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The elucidation of specific functions of protein kinase C (PKC) subtypes in physiological processes is an important challenge for the future development of new drug targets. Subtype-selective PKC agonists and antagonists are useful biological tools for this purpose. Most of the currently used PKC modulators elicit their activities through binding to the ATP binding site of PKC, which shares many features with other kinases. PKC modulators that target the PKC regulatory domain are considered to be advantageous in terms of selectivity, because the structure of the regulatory domain is intrinsic to each PKC subtype. In this paper, we describe the identification of new potent and conventional PKC-selective inhibitors that target the regulatory domain. The inhibitors contain a phorbol skeleton, a naturally occurring potent and selective PKC regulatory domain binder, with a perfluorinated alkyl group and a polyether hydrophilic chain on a terephthaloyl aromatic ring at the C12 position. Both of these substituents are essential for the potent inhibitory activity. Specifically, the binding affinity between PKC and the phorbol ester analogues was improved by an electron-deficient aromatic ring at C12. This finding cannot be explained by the previously proposed binding model and suggests a new binding mode between phorbol esters and PKC.

Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.

The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate alpha-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)(3) and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu(4)NCl, alpha-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the gamma-position of 4, followed by regio- and enantioselective protonation at the alpha-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu(4)NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF.3PPh(3).2EtOH (10 mol %) in the presence of KO(t)Bu (15 mol %), ZnCl(2) (1 equiv), and Bu(4)PBF(4) (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the alpha-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic alpha-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.

A chiral polynuclear Gd complex derived from Gd(O(i)Pr)(3) and FujiCAPO (2 or 3) catalytically generated Gd enolates through two distinct methods; transmetalation from enol silyl ethers and conjugate addition of cyanide to alpha,beta-unsaturated N-acyl pyrroles. These chiral enolates can be enantioselectively protonated by a proton in an asymmetric environment in the polynuclear catalyst. Thus, catalytic enantioselective protonation of enol silyl ethers was promoted by the Gd catalyst (5-10 mol %) in the presence of a stoichiometric amount of 2,6-dimethylphenol. Kinetic studies and dependencies of the enantioselectivity on the silyl group structure and the proton source suggest that the reaction proceeds through a Gd enolate generated through transmetalation. Moreover, the same Gd complex (5-10 mol %) promoted conjugate addition of a cyanide-enantioselective protonation sequential reaction from alpha,beta-unsaturated N-acyl pyrroles. Because Gd isocyanide was determined to be the active nucleophile in the conjugate addition catalyzed by the Gd complex, enantioselective protonation likely proceeded through a Gd enolate in this case as well. The products are versatile dual functional chiral building blocks for organic synthesis.