Regiospecific and Stereoselective Syntheses of (±) Morphine, Codeine, and Thebaine via a Highly Stereocontrolled Intramolecular 4 + 2 Cycloaddition Leading to a Phenanthrofuran System

Stork, Gilbert; Yamashita, Ayako; Adams, J. F.; Schulte, Gary R.; Chesworth, Richard; Miyazaki, Y.; Farmer, Jay J.

doi:10.1021/ja9038505

Cited by 78 publications

(34 citation statements)

References 59 publications

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“…In the search for morphine derivatives with reduced side effects, total synthesis offers an attractive opportunity although an economical route competitive to isolation is currently not within reach. [1,2] Several efforts in the recent past, for example, the elegant synthesis by Magnus, [3] the improved strategy of Fukuyama, [4] the chemoenzymatic approach of Hudlicky, [5] and the innovative route of Stork, [6] express the permanent interest of the scientific community. Among the numerous strategies for construction of the phenanthrene skeleton, an approach based on intramolecular nitrone cycloaddition starting from a suitably substituted aldehyde seems powerful enough for this challenging task.…”

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confidence: 99%

A Total Synthesis of (±)‐Codeine by 1,3‐Dipolar Cycloaddition

2011

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confidence: 99%

A Total Synthesis of (±)‐Codeine by 1,3‐Dipolar Cycloaddition

2011

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“…38 The synthesis began by exposing ( E )-1-methoxybut-1-en-3-yne to Schwartz’s reagent followed by the addition of aldehyde 41 to give (±)- 42 . Heating this compound in a sealed tube in the presence of Et 3 N produced the Diels−Alder adduct (±)- 43 as a 4:1 mixture of diastereomers.…”

Section: The Opiatesmentioning

confidence: 99%

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production

Chambers

DeSousa

Huseman

et al. 2018

ACS Chem. Neurosci.

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Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term “psychotropic drug” is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

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“…49 After its first synthesis in 1952, 50 various synthetic routes for the synthesis of codeine and morphine have been reported in the literature using various methodologies. [51][52][53] Recently, Trost and Tang devised interesting routes for the synthesis of codeine and morphine using hydroamination as one of the key steps. 54 Substrate 27 was converted into secondary amine 29 using diisobutylaluminum hydride (DIBAL-H) and MeNH 2 (Scheme 39.10).…”

Section: Asymmetric and Diastereoselective Hydroamination In Total Symentioning

confidence: 99%

Asymmetric Hydroamination and Reductive Amination in Total Synthesis

Ghorai

Tiwari

Bhattacharyya

2013

Stereoselective Synthesis of Drugs and Natural Products

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Asymmetric hydroamination (AHA) and asymmetric reductive amination (ARA) are one of the most popular strategies for enantioselective synthesis of chiral amines, which are very important from a synthetic and a biological point of view. The addition of the NH bond across an unsaturated CC bond is known as hydroamination. AHA is ideal for industrial processes as it is a 100% atom‐economic reaction and involves readily available substrates. For broadening its scope for a variety of substrates, many metal‐based as well as metal‐free catalytic systems have been developed for asymmetric hydroamination. Along with the synthesis of functionalized chiral amines, AHA has served as a key strategy in the synthesis of the core of various natural products like codeine, pseudodistomin, swainsonine and of drugs like pentazocine. Reductive amination is a widely used efficient synthetic protocol to install an amine group in place of a carbonyl group in an organic compound. The reaction proceeds through the formation of imine and subsequent one‐pot reduction of it to give the product amine. Use of a metal‐chiral ligand combination, chiral Brønsted acid or chiral organocatalyst, or chiral auxiliary in the reaction can give rise to chiral amine products that are often valuable synthetic intermediates en route to many drugs and natural products. Application of these protocols in the total synthesis of drugs and natural products will be discussed along with some experimental procedures.

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Regiospecific and Stereoselective Syntheses of (±) Morphine, Codeine, and Thebaine via a Highly Stereocontrolled Intramolecular 4 + 2 Cycloaddition Leading to a Phenanthrofuran System

Abstract: Total syntheses of the morphine alkaloids are described that use a direct stereoselective formation of the phenanthrofuran system via an intramolecular 4 + 2 cycloaddition of a diene tethered to the 4-position of a 7-methoxybenzofuran-3-carboxylic acid ester.

Cited by 78 publications

References 59 publications

A Total Synthesis of (±)‐Codeine by 1,3‐Dipolar Cycloaddition

A Total Synthesis of (±)‐Codeine by 1,3‐Dipolar Cycloaddition

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production

Asymmetric Hydroamination and Reductive Amination in Total Synthesis

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