Discovery of Peripheral κ-Opioid Receptor Agonists as Novel Analgesics.

κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.

Discovery of highly selective κ-opioid receptor agonists: 10α-Hydroxy TRK-820 derivatives.

κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor are attractive targets in the development of drugs for pain and pruritus. We previously reported the synthesis of 10α-hydroxy TRK-820 (1). In this study, we elucidated the biological properties of 1 and optimized its 6-acyl unit by modifying our synthetic route. Among the 10α-hydroxy TRK-820 derivatives prepared, 26 showed the most potent κ-opioid agonist activity (EC50=0.00466nM) and excellent selectivity and 22 was the most κ-selective agonist.

Catalytic asymmetric epoxidation of alpha,beta-unsaturated esters with chiral yttrium-biaryldiol complexes.

The full details of the asymmetric epoxidation of alpha,beta-unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium-biphenyldiol catalyst, generated from Y(OiPr)3-biphenyldiol ligand-triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various alpha,beta-unsaturated esters. With this catalyst, beta-aryl alpha,beta-unsaturated esters gave high enantioselectivities and good yields (< or = 99% ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5-2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For beta-alkyl alpha,beta-unsaturated esters, an yttrium-binol catalyst, generated from Y(OiPr)3-binol ligand-triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (< or = 97% ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (-)-ragaglitazar, a potential antidiabetes agent.

Cu(I)-catalyzed direct enantioselective cross aldol-type reaction of acetonitrile.

Direct catalytic enantioselective cross aldol-type reaction of an acetate surrogate was developed using Cu alkoxide-chiral phosphine complexes as catalysts. Chemoselective activation and deprotonation of the donor substrate (acetonitrile) by the soft metal alkoxide in a strongly donating solvent (HMPA) are key to success in this reaction. Useful chemical yields and promising enantioselectivities are produced using either DTBM-SEGPHOS or a tuned BIPHEP as a chiral ligand. [reaction: see text]

Catalytic asymmetric epoxidation of alpha,beta-unsaturated esters using an yttrium-biphenyldiol complex.

We succeeded in a catalytic asymmetric epoxidation reaction of alpha,beta-unsaturated esters via a conjugate addition of an oxidant using 2-10 mol % of the yttirium-chiral biphenyldiol catalyst. A variety of substrates with beta-aryl and beta-alkyl substituents were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy esters in up to 97% yield and 99% ee.

A new entry in catalytic alkynylation of aldehydes and ketones: dual activation of soft nucleophiles and hard electrophiles by an indium(III) catalyst.

[reaction: see text] A new entry in catalytic alkynylation of carbonyl compounds was developed in which dual activation of both soft nucleophiles (terminal alkynes) and hard electrophiles (aldehydes and ketones) is achieved using an indium(III) catalyst. Preliminary mechanistic studies using in situ IR and NMR spectroscopic analysis are also discussed.

Dynamic ligand exchange of the lanthanide complex leading to structural and functional transformation: one-pot sequential catalytic asymmetric epoxidation-regioselective epoxide-opening process.

The characteristic property of the lanthanide complex, which easily undergoes a dynamic ligand exchange and alters its structure and function in situ, is described. After the completion of the catalytic asymmetric epoxidation of various alpha,beta-unsaturated amides 2 in the presence of the Sm-(S)-BINOL-Ph3As=O (1:1:1) complex 1 (2-10 mol %), the addition of Me3SiN3 directly to the reaction mixture led to smooth epoxide-opening at room temperature, affording the corresponding anti-beta-azido-alpha-hydroxyamide 4 in excellent overall yield (up to 99%) with complete regioselectivity and excellent enantiomeric excess (up to >99%). The key to the success of the sequential process was the in situ generation of the highly reactive samarium azide complex through dynamic ligand exchange. In situ IR spectroscopy and other experiments provided strong evidence that the samarium azide complex was generated. In addition, the relatively high Lewis basicity of the amide moiety had a key role in the high reactivity of both the epoxidation and the epoxide-opening reactions. Examinations of other nucleophiles such as sulfur or carbon nucleophiles as well as transformations of epoxide-opened products are also described.