Masao Shiozaki

Total Synthesis of Sphingofungin F

Total synthesis of sphingofungin E (1) using an already known d-glucose derivative as a chiral synthon is described.

Stereocontrolled syntheses of chiral intermediates of thienamycin from threonines

Abstract Both stereospecific and stereoselective syntheses of thienamycin intermediates which have the correct configurations at the three contiguous chiral centers are reported.

Toll-like receptor 4-MD-2 complex mediates the signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum.

Flavolipin, an amino acid-containing lipid isolated from Flavobacterium meningosepticum, induces many immune responses. It has been shown that flavolipin does not induce an immune response of macrophages derived from C3H/HeJ mice, which possess a point mutation in Toll-like receptor 4 (TLR4). To determine whether TLR4 or the molecular complex of TLR4 and TLR4 association molecule MD-2 mediates the flavolipin signal, flavolipin responsiveness was examined by measuring NF-κB activation in Ba/F3 cells and Ba/F3 transfectants expressing TLR4 or both TLR4 and MD-2. Flavolipin-induced NF-κB activation was detected in the cells expressing both TLR4 and MD-2, but not in the other cells. Expression of CD14 in the transfectant expressing both TLR4 and MD-2 increased the sensitivity to flavolipin. Furthermore, flavolipin stereoisomers were chemically synthesized, and their abilities to induce NF-κB activation were examined. (R)-Flavolipin, in which the configuration of the lipid moiety is R, induced NF-κB activation via the TLR4-MD-2 complex, but (S)-flavolipin did not. In this study, we demonstrated the involvement of TLR4-MD-2 and CD14 in flavolipin signaling and the importance of the (R)-configuration of the flavolipin lipid moiety for the induction of an immune response via TLR4-MD-2.

Stereocontrolled syntheses of chiral and racemic key intermediates to thienamycin from d-allo-threonine and trans-crotonic acid

Abstract Stereospecific and stereoselective syntheses of cis-12, and stereoselective synthesis of (±)-trans-12 from D -allo threonine and trans-crotonic acid, respectively, are described. The key steps in the syntheses are the formation of the β-lactam ring (4) by cyclization of the amide (3) via a complete S n 2 mechanism and stereocontrolled conversion of the azetidinone (4) to 12, 13 and 14, which are intermediates for the penems and the carbapenems.

Synthesis and biological activity of ester and ether analogues of α-galactosylceramide (KRN7000)

Alpha-Galactosylceramide (alphaGalCer, KRN7000) has been identified as a modulator of immunological processes through its capacity to bind iNKT cells mediated by CD1d molecules. Some analogues in while the amide group in alphaGalCer is replaced with ester or ether groups were synthesized from d-arabinitol or l-ribose to evaluate their ability to activate iNKT cells. Ester analogues 30a, 31a, and 61 showed activity for IFNgamma and IL-4 production of iNKT cells, while ether (31b) and 4-methoxy ester (76) analogues of alpha-galactosylceramide were not active for iNKT cells.

Stereospecific synthesis of chiral precursors of thienamycin from L-threonine

Abstract L-Threonine was transformed, stereospecifically, to a versatile β-lactam (5a) in 3 steps. This β-lactam was further converted to a key intermediate (25) for the synthesis of thienamycin and its biologically active analogues. Furthermore, the compound 5a was changed to iodides (18 and 23), cyanides (19 and 24), chloromethylketone (26) and aldehydes (30 and 31) which appear to have a latent potential as precursors for the syntheses of the carbapenems.

Molecular basis for lipopolysaccharide mimetic action of Taxol and flavolipin.

We previously reported that Taxol™, which mimics the action of LPS on murine macrophages, induces signals via mouse TLR4/MD-2, but not via human TLR4/MD-2. Here we investigated the molecular basis for this species-specific action of Taxol™. Expression of mouse MD-2 conferred both LPS and Taxol™ responsiveness on HEK293 cells expressing mouse TLR4, whereas expression of human MD-2 conferred LPS responsiveness alone, suggesting that MD-2 is responsible for the species-specificity of Taxol™ responsiveness. Furthermore, mouse MD-2 mutants, in which Gln-22 was changed to other amino acids, showed dramatically reduced ability to confer Taxol™ responsiveness, although their ability to confer LPS responsiveness was not affected. These results indicated that Gln-22 of mouse MD-2 is essential for Taxol™ signaling, but not for LPS signaling. In this study, we also found that the TLR4/MD-2 complex, together with CD14, mediated signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum.

Synthesis of optically active azetidin-2-ones from L-threonine

Abstract 3S-(1R-Hydroxyethyl)-4R-phenylsulfonylazetidin-2-one derivative was synthesized from L-threonine in an 8-step process including the novel transformation of the oxirane ring to the azetidin-2-one.

Synthesis of substances related to gibberellins—XXI : Total synthesis of (±)-gibberellins A2, A4, A9, and A10☆

Abstract The formal total synthesis of some of the C 19 -gibberellins in their racemic forms is described in detail.

An alternative synthesis of d-erythro-sphingosine and l-lyxo-phytosphingosine

Abstract Chiral β-lactam 1 obtained from d -(−)-tartaric acid was converted to a d - erythro -sphingosine equivalent 7 in 35% yield, without yielding a 4Z-geometrical isomer, and l - lyxo -phytosphingosine 8 in 45% yield, respectively.