so as to promote further research towards the asymmetric total synthesis of palhinine alkaloids.

Toward the total synthesis of grayanane diterpene mollanol A by a Prins [3 + 2] strategy.

Toward the total synthesis of a novel grayanoid, mollanol A, we developed a concise convergent strategy based on a formal [3 + 2] cyclization initiated by the Prins reaction. In this key intermolecular reaction between an unprotected hydroxyaldehyde and activating-group-free olefins, two chiral carbons and one densely substituted tetrahydrofuran ring were constructed stereoselectively.

K2S2O8-mediated radical cyclisation of 2-alkynylthioanisoles or -selenoanisoles: a green and regioselective route to 3-nitrobenzothiophenes and benzoselenophenes.

An acid, transition-metal, and chromatography-free radical nitration/cyclisation of 2-alkynylthioanisoles or -selenoanisoles has been developed. This is the first example of the use of highly unstable 2-nitrovinyl radicals for C-S bond formation. This facile route efficiently produces 3-nitrobenzothiophenes and benzoselenophenes, which are difficult to access via classical methods. Density functional theory (DFT) calculations were carried out to probe the reaction mechanism. The resulting products were tested for their in vitro anti-tuberculosis activity, and compounds 2d and 2l showed significant activities against sensitive and drug-resistant strains.

Synthesis of the Tricyclic Caged Core of Palhinine Alkaloids Based on a Non-Diels-Alder-Type Strategy.

A concise synthesis of the tricyclo[4.3.1.03,7]decane caged core of palhinine alkaloids was developed with SmI2-mediated cyclization and light-initiated radical addition-fragmentation as key steps. Compared with the reported racemic routes which are all based on Diels-Alder-type key reactions, our strategy would be more readily accessible to the asymmetric total syntheses of the palhinine alkaloids.

Combination of PhI(OAc)2 and 2-Nitropropane as the Source of Methyl Radical in Room-Temperature Metal-Free Oxidative Decarboxylation/Cyclization: Construction of 6-Methyl Phenanthridines and 1-Methyl Isoquinolines.

A room-temperature metal-free method for generating highly unstable methyl radical was realized from the combination of PhI(OAc)2 and 2-nitropropane, which provides an efficient approach to methylated phenanthridines and isoquinolines. The strategy was also extended to the generation of other alkyl radicals and a concise synthesis of Roxadustat.

Separation of Alkyne Enantiomers by Chiral Column HPLC Analysis of Their Cobalt-Complexes.

Separation of the enantiomers of new chiral alkynes in strategic syntheses and bioorthogonal studies is always problematic. The chiral column high-performance liquid chromatography (HPLC) method in general could not be directly used to resolve such substrates, since the differentiation of the alkyne segment with the other alkane/alkene segment is not significant in the stationary phase, and the alkyne group is not a good UV chromophore. Usually, a pre-column derivatization reaction with a tedious workup procedure is needed. Making use of easily-prepared stable alkyne-cobalt-complexes, we developed a simple and general method by analyzing the in situ generated cobalt-complex of chiral alkynes using chiral column HPLC. This new method is especially suitable for the alkynes without chromophores and other derivable groups.

Transition Metal-Free Oxidative Radical Decarboxylation/Cyclization for the Construction of 6-Alkyl/Aryl Phenanthridines.

A radical cascade decarboxylation/cyclization of 2-isocyanobiphenyls with aliphatic carboxylic acids as well as aromatic carboxylic acids under the transition metal-free conditions was reported. This process, which included formation of two new C-C bonds and cleavage of C-COOH bonds, afforded a novel and environmentally friendly approach to producing 6-alkyl/aryl phenanthridines with moderate to good yields.

Benzimidazole-based compounds kill Mycobacterium tuberculosis.

Tuberculosis remains one of the deadliest infectious diseases, killing 1.4 million people annually and showing a rapid increase in cases resistant to multiple drugs. New antibiotics against tuberculosis are urgently needed. Here we describe the design, synthesis and structure-activity relationships of a series of benzimidazole-based compounds with activity against Mycobacterium tuberculosis (Mtb) in a replicating state, a physiologically-induced non-replicating state, or both. Compounds 49, 67, 68, 69, 70, and 72, which shared a 5-nitrofuranyl moiety, exhibited high potency and acceptable selectivity indices (SI). As illustrated by compound 70 (MIC90 < 0.049 µg/mL, SI > 512), the 5-nitrofuranyl group was compatible with minimal cytotoxicity and good intra-macrophage killing, although it lacked non-replicating activity when assessed by CFU assays. Compound 70 had low mutagenic potential by SOS Chromotest assay, making this class of compounds good candidates for further evaluation and target identification.

2-(Ethyl-sulfin-yl)imidazo[1,2-a]pyridine-3-sulfonamide.

The supra-molecular structure of the title compound, C(9)H(11)N(3)O(3)S(2), is defined by two inter-molecular hydrogen bonds. Pairs of N-H⋯N hydrogen bonds link the mol-ecules into centrosymmetric dimers and N-H⋯O hydrogen bonds link the dimers into a tubular chain structure running parallel to the a axis.