Reactions of thebaine derivatives with trifluoroacetyl acetylenes: [4+2]-addition solely

Sandulenko, Irina V.; Semenova, Daria; Zelentsova, Maria V.; Moiseev, S. K.; Koldobskií, A. B.; Перегудов, А. С.; Бушмаринов, Иван С.; Калинин, В. Н.

doi:10.1016/j.jfluchem.2016.07.015

Cited by 4 publications

(6 citation statements)

References 15 publications

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“…The research group of Moiseev [45] reported the reaction of morphinan-6,8-dienes with highly electron deficient acetylenes. Thebaine (4), N 17 -cyclopropylcarbonyl-nortebaine (9e) and N 17 -tert-butoxycarbonyl-northebaine (9f) were reacted with 1-trifluoro-acetylacetylene and 4-trimethylstannyl-1-trifluoroacetylacetylene.…”

Section: Acetylenic Dienophilesmentioning

confidence: 99%

“…The reaction of thebaine ( 4) with 1-trifluoroacteylacetylene resulted in low yields of the ketone (278, 16%, Figure 76) as a result of the nucleophilic attack, but traces of 279 was also detected (LC-MS). In order to hinder the nucleophilic attack of the N 17 of 4 at the acetylenic carbon, Moiseev et al [45] chose an acetylenic dienophile with a donating electron, and bulky trimethylstannyl group was chosen. Reacting 4 with 4-trimethyltin-1trifluoroacetylacetylene, 278 was formed once again as the main isolated product (36%), along with small amounts (1.5%) of the enol ether hydrolysis ( 279) product.…”

Section: Acetylenic Dienophilesmentioning

confidence: 99%

“…The product of the normal β-face [4+2] addition (280) was obtained in 2% yield, and traces of the destannylated Diels-Alder adduct (281) were noticed. When the N 17 -acyl-northebaine derivatives, N 17 -cyclopropylcarbonyl-northebaine (9e, Figure 77) or N 17 -tert-butoxycarbonyl-northebaine (9f, Figure 78), were reacted with the above fluorinated acetylenic dienophiles, there was predominant formation of normal Diels-Alder adducts [45]. N 17 -Cyclopropylcarbonyl-northebaine (9e), upon reaction with diethyl acetylene dicarboxylate, resulted in the product of the [4+2] cycloaddition 282 in 77% yield.…”

Section: Acetylenic Dienophilesmentioning

confidence: 99%

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Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

et al. 2022

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6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.

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Section: Acetylenic Dienophilesmentioning

confidence: 99%

Section: Acetylenic Dienophilesmentioning

confidence: 99%

Section: Acetylenic Dienophilesmentioning

confidence: 99%

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Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

et al. 2022

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“…In this case, and as shown in Scheme 4, the substrate reacted with iodylbenzene (PhIO2) and 1,2-di(pyridin-2-yl)diselane 17 in refluxing benzene for 3 h to deliver enone 18 6 in 56% yield. Treatment of compound 18 with dimethyl sulfate in the presence of potassium tert-butoxide 18 then gave the diene enol ether 19 19 (76%), which was itself reduced with LiAlH4 in refluxing THF for 2 h to afford (-)-thebaine (1) in 73% yield. All the spectral data acquired on this material matched those reported previously, 4,20 but final confirmation of its structure followed from a single-crystal X-ray analysis (see Experimental Section and SI for details).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…(4R,7aR,12bS)-7,9-Dimethoxy-1,2,4,7a-tetrahydro-3H-4,12-methanobenzofuro-[3,2-e]isoquinoline-3-carboxylate (19). Following protocols reported in the literature, 18,29 a magnetically stirred solution of potassium tert-butoxide (280 mg, 2.50 mmol, 3 eq.)…”

Section: Tert-butylmentioning

confidence: 99%

A Seven-Step Total Synthesis of (–)-Thebaine

Tan

Lan

et al. 2022

Synthesis

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The morphinan alkaloid (–)-thebaine (1) is an industrially important chemical intermediate deployed in the semi-synthesis of various opioid medicines. Here, we report a seven-step total synthesis of this natural product from simple, commercially available starting materials. The pivotal substrate 13, which was obtained through successive Suzuki-Miyaura cross-coupling and Mitsunobu substitution reactions, was engaged in a double-Heck cyclization sequence. The tetracyclic product of these processes was subjected to a photochemical hydroamination reaction that generated compound 15, which embodies the full pentacyclic morphinan framework. Over a further three simple steps, this last compound was converted into (–)-thebaine (1).

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