Currently, propofol is widely used as an intravenous anesthetic and sedative in clinical settings. Propofol is hardly soluble in water in nature and is prescribed as an emulsion formulation containing soybean oil, glycerin, and egg phospholipids.1) As a result, the long-term use of a propofol emulsion, for example in post-operative sedation, may not only lead to overload of the fat nutrition 2) but also an increase in the risk of infection in patients by rapid microbial growth at room temperature.3) In addition, clinical problems that have been noted with propofol include vascular pain on injection 4) and strong respiratory depression.5) Based on the points above-mentioned, aiming at the discovery of an anesthetic and sedative as an easy-to-formulate water-soluble drug with reduced respiratory depression, we initiated a search for a compound suitable as a lead. Recently nonbenzodiazepine compounds with selective pharmacological actions on sedation and anti-anxiety have been developed. 6,7) Therefore, amongst the parent skeletons of these nonbenzodiazepine compounds, we took note of the isoindolin-1-one skeleton 6) ( Fig. 1), and synthesized approximately 170 compounds and evaluated their hypnotic effects in mice after intravenous administration.8) Herein, we report the representative preferred compounds with potent sedative-hypnotic actions. ChemistryThe general synthetic method used to prepare isoindolin-1-one derivatives is as shown in Chart 1. Phthalic anhydride 30 was heated with an appropriate amine to afford phthalimides 31, which were then reduced with sodium borohydride to afford the hemiacetals 32. The hemiacetals 32 and the Wittig reagent (Ph 3 PϭCHCO 2 Et) were heated in toluene to afford the ethyl esters 33, which were then hydrolyzed with potassium carbonate to afford the carboxylic acids 34. In the presence of N-(3-dimethylaminopropyl)-NЈ-ethylcarbodiimide hydrochloride and HOBT (1-hydroxybenzotriazole hydrate), reaction with the appropriate 1-alkylpiperazine 35 We

Peridinin, which was isolated from the planktonic algae dinoflagellates causing red tides, is a highly oxidized carotenoid containing an allene and a characteristic (Z)-gamma-ylidenebutenolide function in the main conjugated polyene chain in addition to functionalized cyclohexane rings at both ends of the molecule. We achieved a stereocontrolled total synthesis of peridinin by featuring the Sharpless asymmetric epoxidation under precise reaction conditions, Wittig reaction with silylfuranmethylide followed by photosensitized oxygenation, stereocontrolled Pd-catalyzed one-pot (Z)-gamma-ylidenebutenolide synthesis, and modified Julia-Kocienski olefination. This synthesis is the first example of controlling the stereochemistry of polyfunctional allenic carotenoids.

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