Rhodium(III)‐Catalyzed Intramolecular Annulation through CH Activation: Total Synthesis of (±)‐Antofine, (±)‐Septicine, (±)‐Tylophorine, and Rosettacin

Abstract

The indolizidine structural motif forms the core of many natural products with pharmacological relevance, such as indolizidine [1] and phenanthroindolizidine [2] alkaloids (septicine (1), antofine (2), and tylophorine (3)), camptothecin (4, CPT), [3] and aromathecin alkaloids [4] (rosettacin (5) and 22hydroxyacuminatine (6)). While a number of synthetic methods for the construction of these scaffolds have been reported, [1][2][3][4] the development of conceptually different synthetic approaches is still of great interest.The rhodium(III)-catalyzed oxidative CÀH activation has received significant interest in recent years because of its high efficiency, selectivity, and functional-group tolerance. [5] Generally, these reactions require stoichiometric amounts of external oxidants [Eq. (1)], [6] thus resulting in the generation of undesired waste. Recently, Fagnou et al. reported an oxidizing-directing-group strategy [7] for the rhodium-catalyzed synthesis of isoquinolones by intermolecular CÀH activation of N-methoxy/pivaloyloxy benzamides and alkynes [Eq.(2); Piv = pivaloyl], [8] which not only obviates the need for an external oxidant, but also increases the reactivity and selectivity under mild conditions. During our investigation of the reactivity of a-oximino carbenoids, [9] we observed facile intramolecular N À O insertion of oxime ether moieties, which results in the formation of 2-alkoxy/aryloxy-2H-azirines. [10] The cleavage of the N À O bond plays an important role in Fagnous rhodium-catalyzed intermolecular CÀH activation of N-methoxy/pivaloyloxy benzamides and in our NÀO insertion of a-oximino carbenes. Based on this observation, we became interested in the intramolecular reaction of alkyne-tethered hydroxamic esters [Eq. (3)]. The successful development of this reaction would lead to a general and facile synthesis of hydroxyalkyl-substituted isoquinolone/2pyridone derivatives, which could be readily transformed into indolizidine scaffolds. Herein, we wish to report these results, and the total synthesis of (AE)-antofine, (AE)-septicine, (AE)tylophorine, and rosettacin based on rhodium(III)-catalyzed C À H bond functionalization as the key step.Our synthetic attempts began with the reaction of 7 a by employing Fagnous intermolecular reaction conditions [7] ( Table 1, entries 1 and 2). We found that treatment of 7 a with [(Cp*RhCl 2 ) 2 ] (2.5 mol %) and CsOAc (30 mol %) in MeOH at 60 8C gave isoquinolones 8 a and 8 a' (29:1) in 98 % yield in 0.2 hours (Table 1, entry 1). Similar results were obtained with a reduced catalyst loading (0.5 mol %) and reaction temperature, however, a longer reaction time was required in this case (12 h; Table 1, entry 2). Improved

Catalyst‐Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

“…C À Ha ctivation of arenes,e specially using [Cp*Rh III ]a nd [Cp*Co III ]c atalysts,h as been established as an important strategy in the construction of important complex molecules such as polycycles [1] owing to sufficient metal-substrate interactions.I ng eneral, they are accessed by CÀHa ctivation/intramolecular couplings, [2] sequential twofold CÀH activation and couplings, [3] and C À Ha ctivation/coupling with p-bonds and further interactions with ap roximal group in the arene. [4] Given the power of cycloaddition reactions in synthesis of cyclic products,i ti sd esirable to integrate CÀH activation with cycloaddition reactions.H owever,e xamples are rather limited.…”

Direct Synthesis of Protoberberine Alkaloids by Rh‐Catalyzed C−H Bond Activation as the Key Step

“…The protocol was successfully appliedt ot he synthesis of natural products, such as 13-methylpalmatine (6), dehydrocavidine (7), 13-methylberberrubine (8), corysamine (9), and pseudohydrocorydaline (10), with 65-75 %overall yields under mild reaction conditions by using O 2 as the oxidant. In addition, pyridiniums alts were also formed in good yields from a,b-unsaturated aldehydes and alkyne-amines.…”

“…[4] In recent years,t he intermolecular Rh III or Ru II -catalyzed CÀHa ctivation andc yclization with alkynes represent ap owerful tool for the synthesis of highlyf unctionalized heterocycles. [8] However,o nly two intramolecular reactions for alkyne tethers have been reportedr ecently.P ark and co-workersr evealed aR h III -catalyzed intramolecular annulationo fa lkyne-tethered hydroxamic esterst oa fford 3-hydroxyalkylisoquinolones and 6-hydroxyalkyl-2-pyridones, [9] while MascareÇas, Gulías and co-workers re-portedaRh-catalyzed synthesis of tricyclic isoquinolinesb yt he intramolecular annulations of alkyne-tethered benzamides. [8] However,o nly two intramolecular reactions for alkyne tethers have been reportedr ecently.P ark and co-workersr evealed aR h III -catalyzed intramolecular annulationo fa lkyne-tethered hydroxamic esterst oa fford 3-hydroxyalkylisoquinolones and 6-hydroxyalkyl-2-pyridones, [9] while MascareÇas, Gulías and co-workers re-portedaRh-catalyzed synthesis of tricyclic isoquinolinesb yt he intramolecular annulations of alkyne-tethered benzamides.…”

“…[5][6][7] However, in most cases, the reactions with unsymmetrical alkynes show low regioselectivity.C onsequently,i ntramolecular reactions are highly attractive in terms of regioselectivity,h igh efficiency,a nd versatility for fused heterocyclic compounds.Ahighly enantioselective intramolecular hydroarylation of alkenet ethers by Rh III -catalyzed ortho-directedC ÀHb ond activationsi sk nown. [8] However,o nly two intramolecular reactions for alkyne tethers have been reportedr ecently.P ark and co-workersr evealed aR h III -catalyzed intramolecular annulationo fa lkyne-tethered hydroxamic esterst oa fford 3-hydroxyalkylisoquinolones and 6-hydroxyalkyl-2-pyridones, [9] while MascareÇas, Gulías and co-workers re-portedaRh-catalyzed synthesis of tricyclic isoquinolinesb yt he intramolecular annulations of alkyne-tethered benzamides. [10] .…”

Organokatalytische oxidative Anellierung von Benzamid‐Derivaten mit Alkinen

“…[1] Methoden zur direkten Kupplung nichtfunktionalisierter Verbindungen bilden eine umweltverträgliche und wirtschaftlich attraktive Synthesestrategie für die gewünschten Produkte. [3][4][5][6][7][8] Beeindruckende Anellierungen mit Alkinen wurden zuerst von Fagnou und Mitarbeitern unter Einsatz einer Rhodiumkatalysierten direkten C-H-Aktivierung entwickelt. [1] Isochinoline und Isochinolone sind wichtige heterocyclische Gerüste mit einer großen Bandbreite an biologischen Aktivitäten.…”