Takuya Kanemitsu

Catalytic asymmetric allylation of 3,4-dihydroisoquinolines and its application to the synthesis of isoquinoline alkaloids.

A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homolaudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A.

Asymmetric Synthesis and Catalytic Activity of 3-Methyl-β-proline in Enantioselective anti-Mannich-type Reactions

Enantiomerically pure 3-methyl-β-proline was synthesized using an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-β-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes was subsequently investigated. The catalyst was designed and found to be more soluble in nonpolar organic solvents relative to the unsubstituted β-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading.

FORMAL SYNTHESES OF DIHYDROCORYNANTHEINE AND ISORHYNCHOPHYLLINE VIA PROLINE CATALYZED MANNICH-MICHAEL REACTION

Proline catalyzed Mannich-Michael reaction of 3-ethyl-3-buten-2-one with 9-tosyl-3,4-dihydro-β-carboline proceeded in a highly stereoselective manner. The reaction was applied to formal syntheses of dihydrocorynantheine and isorhynchophylline.

NOVEL SULFONAMIDE CATALYZED ASYMMETRIC HETERO-DIELS-ALDER REACTION OF ETHYL GLYOXYLATE WITH DANISHEFSKY'S DIENE

Novel sulfonamide organocatalysts were prepared from chiral Betti base and various sulfonyl chlorides, and applied to the asymmetric hetero-Diels-Alder reaction of ethyl glyoxylate with Danishefskys diene. The sulfonamides exhibited catalytic activity as hydrogen bond donor. In particular, sulfonamide 3g showed highest catalytic performance for the reaction. Sulfonamide 3g catalyzed asymmetric reaction followed by treatment with TFA obtained corresponding 6-substituted 2,3-dihydropyran-4-ones in moderate yield and enantioselectivity.

Asymmetric Acyl-Strecker Reaction Promoted by Novel Thiourea Organocatalyst

Asymmetric acyl-Strecker reaction using novel thiourea organocatalyst is described. Screening experiments of the catalysts revealed that a bifunctional organocatalyst afforded an enantio-enriched product via an unique mechanism. That is, dihydroisoquinoline derivatives were converted to a corresponding 1-cyano-1,2,3,4-tetrahydroisoquinolines using the bifunctional thiourea catalyst derived from Betti base in moderate yield and enantioselectivity. .

The novel bisphosphonate disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate increases bone mass in post-ovariectomy rats.

The novel bisphosphonate (BP) disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate (MPMBP) is a non-nitrogen-containing BP with an antioxidant side chain that possesses anti-inflammatory properties. We investigated the systemic effects of this compound on bone loss induced by ovariectomy (OVX) in adult rats. Micro-computed tomography revealed that MPMBP increased bone mass and density in both the metaphysis and diaphysis, and improved the structural properties important for mechanical strength of osteoporotic bone. Sequential bone labeling with tetracycline and calcein indicated that MPMBP decreased longitudinal growth of the primary spongiosa (PS), but stimulated cortical bone formation in the diaphysis. MPMBP increased type I collagen accumulation in the PS, and decreased the number and size of adipocytes in the bone marrow, suggesting inhibition of increased bone marrow adipogenesis induced by OVX. Furthermore, MPMBP reduced the number of bone resorbing cathepsin K-positive osteoclasts induced by OVX. These results suggest that MPMBP could improve bone loss induced by estrogen deficiency. Both stimulation of bone formation and inhibition of bone resorption might play a role in the increase in bone mass and bone density after MPMBP treatment.