Abstract:
Aristolactams are a subgroup of aporphinoids, with a common phenanthrene motif which is thought to be responsible for many interesting physicochemical and biological properties of these compounds. Among all the aristolactams discovered, (+)-aristolactam GI (127) displays a rather unique structural feature of having both the aristolactam scaffold linked to a phenylpropanoid unit, the latter of which allows 127 to belong to yet another important class of compounds called lignans. This project aims to investigate the first total synthesis of (+)-aristolactam GI (127).The synthesis began with an initial goal of achieving a MOM-protected aristolactam fragment (132), which could be used for the 1,4-benzodioxane formation step. Starting from veratraldehyde 135, intermediate isoindolin-1-one 143 was obtained. However, the subsequent selective MOM protection step of the catechol in 143 was not efficient enough to obtain sufficient amount of target product 144 for the forthcoming steps. Envisioning there would be more linear steps after 144, this synthetic plan was then considered implausible and was therefore abandoned. In the revised synthetic route, 2-hydroxy-4-methylbenzaldehyde 145 was chosen as the new starting material, in hopes of differentiating the two phenol protecting groups from an earlier stage. Thus, phenol 149was prepared. However, this route, again, was abandoned due to the unsuccessful syntheses of desired ketone 150 or aldehyde 152. Fortunately, this problem was solved by employing an isopropyl (i-Pr) protecting group instead, which had greater stability than a MOM group to various reaction conditions. After i-Pr-protected aristolactam 173 had been synthesized, two model studies were undertaken. Results from these model experiments, however, suggested that the i-Pr group would be problematic for the later deprotection and cyclization steps. As a consequence, MOM-protected analogue of 173 (aristolactam 191) was prepared (18 steps from 145). For the phenylpropanoid unit, functionalized alcohols 202 were also prepared (through a 7-step synthesis from methyl (R)-lactate (133) and bromide 183). Upon joining these two fragments (aristolactam 191and alcohol202) through a Mitsunobu reaction, desired adduct 203 was generated, which was successfully converted to the final target (+)-aristolactam (127), thereby completing the first total synthesis of this novel 1,4-benzodioxane-linked aristolactam-lignan hybrid.