Asymmetric Total Synthesis of (−)-Thebainone A

Morphine (5) and its congeners are among the oldest and most studied alkaloid natural products, many of which have potent neurological and immunological activity. (33) They generally possess a poly bridged/fused ring system, a quaternary center, a basic tertiary amine moiety and a 1,2,3,4-tetrasubstituted arene. As a unique member in the morphine-family alkaloids, thebainone A (7) contains an enone moiety in the C ring, which has served as a precursor to synthesize morphine (5) and codeine (6). (34) However, the asymmetric synthesis of thebainone A was not reported previously. We devised a deconstructive strategy to synthesize (−)-thebainone A, in which the nitrogen-containing D ring is constructed in the end from an ether precursor (87a), and the fused A/B/C ring core structure, along with a quaternary carbon center, is assembled via an asymmetric cut-and-sew reaction (Scheme 20A). (10d)

Scheme 20. Deconstructive Asymmetric Total Synthesis of (−)-Thebainone A

In a forward manner, the cut-and-sew precursor 88a was prepared in four steps from compounds 89 and 90 (Scheme 20B). The challenges of the key C–C activation-enabled (4 + 2) cycloaddition with compound 88a were associated with the presence of an acid-sensitive ketal, a trisubstituted olefin coupling partner, and a relatively long linker. Ultimately, the use of [Rh(COD)2]NTf2 and DTBM-segphos as the catalyst combination afforded high yield and excellent e.e. with 1,2-difluorobenzene as the solvent. This condition can also be used to construct other tetracycles with different olefin coupling partners, linkers, and functional groups (Scheme 20C). With ketone 87a in hand, the cyclic ether C–O bond was selectively cleaved by BBr3, and alkyl bromide 91 was accessed in four steps. Subsequently, ketone protection, SN2 amination, and Ac deprotection were achieved in one pot. The following dehydration with Martin’s sulfurane gave amine 92. The piperidine D ring was constructed by a radical-mediated hydroamination of the alkenyl group through reduction of the tosylamide moiety. Finally, selective deprotection of the middle methyl ether by NaSEt gave ketone 93, followed by desaturation by Stahl’s protocol, (35) and furnished the first enantioselective total synthesis of (−)-thebainone A (7). It is worthy to note that intermediate 93 is also a known precursor to morphine (5) and codeine (6).