Total Synthetic Approaches Research Articles

The isolation, bioactivity, and synthesis of natural products from Litsea verticillate with anti-HIV activities

Natural products isolated from Litsea verticillata have attracted considerable attention from the chemical community due to their unique structures and promising anti-HIV activities. Recent progresses in the isolation and bioactivity studies for these natural molecules were summarized comprehensively. From the 23 previously uncharacterized compounds isolated from the plant Litsea verticillata, litseaverticillol B demonstrated the most potent anti-HIV activity in vitro, with IC50 ranging from 2 to 3 μg/mL. Meanwhile, litseaverticillol E displayed the highest selectivity index (SI = 3.1), indicating a favorable balance between antiviral potency and cellular toxicity. The plausible biosynthetic pathways and the total synthetic approaches for the representative members (litseaverticillols) were introduced in detail.

Biomimetic total synthesis of (-)-galanthamine via intramolecular anodic aryl-phenol coupling.

(-)-Galanthamine as a drug for the treatment of Alzheimer's disease has attracted synthetic chemists for decades. However, previous total synthetic and biomimetic approaches often use stoichiometric oxidants (metal oxidants or hypervalent iodine) to prepare the target product. Anodic oxidative coupling offers a sustainable alternative method which is, for the first time, successfully applied to the total synthesis of (-)-galanthamine. We report a new asymmetric total synthesis of (-)-galanthamine by using an anodic aryl-phenol coupling as the key synthetic step.

Direct enantioselective synthesis of pyrrolizidines

Stereoselective synthesis of natural and unnatural compounds containing the pyrrolizidine skeleton is of immense interest to synthetic organic chemists due to their enormous biological importance. In addition to the numerous total synthetic approaches, the development of direct synthetic strategies for the enantioselective preparation of pyrrolizidines has shown rapid progress in the last decade. The 1,3-dipolar cycloaddition reaction of a dipole and a dipolarophile has been found to be the most useful tool for the direct asymmetric synthesis of pyrrolizidines, and Michael addition followed by cyclisation is implicated for the preparation of pyrrolizidinones. In this digest review, we discuss the direct approaches for the preparation of optically active pyrrolizidines and pyrrolizidinones.

Fused Dibenzo[a,m]rubicene: A New Bowl-Shaped Subunit of C70 Containing Two Pentagons.

Total synthetic approaches of fullerenes are the holy grail for organic chemistry. So far, the main attempts have focused on the synthesis of the buckminsterfullerene C60. In contrast, access to subunits of the homologue C70 remains challenging. Here, we demonstrate an efficient bottom-up strategy toward a novel bowl-shaped polycyclic aromatic hydrocarbons (PAH) C34 with two pentagons. This PAH represents a subunit for C70 and of other higher fullerenes. The bowl-shaped structure was unambiguously determined by X-ray crystallography. A bowl-to-bowl inversion for a C70 fragment in solution was investigated by dynamic NMR analysis, showing a bowl-to-bowl inversion energy (ΔG(⧧)) of 16.7 kcal mol(-1), which is further corroborated by DFT calculations.

The Echinocandins: Total and Semi-Synthetic Approaches in Antifungal Drug Discovery

The echinocandins are a new class of antifungal lipopeptides for the treatment of serious nosocomial mycoses. The three currently approved drugs, caspofungin, micafungin, and anidulafungin, were each discovered through the syn- thetic modification of echinocandin natural products obtained from fermentation. This review is intended for the medici- nal chemist who is actively pursuing or has a general interest in the synthetic modification of natural products as a means to identify drug candidates. It provides a survey of the synthetic strategies that produced the approved echinocandin thera- peutics and a discussion of more recent efforts to identify a new generation of echinocandin drug candidates. Both total synthetic approaches starting from the constituent amino acids and semi-synthetic approaches relying on fermentation- produced lipopeptide are addressed. These various efforts by chemists from industry and academia have not only illumi- nated the interesting chemistry of these natural products, but have provided the means by which improvements in antifun- gal potency and spectrum, pharmacokinetic profile, solubility, stability, and safety can be realized. The ultimate success of these efforts can be judged by considering the important role the echinocandins are already playing in the treatment of se- rious fungal infection.

Galanthamine, a Natural Product for the Treatment of Alzheimers Disease

(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis. In addition, galanthamine had since been tested for use in anesthesiology, from facial nerve paralysis to schizophrenia. Galanthamine is a long-acting, selective, reversible and competitive AChE inhibitor that has recently been tested in AD patients and found to be readily absorbed, to be a performance enhancer on memory tests in some patients, and to be well tolerated, although some cholinergic side effects were observed. A number of total synthetic approaches have been reported, and a method for the industrial scale-up preparation of galanthamine is now being developed and patented. A variety of galanthamine derivatives have also been synthesized aiming to develop an agent free from cholinergic adverse effects. Galanthamine is a natural product that complements other synthetic drugs for the management of AD. In this account we will review the recent patent literature showing the most important advance on the chemistry of galanthamine.

The cryptophycins: Their synthesis and anticancer activity

The cryptophycins are a unique family of 16-membered macrolide antimitotic agents isolated from the cyanobacteria Nostoc sp. Their molecular target is tubulin protein wherein they are the most potent known stabilizers of microtubule dynamics and depolymerize microtubules at higher concentrations. They also deactivate the Bcl2 protein and produce apoptotic response much more quickly and at considerably lower concentrations than clinically utilized compounds. The presence of several amide and ester linkages within the cryptophycin core provides access to very convergent total synthetic approaches. Likewise, the modularity of the structure renders their synthesis amenable to structure-activity studies in several regions of the molecule. The in vivo hydrolytic instability of the C5 ester was a key obstacle to the successful identification of a clinical candidate. This problem was ameliorated by increased substitution at C6 as in the presence of gem-dimethyl substitution in the clinical candidate, cryptophycin-52.

The total synthesis of ganglioside GM3

Previous syntheses of ganglioside GM3 (NeuAcα3Galβ4Glcβ1Cer) are reviewed, and both chemoenzymatic and chemical total synthetic approaches were investigated. In a chemoenzymatic approach, (2 S,3 R,4 E)-5‴-acetyl-α-neuraminyl-(2‴→3″)-β-galactopyranosyl-(1″→4′)-β-glucopyranosyl-(1′↔1)-2-azido-4-octadecene-1,3-diol (azidoGM3) was readily prepared utilizing recombinant β-Gal-(1″→3′/4′)-GlcNAc α-(2‴→3″)-sialyltransferase enzyme, and was evaluated as a synthetic intermediate to ganglioside GM3. The chemical total synthesis of ganglioside GM3 was performed on one of the largest scales yet reported. The highlights of this synthesis include minimizing the steps necessary to prepare the lactosyl acceptor as a useful anomeric mixture, which was present in excess for the highly regioselective and fairly stereoselective sialylation with a known neuraminyl donor to give the protected GM3 trisaccharide. The synthetic methodology maximized convergence by a subsequent glycosidic coupling of the well-characterized GM3 trisaccharide trichloroacetimidate derivative with protected ceramide. The ganglioside GM3 was nearly homogeneous as the two glycosidic couplings utilized preparative HLPC purifications, and variations in the sphingosine base and fatty acyl group were under 0.1 and 0.2%, respectively.