Ene‐Yne Metathesis

Diver, Steven T.; Griffiths, Justin R.

doi:10.1002/9781118711613.ch4

Cited by 15 publications

(9 citation statements)

References 155 publications

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“…It is likely that this transformation proceeds via reaction of the ruthenium alkylidene precatalyst with the allyl component of 3,followed by intramolecular reaction with the alkyne to ultimately give alkylidene intermediate 12. [21] Ring closing metathesis with the a,b-unsaturated ketone affords the tetracycle 2 as effectively the sole product in this transformation. [22] In practice this step could be combined with as ubsequent 1,6-addition through removal of the tertbutoxycarbonyl group with trifluoroacetic acid to afford an Nmethyl ammonium salt followed by free-basing with sodium carbonate to trigger the carbon-nitrogen bond formation.…”

mentioning

confidence: 98%

A Cascade Strategy Enables a Total Synthesis of (±)‐Morphine

et al. 2016

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Morphine has been at arget for synthetic chemists since Robinson proposed its correct structure in 1925, resulting in al arge number of total syntheses of morphine alkaloids. Here we report atotal synthesis of (AE)-morphine that employs two key strategic cyclizations:1 )ad iastereoselective lightmediated cyclization of an O-arylated butyrolactone to form atricyclic cis-fused benzofuran and 2) acascade ene-yne-ene ring closing metathesis to forge the tetracyclic morphine core. This approach enables as hort and stereoselective synthesis of morphine in an overall yield of 6.6 %.Morphine (1), named by Sertürner for its tendency to induce sleep,isthe most abundant alkaloid isolated from the opium poppy Papaver somniferum.[1] As the main constituent of opium, morphinesp ain relieving properties have been exploited for thousands of years,a nd in modern times have resulted in its place on the World Health Organizationslist of essential medicines.[2] Its correct structure was proposed by Robinson in 1925, [3] and was confirmed by Gates (through total synthesis,1 952) [4] and Hodgkin (using X-ray crystallography,1955).[5] Currently,all medicinal (and illicit) morphine is derived from natural sources;t here is no synthetic route that competes on scale and cost with isolation from natural sources.This problem has been elegantly outlined in arecent perspective from Hudlicky,w hich focuses on his groups chemoenzymatic approaches to the morphine skeleton, [6] and in other reviews which focus on the range of strategies employed in total syntheses of morphine alkaloids.[7] Nonetheless,t he combination of potent biological effects and ac omplex pentacyclic structure bearing five contiguous stereocentres has made morphine and its associated alkaloids an enduring challenge for synthetic chemistry,r esulting in more than 30 total or formal syntheses of morphine alkaloids. [8,9] Our proposed strategy for the total synthesis of morphine is outlined below (Scheme 1). It has been demonstrated by Fuchs that the piperidine ring in morphine (1)can be made by an intramolecular 1,6-addition of an amine analogous to that in 2.[10] This requires an a,b,g,d-unsaturated ketone,which we envisaged could be constructed via acascade ene-yne-ene ring closing metathesis from the heavily functionalized benzofuran 3. [11,12] Ametathesis cascade cyclization offers the potential for anew end-game to the total synthesis of morphine in which the requisite functional groups are installed prior to the formation of the Band Crings.This has the advantage of minimizing late-stage functional group interconversions once the ABCD tetracycle is complete. Theb enzofuran 3 could be synthesized from the tricyclic butyrolactone 4 by as eries of functional group interconversions to install the vinyl ketone and alkyne functional groups. We recognized that the cis-fused butyrolactone 4,bearing an all-carbon quaternary stereocentre,c ould be generated via ap hotocyclization from substituted butenolide 5,w ith the relative stereochemistry ac onsequence of the 5,5-c...

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confidence: 98%

A Cascade Strategy Enables a Total Synthesis of (±)‐Morphine

et al. 2016

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“…Especially in the case of the l hanges were significant (from 14% to 66% for 4d and from 9% to 63% for 4b). ne-yne metathesis is a highly selective and atom-economical methodology for the synthes enes, which are valuable building blocks in organic synthesis [79]. To picture the applica e of the studied catalysts, two members of the ene-yne class of compounds were investig catalysts 4a-e. Reactivity profiles for the metathesis of allyl 1,1-diphenylpropargyl ether established first (Scheme 6).…”

Section: Comparative Catalytic Activity Studies Of Nitro-catalysts 4a-ementioning

confidence: 99%

The Influence of Various N-Heterocyclic Carbene Ligands on Activity of Nitro-Activated Olefin Metathesis Catalysts

et al. 2020

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A set of nitro-activated ruthenium-based Hoveyda-Grubbs type olefin metathesis catalysts bearing sterically modified N-hetero-cyclic carbene (NHC) ligands have been obtained, characterised and studied in a set of model metathesis reactions. It was found that catalysts bearing standard SIMes and SIPr ligands (4a and 4b) gave the best results in metathesis of substrates with more accessible C–C double bonds. At the same time, catalysts bearing engineered naphthyl-substituted NHC ligands (4d–e) exhibited high activity towards formation of tetrasubstituted C–C double bonds, the reaction which was traditionally Achilles’ heel of the nitro-activated Hoveyda–Grubbs catalyst.

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“…In ingeniously elaborated procedures, olefin metathesis has been frequently employed as such or associated with name reactions like Grignard, Wittig, Diels-Alder, Suzuki-Miyaura, Heck, etc., resulting in the assembly of diverse intricate building blocks of the targeted structures [44]. Among the various embodiments of olefin metathesis, the highly chemoselective enyne metathesis reaction [45][46][47][48][49] has led to some of the most striking advances in the development of modern, efficient synthetic protocols [50,51]. Thus, the present account focuses on the impressive potential of enyne metathesis in providing sustainable access to bioactive organic compounds, when used in conjunction with a number of name reactions.…”

Section: Introductionmentioning

confidence: 99%

“…Enyne metathesis is a fundamental chemical transformation involving an alkene and an alkyne to produce a dienic structure through unsaturated bond reorganization [45,46]. This process may follow an intra-or intermolecular course (Scheme 1, A or B).…”

Section: Introductionmentioning

confidence: 99%

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

Drăguţan¹,

Drăguţan²,

Demonceau³

et al. 2020

Beilstein J. Org. Chem.

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This account surveys the current progress on the application of intra- and intermolecular enyne metathesis as main key steps in the synthesis of challenging structural motifs and stereochemistries found in bioactive compounds. Special emphasis is placed on ruthenium catalysts as promoters of enyne metathesis to build the desired 1,3-dienic units. The advantageous association of this approach with name reactions like Grignard, Wittig, Diels–Alder, Suzuki–Miyaura, Heck cross-coupling, etc. is illustrated. Examples unveil the generality of such tandem reactions in providing not only the intricate structures of known, in vivo effective substances but also for designing chemically modified analogs as valid alternatives for further therapeutic agents.

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Ene‐Yne Metathesis

Cited by 15 publications

References 155 publications

A Cascade Strategy Enables a Total Synthesis of (±)‐Morphine

A Cascade Strategy Enables a Total Synthesis of (±)‐Morphine

The Influence of Various N-Heterocyclic Carbene Ligands on Activity of Nitro-Activated Olefin Metathesis Catalysts

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

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