P-42 Development of the Chiral Synthon Using PLE and Its Application

• Katoh Takahiro

  Kyoto Pharmaceutical University

• Awasaguchi Ken-ichiro

  Kyoto Pharmaceutical University

• Mori Daisuke

  Kyoto Pharmaceutical University

• Kakiya Kiyoshi

  Kyoto Pharmaceutical University

• Kajimoto Tetsuya

  Kyoto Pharmaceutical University

• Node Manabu

  Kyoto Pharmaceutical University

Bibliographic Information

Other Title

• P-42 PLEを用いた不斉合成素子の開発とその応用(ポスター発表の部)

Abstract

We have in recent succeeded in the formal total synthesis of (+)-carbacyclin and (+)-ferruginine by applying porcine pancreatic lipase (PPL) or porcine liver esterase (PLE) catalyzed reactions to σ-symmetrical β-ketodiesters at a key step to prepare chiral synthons. Herein, we would like to report a new type of PLE catalyzed dealkoxycarbonylation, in which σ-symmetrical substrates of β-ketodiesters (1a-f) have quarternary carbons at α and α' positions, affording optically active methyl 2,5-dimethylcyclohexanone-2-carboxylate (2). Furthermore, (-)-podocarpic acid was prepared from 2 in a short step to show its usefulness as a chiral synthon for the synthesis of diterpenoids. Preparation of the substrate of the PLE catalyzed reaction seemed to be difficult. We prepared 1a from commercially available 2,5-dimethyl-cyclohexanone (3) by taking advantage of intramolecular aldol condensation as follows. Treatment of 3 with sodium hydride and methyl 2-hydroxy-2-methoxyacetate and successive quenching of the reaction with methyl iodide afforded methyl 2-(1,3-dimethyl-2-oxycyclohexyl)-2-methoxyacetate (4). The intramolecular aldol condensation of 4 with sodium hydride gave [3.2.1]-bicyclic ketone, which was transformed to 5 with sodium hydride and methyl tosylate. The double bond of 5 was oxidatively cleaved with osmium tetroxide in the presence of sodium periodate to yield 1a. Next, 1a was treated with PLE (3000units/mmol substrate) in phosphate buffer solution (PBS: 100mM, pH8) containing some kinds of organic solvents. After testing several cosolvent, it was found that the reaction using acetonitrile provide buffer results than those using other solvents. Moreover, further optimization of the reaction condition was attained by changing substrates of diester, reaction time, and interval time of adding the enzyme. After running the reaction under several conditions, the reaction in which 1,500 units of enzyme were added into the mixed solvent composed of PBS and acetonitrile twice with the intervals of 12 hours and total 48 hours period gave satisfactory chemical yield and high enantiomeric excess (Table 1). Finally, optically active (-)-podocarpic acid (15) were tried to synthesize by using 2 as a key chiral synthon, while racemic 15 have been synthesized by many groups because of the utility as the starting material of many naturally occurring compounds. (+)-β-Ketoester 2 was treated with lithium acetylide prepared by Corey-Fuchs's method to give propargyl alcohol, of which triple bond was reduced by conventional catalytic hydrogenation with Pd-C to afford a mixture of diastereomers (12). Treatment of 12a with Eaton's reagent gave methyl (-)-O-methylpodocarpate (13), which can be obtained in enantiomerically pure form by recrystallization in good yield. Demethylation reaction with AlCl_3 and odorless sulfide gave (-)-podocarpic acid [(-)-15].

Journal

• Symposium on the Chemistry of Natural Products, symposium papers

  Symposium on the Chemistry of Natural Products, symposium papers 47 (0), 565-570, 2005

  Symposium on the Chemistry of Natural Products Steering Committee

Details

• CRID: 1390001206077503872
• NII Article ID: 110006682607
• DOI: 10.24496/tennenyuki.47.0_565
• ISSN: 24331856
• Text Lang: ja
• Data Source:
  • JaLC
  • CiNii Articles
• Abstract License Flag: Disallowed