Kennosuke Itoh

Asymmetric cycloaddition reactions of diazoesters with 2-alkenoic acid derivatives catalyzed by binaphthyldiimine-Ni(II) complexes.

The catalytic activity of chiral binaphthyldiimine (BINIM)-Ni(II) complexes for asymmetric enantioselective diazoalkane cycloadditions of ethyl diazoacetate with 3-acryloyl-2-oxazolidinone and 2-(2-alkenoyl)-3-pyrazolidinone derivatives was evaluated. The cycloadditions of 3-acryloyl-2-oxazolidinone and its 5,5-dimethyl derivative, in the presence of the BINIM-Ni(II) complex (10 mol %; prepared from (R)-BINIM-4Ph-2QN (ligand C) and Ni(ClO(4))(2)·6H(2)O) afforded 2-pyrazolines having a methine carbon substituted with an oxazolidinonyl group in moderate ratios (70:30 to 72:28), along with high enantioselectivities (90-92% ee) via 1,3-proton migration. On the basis of the investigations on the counteranions of the Ni(II) complex, the N-substituent of pyrazolidinone, and reaction temperatures, the optimal enantioselectivity (97% ee) and ratio (85:15) of 2-pyrazoline were obtained for the reaction of 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-Ni(II) ((R)-C/Ni(II)) complex prepared using Ni(BF(4))(2)·6H(2)O. In the cases of 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone, 1-benzyl-2-(2-butenoyl)-5,5-dimethyl-3-pyrazolidinone, and 1-benzyl-5,5-dimethyl-2-(3-ethoxycarbonyl)propenoyl-3-pyrazolidinone, the use of the (R)-BINIM-2QN-Ni(II) ((R)-A/Ni(II)) complex gave good to high enantioselectivities (85-93% ee) with the sole formation of the 2-pyrazoline having a methine carbon substituted with a pyrazolidinonyl group. Relatively good enantioselectivity (77% ee) was observed for the reaction between 2-acryloyl-5,5-dimethyl-1-naphthylmethyl-3-pyrazolidinone and an α-substituted diazo ester, ethyl 2-diazo-3-phenylpropanoate, which has yet to be employed as a diazo substrate in asymmetric cycloaddition reactions catalyzed by a chiral Lewis acid.

Chiral Lewis acid catalyzed asymmetric cycloadditions of carbonyl ylides generated from diazoimide derivatives and their synthetic applications to indolizidine alkaloids.

Highly enantioselective 1,3-dipolar cycloaddition reactions, catalyzed by chiral Lewis acids, between several 3-(2-alkenoyl)-2-oxazolidinones and carbonyl ylides that were generated from N-diazoacetyl lactams are described. Reactions of N-diazoacetyl lactams that possess 5-, 6-, and 7-membered rings were transformed to the corresponding epoxy-bridged indolizidines, quinolizidines, and 1-azabicyclo[5.4.0]undecanes with good to high enantioselectivities. Regio- and stereoselective ring-opening of the epoxy-bridged indolizidine cycloadduct gave the corresponding alcohol as a single diastereomer. The sequence of asymmetric cycloaddition followed by ring-opening was applied to the syntheses of several chiral indolizidine derivatives, including (+)-tashiromine.

Diastereoselective synthesis of tetrahydrofurans by Lewis acid catalyzed intermolecular carbenoid-carbonyl reaction-cycloaddition sequences: unusual diastereoselectivity of Lewis acid catalyzed cycloadditions.

The effects of including metal salts for three-component reactions involving α-alkyl-α-diazo esters, aromatic aldehydes, and 3-(2-alkenoyl)-2-oxazolidinones are described, in terms of yields and diastereoselectivities. Metal tetrafluoroborates (10-30 mol %) such as Co(BF4)2·6H2O, Ni(BF4)2·6H2O, and AgBF4 were effective in delivering high yields and diastereoselectivities (93:7 to 99:1) of the corresponding tetrahydrofuran derivatives while suppressing the competitive formation of 1,3-dioxolane. Using (S)-3-(2-alkenoyl)-4-isopropyl-2-oxazolidinones as the dipolarophiles in the three-component reactions, in the presence of Ni(BF4)2·6H2O or Co(ClO4)2·6H2O (10-30 mol %), optically active tetrahydrofurans that possess four successive asymmetric centers were synthesized in high diastereoselectivities (99:1). On the basis of the configuration of the cycloadduct using the X-ray analysis, the high diastereoselectivity could be explained by the unusual Re-face approach to the dipolarophile in the presence of the Lewis acid, proceeding through the s-cis conformer of the 3-(2-alkenoyl)-2-oxazolidinone with the two carbonyls in opposing directions (dipole-dipole interaction).

Chiral Lewis Acid-Catalyzed Enantioselective Cycloadditions between Indoles and Cyclic Carbonyl Ylides Derived from Diazodiketone or Diazoketoester Derivatives.

Asymmetric 1,3-dipolar cycloaddition reactions between N-methylindoles and several cyclic carbonyl ylides that were derived from diazodiketone or diazoketoester precursors in the presence of both achiral Rh and chiral lanthanoid metal catalysts are described. For the six-membered cyclic carbonyl ylides derived from 1-diazo-5-aryl-2,5-pentanedione precursors, the cycloaddition reactions were carried out using Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Lu(OTf)3 complex (10 mol %) as catalysts, resulting in high enantioselectivities (83% to >98% ee (exo)) along with relatively good exo-selectivities (exo:endo = 65:35 to 94:6) and yields (63-85%). For the five-membered cyclic carbonyl ylide derived from 1-diazo-2,4-pentandione precursor, the cycloaddition reaction with 5-bromo-1-methylindole was carried out in the presence of Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Er(OTf)3 complex (30 mol %) as catalysts, resulting in relatively good enantioselectivity (78% ee) and endo-selectivity (endo:exo = 81:19).

Synthesis and evaluation of novel opioid ligands with a C-homomorphinan skeleton.

As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds.

Three-Component Reactions of Diazoesters, Aldehydes, and Imines Using a Dual Catalytic System Consisting of a Rhodium(II) Complex and a Lewis Acid

A dual catalytic system, dirhodium tetrapivalate/ytterbium(III) triflate, enables the three-component reactions of α-alkyl-α-diazoesters, aromatic aldehydes, and N-benzylidenebenzylamine derivatives to afford the corresponding β-amino alcohols in good yields after hydrolysis of the oxazolidine cycloadducts, whereas no β-amino alcohols are obtained in the absence of ytterbium(III) triflate. A similar dual catalytic system, dirhodium tetraacetate/ytterbium(III) triflate, is found to be effective in accelerating the reactions of α-aryl-α-diazoesters in high yields. Furthermore, the reactions using dimethyl diazomalonate are described.

C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics

Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the μ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.

Preparation of new nitrogen-bridged heterocycles. 69. Synthesis and Reaction of 1-(α-Hydroxybenzyl)thieno [3,4-b] indolizine Derivatives

The title compounds, l-(a-hydroxybenzyl)thieno[3,4-o]indolizine derivatives, were obtained in good yields by the reduction of the corresponding l-benzoylthieno[3,4-6]indolizines with sodium borohydride in refluxing ethanol. These compounds were considerably unstable and decomposed gradually even at room temperature, but, on exposure to acetic acid, unexpected condensation took place to afford a,]indolizin-l-yl)toluenes in low to moderate