From C-H Activation to Biomimetic Synthesis: The Construction and Reconstruction of Yuremamine

Abstract

This thesis describes a synthetic journey that culminated in the structural revision of yuremamine (2), a natural product isolated from the entheogenic plant Mimosa tenuiflora. The initial synthetic approach to yuremamine examined the use of iterative sp3 arylation reactions to install the aryl groups in a regioselective and diastereoselective fashion. Model studies identified 176 and 142 as the best aryl iodide substrates and 8-aminoquinoline as the best directing group for the sp3-arylations reactions. Sequential sp3-arylations with 176 and 142 occurred with the desired cis-selectivity to give the diarylated indane 186. O HN N MOMO OMOM OMe (±)-186 OMe MeO O HN N 163 MOMO OMOM I O HN N MOMO OMOM (±)-178 176 142 OMe I OMe MeO sp3 arylation sp3 arylation N OH OH HO OH HO HO NMe2 yurem2amine N OH HO OH HO HO NMe2 I I DG 2 x sp3 arylation Model studies We sought to apply the successful results from the model study in the synthesis of yuremamine itself. Early sp3 arylation reactions on pyrroloindole substrates 308 and 330 with the aryl iodide 142 indicated C-1 underwent arylation in preference to C-3, giving the products 318 and 331 with good cis-diastereoselectivity, albeit in low yield and accompanied by the C-9 arylated product 319. The side reactions could be eliminated by using the methyl-substituted pyrroloindole 338, which underwent the desired sp3-arylation with aryl iodide 176, giving the C-1 arylated product 348. The second sp3 arylation of 348 with aryl iodide 142 proceeded at the desired C3 site giving the diarylated yuremamine core structure 360, which unfortunately possessed the aryl groups in a 1,3-trans relationship resulting from epimerisation during the reaction conditions. Given the unsuccessful sp3-arylation approach, a new synthetic strategy to yuremamine was devised that was based on our own proposed biosynthesis of the natural product, which hinged on the skeletal rearrangement of flavanoidal indole 408. The Lewis acid-mediated condensation of N,N-dimethyltryptamine (DMT) with flavan-3,4- diol 439 gave flavanoidal indole 408 with excellent β-diastereoselectivity. Upon conversion of 408 to its TFA salt, its NMR data was identical to that of the natural product. Detailed NMR analysis of 408, along with its spectroscopic comparison with the authentic sample of the natural product and X-ray crystal structure unequivocally supported the structural revision of yuremamine from the putative pyrroloindole 2 to flavanoidal indole 408, which was initially proposed as a biosynthetic intermediate.