Asymmetric synthesis of (−)-naltrexone

Dongbang, Sun; Pedersen, Blaine; Ellman, Jonathan A.

doi:10.1039/c8sc03748e

Cited by 19 publications

(18 citation statements)

References 74 publications

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“…To synthesize pseudoanisatin ( 5 ), or a related compound like debenzoyldunnianin ( 61 ), oxidation of the conserved C14 position was unavoidable. While ambitious, late-stage C–H functionalization reactions have been employed in synthesis, and we deemed 60 well-poised for a directed oxidation from the C3 alcohol unit to the C14 methyl center (see dashed green arrow in Scheme ). To our great dismay, alkoxy radical generating conditions, including hypoiodite photolysis (PhI(OAc) 2 , I 2 ), nitrite photolysis, or lead- and mercury-based transformations (Pb(OAc) 4 and HgO, respectively), were unsuccessful at accessing any desired C14 oxidation.…”

Section: Resultsmentioning

confidence: 99%

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes

et al. 2019

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The Illicium sesquiterpenes are a family of natural products containing over 100 highly oxidized and structurally complex members, many of which display interesting biological activities. This comprehensive account chronicles the evolution of a semisynthetic strategy toward these molecules from (+)-cedrol, seeking to emulate key aspects of their presumed biosynthesis. An initial route generated lower oxidation state analogs, but failed in delivering a crucial hydroxy group in the final step. Insight gathered during these studies, however, ultimately led to a synthesis of the pseudoanisatinoids along with the allo-cedrane natural product 11-O-debenzoyltashironin.A second-generation strategy was then developed to access the more highly oxidized majucinoid compounds including jiadifenolide and majucin itself. Overall, one dozen natural products can be accessed from an abundant and inexpensive terpene feedstock. A multitude of general observations regarding site-selective C(sp 3 )-H bond functionalization reactions in complex polycyclic architectures are reported.

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Section: Resultsmentioning

confidence: 99%

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes

et al. 2019

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“…We envisioned that with readily available inputs, an intramolecular C–H activation, alkenylation, electrocyclization, and reduction sequence could provide rapid access to fused bicyclic cores that in just a few additional steps could be taken on to diverse morphinan products. To demonstrate this approach, we reported total syntheses of the enantiomer of the semisynthetic opioid agonist (+)-ketorfanol , and the more complex opioid antagonist (−)-naltrexone, , which is widely used to treat opioid addiction.…”

Section: Asymmetric Synthesis Of (+)-Ketorfanol and (−)-Naltrexonementioning

confidence: 99%

“…The feasibility of accessing the morphinan core by a torquoselective Rh(I)-catalyzed C–H alkenylation/electrocyclization cascade paved the way for our efficient preparation of the more complex opioid antagonist (−)-naltrexone (Scheme ). This antagonist has seen extensive use for the treatment of drug abuse but has previously been prepared only from other natural products such as (−)-thebaine, which is isolated in small quantities from opium (0.3–1.5%) …”

Section: Asymmetric Synthesis Of (+)-Ketorfanol and (−)-Naltrexonementioning

confidence: 99%

Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C−H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxysubstituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C−H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric s...

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“…The Sharpless asymmetric dihydroxylation (AD) is a reliable enantioselective reaction that is used in industrial processes, natural product syntheses and drug molecule syntheses, such as, the opioid receptor antagonist (–)‐Naltrexone …”

Section: Introductionmentioning

confidence: 99%

A Structure‐Reactivity Relationship of the Tandem Asymmetric Dihydroxylation on a Biologically Relevant Diene: Influence of Remote Stereocenters on Diastereofacial Selectivity

2019

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The Sharpless asymmetric dihydroxylation (AD) finds widespread use in natural product and drug molecule syntheses, in part, due to its efficiency and predictability. However, the tandem AD of dienes is much less studied, but important in complex molecular synthesis. Herein, a biologically relevant tandem AD is reported, and several anomalies are discovered with the accepted model. These include the formation of unpredicted diastereoisomers, with matched and mismatched stereo- [a]

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Asymmetric synthesis of (−)-naltrexone

Abstract: The asymmetric synthesis of (–)-naltrexone was achieved by a Rh(i)-catalyzed C–H alkenylation and torquoselective electrocyclization cascade and late-stage C–H hydroxylation.

Cited by 19 publications

References 74 publications

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes

Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

A Structure‐Reactivity Relationship of the Tandem Asymmetric Dihydroxylation on a Biologically Relevant Diene: Influence of Remote Stereocenters on Diastereofacial Selectivity

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