Catalytic Asymmetric Synthesis of Physiologically Active Related compounds Bearing Lactone or Lactam Ring

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16550103
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Synthetic chemistry
• Research Institution: Kinki University
• Principal Investigator: OKADA Yoshiharu Kinki University, School of Engineering, Assistant Prof., 工学部, 助教授 (30253553)
• Co-Investigator(Kenkyū-buntansha): NOMURA Masato Kinki University, School of Engineering, Prof., 工学部, 教授 (60140315)
• Project Period (FY): 2004 – 2005
• Keywords: Triethyl Phosphonoacetate / Phosphine-carboxylic Acid / Asymmetric Synthesis / Chiral Ligand / Thiazolidine Derivative / Isocyanate

Research Abstract

In the transition metal complex catalyzed asymmetric synthesis, one of the most important needs is the development of effective chiral ligands. We describe here the synthesis of a bulky type of 2-diphenylphosphino-9,10-dihydro-9,10-ethanoanthracene bearing carboxyl group. Reaction of 1 with methyl acrylate gave an isomer mixture of 2a-d in 94% yield. Recrystallization of the mixture from ethyl acetate-hexane gave a pure 2b as a first crystal. Recycling preparative HPLC of the filtrate with CHCl_3 was succeeded to separate 2a. Reduction of 2b with HSiCl_3 and subsequent alkaline hydrolysis gave (±)-2-diphenylphosphino-9,10-dihydro-9,10-ethanoanthracene-12(anti)-carboxylic acid (3b) in 43% yield. Resolution of (±)-3b with (-)-α-methylbenzyl-amine was succeeded to give an optically pure (-)-3b, [α]_D^<23>=-37.55 (c 0.39, CHCl_3). The reaction of triethyl sodiophosphonoacetate with 2-cyclohexenyl acetate in the presence of Pd(OAc)_2・(-)-3b (1.5 mol%) gave the allylic alkylation product in 96% (53%ee).
On the other hand, many compounds containing thiazolidinedione moiety such as rosiglitazone and pioglitazone have been useful as the medicine. However, the convenient synthesis of thiazolidine derivatives having phosphorus functional group has been rarely reported, to our knowledge. We now report the synthesis and synthetic application of 5-(diethylphosphono)-1,3-thiazolidine derivatives. Treatment of triethyl phosphonoacetate with sodium hydride and powdered sulfur generated thiolate anion intermediate. And subsequent reaction with phenyl isocyanate (4a) gave thiocarbamate 5a in 40% yield. While similar reaction with benzyl isocyanate (4b) gave 3-benzyl-5-(diethylphosphono)-1,3-thiazolidinedione (6b) in 8% yield together with thiocarbamate 5b in 25% yield.