Tetsuaki Tanaka

Medicinal Chemistry of Annonaceous Acetogenins: Design, Synthesis, and Biological Evaluation of Novel Analogues

Most Annonaceous acetogenins are characterized by between one and three THF ring(s) with one or two flanking hydroxyl group(s) in the center of a C32/34 fatty acid, and the terminal carboxylic acid is combined with a 2-propanol unit to form an α,β-unsaturated γ-lactone. While many studies have addressed the properties and synthesis of natural acetogenins due to their attractive biological activities and unique structural features, a number of analogues have also been described. This review covers the design, synthesis, and biological evaluation of acetogenin analogues.

Total synthesis of (-)-agelastatin A

A new route to (-)-agelastatin A is reported. The requisite nitrogen functionalities of the agelastatin core have been installed by intramolecular aziridination of an azidoformate and subsequent regioselective azidation, leading to net trans-diamination of the double bond. The present synthesis also demonstrates two new protocols for the preparation of an imidazolidinone hemiaminal motif from an oxazolidinone intermediate which comprise sequential N-tert-butoxycarbonylation, urea formation, hydrolysis, and oxidative cyclization, and direct aminolysis and subsequent oxidative cyclization.

Asymmetric Total Synthesis of (+)-Hexachlorosulfolipid, a Cytotoxin Isolated from Adriatic Mussels

The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph(3)P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.

Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon Motifs: A Nucleophilic Multiple Chlorination Process Revisited

Polychlorinated hydrocarbon motifs have been synthesized in enantiomerically pure forms by means of nucleophilic multiple chlorinations of chiral epoxides, which stereospecifically incorporate halogen atoms into oxygenated molecular scaffolds. The present study demonstrates the scope of the N-chlorosuccinimide (NCS)/organophosphine reagent system that forms multiple sp(3)C-Cl bonds in a regularly repeating pattern with proper stereochemical configurations and evaluates its applicability to various epoxides having elaborate structures. It is noteworthy that tetrachlorinated motifs are produced in one step from bisepoxides by using NCS/Ph(3)P. Furthermore, Ph(2)PCl used in combination with NCS has been found to serve as a potentially useful alternative to NCS/Ph(3)P, especially for promoting dichlorination reactions of alkenyl-substituted epoxides.

Samarium(II)-Mediated Spirocyclization by Intramolecular Aryl Radical Addition onto an Aromatic Ring

Samarium(II)-mediated spirocyclization by intramolecular addition of aryl radicals onto an aromatic ring was achieved by the reaction of N-(2-iodophenyl)-N-alkylbenzamides with SmI2 in the presence of HMPA, yielding spirocyclic indolin-2-one derivatives. The ether congeners afford spirocyclic benzofuran derivatives in moderate yields by aryl radical addition onto a benzene ring without having an electron-withdrawing group. The reaction with other aryl groups such as naphthalene and indole rings is also described.

Total Synthesis of (±)-Platencin

A novel route to (±)-platencin is reported, in which the highly stereoselective alkylative quaternization of a cyclohexenone scaffold via 1,4-diastereoinduction and two radical carbon-carbon bond-forming reactions that involve titanium(III)-mediated cyclization and stannyl-radical-mediated skeletal rearrangement are utilized.

Total Synthesis of the β-Catenin Inhibitor, (−)-Agelastatin A: A Second-Generation Approach Based on Radical Aminobromination

The second-generation approach to (-)-agelastatin A has been established. The present strategy features the FeBr(2)-mediated radical cyclization of 2-cyclopentenyloxycarbonyl azide that allows for the stereoselective installation of a cis-vicinal aminobromo functionality suitable for producing the BCD-ring system of agelastatin A. The aminobromination method streamlines access to oxazolidinone, a key intermediate in the previously reported synthesis, thereby culminating in the new total synthesis of (-)-agelastatin A.

Total Synthesis of (±)-Kainic Acid: A Photochemical C–H Carbamoylation Approach

A novel photochemical C-H carbamoylation of an octahydroisoindole derivative with PhNCO has allowed the authors to provide a unique access to a highly functionalized proline motif from which total synthesis of (±)-kainic acid, a bioactive marine alkaloid, has been accomplished.

Synthesis of hybrid acetogenins, α,β-unsaturated-γ-lactone-free nitrogen-containing heterocyclic analogues, and their cytotoxicity against human cancer cell lines

A series of alpha,beta-unsaturated-gamma-lactone-free nitrogen-containing heterocyclic analogues of solamin, a natural mono-THF acetogenin, have been synthesized and their cytotoxicity was investigated against 39 tumor cell lines. One of them, 1-methylpyrazol-5-yl derivative, showed selective increase of cytotoxicity against NCI-H23 with 80 times higher potency than solamin.

Direct construction of bicyclic heterocycles by palladium-catalyzed domino cyclization of propargyl bromides.

The palladium-catalyzed domino cyclization of propargyl bromides having two nucleophilic functional groups is described. Treatment of 1,7-diamino-5-bromohept-3-yne derivatives with catalytic Pd(PPh3)4 in the presence of NaH in MeOH gives the 2,7-diazabicyclo[4.3.0]non-5-enes in good yields. Interestingly, the regioselectivity of the reaction is completely controlled by the relative reactivity of the amine functional groups, irrespective of the position of the nucleophiles. The malonate derivative also undergoes domino cyclization to produce a hexahydroindole derivative.