Synthesis of strychnine and the Wieland-Gumlich aldehyde

Article abstract of DOI:10.1021/ja00071a025

The tetracyclic amine 9 was converted through several steps into secondary amine 13 and acetylated with (phenylthio)acetic acid activated by bis(2-oxo-3-oxazolidinyl)phosphinic acid to give amide 15. Treatment of 15 with sodium hydride in tetrahydrofuran at 25 °C resulted in rapid conversion into a single diastereomer, 16. This same conjugate addition has been conducted at the sulfoxide oxidation level and also with a chiral sulfoxide to provide optically active compounds (Scheme VI). Conversion of sulfoxide 19 into dione 27 followed by ketalization and reduction gave tertiary amine 34. Deprotection and oxidation with mercuric acetate gave the core strychnine skeleton 36. The β-aminoacrylate double bond in 36 was reduced to give 39 followed by epimerization to give 40. Ester 40 was protected as the sulfonamide derivative 44, and the ester was reduced to give 45. Alcohol 45 undergoes normal acid hydrolysis to give hemiketal 47 (Scheme X). The Wieland-Gumlich aldehyde 48 was converted into the relay compound by the route shown in Scheme XI, thus providing a convenient correlation and short route to 47. Hemiketal 47 was converted into ketone 52 and treated with (EtO)₂P(O)CH₂CN/KN(SiMe₃)₂/THF at 25 °C to give the two geometrical isomers 53 (E) and 54 (Z) (overall 72%) in a ratio of 3:2. The incorrect stereoisomer could be recycled by irradiation in benzene to give a mixture of 53 and 54. Reduction of 53 gave the required allylic alcohol 55. Desilylation of 55 gave diol 56. The synthesis of strychnine and the Wieland-Gumlich aldehyde was completed by selective silylation of the allylic hydroxyl group in 56 and oxidation to give the unstable aldehyde 58. Desilylation of 58 gave the protected Wieland-Gumlich aldehyde 49, which was deprotected by treatment with sodium anthracenide to give 48. The conversion of 48 into strychnine was reported by Robinson in 1953.