A Simple Enantioselective Route to Functionalized Indolizidines: Synthesis of (+)‐Ipalbidine and (+)‐Antofine

Pansare, Sunil V.; Lingampally, Rajinikanth; Dyapa, Rajendar

doi:10.1002/ejoc.201100125

Cited by 27 publications

(13 citation statements)

References 66 publications

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“…Because of both their remarkable biological profiles and unusual pentacyclic archi- Angewandte Chemie tectures, phenanthroindolizidine alkaloids, such as antofine (2) and tylophorine (3), are attractive targets for total synthesis. [2,17] Alkaloids 1, 2, and 3 could be readily prepared from amides 9 y and 9 z (Scheme 2). In the presence of [(Cp*RhCl 2 ) 2 ] (2.5 mol %), the reaction of 9 y and 9 z produced 2-pyridones 10 y and 10 z in excellent yields.…”

mentioning

confidence: 99%

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

2012

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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

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confidence: 99%

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

2012

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“…[2,17] Alkaloids 1, 2, and 3 could be readily prepared from amides 9 y and 9 z (Scheme 2). In the presence of [(Cp*RhCl 2 ) 2 ] (2.5 mol %), the reaction of 9 y and 9 z produced 2-pyridones 10 y and 10 z in excellent yields.…”

Section: Scheme 1 Proposed Mechanismmentioning

confidence: 99%

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

Liu

Park

2012

Angewandte Chemie

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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

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“…We also investigated the effect of reaction temperature (Table 2, entries 8 and 14- 16). The results showed that yields and enantioselectivities have not changed 5 significantly except for the increase of diastereoselectivity (82:18 dr) ( Under the above optimized conditions, the scope of the asymmetric Michael addition reaction was investigated by applying different aldehydes and nitroalkenes in the presence of 20 10 mol % of catalyst 5 and 10 mol% of benzoic acid in toluene at 0 °C. The results are summarized in Table 3.…”

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confidence: 97%

“…35 Additionally, catalyst 5 could be applied for the Michael addition of alkyl-substituted nitroalkene to aldehydes with high yield (94%) and excellent enantioselectivities (99%, entriy 18). On the basis of above condition, the catalytic direct asymmetric Michael addition of ketones to nitroalkenes was also 5 investigated, and the results are summarized in Table 4. As shown in Table 4, a dramatic lack of selectivity (55:45 dr, and 2% ee) was observed when using aliphatic ketone (Table 4, entry1).…”

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confidence: 99%

“…With these compounds as starting materials, ten amides (2-11) were easily 55 prepared in two steps in 84-91% overall yield (Scheme 1 and Scheme 2, for the general procedure see experimental section). Initially, the model reaction of propanal (12a) with nitrostyrene (13a) was carried out in the presence of 10 mol % of catalyst and 10 mol % of benzoic acid as an additive in toluene under room 5 temperature (Table 1). As shown in Table 1, catalysts 1-11 exhibited significantly different catalytic activity and enantioselectivity toward the process.…”

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confidence: 99%

See 1 more Smart Citation

Organocatalytic asymmetric Michael addition of aldehydes and ketones to nitroalkenes catalyzed by adamantoyl l-prolinamide

Wang

Lin

et al. 2015

RSC Adv.

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A Simple Enantioselective Route to Functionalized Indolizidines: Synthesis of (+)‐Ipalbidine and (+)‐Antofine

Cited by 27 publications

References 66 publications

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

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

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

Organocatalytic asymmetric Michael addition of aldehydes and ketones to nitroalkenes catalyzed by adamantoyl l-prolinamide

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