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

Varghese, Vimal; Hudlický, Tomáš

doi:10.1002/chin.201441228

Cited by 6 publications

(10 citation statements)

References 12 publications

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“…59 It took another 20 years before the design of an intermediate such as 21 finally materialized, resulting in a very short synthesis of hydromorphone. 50 We learned an important lesson on information processing, retention of information, and pattern recognition.…”

Section: Cycloaddition Approachesmentioning

confidence: 99%

“…Returning to our cycloaddition strategy, we were rewarded with one of the shortest syntheses of a morphinan. 50 Scheme 11 shows the solution to the cycloaddition design we had pursued more than 20 years ago. Coupling of the C-ring unit with phenol 95 and elaboration to styrene 97 provided the precursor to the oxidative dearomatization accomplished with Pb(OAc) 4 or IBX.…”

Section: Return To the Original Ideamentioning

confidence: 99%

“…The required components for completing the design were known, even to us; but these were not in the forefront of our chemical imagination at the time, and we did not integrate this existing information with pattern recognition . It took another 20 years before the design of an intermediate such as 21 finally materialized, resulting in a very short synthesis of hydromorphone . We learned an important lesson on information processing, retention of information, and pattern recognition.…”

Section: Development Of Our Design For Morphinansmentioning

confidence: 99%

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The Quest for a Practical Synthesis of Morphine Alkaloids and Their Derivatives by Chemoenzymatic Methods

Reed

Hudlický

2015

Acc. Chem. Res.

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We became interested in approaches to morphine in the early 1990s following our immersion into the new program on the enzymatic dihydroxylation of aromatics. Larry Kwart, a former classmate of one of us at Rice University, who worked with our group at Virginia Tech in the mid-1980s, introduced to us the use of blocked mutants of Pseudomonas putida (Pp39D) for the production of arene-cis-dihydrodiols. Larry had gained expertise in microbiology from a postdoctoral stay with David Gibson, who discovered this unique enzymatic transformation, and he helped us to establish a strong program in chemoenzymatic synthesis that continues to this day. Without his pioneering effort, none of our accomplishments in chemoenzymatic synthesis, including the various approaches to morphine, would have materialized. Here we trace the evolution of our approaches to morphine alkaloids and some commercial opiate-derived medicinal agents. The design features and chronology of our approaches are discussed in a way that allows the reader to appreciate a number of errors that were made in conception as well as in execution. Experience acquired from many failed or less-than-effective attempts has finally led to an "almost reasonable" total synthesis, the key concept being based on our very first but unsuccessful attempt more than two decades ago. The irony of this accomplishment has not been lost on us. Each section of this Account presents a summary of distinctly different approaches to morphine alkaloids. Each ends with a short and philosophical lesson that was (or should have been) learned in the process. We intend for this Account to offer more than the history of a search for the perfect design solution to a synthetic problem. In today's era of rapid and often careless publication of results, it should serve also as a reminder that the success and the integrity of synthetic ventures depends on perseverance, adjustment of strategy, improvements of previous attempts, and serious attention to the quality of experimental data. Although somewhat satisfied with our latest accomplishment in morphinan synthesis, we plan to improve our design in the hope that a six-step synthesis is no longer in the realm of fantasy. With more than 20 years of effort in this area, our continuing involvement may qualify as obsession.

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Section: Cycloaddition Approachesmentioning

confidence: 99%

Section: Return To the Original Ideamentioning

confidence: 99%

Section: Development Of Our Design For Morphinansmentioning

confidence: 99%

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The Quest for a Practical Synthesis of Morphine Alkaloids and Their Derivatives by Chemoenzymatic Methods

Reed

Hudlický

2015

Acc. Chem. Res.

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“…Second, synthetic biologists have recently achieved the complete biosynthesis of thebaine and derivatives in yeast, which, however, is far from practical application. Moreover, synthetic chemists have developed over 30 total syntheses of morphine and congeners, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] but none of these de novo approaches, especially those to oxycodone (3) [18][19][20][21][22] and related derivatives 4-7, are competitive in cost with the current farming/isolation/semisynthesis protocol. An important solution to the practical synthesis of opioids would be to mimic the methods employed by the Mother Nature.…”

Section: Introductionmentioning

confidence: 99%

Bioinspired Scalable Total Synthesis of Opioids

Zhou

et al. 2021

CCS Chem

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As one of the largest and most representative families of natural medicines harvested from plants, the mass production of opioids legitimately occupies large farmland for the cultivation of opium poppies in the world, causing serious regulation difficulty and supply uncertainty. Due to their complex structures, chemical synthesis of opioids has been criticized infeasible for large-scale production in view of lengthy synthetic steps and low overall efficiency. Here we report a practical and scalable total synthesis of oxycodone, codeine, and related opioids by imitating the biosynthetic dearomatization arene coupling reaction, which allows efficient preparation of a key thebaine-like core on decagram scale.For the synthesis of oxycodone and codeine, less than eight continuous operations and one column chromatography purification were required throughout the synthesis in 11% and 13%

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“…Non-heme Fe-dioxygenases have been reported for stereoselective cis -dihydroxylation of arenes. 3 − 5 More recently, enzymatic Birch-type reductions 6 − 8 and dearomatizing arene oxidations 9 have also been reported.…”

mentioning

confidence: 96%

Biocatalytic Aromaticity-Breaking Epoxidation of Naphthalene and Nucleophilic Ring-Opening Reactions

Zhang

Younes

et al. 2021

ACS Catal.

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Aromatic hydroxylation reactions catalyzed by heme-thiolate enzymes proceed via an epoxide intermediate. These aromatic epoxides could be valuable building blocks for organic synthesis giving access to a range of chiral trans-disubstituted cyclohexadiene synthons. Here, we show that naphthalene epoxides generated by fungal peroxygenases can be subjected to nucleophilic ring opening, yielding non-racemic trans-disubstituted cyclohexadiene derivates, which in turn can be used for further chemical transformations. This approach may represent a promising shortcut for the synthesis of natural products and APIs.

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

Cited by 6 publications

References 12 publications

The Quest for a Practical Synthesis of Morphine Alkaloids and Their Derivatives by Chemoenzymatic Methods

The Quest for a Practical Synthesis of Morphine Alkaloids and Their Derivatives by Chemoenzymatic Methods

Bioinspired Scalable Total Synthesis of Opioids

Biocatalytic Aromaticity-Breaking Epoxidation of Naphthalene and Nucleophilic Ring-Opening Reactions

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