33 触媒的不斉野崎-檜山反応の開発とHMG-CoA還元酵素阻害剤FR901512の不斉全合成(口頭発表の部)
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The nucleophilic addition of organochromium reagents to aldehydes (Nozaki-Hiyama reaction) is one of the most useful C-C bond-forming reactions, due to its high chemoselectivity and mild conditions. We have developed a new chiral ligand 1 effective for the asymmetric catalysis of Nozaki-Hiyama reactions. Various aldehydes were generally allylated or methallylated with good to excellent enantioselectivity (86-96% ee). Enantioselective synthesis of homopropargylic or allenic alcohols has also been achieved by choosing an appropriate propargyl halide (51-98% ee, 72-83% ee, respectively). Another remarkable feature of this ligand is the stability of the Cr-ligand complex, which was recovered after the reaction and recycled without diminishing the enantioselectivity and yield. We applied this powerful catalytic asymmetric reaction to the total synthesis of FR901512(7), which potently inhibits cholesterol synthesis. Since the stereochemistry of 7 has not been determined, we decided to develop the stereo-divergent synthetic route to all the stereoisomers of 7 to determine the absolute stereochemistry. The catalytic asymmetric Nozaki-Hiyama methallylation of aldehyde 12 with chiral ligand 1b gave alcohol 13 (92% ee), and the following ring-closing methathesis and highly diastereoselective hydrogenation afforded either cis-16 (94% de) or trans-16 (>99% de). Asymmetric allylation of homologated aldehyde 22 proceeded successfully to afford homoallyl alcohol 23 (91% de) again. After conversion of alcohol 23 to α,β-unsaturated lactone 24, diastereoselective epoxidation and reduction completed the asymmetric total synthesis of FR901516(8). Methanolysis and hydrolysis of 8 afforded FR901512(7) with agreement of all spectroscopic properties. Application of the developed catalytic asymmetric Nozaki-Hiyama reaction to the side-chain synthesis of calcitriol lactone will be also reported.
- 天然有機化合物討論会の論文
- 2006-09-15
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