title: Total synthesis of the aristolochic acids, their major metabolites, and related compounds.
abstract: Plants from the Aristolochia genus have been recommended for the treatment of a variety of human ailments since the time of Hippocrates. However, many species produce the highly toxic aristolochic acids (AAs), which are both nephrotoxic and carcinogenic. For the purposes of extensive biological studies, a versatile approach to the synthesis of the AAs and their major metabolites was devised based primarily on a Suzuki-Miyaura coupling reaction. The key to success lies in the preparation of a common ring-A precursor, namely, the tetrahydropyranyl ether of 2-nitromethyl-3-iodo-4,5-methylendioxybenzyl alcohol (27), which was generated in excellent yield by oxidation of the aldoxime precursor 26. Suzuki-Miyaura coupling of 27 with a variety of benzaldehyde 2-boronates was accompanied by an aldol condensation/elimination reaction to give the desired phenanthrene intermediate directly. Deprotection of the benzyl alcohol followed by two sequential oxidation steps gave the desired phenanthrene nitrocarboxylic acids. This approach was used to synthesize AAs I-IV and several other related compounds, including AA I and AA II bearing an aminopropyloxy group at position-6, which were required for further conversion to fluorescent biological probes. Further successful application of the Suzuki-Miyaura coupling reaction to the synthesis of the N-hydroxyaristolactams of AA I and AA II then allowed the synthesis of the putative, but until now elusive, N-acetoxy- and N-sulfonyloxy-aristolactam metabolites.
authors.affiliation: Department of Pharmacological Sciences, and ‡Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
authors.forename: Sivaprasad
authors.initials: S
authors.lastname: Attaluri
authors.forename: Charles R
authors.initials: CR
authors.lastname: Iden
authors.forename: Radha R
authors.initials: RR
authors.lastname: Bonala
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
mesh_terms: D034341:Aristolochic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D018736:DNA Adducts; D007769:Lactams / Q000138:chemical synthesis
chemical_list: D034341:Aristolochic Acids; D018736:DNA Adducts; D007769:Lactams