Toshiyuki Shimazaki

A highly efficient synthesis of optically pure γ-iodo allylic alcohols and their conversion into various optically active allylic alcohols

Abstract Kinetic resolution of γ-iodo allylic alcohols 1 by the Sharpless asymmetric epoxidation reaction proceeds with very large rate differences for the two enantiomers, thus providing a highly efficient method for preparation of optically pure 1 . The alcohols 1 thus prepared can be readily converted into various secondary allylic alcohols through the coupling reaction with nucleophiles.

A highly efficient synthesis of γ-halo allylic alcohols and propargylic alcohols with high optical purity: practical method for synthesis of the prostaglandin ω-chain

Abstract Kinetic resolution of γ-trimethylsilyl allylic alcohols 5 by the sharpless process combined with the reactivity of epoxysilyl or vinylsilyl compounds affords a highly efficient method for preparation of optically pure γ-halo secondary allylic alcohols of type 1 – 4 and propargylic alcohols 14 , thus providing a practical route to the prostaglandin ω-chain.

Synthesis and physiological activities of both enantiomers of coriolic acid and their geometric isomers

Abstract Both enantiomers of coriolic acid and their geometric isomers are synthesized highly selectively. These acids are found to exhibit similar inhibition activity toward spore germination of rice blast fungus.

Highly stereocontrolled, multigram scale synthesis of leukotriene B4

Abstract Leukotriene B4 ( 1 ) is synthesized in quantity by combining the enyne 3 with the vinyl iodide 5 via the vinylborane. The two fragments 3 and 5 are prepared readily by using the kinetic resolution of the corresponding racemic alcohols d1- 2 and d1- 4 as a key step.

A highly practical synthesis of chiral (E)-1-trimethylsilyl-1-alken-3,4-diols via the Sharpless asymmetric epoxidation of 1,5-bis(trimethylsilyl)-1,4-pentadien-3-ol: formal total synthesis of lipoxin B

The Sharpless asymmetric epoxidation of the alcohol 4 proceeds with an extremely high efficiency to afford the epoxide 5 from which the title chiral alcohol 2 is synthesized in good overall yield. By using the alcohol 2 the Nicolaous lipoxin B intermediates 18 and 20 are prepared in a stereoselective way.

Important contribution of the methylene part of LTB4 toward binding affinity to the LTB4 receptors and rise in intracellular-free calcium concentration.

In order to examine a role of the C(16)-C(20) methylene part of leukotriene B4 (LTB4) toward the activation of leukocytes, we synthesized the LTB4-analogues in which the length of the C(16)-C(20) part of LTB4 is varied systematically while the two hydroxyl groups at C(5) and C(12) positions and the 6(Z), 8(E), 10(E) conjugated triene unit remained untouched. We examined their binding affinity to the LTB4 receptors present in the rat polymorphonuclear leukocytes (PMNLs) and their ability to raise intracellular-free calcium concentration ([Ca2+]i) in the rat PMNLs loaded with fura-2. As the length of the chain of LTB4 was increased or decreased one by one, the binding affinity to the LTB4 receptors diminished, and the analogues of more than three carbon atoms shorter chain were of about three log order less activity than LTB4. The biological potency as assessed in [Ca2+]i rises pararelled that of the binding affinity to the PMNL membrane. These results indicate that the C(16)-C(20) part of LTB4 plays important role for the activity. In a similar way we prepared the LTB4-analogues of a different chain length between C(2)-C(4) of LTB4 and tested their biological activity. We found that the C(2)-C(4) part of LTB4 also affects the activity.

Some newly synthesized leukotriene B4 analogs inhibit LTB4-induced lysozyme release from rat polymorphonuclear leukocytes

Antagonistic activities of newly synthesized LTB4 analogs, which possess the same olefinic geometry and the same hydroxyl group stereochemistry as natural LTB4, were investigated by studying lysozyme release from rat polymorphonuclear leukocytes (PMNLs). 14,15-Dihydro LTB4(LTB3) induced lysozyme release from PMNLs as well as LTB4, while 14,15-dehydro LTB4 did not cause lysozyme release but instead clearly inhibit LTB4-induced lysozyme release. Compounds containing aminocarbonyl groups partially retained lysozyme releasing activity. A displacement of the hydrocarbon chain at C13-20 by cyclohexenyl and beta-cyclohexylethyl groups had little effect on lysozyme release, but did strongly inhibit release induced by LTB4. These results may be useful in developing LTB4 antagonists.

12 (R)-methyl-leukotriene B3: A stable leukotriene B analogue toward the reductase metabolism

Biological potencies of 12(R)-methyl-LTB3 [12(R)-Me-LTB3] and 12(S)-Me-LTB3 and their stability toward reductase metabolism are described. 12(R)- and 12(S)-Me-LTB3 of more than 95% chemical purity were synthesized highly stereoselectively via the palladium catalyzed coupling reaction of the vinylborane derived from the enzyme 1 and Sia2BH with the iodide 2 of R and S configuration. To assess biological activity of 12-Me-LTB3, cytosolic free calcium ([Ca2+]i) rise in rat PMNLs and binding affinity to the LTB4 receptors were compared with those of natural LTB4. The potency of 12(R)-Me-LTB3 was found to be almost equal to LTB4, while, by complete contrast, 12(S) isomer showed very low activity of 1/200-1/400. These results indicate that the C(12) hydroxyl group of R configuration is essential to elicit the biological activity and that [Ca2+]i rise elicited by 12-Me-LTB3 is mediated through interaction with the LTB4 receptors. Stability of 12(R)-Me-LTB3 toward the reductase metabolism was evaluated by using rat PMNLs. Thus, rat PMNLs were incubated at 37 degrees C with 12(R)-Me-LTB3 and LTB4, respectively. The amount of 12(R)-Me-LTB3 was almost unchanged up to 30 min under these conditions, though LTB4 was rapidly consumed in a time-dependent manner, thus strongly indicating that 12(R)-Me-LTB3 is not metabolized via the reductase pathway.

A practical preparation of α-hydroxy and α,β-dihydroxy aldehydes, useful intermediates for the synthesis of arachidonic acid metabolites, starting with D-glyceraldehyde acetonide

Optically active α-hydroxy and α,β-dihydroxy aldehydes, useful intermediates for synthesis of lipoxygenase metabolites of arachidonic acid, are synthesized highly diastereoselectively starting with readily available D-glyceraldehyde acetonide.