Shigeki Sano

ASYMMETRIC TOTAL SYNTHESIS OF ISP-I (MYRIOCIN, THERMOZYMOCIDIN), A POTENT IMMUNOSUPPRESSIVE PRINCIPLE IN THE ISARIA SINCLAIRII METABOLITE

Abstract Asymmetric total synthesis of ISP-I has been achieved by utilizing highly selective E -olefin formation based on the Schlosser-modified Wittig reaction and highly diastereoselective aldol reactions employing both chiral heterocyclic derivatives, 3-acetyl-(4 S )-isopropyl-1,3-thiazolidine-2-thione and ethyl [(5 R )-2,5-dihydro-5-isopropyl-3,6-diethoxypyrazin]-2-yl carboxylate.

Synthesis and reactivities of 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione (ICG-ATT) as a new near-infrared fluorescent-labeling reagent

A new near-infrared fluorescent-labeling reagent (ICG-ATT) bearing the 3-acyl-1,3-thiazolidine-2-thione (ATT) moiety with the chemoselective acylation feature and the dye moiety of indocyanine green (ICG) has been developed. Synthesis and reactivities of the ICG-ATT are described.

Toward (Z)-selective Horner–Wadsworth–Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid

Abstract The stereoselective Horner–Wadsworth–Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid utilizing i -PrMgBr afforded ( Z )-α-fluoro-α,β-unsaturated carboxylic acids as the major products.

Enantioselective Horner–Wadsworth–Emmons reaction for the asymmetric synthesis of α-fluoro-α,β-unsaturated esters

Abstract The enantioselective Horner–Wadsworth–Emmons reaction of 2-fluoro-2-diethylphosphonoacetates with σ-symmetric prochiral 2-substituted-1,3-dioxan-5-ones and 4-substituted-cyclohexanones was investigated by employing Sn(OSO 2 CF 3 ) 2 and N -ethylpiperidine in the presence of an external chiral ligand, ( S )-(−)-1-methyl-2-(1-piperidinomethyl)pyrrolidine. A chiral α-fluoro-α,β-unsaturated ester was obtained in up to 80% ee.

Tandem reduction–olefination for the stereoselective synthesis of (Z)-α-fluoro-α,β-unsaturated esters

Abstract A tandem stereoselective reduction–olefination reaction of ethyl 2-acyl-2-fluoro-2-diethylphosphonoacetate employing NaBH 4 in EtOH was developed. The one-pot reaction gave α-fluoro-α,β-unsaturated esters with excellent ( Z )-selectivity. A plausible mechanism involving a diastereoselective reduction predicted by the Felkin–Anh model, followed by olefination similar to the Horner–Wadsworth–Emmons reaction, has been proposed.

Desulfurilative self-coupling reaction of 1,3-thiazolidine-2-thiones and intramolecular non-bonded S⋯S interaction in the crystallographic structure of the products

Abstract An attempt at an asymmetric Pummerer-type reaction of trans-4-benzyloxythiane-1-oxide (1) with 3-trifluoroacetyl-4S-isopropyl-1,3-thiazolidine-2-thione (2) resulted in failure but an attractive desulfurilative self-coupling reaction of 4S-isopropyl-1,3-thiazolidine-2-thione (6) occurred to give 4S-isopropyl-3-(4S-isopropyl-1,3-thiazolin-2-yl)-1,3-thiazolidine-2-thione (5). The same desulfurilative self-coupling reaction of compound 6 or 11 efficiently proceeded by treatment of diphenyl sulfoxide (7a) or methyl phenyl sulfoxide (7b) with 2 or 3-trifluoroacetyl-1,3-thiazolidine-2-thione (8) to afford each corresponding product 5 or 9. Eventually, we found a practically useful method for the synthesis of 5 and 9 by exploiting TiCl4 and sodium salt 12 or 13 of 1,3-thiazolidine-2-thiones. Interestingly, intramolecular non-bonded S⋯S interactions were recognized in the crystallographic structures of 5 and 9.

Syntheses and reactions of the diethyl α-alkynylmalonates involving the generation of conjugated allenyl esters as the latent active species: A new approach to the development of cysteine proteinase inhibitors

Abstract Various diethyl α-alkynylmalonates (DAM) having potential as cysteine proteinase inhibitors were synthesized by treatment of diethyl acetyliminomalonate (or ketomalonate) with several lithium acetylides. Hydrolytic decarboxylation of the DAM under the mild basic conditions afforded oxazole derivatives or allenyl esters which caused the Michael type reaction with EtSH.

New enantiodivergent procedure for the syntheses of chiral α-substituted serines from α-alkyl-α-aminomalonates utilizing enzymatic hydrolysis

Porcine liver esterase (PLE)- or rabbit liver esterase (RLE)-catalyzed hydrolysis of the pro-S ester group of diethyl α-alkyl-α-(benzyloxycarbonylamino)malonates 2a-c afforded (R)-ethyl α-alkyl-α-(benzyloxycarbonylamino)malonates 3a-c each in excellent enatiomeric excess. Enantiodivergent reductions of these acid esters 3a-c readily furnished both the corresponding enantiomeric α-substituted serines (R)- and (S)-5a-c.

Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell–bone marrow interaction.

Remarkable discrepancy in the predominant structures of acyl(or thioacyl)aminothiadiazoles, acyl(or thioacyl)aminooxadiazoles and related compounds having the potential for rotational, geometrical and tautomeric isomerism

X-Ray crystallographic structures of 5-ethyl-2-trifluorothioacetylamino-1,3,4-thiadiazole 2 , 5-ethyl-3- p -nitrobenzyl-2-trifluorothioacetylimino-1,3,4-thiadiazoline 4 and 5- n -propyl-2-trifluoroacetylamino-1,3,4-thiadiazole 7 proved to be monomeric or dimeric bearing intermolecular hydrogen bondings and/or an intramolecular nonbonded 1,5-type S⋯S or S⋯O interactions. In contrast, the X-ray crystallographic structure of 5-ethyl-2-trifluoroacetylamino-1,3,4-oxadiazole 5 was shown to be dimeric involving ordinal intra- and intermolecular hydrogen bondings without any close contact. The ab initio computational studies (HF/6-311G*) of the four monomeric formylamino- and thioformylaminothiadiazoles(or -oxadiazoles) and formylimino- and thioformyliminothiadiazolines(or -oxadiazolines) structures 8 – 11 clarified the relative structure–stability order and a remarkable discrepancy in the predominant structures of the acylamino- and thioacylaminothiadiazoles and -oxadiazoles having the potential for rotational, geometrical and tautomeric isomerism.