Application of metalated enamines to alkaloid synthesis. An expedient approach to the synthesis of morphine-based analgesics

Evans, David A.; Mitch, Charles H.; Thomas, R; Zimmerman, Dennis M.; Robey, Roger L.

doi:10.1021/ja00538a065

Cited by 78 publications

(23 citation statements)

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“…With the alkene 13 in hand, functionalization leading to the enamine 14 bearing the desired ethyl group, or any alkyl or aralkyl group was easily achieved using the method of Evans et al,26 and earlier reports from our laboratory 6, 7, 9–11. A simple two-step procedure, originally conceived for the synthesis of the pyridin-6-ols,18 involved bromination of the alkene with NBS followed by NaCNBH 3 reduction in acidic medium and gave the late stage intermediate 15 .…”

Section: Resultsmentioning

confidence: 99%

Probes for narcotic receptor mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

Iyer

Lee

Deschamps

et al. 2010

Bioorganic & Medicinal Chemistry

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A series of N-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have been prepared using a simple synthetic route previously designed for synthesis of related cis-2-methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols. The new phenolic compounds, where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxidebridged ring, do not interact as well as the pyridin-6-ols with opioid receptors. The N-parafluorophenethyl derivative had the highest μ-opioid receptor affinity of the examined compounds (K i = 0.35 μM).

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Section: Resultsmentioning

confidence: 99%

Probes for narcotic receptor mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

Iyer

Lee

Deschamps

et al. 2010

Bioorganic & Medicinal Chemistry

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“…The second step was the stereoselective alkylation of enamine 80 using methodology developed previously by Evans. [164] In the procedure described by Lilly, alvimopan was then prepared from 23 in a five-step procedure (Scheme 5). Michael addition of 23 to methyl methacrylate provided the methyl ester 83.…”

Section: N-methylnaltrexonementioning

confidence: 99%

Mu Opioid Receptor Antagonists: Recent Developments

2007

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For thousands of years mu opioid agonists such as morphine have been utilized for their analgesic properties. Today, morphine and related compounds are still used as a first line therapy in the treatment of moderate to severe pain. However, despite the clear benefits of mu agonists in pain management, severe side effects such as dependence and respiratory depression are associated with use of these drugs. To date, there are only two approved mu opioid antagonists for use in the treatment of these adverse effects, that is, naloxone and naltrexone. However, many other clinical and therapeutic areas have been linked to mu opioid receptor antagonism. These include treatment of opioid induced pruritis of the skin, obesity, and Parkinson‐induced tardive dyskinesia. Currently there are two compounds, N‐methylnaltrexone and alvimopan, under FDA review as possible treatments for opioid induced bowel dysfunction and postoperative ileus. These compounds are of special interest as they are peripherally restricted. This attribute enables treatment of peripheral side effects induced by opioid agonists without reversal of the centrally mediated analgesia of the agonist. In this article we discuss the structural classes of mu opioid antagonists, their potential clinical applications, and review the relevant patents of the last ten years.

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“…A useful feature of this route is the well precedented synthesis of enamine moiety 5 based on the method of Evans6 and utilized in our oxide-bridged phenylmorphan syntheses 3c–f, 3j. With the necessary enamine in hand, additional functionalization needed to close the oxide-bridge can be achieved with relative ease.…”

Section: Resultsmentioning

confidence: 99%

Probes for Narcotic Receptor Mediated Phenomena. 38. An Expeditious Synthesis of rac-cis-4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol and rac-cis-2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol

Iyer¹,

Deschamps²,

Jacobson³

et al. 2009

HETEROCYCLES

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A high-yielding five-step synthesis of cis-benzofuropyridin-6-ols provided an improved route to compounds with low to subnanomolar affinity at opioid receptors and high antinociceptive potency. This synthesis provided the known rac- cis-4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro [2,3-c]pyridin-6-ol (1a) in high yield, and the novel rac-cis- 2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b). It was achieved using NBS to prepare the key intermediate 7. Di-demethylation followed by subsequent displacement of the bromine by the phenolic ion in hot Et 3 N gave the desired 1a. The structure of 1a was confirmed by X-ray crystallography.

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Application of metalated enamines to alkaloid synthesis. An expedient approach to the synthesis of morphine-based analgesics

Cited by 78 publications

References 1 publication

Probes for narcotic receptor mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

Probes for narcotic receptor mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

Mu Opioid Receptor Antagonists: Recent Developments

Probes for Narcotic Receptor Mediated Phenomena. 38. An Expeditious Synthesis of rac-cis-4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol and rac-cis-2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol

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