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

Abstract

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...

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine

“…Finally, (‒)-codeine was readily converted to (‒)-morphine ( 1a ) by demethylation with boron tribromide 54 in 81% yield. The spectra data of synthetic (‒)-morphine and (‒)-codeine are consistent with the reported ones from literatures 7,8 .

Fig. 5Asymmetric total synthesis of (‒)-codeine ( 1b ) and (‒)-morphine ( 1a ).

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Bioinspired Scalable Total Synthesis of Opioids

“…A survey of different palladium catalysts (see SI) revealed that the commercially available Pd-complex containing PPh t Bu 2 (without addition of external ligand) afforded improved results (79% yield with 18a, entry 12; 85% yield with 18b, entry 13). Furthermore, bases with potassium cation proved important to maintain the reaction yields (entries [13][14][15][16] and the use of t BuOK allowed for an 89% isolated yield of 17b with complete conversion of 18b (entry 17). Reducing the loading of t BuOK from 2.0 to 1.4 equiv.…”

“…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.…”

Interpol review of controlled substances 2016–2019

“…Morphine: 2016 A voltammetric sensor for determination of paracetamol in the presence of morphine [ 313 ]; a short cascade strategy for the stereoselective synthesis of morphine [ 314 ]; extraction of morphine from poppy seeds [ 315 ]; HPLC method for the simultaneous determination of morphine sulfate and naltrexone hydrochloride content in bulk, solid dosage forms [ 316 ]; life cycle assessment from opium poppy farming to the packaging of morphine [ 317 ]; LC-HRMS for the characterization of transformation products and comparison between irradiated samples and those that have not been irradiated [ 318 ]; determination of Morphine in pharmaceutical products by on-line SPE-HPLC [ 319 ]; 2017 solid state vibrational spectroscopic properties of morphine sulfate pentahydrate studied using FTIR-ATR [ 320 ]; review of the research progress on the synthesis of Morphine alkaloids [ 321 ]; Impurity profiling of morphine by LC-HESI-MS [ 322 ]; design and synthesis of carboxylic group functionalized hollow microporous organic capsules for encapsulation of morphine for prolonged release [ 323 ]; characterization of Morphine, Morphine Hydrochloride, and their Hydrates using 1-dimensional and 2-dimensional solid-state NMR and complemented with powder X-ray diffraction, FTIR, and Raman [ 324 ]; one-pot multicomponent approach to synthesize a new series of morphine derivatives [ 325 ]; high-performance thin-layer chromatography-densitometry method for the quantitative analysis of morphine in the tablets of the Ayurvedic medicines [ 326 ]; tandem Brook rearrangement/silicon Polonovski reaction/fragmentation to give formamide derivatives in moderate yields [ 327 ]; asymmetric total synthesis of (−)-morphine [ 328 ]; stability studies of opioid analgesic, morphine-6-O-sulfate in various buffers and biological matrices and analyzed by HPLC-DAD analysis [ 329 ]; Quantum dots (QDs)-labeled antibody fluorescence immunoassays (FLISA) for the rapid detection of morphine for on-site screening of poppy shell added illegally in hot pot soup base [ 330 ]; rapid construction of the 6/6/5 tricyclic framework via a tandem radical cyclization reaction [ 331 ]; Arymo ER - a new abuse deterrent Morphine formulation [ 332 ]; ALERRT((R)) to quantitative measure the effort required to compromise prescription opioid abuse-deterrent tablets [ 333 ]; comparison of the abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with morphine sulfate ER tablets [ 334 ]; compare abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets [ 335 ]; synthesis of morphinans using a programmed serial stereochemical relay […”