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 22-hydroxyacuminatine (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/2-pyridone 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

Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate

“…The described derivatization strategy greatly expands the methods available for direct functionalization of native natural products and provides a rapid and systematic approach for further exploiting natural products for chemical genetics and addressing the ‘small molecule target identification problem.’ Other emerging methods for direct C–H functionalization 40,41 are also expected to be applicable and will potentially enable a truly universal approach for exploiting natural products for chemical genetics. 26,46,47 …”

A General Cp*CoIII‐Catalyzed Intramolecular C−H Activation Approach for the Efficient Total Syntheses of Aromathecin, Protoberberine, and Tylophora Alkaloids

“…First, two different aromathecin alkaloids that show biological activities as Topo‐I‐inhibitors were synthesized in three high‐yielding steps from isoquinolone compounds 2 a and 2 v (Scheme a). After the Mitsunobu reaction ( 3 a , 3 v ) and sequential oxidation using SeO 2 /PCC ( 4 a , 4 v ), the desired aromathecin alkaloids ( 5 a , 5 v ) could be obtained in high overall efficiency . Additionally, the isoquinolones 2 y and 2 z were converted to the 8‐oxyprotoberberine core ( 6 y , 6 z ) under Mitsunobu conditions in good‐to‐high yields (Scheme b).…”

Rh(III)- and Ir(III)-Catalyzed C–C Bond Cross Couplings from C–H Bonds

“…were designed and applied in redox-neutral couplings with alkynes [49][50][51][52][53][54]. In addition, an intramolecular version of this transformation was used as a key step allowing construction of indolizidine-based natural products like (AE)-antofine and (AE)-septicine [55] and (AE)-goniomitine, bearing a pyrido [1,2-a] indole core [56,57] (3).…”