Enantioselective Synthesis of (−)‐10‐Hydroxyacutuminine

Abstract

An enantioselective synthesis of (À )-10hydroxyacutuminine is reported. Central to our strategy is a photochemical [2+2] cycloaddition that forges two of the quaternary stereocenters present in the acutumine alkaloids. A subsequent retro-aldol/Dieckmann sequence furnishes the spirocyclic cyclopentenone. Efforts to chlorinate the acutumine scaffold at C10 under heterolytic or radical deoxychlorination conditions led to the synthesis of an unexpected cyclopropane-containing pentacycle.

Developments in the Synthesis of Hasubanan Alkaloids

“…Reisman, 2022 [38] (À )-10-hydroxyacutuminine Enolate addition to chiral sufinyl imine Chiral auxiliary Scheme 3. Collective synthesis of hasubanan alkaloids via Robinson annulation of α-cyanomethyl-β-tetralone.…”

“…In order to show how this scheme could be transformed for acutumine alkaloids synthesis, Reisman used the adapted protocol (Scheme 16). [38] Since acutumine alkaloids lack aromatic ring, the initial steps are conceptually the same but another strategy had to be developed for CÀ C bond formation. In this case it was [2 + 2]-photocyclization of the furan derivative 46, followed by retro-aldol reaction and Dieckmann condensation.…”

The Role of N-Substitution in Regio- and Stereoselective Vinylogous Imidonaphthoquinone (VINAquinone) [2 + 2] Photocycloadditions

“…Although cyclobutane formation and fragmentation sequences have been employed previously, we were unaware of their use to generate spiro-fused quinones or naphthoquinones. , In addition to this, only a few examples of intramolecular [2 + 2] photocycloadditions of naphthoquinones have been reported. , The most relevant of these to our proposed sequence was communicated by Mori, Bach, and co-workers in 2022. , They described the intramolecular photocycloadditions of naphthoquinones 4 – 6 having a three-carbon tether between a terminal alkene and the naphthoquinone (Scheme ). Interestingly, while the reaction of 4 gave 7 as the major product, it also gave a small amount of crossed-cycloadduct 10 .…”

Catalytic Asymmetric Synthesis of Aza-Quaternary Carbon Cyclohexadieneones Enabled by Aminative Dearomatization of Phenols

“…For instance, aza-quaternary carbon cyclohexadieneone is the core structure of natural products demecolcinone (I) and erysodienone (II) and anticancer compound (III) . Additionally, the multiple unsaturations and functional groups make such structural units attractive platforms for total synthesis of natural alkaloids, such as 10-hydroxyacutuminine (IV), hasubanonine (V), and cylindricine C (VI) . Given the importance of aza-quaternary carbon cyclohexadieneones, their enantioselective synthesis is necessary.…”

“…Given the importance of aza-quaternary carbon cyclohexadieneones, their enantioselective synthesis is necessary. However, current approaches are usually indirect and rely on the use of chiral starting materials or reagents. − Oxidative dearomatization of a para -substituted phenol using commercially available hypervalent iodine reagent (e.g., PhI­(OAc) 2 , PhI­(O 2 CCF 3 ) 2 ) or other oxidants proves to be a direct synthetic route to an aza-quaternary carbon cyclohexadienone . While effective, this classical strategy only affords prochiral or racemic products …”