Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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A Nine-Step Formal Synthesis of (±)-Morphine Julie Brousseau,† Amandine Xolin,† and Louis Barriault* Center for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, Canada K1N 6N5
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ABSTRACT: A nine-step stereoselective formal synthesis of (±)-morphine from readily available o-vanillin is presented. The carbocyclic structure of morphine was quickly assembled through an orchestration of the intermolecular Diels−Alder/ Claisen/Friedel−Crafts sequential reaction. This approach involves many one-pot procedures and no protecting groups, and only a few chromatographic purifications are required.
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solated from the opium poppy Papaver Somniferum by Sertürner in 1805,1 morphine (1) is well-known for its powerful analgesic properties (Scheme 1). Although Merck put
Our retrosynthetic analysis was driven by the goal of minimizing the use of protecting groups and nonstrategic redox manipulations to quickly assemble the morphine carbocyclic framework.6 The strategic disconnections of 1 shown in Scheme 1 were built upon innovative syntheses of morphine and its derivatives.4 As such, the D ring in 1 could be installed via a radical hydroamination at C-9 from the known intermediate 2.5v,ap At the outset of our synthetic analysis, we took cognizance of the benzofuran scaffold 3 (rings A, E, C) as a central intermediate. One can imagine in a forward sense that the stereochemical information embedded in 3 could be transmitted through a telescopic Claisen rearrangement/ Friedel−Crafts reaction to give the phenanthrofuran 2. We envisioned an intermolecular Diels−Alder reaction between Danishefsky’s diene 5 and the benzofuran 4 (readily available from o-vanillin 6) to prepare the intermediate 3. The Diels− Alder strategy has been employed previously in the synthesis of various morphinans by Gates,3 Tius,5l Stork,5ae and Hudlicky5ao (Scheme 2). In most of the cases, more than 20 steps were required to reach the final targets. As described in this paper, the use of an intermolecular [4 + 2] cycloaddition combined with one pot-processes greatly simplifies the synthesis of the phenanthrofuran core of morphine. As shown in Scheme 3, our synthesis began with the known condensation between ethyl diazoacetate and o-vanillin (6) followed by treatment with concentrated H2SO4 to afford the benzofuran 4 in 40% yield.7 The Diels−Alder reaction between 4 and 5 leading to the cycloadduct 7 followed by the deprotection/elimination to obtain the cyclohexenone 8 proved to be problematic.8 After the Diels−Alder reaction, the cycloadduct 7 was obtained as an equal mixture of diastereomers endo/exo. The lack of stereocontrol at C-14 was irrelevant as the elimination of the methoxy group should give the enone 8. However, the treatment of 7 with TBAF or another source of fluoride anions did not lead to the expected outcome; only the rearranged phenol 8a along with some
Scheme 1. Retrosynthetic Analysis of (±)-Morphine (1)
morphine on the market as early as 1827, the structure of the natural product was not elucidated until 1925 by Robinson.2 To date, morphine (1) and its analogues are still among the most potent and ubiquitous analgesic agents. The worldwide production of morphine exceeds 400 tons per year, mostly isolated from natural extraction. Since the original synthesis described by Gates3 in 1952, more than 30 total and formal syntheses have been reported.4,5 Despite these considerable efforts, no chemical synthesis of morphine or its derivatives competes with natural extraction in terms of scale and production cost.4f Synthetic difficulties arise from the complex pentacyclic framework of the molecule and the dissonant relationship in its connectivity.4c Therefore, the development of a practical and efficient morphine synthesis remains a significant challenge and presents the potential for development of new chemistry. In this context, we describe a nine-step formal synthesis of (±)-morphine (1) enabled by a careful orchestration of transformations that quickly assembles the carbocyclic framework. The rapid access to this advanced intermediate was facilitated by a careful orchestration of telescopic transformations. © XXXX American Chemical Society
Received: January 4, 2019
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DOI: 10.1021/acs.orglett.9b00044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Having the morphine phenanthrofuran core 10 in hand, we envisaged the installation of the allylic alcohol moiety in the Cring through a sequential C−H oxidation/reduction process at C-6.5w As described, a one-pot allylic oxidation using selenium dioxide followed by the addition of the Dess−Martin periodinane afforded enone 11, which was immediately treated, without further purification, with diisobutylaluminum hydride in THF at −78 °C. As expected, the 1,2-reduction of the enone moiety proceeded on the less hindered face alongside the conversion of the neopentyl ester to the corresponding aldehyde unit to give compound 12 in 27% yield over two steps as the sole diastereomer. The low yield is mainly due to the instability of compound 11, which degrades under basic conditions or on silica gel. A Wittig reaction was then performed on aldehyde 12, producing the corresponding enol ether, which after a treatment with a concentrated solution of HCl (12 M) generated the homologated aldehyde 13 in 63% yield. At this point, typical reductive amination conditions employing methylamine and sodium borohydride were used, and the coveted amine 2 was obtained in 88% yield. Spectral data of compound 2 are identical to those previously reported.5v The conversion of amine 2 to 1 has been realized in two and three steps by Trost5v and Li,5ap respectively. The interception of this late-stage intermediate thus completed the formal synthesis of morphine (1). In conclusion, formal synthesis of (±)-morphine (1) was achieved in nine steps from commercially available starting materials. A unique feature of our synthesis involves a careful orchestration of one-pot processes leading to the synthesis of the morphine phenanthrofuran framework 10 in only five steps. From this intermediate, strategic functional group manipulations were achieved, minimizing the number of steps required for the formation of the natural product.
Scheme 2. Previous Morphinan Syntheses Using a Diels− Alder Reaction
degradation products were observed. It is reasoned that under these conditions, a E1cb elimination is initiated followed by a decarboxylative aromatization that could lead to 8a.8 After considerable experimentation, we found that heating 4 and 5 neat at 160 °C afforded 7 which upon the addition of a solution of PTSA (40 mol %) in toluene gave the desired cycloadduct 8 along with small quantities of phenol 8a and other unidentified byproducts. Owing to the high instability of 8, the crude reaction mixture was immediately treated with LSelectride to give the allylic alcohol 3 as a single diastereomer in 53% isolated yield over two steps. The allylic alcohol was transformed to the desired vinyl ether 9 in preparation for the formation of the B-ring.9 Thus, a one-pot Claisen rearrangement/Friedel−Crafts alkylation of 9 built the entire morphine framework in 61% yield.5aa,ai The addition of 2,6-lutidine was critical to the success of the Claisen rearrangement given the acid-sensitive nature of 9. Scheme 3. Nine-Step Formal Synthesis of (±)-Morphine (1)
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DOI: 10.1021/acs.orglett.9b00044 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00044. Experimental procedures and analytical data for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Louis Barriault: 0000-0003-2382-5382 Author Contributions †
J.B. and A.Z. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Natural Sciences and Engineering Research Council (Discovery grant to L.B.), the governments of Ontario and Quebec (Ph.D. scholarships to J.B.), and the University of Ottawa for support of this research.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b00044 Org. Lett. XXXX, XXX, XXX−XXX
