Hiroshi Kogen

A unified synthesis of (+)-rubrobramide, (+)-talaramide A, and (−)-berkeleyamide D was achieved from the vinylogous esters by a skeletal diversification strategy based on regioselective 5- exo or 6- endo cyclization.

Ticagrelor is an oral antiplatelet agent that has been approved for preventing de novo and recurrent acute coronary syndrome. To date, only a few studies have attempted to clarify population differences in the pharmacokinetics and pharmacodynamics of ticagrelor between Caucasians and Asians. Our aim was to develop a simple quantification method for ticagrelor and its pharmacologically active metabolite M8 (AR-C124910XX) in human plasma and urine. First, we concisely synthesized M8 from ticagrelor via a five-step sequence: the hydroxyethyl group of ticagrelor was removed by bromination and subsequent zinc-mediated chemoselective reduction. Then, we developed a simple liquid chromatography–mass spectrometry method using ticlopidine as an internal standard. Ticagrelor, M8, and internal standard were separated with a reverse-phase C₁₈ column, and ticagrelor and M8 were detected at m/ z [+] of 523.25 and 479.25, respectively, with good sensitivity and precision in the concentration ranges of 10 to 100 µM and 5 to 50 µM, respectively. This novel liquid chromatography–mass spectrometry system may be attractive to investigators in private laboratories because it is less costly than liquid chromatography/mass spectrometry/mass spectrometry systems. Our method is expected to accelerate further clinical studies on the disposition and pharmacodynamics of ticagrelor.

Paraphaeosphaeride C is a demethoxy derivative of phaeosphaeride A and exhibits STAT3 inhibitory activity. Our previous papers reported the total synthesis of phaeosphaeride A using a diastereoselective vinyl anion aldol reaction as the key step to construct the dihydropyran ring. In this work, the first total synthesis of the proposed structure of paraphaeosphaeride C was achieved via a similar synthetic strategy. The synthetic compound was characterized through extensive nuclear magnetic resonance (NMR) analysis but the ¹H and ¹³C-NMR data for this compound did not correspond to those reported in the literature for paraphaeosphaeride C.

A catalytic asymmetric intramolecular Darzens reaction of 2-halomalonate derivatives was developed for the enantioselective preparation of chiral building blocks for epoxide-containing natural products. Among the screened catalysts, some phase-transfer catalysts gave the desired epoxide in moderate enantioselectivity, albeit in low yield. The epoxide product would be useful as versatile chiral building blocks for natural product synthesis.

Epothilone D, a microtubule-stabilizing macrolide, is an attractive synthetic target molecule as a potential anti-cancer drug candidate. As part of our ongoing synthetic studies of this natural product, this paper describes the synthesis of the thiazole-containing northern segment of epothilone D via an E-selective bromomethylenation and a Ni/Cr-mediated cross-coupling reaction.

The first total synthesis of C3- and C9-oxidized ent-longipinane-type sesquiterpenoids containing acetoxymarsupellone, marsupellins A and B, has been accomplished. This unique core common to C3- and C9-oxidized ent-longipinane-type sesquiterpenoids was constructed via a new intramolecular reductive cyclization reaction of an epoxycyanohydrin derivative using Cp₂TiI.

(−)-L-755,807, which was isolated from an endophytic fungus, Microsphaeropsis sp., consists of a characteristic epoxy-γ-lactam ring and a tetraene-containing side chain, and exhibits bradykinin B2 receptor antagonist activity. The first total synthesis of (−)-L-755,807 was accomplished through a convergent approach, employing a late-stage coupling between the ring and side-chain segments. The ring segment was efficiently synthesized by a novel syn-selective Darzens reaction between di-tert-butyl bromomalonate and α-alkoxy aldehyde, and the side-chain segment was prepared by a highly stereoselective Horner-Wadsworth-Emmons reaction as a key step to construct the tetraene part. This synthesis enabled us to assign the relative and absolute configurations of (−)-L-755,807. Furthermore, we discovered an additional biological activity of this compound, namely, potent amyloid β aggregation inhibitory activity, which could be useful in the treatment of Alzheimer’s disease. The epoxy-γ-lactam moiety was identified as a likely pharmacophore for this activity. In this article, we describe the total synthesis, stereochemical assignment, and biological evaluation of (−)-L-755,807.