Ikuhide Fujisawa

Williamson Ether Synthesis with Phenols at a Tertiary Stereogenic Carbon: Formal Enantioselective Phenoxylation of β‐Keto Esters

The enantioselective formation of α-aryloxy-β-keto esters is described for the first time. Lewis acid catalyzed enantioselective chlorination of β-keto esters and subsequent SN 2 reactions with phenols yielded α-aryloxy-β-keto esters with up to 96% ee. Favorskii rearrangement of α-chloro-β-keto esters was also found to give 1,2-diesters with slightly reduced enantiopurity.

Crystal Structure of an L-Carnitine Complex with Pyrogallol[4]arene

L-Carnitine is essential for the transport of long-chain fatty acids from cytosol into mitochondria for generating metabolic energy. The survey of crystal structures of carnitine-containing proteins in the Protein Data Bank reveals that carnitine can take several conformations with the quarternary trimethylammonium terminal being always bound to aromatic residues through cation- interactions in acyltransferases or carnitine-binding proteins. In order to demonstrate the importance of cation- interaction as a carnitine recognition mechanism in the artificial receptor-ligand system that mimics the carnitine-binding sites, we have determined the crystal structure of a complex formed between L-carnitine and pyrogallol(4)arene (pyrogallol cyclic tetramer: PCT) as a carnitine receptor, 2PCT∙2(L-carnitine)∙4EtOH. There form two crystallographically independent monomeric (PCT∙L-carnitine) substructures, which further form an obliquely arranged capsule-like dimeric (PCT∙L-carnitine)2 structure through a pair of O-H (PCT)∙∙∙O (L-carnitine) hydrogen bonds. This is the first report of PCT complex with chiral molecules. In each of the two monomeric (PCT∙L-carnitine) substructures, the L-carnitine molecule takes the elongated form with an intramolecular hydrogen bond between the hydroxyl group and the carboxylate oxygen, and the cationic trimethylammonium moiety is incorporated into the cavity of the bowl-shaped PCT molecule through cation- interactions. These features are similar to those at the D- carnitine-binding site in the crystal structure of the glycine betaine/carnitine/choline- binding protein complex.

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via SN2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.

Ligand Exchange Reaction on a Ru(II)–Pheox Complex as a Mechanistic Study of Catalytic Reactions

A ligand exchange of one of the acetonitrile ligands of the (acetonitrile)4Ru(II)–phenyloxazoline complex (Ru(II)–Pheox) by pyridine was demonstrated, and the location of the exchange reaction was examined by density functional theory (DFT) calculations to study the mechanism of its catalytic asymmetric reactions. The acetonitrile was smoothly exchanged with a pyridine to afford the corresponding (pyridine)(acetonitrile)3Ru(II)–Pheox complex with a trans orientation (C–Ru–N(pyridine)) in a quantitative yield, and the complex was analyzed by single-crystal X-ray analysis. DFT calculations indicated that the most eliminable acetonitrile is the trans group, which is consistent with the X-ray analysis. The direction of the ligand exchange is thus determined on the basis of the energy gap of the ligand elimination instead of the stability of the metal complex. These results suggested that a reactant in a Ru–Pheox-catalyzed reaction should approach trans to the C–Ru bond to generate chirality on the Ru center.