シクロプロパン環の開裂反応を利用した生理活性天然有機化合物の合成研究
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The cleavage reaction of cyclopropane ring is one of the useful method in organic synthesis. Especially, the sequence of cyclopropanation-homoconjugate addition is one of the accessible methods for the synthesis of natural products possessing ring and side-chain contiguous chiral centers. This paper deals with the synthetic studies of biologically active natural products possessing such chiral centers by using the ring opening reaction of double activated cyclopropanes. Methyl 6-exo-methyl-2-oxobicyclo[3. 1. 0]hexane-1-carboxylate (1), the main starting material for the synthesis of target moleculars has been synthesized in chapter 1. Alkylation of the dianion of methyl acetoacetate with 1-chloro-2-butene followed by diazo transfer and copper-mediated cyclopropanation to give cyclopropane (1) in moderate yield. Three other cyclopropane derivatives (4, 8 and 10) have been prepared in the same manner. Optically active cyclopropane derivatives (19 and 20) has been obtained from l-menthyl acetoacetate (12) by optical resolution of diastereomeric mixture (15+16). The stereochemical course of homoconjugate addition to an activated cyclopropane has been elucidated in chapter 2. It has been apparent that the opening reaction proceed with inversion of absolute configuration at the apical carbon of the cyclopropane. (2RS, 3RS) -2-Methyl-3-[(1RS) -1, 5-dimethylhexyl]cyclopentanone (35), the key intermediate in the synthesis of vitamin D_3, has been prepared stereoselectively using the cuprous iodide-mediated homoconjugate addition of Grignard reagent in chapter 3. Treatment of 1 with 4-methylpentylmagnesium bromide in the presence of cuprous iodide to give keto ester (49). Methylation followed by decarbomethoxylation gave desired ketone (35). 1- (1'-Hydroxyethyl) -7, 7a-dihydro-5 (6H) -indanone-7a-carboxylic acid-7a, 1'-lactone (58), a potential intermediate for the synthesis of steroid (55) containing E (lactone) ring, was synthesized stereoselectively using the acid catalyzed homoconjugate addition of methanol to cyclopropane (1) in chapter 4. The reaction gave 1, 5-adduct (21), which was converted to diketone (60) by treatment with methyl vinyl ketone. Lactonization followed by aldol condensation gave desired tricyclic lactone (58). Chapter 5 deals with a preparation of(2RS)-2-[(1RS)-3-oxocyclohexyl]propanoic acid (71), the key intermediate in the synthesis of the naturally occurring juvenile hormone juvabione (70), by employing the homoconjugate addition of cyanide anion to bicyclo [4, 1, 0]heptane derivative (10). Treatment of 10 with sodium cyanide in dimethylsulfoxide gave cyanide (73). Decarbomethoxylation followed by acid hydrolysis gave desired keto acid (71). Plinol A (83), B (84), C (85) and D (86) have been derived from linalool by an ene reaction. The short step synthesis of plinol A and B have been achieved starting from methoxy keto ester (21) via ketone (99) in six steps in chapter 6. Bicyclic lactone (23) was converted to plinol C in eight step sequences. The key reaction of the synthesis is stereoselective introduction of C-1 methyl group of plinol C to ketone (102). In addition, enantioselective synthesis of plinol A and C has been achieved starting from (+)-23. In chapter 7, the synthesis of (2RS, 3SR)-2-hydroxyethyl-3-[(1RS)-1-hydroxyethyl]cyclopentanone derivative (157), a potential intermediate in the synthesis of thienamycin, has been discussed. Introduction of C2 unit to keto ester (21) at C-2 position afforded 146 which was transformed into secondary alcohol (153) in six steps. Mitsunobu reaction of 153 gave desired cyclopentanone (157) possessing correct stereochemistry in thienamycin. The synthesis of (±)-1'-epiinvictolide (163) has been reported in charpter 8. The cyclopropane (1) was treated with n-propylmagnesium bromide in the presence of cuprous iodide to give keto ester (166), which was transformed into ketone (168) by methylation followed by decarbomethoxylation. 1, 3-Carbonyl transposition of 168 using Wharton rearrangement afforded ketone (174). Baeyer-Villiger oxidation of 174 followed by methylation to give (±)-1'-epiinvictolide, the stereoisomer of queen recognition pheromone of red imported fire ant. An iridoid monoterpene hop ether (180), a constituent of the volatile oil of Japaniese hops, has been synthesized in chapter 9. Bicyclic lactone (23) was converted to methyl ketone (186) in four step sequences containing katalization, reduction, silylation and oxidation. (±)-Hop ether (180) was obtained after introduction of methyl group followed by desilylation, cyclization, deketalization and methylenation. Stereocontrolled total synthesis of (±)-dihydronepetalactone (190), physiologically active compornent for the Felidae animals, has been accomplished in chapter 10. The cyclopropane (1) was treated with sodium cyanide in dimethylsulfoxide to give cyanide (191). It was transformed into unsaturated lactone (197) in six steps by usual operations. The lactone (197) was converted to dihydronepetalactone (190) by stereoselective introduction of C-1 methyl group using Gilmann reagent. Chapter 11 deals with the unsuccessful approach for the synthesis of other biologically active natural products (rudmollin (198), valerenal (208) and sarkomycin (229)).
- 大阪府立大学の論文
- 1991-03-31