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Camptothecin-like compounds are actively employed as anticancer drugs in clinical treatments. The aromathecin family of compounds, which contains the same indazolidine core structure as the camptothecin family of compounds, is also expected to display promising anticancer activity. Therefore, the development of a suitable and scalable synthetic method of aromathecin synthesis is of great research interest. In this study, we report the development of a new synthetic approach for constructing the pentacyclic scaffold of the aromathecin family by forming the indolizidine moiety after synthesizing the isoquinolone moiety. Thermal cyclization of 2-alkynylbenzaldehyde oxime to the isoquinoline N-oxide, followed by a Reissert–Henze-type reaction, forms the key strategy in this isoquinolone synthesis. Under the optimum reaction conditions for the Reissert–Henze-type reaction step, microwave irradiation-assisted heating of the purified N-oxide in acetic anhydride at 50 °C reduced the formation of the 4-acetoxyisoquinoline byproduct to deliver the desired isoquinolone at a 73% yield after just 3.5 h. The eight-step sequence employed afforded rosettacin (simplest member of the aromathecin family) at a 23.8% overall yield. The synthesis of rosettacin analogs was achieved by applying the developed strategy and may be generally applicable to the production of other fused indolizidine compounds.

A shorter synthesis of the demethyl(oxy)aaptamine skeleton was developed via oxidative intramolecular cyclization of 1-(2-azidoethyl)-6-methoxyisoquinolin-7-ol followed by dehydrogenation with a hypervalent iodine reagent. This is the first example of oxidative cyclization at the ortho-position of phenol that does not involve spiro-cyclization, resulting in the improved total synthesis of 3-(phenethylamino)demethyl(oxy)aaptamine, a potent anti-dormant mycobacterial agent.

The first total synthesis of loroxanthin (1) was accomplished by Horner-Wadsworth-Emmons reaction of C25-apocarotenal 8 having a silyl-protected 19-hydroxy moiety with C15-phosphonate 25 bearing a silyl-protected 3-hydroxy-ε-end group. Preparation of apocarotenal 8 was achieved via Stille coupling reaction of alkenyl iodide 10 with alkenyl stananne 9, whereas phosphonate 25 was prepared through treatment of ally alcohol 23 with triethyl phosphite and ZnI2. The ally alcohol 23 was derived from the known (3R,6R)-3-hydroxy C15-aldehyde 20, which was obtained by direct optical resolution of racemate 20 using a semi-preparative chiral HPLC column.

The total synthesis of multifidene, a sex pheromone found in brown algae, is described. The synthesis features the highly enantioselective and diastereoselective addition reaction of an aldehyde to a nitroolefin in the presence of a Hayashi–Jørgensen catalyst and a Nef reaction initiated by visible light irradiation. These key reactions enabled the 11-step synthesis from commercially available compounds. The synthetic pheromones are examined with gametes.

An asymmetric Claisen rearrangement using Oppolzer’s camphorsultam was developed. Under thermal conditions, a geraniol-derived substrate underwent the rearrangement with good stereoselectivity. The absolute configuration of the newly formed all-carbon quaternary stereocenter was confirmed by the total synthesis of (+)-bakuchiol from the rearrangement product.

Nostosins A and B were isolated from a hydrophilic extract of Nostoc sp. strain from Iran, which exhibits excellent tryps inhibitory activity. Nostosin A was the most potent natural tripeptide aldehyde as trypsin inhibitor up to now. Both R‐ and S‐2‐hydroxy‐4‐(4‐hydroxy‐phenyl) butanoic acid (Hhpba) were prepared and incorporated into the total synthesis of nostosin B, respectively. Careful comparison of the NMR spectra and optical rotation data of synthetic nostosin B (1a and 1b) with the natural product led to the unambiguous identification of the R‐configuration of the Hhpba fragment, which was further confirmed by co‐injection with the authentic sample on HPLC using both reversed phase column and the chiral AD‐RH column.

The development of a novel cyclic glucosyl ceramide cassette acceptor for efficient glycolipid syntheses was investigated. p-Methoxybenzyl (PMB) groups were selected as protecting groups at C2 and C3 of the glucose residue with the aim of improving the functionality of the cassette acceptor. The choice of the PMB group resulted in a loss of β-selectivity, which was corrected by using an appropriate tether to control the spatial arrangement and the nitrile solvent effect. To investigate the effect of linker structure on the β-selectivity of intramolecular glycosylation, several linkers for tethering the glucose and ceramide moiety were designed and prepared, namely, succinyl, glutaryl, dimethylmalonyl, and phthaloyl esters. The succinyl ester linker was the best for accessing the cassette form. The newly designed glucosyl ceramide cassette acceptor was then applied in the total synthesis of ganglioside GalNAc-GM1b.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquidmalignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin–GB1 complex.

A unified synthetic route for the total syntheses of eribulin and a macrolactam analog of halichondrin B is described. The key to the success of the current synthetic approach includes the employment of our reverse approach for the construction of cyclic ether structural motifs and a modified intramolecular cyclization reaction between alkyl iodide and aldehyde functionalities to establish the all-carbon macrocyclic framework of eribulin. These syntheses, together with our previous work on the total syntheses of halichondrin B and norhalichondrin B, demonstrate and validate the powerful reverse approach in the construction of cyclic ether structural motifs. On the other hand, the unified synthetic strategy for the synthesis of the related macrolactam analog provides inspiration and opportunities in the halichondrin field and related polycyclic ether areas.

A simple electrochemically mediated method for the conversion of alkyl carboxylic acids to their borylated congeners is presented. This protocol features an undivided cell setup with inexpensive carbon-based electrodes and exhibits a broad substrate scope and scalability in both flow and batch reactors. The use of this method in challenging contexts is exemplified with a modular formal synthesis of jawsamycin, a natural product harboring five cyclopropane rings.