Michael reaction of malonates to nitroolefins with chiral bifunctional organocatalysts, bearing both a thiourea and tertiary amino group, afforded Michael adducts with high yields and enantioselectivities (up to 95%, up to 93% ee).

The catalytic asymmetric formation of a carbon-carbon bond represents one of the most challenging fields in organic chemistry. A number of asymmetric Michael additions to a,bunsaturated carbonyl acceptors catalyzed by chiral catalysts have been reported.[1] However, the acceptors employed in the asymmetric Michael additions of 1,3-dicarbonyl compounds generally have been restricted to enones [2][3][4] and nitroalkenes.[5] Similarly, although organocatalysts that bear chiral secondary amine groups have been shown to be efficient catalysts for the Michael reaction with such acceptors, [6] their applications to a,b-unsaturated acid derivatives seems to be difficult. Therefore, the development of general and highly enantioselective versions of the reactions of a,bunsaturated acid derivatives still remains a challenging goal. Quite recently, two groups achieved the initial breakthroughs on these problems. The Jacobsen and Kanemasa groups independently reported the highly enantioselective metalcatalyzed Michael additions of malononitrile, which is equivalent to a 1,3-dicarbonyl compound, to a,b-unsaturated imides. [7,8] However, there have been no reports of such asymmetric Michael addition without any metal catalysts. Herein, we report the first enantioselective Michael reactions of malononitrile to acyclic a,b-unsaturated imides in the presence of a chiral organocatalyst.Although we recently reported that the bifunctionalthiourea-catalyzed Michael reaction of 1,3-dicarbonyl compounds to nitroalkenes proceeded with high enantioselectivity (up to 93 % ee), [9] the same reaction of other nucleophiles such as malononitrile to nitroalkenes gave the corresponding product with low enantioselectivity. To extend the synthetic utility of the bifunctional thiourea 1 a in the asymmetric reaction, we undertook the screening of proper Michael acceptors other than nitroalkenes to react with malononitrile. For the purpose, a,b-unsaturated imides seem to have an ideal structure to form hydrogen bonds with the thiourea catalyst 1 a as shown in Scheme 1.

A series of water-soluble telechelic dithiol monomers bearing multiple guanidinium ion (Gu(+)) units in their main chains were synthesized for packaging siRNA by template-assisted oxidative polymerization at their thiol termini. In the presence of siRNA, oxidative polymerization of (TEG)Gu4 affords a uniform-sized (7 ± 2 nm) nanocaplet containing siRNA (P(TEG)Gu4⊃siRNA; P(TEG)Gu4 = polymerized (TEG)Gu4). When this small conjugate is incubated with live cells, cellular uptake occurs, and the nanocaplet undergoes depolymerization in the reductive cytosolic environment to liberate the packaged siRNA. Consequently, gene expression in the live cells is suppressed.

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A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified as a potent mimic of the 5-methoxy indole core of melatonin, and introduction of a cyclohexylmethyl group at the 7-position of this scaffold afforded an MT(2)-selective ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound 15 was identified as a potent full agonist for the MT(2) subtype and exhibited reentrainment effects to a new light/dark cycle in ICR mice at 3-30 mg/kg. This result demonstrated the involvement of the MT(2) receptors in chronobiotic activity.

Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.062 nM; MT(2), K(i) = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.

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Enantioselective syntheses O 0031 Enantio-and Diastereoselective Michael Reaction of 1,3-Dicarbonyl Compounds to Nitroolefins Catalyzed by a Bifunctional Thiourea. -In this context, a simple route to the antispastic agent (R)-baclofen (XVIII) becomes possible. -(OKINO, T.; HOASHI, Y.; FURUKAWA, T.; XU, X.; TAKEMOTO*, Y.; J. Am. Chem. Soc. 127 (2005) 1, 119-pp; Grad. Sch. Pharm. Sci., Kyoto Univ., Sakyo, Kyoto 606, Japan; Eng.) -Lindner 21-034