Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine<sup>1</sup><sup>,</sup>

Parker, Kathlyn A.; Fokas, Demosthenes

doi:10.1021/jo0513008

Cited by 78 publications

(33 citation statements)

References 43 publications

(28 reference statements)

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“…Several approaches have been developed to introduce this substituent based on the intramolecular Heck reaction, [2a,e, 8] the tandem radical cyclization, [9] 1,4-addition of vinyl magnesium bromide (in the presence of copper(I) bromide) to a,b-enone, [10] CpCO-mediated [2 + 2 + 2] cyclization of functionalized 4-(3-butynyl)benzofurans, [11] or by aldol condensation.…”

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confidence: 99%

Diastereoselective Total Synthesis of (±)‐Codeine

Varin

Barré

Iorga

et al. 2008

Chemistry A European J

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Codeine 1 and morphine 2, the principal constituents of opium, continue to attract the attention of organic chemists thanks to both their biological activities and their unique structure.[1] Their complex pentacyclic skeleton, which includes a quaternary carbon center, has stimulated extensive efforts. To date there have been more than 20 total syntheses of codeine (1), morphine (2), and thebaine (3).[2] We were interested in the synthesis of codeine for two reasons: first, codeine was found to be an allosteric potentiating ligand of nicotinic receptors, [3] and second we have a general program underway in the laboratory in which we have shown that tricyclic spirocyclohexadienones are valuable intermediates for the synthesis of natural products in the Amaryllidacea galanthamine-type, maritidine-type, and Aspidosperma alkaloids. [4] In an effort to develop new allosteric potentiating ligands of nicotinic receptors with a codeine-type scaffold, we initiated our own studies of a total synthesis of codeine. Herein we disclose a total diastereoselective synthesis of (AE )-codeine (1), which involves a new construction of the morphinan skeleton. The present study provides an efficient method for the elaboration of the quaternary carbon at C-13 and for the highly diastereoselective introduction of the C-14 stereogenic center of the morphinan system.Our retrosynthetic analysis of (AE )-codeine (1) is shown in Scheme 1. Codeine could be obtained from amine intermediate 4 by using an intramolecular hydroamination reaction to form the D ring. Compound 4 could in turn be prepared from aldehyde 5. In our synthetic pathway, we planned to use for the first time a Claisen-type rearrangement to introduce the C-14 substituent. This type of rearrangement applied to compound 6 would provide a precursor of the aldehyde 5 and control the stereochemistry of the substituent at C-14 of 5. The tricyclic amine 6 would be obtained from the spirocyclohexadienone 7 by a lactone ring opening with an amine followed by a spontaneous intramolecular Michael

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confidence: 99%

Diastereoselective Total Synthesis of (±)‐Codeine

Varin

Barré

Iorga

et al. 2008

Chemistry A European J

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“…Chemie amide according to conditions adapted from the work of Parker and Fokas [12] and Chida and co-workers, [13] and similar in concept to Trosts lithium amide cyclization [2c,d] noted above. The reductive cyclization of 23 to 25 was superior to the hydroamination conditions [Hg(OAc) 2 , followed by LiAlH 4 ] we have used previously, [2a,b] and gave 25 in 82-86 % yield.…”

Section: Methodsmentioning

confidence: 99%

“…It is possible that only one diastereomer of 5 underwent the cycloaddition, thus further optimization of this step will be required. The establishment of the ethylamino bridge in 25 was accomplished by a nitrogen-centered radical cyclization enabled by a dissolved-metal reduction of the tosyl amide according to conditions adapted from the work of Parker and Fokas [12] and Chida and co-workers, [13] and similar in concept to Trosts lithium amide cyclization [2c,d] noted above. Even though the endocyclic diene is quite reactive, the exclusive formation of 6 can be attributed to steric reasons, which deny the dienophile the proximity of the endocyclic diene.…”

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confidence: 99%

ChemInform Abstract: Short Chemoenzymatic Total Synthesis of ent‐Hydromorphone: An Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition/Amination Sequence.

Varghese

Hudlický

2014

ChemInform

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A short synthesis of ent-hydromorphone has been achieved in twelve steps from b-bromoethylbenzene. The key transformations involved the enzymatic dihydroxylation of the arene to the corresponding cis-dihydrodiol, Mitsunobu coupling with the ring A fragment, oxidative dearomatization of the C3 phenol, and the subsequent [4+2] cycloaddition to form ring B of the morphinan. The synthesis was completed by intramolecular amination at C9.

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“…What role does organic chemistry play in the field of psychoactive drug synthesis and use? As one reads through the annals of published efforts, it is clear that legendary figures in the field, ranging from Larry Overman 11 and Phil Magnus, 12 to Kathy Parker 13 and James White, 14 have trained scores of students using these molecules as training tools. While the approaches are scholarly in nature, one cannot help but recognize the dichotomy: academic lessons assist in fueling both licit and clandestine drug use.…”

Section: Scope Of This Reviewmentioning

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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Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,

Cited by 78 publications

References 43 publications

Diastereoselective Total Synthesis of (±)‐Codeine

Diastereoselective Total Synthesis of (±)‐Codeine

ChemInform Abstract: Short Chemoenzymatic Total Synthesis of ent‐Hydromorphone: An Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition/Amination Sequence.

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

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Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine1,

Cited by 78 publications

References 43 publications

Diastereoselective Total Synthesis of (±)‐Codeine

Diastereoselective Total Synthesis of (±)‐Codeine

ChemInform Abstract: Short Chemoenzymatic Total Synthesis of ent‐Hydromorphone: An Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition/Amination Sequence.

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

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Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine¹^,