Total Synthesis of (-)-Sigillin A: A Polychlorinated and Polyoxygenated Natural Product

The total synthesis of (−)-sigillin A, a highly chlorinated and oxygenated octahydroisocoumarin, is described herein. A hexahydroisocoumarin skeleton was constructed from (R)-4-(trichloromethyl)oxetan-2-one in seven steps. Its unique manganese oxidation provided an enone as the key intermediate of sigillin A. Stereoselective installation of two hydroxy groups and formation of gem-dichloroalkene from the corresponding ketone led to the total synthesis of (−)-sigillin A in a total of 16 steps

Synthesis of Polycyclic Spirocarbocycles via Acid-Promoted Ring-Contraction/Dearomative Ring-Closure Cascade of Oxapropellanes

We report herein the development of an acid-promoted rearrangement of oxa[4.3.2]propellanes to afford polyaromatic-fused spiro[4.5]carbocycles. DFT calculations suggest that the reaction pathway involves generation of a cyclobutyl cation, ring contraction to the cyclopropylcarbinyl cation, and dearomative ring closure by an internal 2-naphthol moiety. The resulting spirocarbocycles are synthetically valuable, as they could be transformed into two different polycyclic aromatic hydrocarbons via skeletal rearrangement. Syntheses of optically pure spirocarbocycles via a central-to-axial-to-central chirality transfer are also described

AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge

Computer-aided synthesis planning (CASP) aims to assist chemists in performing retrosynthetic analysis for which they utilize their experiments, intuition, and knowledge. Recent breakthroughs in machine learning (ML) techniques, including deep neural networks, have significantly improved data-driven synthetic route designs without human intervention. However, learning chemical knowledge by ML for practical synthesis planning has not yet been adequately achieved and remains a challenging problem. In this study, we developed a data-driven CASP application integrated with various portions of retrosynthesis knowledge called “ReTReK” that introduces the knowledge as adjustable parameters into the evaluation of promising search directions. The experimental results showed that ReTReK successfully searched synthetic routes based on the specified retrosynthesis knowledge, indicating that the synthetic routes searched with the knowledge were preferred to those without the knowledge. The concept of integrating retrosynthesis knowledge as adjustable parameters into a data-driven CASP application is expected to enhance the performance of both existing data-driven CASP applications and those under development

Helical Nanographenes Embedded with Contiguous Azulene Units

うねり構造をもつグラフェンナノリボンの精密合成に成功 --非ベンゼノイド構造の新規構築反応を開発--. 京都大学プレスリリース. 2020-07-20.The azulene moiety, composed of contiguous pentagonal and heptagonal rings, is a structural defect that alters the electronic, magnetic, and structural properties of graphenes and graphene nanoribbons. However, nanographenes embedded with an azulene cluster have not been widely investigated because these compounds are difficult to synthesize in their pure form. Herein, azulene-embedded nanographenes bearing a unique cove-type edge were synthesized by a novel synthetic protocol. Experimental and theoretical investigations revealed that this cove edge imparts stable helical chirality, unlike normal cove edges. The in-solution self-association behavior and the structural, electronic, and electrochemical properties were also described in detail

Oxa- and Azacycle-formation via Migrative Cyclization of Sulfonylalkynol and Sulfonylalkynamide with NHeterocyclic Carbene

An N-heterocyclic carbene promotes cyclization of sulfonylalkynols and sulfonylalkynamides that accompanies 1,2-migration of the sulfonyl groups. This reaction provides a novel access to oxa- and azacycles possessing a pendent vinyl sulfone functionality, which in turn is amenable for further transformations

Striking Difference between Succinimidomethyl and Phthalimidomethyl Radicals in Conjugate Addition to Alkylidenemalonate Initiated by Dimethylzinc

We used dimethylzinc to develop a conjugate addition reaction of imidomethyl radicals to alkylidenemalonates using dimethylzinc, in which we observed a significant difference between succinimidomethyl and phthalimidomethyl radicals. This reaction provides new access to γ- aminobutyric acid derivatives, which often function as neurotransmitters

Optical resolution via catalytic generation of chiral auxiliary

A new catalytic method for separating enantiomers of racemic compounds is proposed. Catalytic asymmetric addition of chiral trans-2-substituted cyclohexanols to imines provided diastereomeric mixtures of aminals, and the subsequent separation of the enantiomers by silicagel column chromatography and the hydrolysis of the aminals produced the alcohols in an optically active form

Site-selective benzoin-type cyclization of unsymmetrical dialdoses catalyzed by N-heterocyclic carbenes for divergent cyclitol synthesis

A highly site-selective N-heterocyclic carbene (NHC)-catalyzed benzoin-type cyclization of unsymmetrical dialdoses is developed to enable a divergent cyclitol synthesis. The choice of chiral NHCs and protecting groups affects the site-selectivity. The resulting inososes are converted into epi-, muco- and myo-inositol, and their chiral protected derivatives are formed in good yields

Desymmetrization of acid anhydride with asymmetric esterification catalyzed by chiral phosphoric acid

Asymmetric desymmetrization of σ-symmetric acid anhydrides was achieved with chiral phosphoric acid as a Brønsted acid catalyst. The key of success was finding of benzhydrol and 2,2-diphenylethanol as the nucleophiles of choice. The corresponding half esters were obtained in good yields with high selectivity

Catalytic Chiral Leaving Group Strategy for Asymmetric Substitutions at sp3-Hybridized Carbon Atoms : Kinetic Resolution of β-Amino Alcohols by p-Methoxybenzylation

We developed a catalytic strategy for asymmetric substitution reactions at sp3-hybridized carbon atoms using a chiral alkylating agent generated in situ from trichloroacetimidate and a chiral phosphoric acid. The resulting chiral p-methoxybenzyl phosphate selectively reacted with β-amino alcohols rather than those without the β-NH functionality. An electronically and sterically tuned chiral phosphoric acid was developed to enable the kinetic resolution of amino alcohols, with good enantioselectivity, through p-methoxybenzylation