石川 勇人

There are many indole alkaloids that contain diverse functional groups attached to the benzene ring on the indole core. Promising biological activities of these alkaloids have been reported. Herein, we report the indole C5-selective bromination of indolo[2,3-a]quinolizidine alkaloids by adding nearly equimolar amounts of Br3·PyH and HCl in MeOH. The resulting reaction plausibly proceeds through an indoline intermediate by the nucleophilic addition of MeOH to the C3-brominated indolenine intermediate. Data support the intermediacy of a C3-, C5-dibrominated indolenine intermediate as a brominating agent. These conditions demonstrate excellent selectivity for indole C5 bromination of natural products and their derivatives. Thus, these simple, mild, and metal-free conditions allow for selective, late-stage bromination followed by further chemical modifications. The utility of the brominated product prepared from naturally occurring yohimbine was demonstrated through various derivatizations, including a bioinspired heterodimerization reaction.

The first enantioselective total synthesis of kopsiyunnanine B, which has a unique folded and complex pentacyclic structure containing six contiguous chiral centers, has been achieved along our originally proposed biosynthetic pathway. The key reaction of this synthesis includes a bioinspired cascade that builds three ring structures and three chiral centers in one step and features the stereoselective reduction of a β-acrylate and oxidation to an oxindole.

The aggregation of amyloid-β (Aβ) remains the most acceptable pathological hallmark of Alzheimer's disease (AD). In search for natural products exhibiting anti-amyloidogenic effects, phytochemical analyses were conducted on Uncaria lanosa f. philippinensis leading to the purification of oxindole alkaloid uncarine E (isopteropodine) (1), the phenylethanoid tyrosol (2), the megastigmane vomifoliol (3), and the previously reported alkaloids mitraphylline and isomitraphylline. This is the first report of compounds 1-3 in the title plant, and tyrosol (2) from the genus Uncaria. Assessment of the anti-amyloidogenic potential using Thioflavin T assay showed 91% (at 50 µM) and 70% (at 25 µM) inhibitions for compound 1. Tyrosol (2) gave 76% (at 50 µM) and 63% (at 25 µM) inhibitions. These compounds may be further tested to elucidate their mechanism in the prevention of Aβ aggregation. To the best of our knowledge, this is the first report on the anti-amyloid aggregation activity of compounds 1 and 2.

The enantioselective total syntheses of (-)-silicine and (-)-20-episilicine, which contain a chiral piperidine with three contiguous chiral centers (D-ring) and a strained seven-membered ring (C-ring) attached to an indole, were achieved. The key steps of these syntheses included a chiral secondary amine-catalyzed formal aza-[3 + 3] cycloaddition reaction and Lewis acid-mediated irreversible ring-closing reaction. In addition, the stereochemistry at C20 was controlled at a later stage in the syntheses.