Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

Abstract

Herein, we describe the development of ad econstructive strategy for the first asymmetric synthesis of (À)thebainone A, capitalizing on an enantioselective CÀCb ond activation and aC ÀOb ond cleavage reaction. The rhodiumcatalyzeda symmetric "cut-and-sew" transformation between sterically hindered trisubstituted alkenes and benzocyclobutenones allowed efficient construction of the fused A/B/C rings and the quaternary center of the natural product. The newly optimizedconditions show broad substrate scope and excellent enantioselectivity (up to 99.5:0.5 er). Taking advantage of boron-mediated ether bond cleavage,w ec ompleted the synthesis of the morphine alkaloid (À)-thebainone Ab yt wo complementary routes. Figure 1. Morphine and related alkaloids.

Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

“…Notably,t he asymmetric "cut-andsew" reaction can be run on a2g scale with ar educed catalyst loading without loss of enantioselectivity (entry 14). Thes tructure and relative configuration of compound 6 were confirmed by X-ray crystallography; [14] its absolute stereochemistry was later confirmed by X-ray crystallography of its derivative 16 (see below, Scheme 6). [14] Scope of the Enantioselective "Cutand-Sew" Reaction Theh igh efficiencya nd selectivity enabled by the new catalytic conditions motivated us to examine the scope of the enantioselective "cut-and-sew" transformation with different cyclic trisubstiuted alkenes Tabelle 1: Selected optimization of the CÀCactivation reaction with substrate 7a.…”

“…Chemie Forschungsartikel 13170 www.angewandte.de protection followed by in situ ketal removal afforded ketone 12 [14] in 94 %y ield over two steps on gram scales.T here are substantial challenges to cleave the C À Ob ond of the dihydropyran moiety in intermediate 12:1 )the ether bond lacks sufficient ring strain for opening;2 )the presence of other oxygen functional groups,including ketones and esters, in the substrate can inhibit Lewis acid coordination;a nd 3) due to the rigid molecular scaffold, the CÀOb ond reformation was found to be facile,which became asignificant difficulty for handling the ring-opened product. Ultimately, we found that treatment of 12 with BBr 3 (5 equiv) in DCM at À30 8 8Cf or 72 hd elivered the diphenol intermediate ( 13)i n good yield.…”

“…On ag ram scale, the yield of 14 dropped to 28 %p lus 32 %o ft he partially protected product (13 a)a nd 28 %o ft he prior substrate (12). [14] However, 13 a can be further transformed to 14 in 68 %yield, along with forming 18 %of12 that can be cycled, combined, and reused. With asufficient amount of 14 in hand, the subsequent ketone protection and amination through an S N 2reaction, followed by removal of the Ac protecting group, occurred smoothly in one pot to provide 15 with 76 %y ield.…”

Skeleton Reorganization of Substituted Benzocyclobutenols through Rh-Catalyzed C–C Bond Cleavage Manipulated by Hydrogen Transfer

“…In recent years, Dong and co-workers reported a variety of beautiful examples that realized the intramolecular rearrangement of benzocyclobutenones through Rh-catalyzed C–C bond activation and a subsequent insertion with 2π units . Encouraged by these promising results, we are interested in the reorganization of the intramolecular skeleton of benzocyclobutenols for the following reasons: (1) the different mechanisms to cleave the C–C bond in benzocyclobutenones and benzocyclobutenols (oxidative addition vs β-carbon elimination) may lead to different subsequent transformations, (2) the reaction of benzocyclobutenols might proceed under milder conditions than that of benzocyclobutenones due to the higher tendency of β-carbon elimination, and (3) the intramolecular reactions of benzocyclobutenols may offer the opportunity to construct more complicated cyclic compounds in contrast to the well-developed intermolecular reactions.…”

Rh-Catalyzed Cascade C–C/Colefin–H Activations and Mechanistic Insight

“…Atom-economical synthesis has been spurring a variety of novel transformations, among which transition-metal (TM)-catalyzed disconnection/recombination of an inert C–C σ bond (“cut and sew” process) has emerged as a hot topic in both complex ring system assembly and in natural product synthesis . The normal “cut and sew” process is initiated by a low-valence TM, which will be oxidatively added (OA) by an inert C–C bond, leading to a metallacycle (Scheme ).…”