Optically active sulfoximines are a promising substance in medicinal chemistry. However, a methodology for preparing chiral sulfoximines in a stereoselective manner has been underdeveloped. Here, we report an asymmetric synthesis of chiral sulfoximines having an aryl group by the newly developed sulfurselective arylation of easily accessible chiral sulfinamides. The utility of the present method is demonstrated by the asymmetric synthesis of a key intermediate of a COX-2 inhibitor.
Innovation in drug discovery critically depends on the development of new bioisosteric groups.C hiral sulfoximines,w hich contain at etrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents,r epresent an emerging chiral bioisostere in medicinal chemistry.Chiral sulfoximines are conventionally prepared by as tereospecific nitrene transfer reaction to chiral sulfoxides; however,t he number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of ac lass of hitherto difficult-to-access chiral sulfoximines with two structurally similar alkyl chains.Our synthetic approach is based on the sulfur-selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions.T his stereospecific S-alkylation offers ag eneral and scalable approacht ot he asymmetric synthesis of chiral sulfoximines,w hichr epresent important substructures in bioactive molecules.
A highly stereoselective synthesis of hitherto less accessible chiral α-tertiary amines with multiple structurally similar linear carbon chains was achieved through chiral auxiliary mediated addition of organolithium reagents to the geometrically well-controlled alkynyl Z-ketimines. This stereoselective nucleophilic addition offers a general approach to the asymmetric synthesis of nitrogen-containing chiral materials.
2-O-α-d-Glucopyranosyl-l-ascorbic acid (AA-2G) is one of the stable ascorbic acid (AA) derivatives known as provitamin C agents. We have previously synthesized two types of monoacylated derivatives of AA-2G, 6-O-acyl-2-O-α-d-glucopyranosyl-l-ascorbic acids having a straight-acyl chain of varying length from C4 to C18 (6-sAcyl-AA-2G) and a branched-acyl chain of varying length from C6 to C16 (6-bAcyl-AA-2G) in order to improve the bioavailability of AA-2G. In this study, 6-sAcyl-AA-2G and 6-bAcyl-AA-2G per se showed the inhibitory effects on hyaluronidase activity and degranulation. 6-sAcyl-AA-2G exhibited strong inhibitory effects on hyaluronidase activity and degranulation in a concentration-dependent manner, and the inhibitory effects tended to become stronger with increasing length of the acyl chain. 2-O-α-d-Glucopyranosyl-6-O-hexadecanoyl-l-ascorbic acid (6-sPalm-AA-2G), which has a straight C16 acyl chain, was the most potent effective for inhibition of hyaluronidase activity and for inhibition of degranulation among the 6-sAcyl-AA-2G derivatives and the two isomers of 6-sPalm-AA-2G. Furthermore, percutaneous administration of 6-sPalm-AA-2G significantly inhibited IgE-mediated passive cutaneous anaphylaxis reaction in mice. These findings suggest that 6-sPalm-AA-2G will be useful for treatment of allergies.
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