Selective Deconstructive Lactamization of the Indolo[2,3‐<i>a</i>]quinolizine Skeleton for the Total Synthesis of (+) and (−)‐Cuscutamine

Recoba‐Torres, Adriana; Cruz‐Gregorio, Silvano; Quintero, Leticia; Sandoval‐Lira, Jacinto; Romero‐Ibañez, Julio; Sartillo‐Piscil, Fernando

doi:10.1002/ejoc.202200292

Cited by 6 publications

(8 citation statements)

References 39 publications

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“…Execution of the proposed idea was performed with N -benzyl piperidine 3 . The first step, which involves the selective and dual C–H oxidation of 3 to 4a can be successfully achieved by following any of the two reported protocols, , one in which the oxoammonium cation is formed in situ by reacting TEMPO with NaClO 2 and NaOCl (Method A), or by using TEMPO + cation freshly prepared plus NaClO 2 (Method B) . Subsequently, the phosphonium salt [Ph 3 P + CH 2 CO 2 Me]Br – , which produces the corresponding stabilized P-ylide under base conditions, was selected for testing the title reaction.…”

Section: Resultsmentioning

confidence: 99%

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β-Alkenylation of Saturated N-Heterocycles via a C(sp³)–O Bond Wittig-like Olefination

Nolasco-Hernández,

Quintero,

Cruz-Gregorio

et al. 2024

J. Org. Chem.

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Although the C−H α functionalization of N-heterocycles is, in fact, an easy chemical transformation, the C−H β functionalization is, on the contrary, a quite difficult chemical process. Here, we present a two-step protocol that allows the ready conversion of pyrrolidines, piperidines, and an azepane into their corresponding 3-exo-alkenyl lactams via the transient formation of 3-alkoxyamino lactams followed by a Wittig-like C(sp 3 )−O bond olefination with stabilized ylides from phosphonium salts mediated by t-BuOK. Additionally, as a proof of the synthetic effectiveness of this novel methodology, the first synthesis of the natural product callylactam A was achieved through a TiCl 4 -catalyzed double bond isomerization of a 3-exo-alkenyl 2-piperidone to its endo-isomer.

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Section: Resultsmentioning

confidence: 99%

“…To a solution of cyclic amine (pyrrolidine, piperidine, or azepane) (2.17 mmol) in CH 3 CN (72.3 mL) was added 2,2,6,6-tetramethyl-1-oxo-piperidinium tetrafluoroborate (6.5 mmol). 9 Immediately, NaClO 2 (7.6 mmol) was added. The mixture was allowed to stir for 15 min at rt.…”

Section: Experimental Partmentioning

confidence: 99%

β-Alkenylation of Saturated N-Heterocycles via a C(sp³)–O Bond Wittig-like Olefination

Nolasco-Hernández,

Quintero,

Cruz-Gregorio

et al. 2024

J. Org. Chem.

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“…Oxidation of lactam 78 with m CPBA leads to the α-ketoamide 80 , which readily reacts via Baeyer–Villiger oxidation and subsequent decarboxylation to the γ-lactam 82 (Scheme c) . This interesting transformation was developed during studies toward the total synthesis of (+)- and (−)-Cuscutamine (not shown) …”

Section: Oxidation Reactionsmentioning

confidence: 99%

“…731 This interesting transformation was developed during studies toward the total synthesis of (+)-and (−)-Cuscutamine (not shown). 732 Under modified conditions, the enamine 66 can engage in various radical transformations. For example, a NO 2 radical derived from tert-butylnitrite 733 or an α-carbonyl radical derived from acetone with dicumyl peroxide (DCP) and copper chloride 734 were shown to add to enamines of type 66, forming after renewed oxidation and deprotonation nitrotetrahydropyridines 67 or ketones 68 (Scheme 30d and 30e).…”

Section: Physical Properties and Reactivitymentioning

confidence: 99%

Organic Synthesis Using Nitroxides

Leifert

Studer

2023

Chem. Rev.

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Nitroxides, also known as nitroxyl radicals, are long-lived or stable radicals with the general structure R 1 R 2 N−O • . The spin distribution over the nitroxide N and O atoms contributes to the thermodynamic stability of these radicals. The presence of bulky N-substituents R 1 and R 2 prevents nitroxide radical dimerization, ensuring their kinetic stability. Despite their reactivity toward various transient C radicals, some nitroxides can be easily stored under air at room temperature. Furthermore, nitroxides can be oxidized to oxoammonium salts (R 1 R 2 N�O + ) or reduced to anions (R 1 R 2 N−O − ), enabling them to act as valuable oxidants or reductants depending on their oxidation state. Therefore, they exhibit interesting reactivity across all three oxidation states. Due to these fascinating properties, nitroxides find extensive applications in diverse fields such as biochemistry, medicinal chemistry, materials science, and organic synthesis. This review focuses on the versatile applications of nitroxides in organic synthesis. For their use in other important fields, we will refer to several review articles. The introductory part provides a brief overview of the history of nitroxide chemistry. Subsequently, the key methods for preparing nitroxides are discussed, followed by an examination of their structural diversity and physical properties. The main portion of this review is dedicated to oxidation reactions, wherein parent nitroxides or their corresponding oxoammonium salts serve as active species. It will be demonstrated that various functional groups (such as alcohols, amines, enolates, and alkanes among others) can be efficiently oxidized. These oxidations can be carried out using nitroxides as catalysts in combination with various stoichiometric terminal oxidants. By reducing nitroxides to their corresponding anions, they become effective reducing reagents with intriguing applications in organic synthesis. Nitroxides possess the ability to selectively react with transient radicals, making them useful for terminating radical cascade reactions by forming alkoxyamines. Depending on their structure, alkoxyamines exhibit weak C−O bonds, allowing for the thermal generation of C radicals through reversible C−O bond cleavage. Such thermally generated C radicals can participate in various radical transformations, as discussed toward the end of this review. Furthermore, the application of this strategy in natural product synthesis will be presented.

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“…Unfortunately, these catalysts are generally quite expensive and toxic, causing economic and ecological drawbacks [19,20]. Most recently, a dual C-H oxidation of piperidines to their corresponding piperidin-2-one derivatives under transition-metal-free conditions has shown to be an efficient, accessible, and eco-friendly approach for accessing biologically important alkaloids [21][22][23]. Although the 3,4-dioxygenated-2-pyperidone system could be considered a noncomplex molecular motif, there are only a few known approaches to accessing them in an asymmetric fashion [12].…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of trans-3-Alkoxyamino-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and Its CAL-B-Assisted Enzymatic Resolution

et al. 2023

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A general chemo-enzymatic approach to synthesize both enantioenriched trans-3-alkoxyamino-4-oxy-2-piperidones, which are important scaffold for various naturally occurring alkaloids, is reported. To this end, a selective transition-metal-free dual C−H oxidation of piperidines mediated by the TEMPO oxoammonium cation (TEMPO+) was used, followed by enzymatic resolution of the corresponding alkoxyamino-2-piperidones with Candida antarctica lipase (CAL-B), to yield the title compounds in high enantiomeric excess (ee). The absolute configuration of both enantioenriched compounds was determined using chemical correlation and circular dichroism (CD) spectroscopy. The former method highlights the oxidative ring contraction of the trans-alkoxyamine-2-piperidone ring into its corresponding 2-pyrrolidinone.

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Selective Deconstructive Lactamization of the Indolo[2,3‐a]quinolizine Skeleton for the Total Synthesis of (+) and (−)‐Cuscutamine

Cited by 6 publications

References 39 publications

β-Alkenylation of Saturated N-Heterocycles via a C(sp³)–O Bond Wittig-like Olefination

β-Alkenylation of Saturated N-Heterocycles via a C(sp³)–O Bond Wittig-like Olefination

Organic Synthesis Using Nitroxides

Asymmetric Synthesis of trans-3-Alkoxyamino-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and Its CAL-B-Assisted Enzymatic Resolution

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Selective Deconstructive Lactamization of the Indolo[2,3‐a]quinolizine Skeleton for the Total Synthesis of (+) and (−)‐Cuscutamine

Cited by 6 publications

References 39 publications

β-Alkenylation of Saturated N-Heterocycles via a C(sp3)–O Bond Wittig-like Olefination

β-Alkenylation of Saturated N-Heterocycles via a C(sp3)–O Bond Wittig-like Olefination

Organic Synthesis Using Nitroxides

Asymmetric Synthesis of trans-3-Alkoxyamino-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and Its CAL-B-Assisted Enzymatic Resolution

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Product

Resources

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β-Alkenylation of Saturated N-Heterocycles via a C(sp³)–O Bond Wittig-like Olefination

β-Alkenylation of Saturated N-Heterocycles via a C(sp³)–O Bond Wittig-like Olefination