Total Synthesis of (±)-Thebainone A by Intramolecular Nitrone Cycloaddition

Wang, Yuzhou; Hennig, André; Küttler, Thomas; Hahn, Christian; Jäger, Anne; Metz, Peter

doi:10.1021/acs.orglett.0c00905

Cited by 11 publications

(5 citation statements)

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“…Finally, (−)‐thebainone A ( 4 ) was prepared through the α,β‐desaturation of ketone 5 using the Pd(TFA) 2 /DMSO system described by Stahl and co‐workers (see Table S2 for details) [5c, 18] . The spectroscopic data of synthetic (−)‐thebainone A ( 4 ) match those reported previously [6a] . Thus, using this route, the asymmetric total synthesis of (−)‐thebainone A was accomplished from compound 6 in 9 steps and 13 % overall yield.…”

Section: Resultssupporting

confidence: 80%

“…The Tius group in 1992 developed the second total synthesis of racemic thebainone A in 24 steps taking advantage of a chemo‐ and regiospecific Diels–Alder reaction [7] . Very recently, another elegant racemic synthesis of this natural product was reported by Metz and co‐workers in 22 steps, which features an intramolecular nitrone cycloaddition and a Heck cyclization as the key steps [6a] . To the best of our knowledge, enantioselective synthesis of thebainone A is not known yet.…”

Section: Introductionmentioning

confidence: 99%

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Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

2021

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Herein, we describe the development of ad econstructive strategy for the first asymmetric synthesis of (À)thebainone A, capitalizing on an enantioselective CÀCb ond activation and aC ÀOb ond cleavage reaction. The rhodiumcatalyzeda symmetric "cut-and-sew" transformation between sterically hindered trisubstituted alkenes and benzocyclobutenones allowed efficient construction of the fused A/B/C rings and the quaternary center of the natural product. The newly optimizedconditions show broad substrate scope and excellent enantioselectivity (up to 99.5:0.5 er). Taking advantage of boron-mediated ether bond cleavage,w ec ompleted the synthesis of the morphine alkaloid (À)-thebainone Ab yt wo complementary routes. Figure 1. Morphine and related alkaloids.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

2021

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“…In 2020, Metz and co-workers described the total synthesis of thebainone A 357, harnessing an intramolecular nitrone cycloaddition and a Heck cyclization to construct the natural product scaffold (Scheme 48). 107 From ester 349, which was accessed in 4 steps from isovanillin, a Heck cyclization using Pd 2 (dba) 3 and Ag 2 CO 3 induced formation of spirolactone 350 in 83% yield. Deprotection of the ketone and aldehyde, followed by treatment with N-methylhydroxylamine induced a diastereoselective nitrone cycloaddition to achieve isoxazolidine 351.…”

Section: Total Syntheses Of Morphinanmentioning

confidence: 99%

Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020)

Kim

Ngamnithiporn

et al. 2023

Chem. Rev.

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The tetrahydroisoquinoline (THIQ) natural products constitute one of the largest families of alkaloids and exhibit a wide range of structural diversity and biological activity. Ranging from simple THIQ natural products to complex trisTHIQ alkaloids such as the ecteinascidins, the chemical syntheses of these alkaloids and their analogs have been thoroughly investigated due to their intricate structural features and functionalities, as well as their high therapeutic potential. This review describes the general structure and biosynthesis of each family of THIQ alkaloids as well as recent advancements of the total synthesis of these natural products from 2002 to 2020. Recent chemical syntheses that have emerged harnessing novel, creative synthetic design, and modern chemical methodology will be highlighted. This review will hopefully serve as a guide for the unique strategies and tools used in the total synthesis of THIQ alkaloids, as well as address the longstanding challenges in their chemical and biosynthesis.

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“…It is used to relieve severe pain. Wang et al, in 2020, reported the total synthesis of (±)-Thebainone A [ 36 ]. The total synthesis commenced from isovaniline 102 , which was converted to isoxazolidine 103 over a few steps.…”

Section: Review Of the Literaturementioning

confidence: 99%

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

et al. 2022

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The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years.

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Total Synthesis of (±)-Thebainone A by Intramolecular Nitrone Cycloaddition

Abstract: Using an intramolecular nitrone cycloaddition and a Heck cyclization as the crucial transformations, a total synthesis of the racemic morphine alkaloid thebainone A was accomplished in 22 steps commencing with isovanillin.

Cited by 11 publications

References 50 publications

Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020)

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

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