Total synthesis of the stemodane-type diterpenoids (±)-stemodin and (±)-maritimol. Formal total synthesis of (±)-stemodinone and (±)-2-desoxystemodinone

Abstract

Total syntheses of the stemodane-type diterpenoids (±)-stemodin (2) and (±)-maritimol (4), as well as formal total syntheses of (±)-stemodinone (3) and (±)-2-desoxystemodinone (5), are described. The known ketol 12 was converted into the tricyclic enone 7. Photoaddition of aliène to 7 gave (96%) a mixture of the photoadducts 20–23 (40:51:6:3, respectively). Ozonolysis of 20, followed by treatment of the resultant dione 24 with MeONa–MeOH (room temperature, 2.5 h), provided the keto ester 26 (94%). Subjection of 21 to an identical sequence of reactions gave (86%) the same product 26. On the other hand, when the dione 25 was treated with MeONa–MeOH under much milder conditions (0 °C, 5 min), the isomeric keto esters 27 (39%) and 28 (33%) were produced. Both 27 and 28, upon reaction with MeONa–MeOH at room temperature, were converted efficiently into 26. Reduction (NaBH4 or Lisec-Bu3BH) of 26 provided separable mixtures of the ester alcohol 32 and the lactone 33, which could be transformed readily into the dimesylates 35 and 39, respectively. Reaction of 35 and 39 with NaCN in warm hexamethylphosphoramide afforded the dinitriles 37 and 40, both of which, upon treatment with t-BuOK in refluxing t-BuOH, produced the sameenaminonitrile 41. Acid hydrolysis of 41 provided the dione 42. Preparatively, compound 26 could be transformed conveniently into the dione 42 (52% overall yield) without separation of mixtures of isomeric synthetic intermediates. Treatment (CH2Cl2, −95 °C) of 42 with Mc3Sil–Et3N, followed by oxidation of the resultant products 46 and 47 with Pd(OAc)2 in acetonitrile, gave the bis enones 48 (67%) and 49 (19%). Compound 48 was converted into the dione 52 which, upon reaction with (i-PrO)3 TiMe in ether, provided an 86:14 mixture of the keto alcohols 53 and 54 (63% from 48). Reduction (NaBH4) of 53 afforded (±)-maritimol (4). On the other hand, conversion of the 86:14 mixture of 53 and 54 into the p-toluenesulfonylhydrazones 55 and subsequent reaction of 55 with NaH in refluxing toluene gave the alkene alcohols 56 (58%) and 57 (12%). Hydroboration–oxidation (9-BBN, refluxing tetrahydrofuran; NaOH, H2O2) of 56 afforded (88%) (±)-stemodin (2).