Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Asymmetric synthesis of (À)-naltrexone† Cite this: Chem. Sci.,2019,10,535 Sun Dongbang, Blaine Pedersen and Jonathan A. Ellman * All publication charges for this article (À)-Naltrexone, an opioid antagonist used extensively for the management of drug abuse, is derived from have been paid for by the Royal Society fi À of Chemistry naturally occurring opioids. Herein, we report the rst asymmetric synthesis of ( )-naltrexone that does not proceed through thebaine. The synthesis starts with simple, achiral precursors with catalytic enantioselective Sharpless dihydroxylation employed to introduce the stereogenic centers. A Rh(I)- catalyzed C–H alkenylation and torquoselective electrocyclization cascade provides the hexahydro isoquinoline bicyclic framework that serves as the precursor to the morphinan core. The acidic conditions used for Grewe cyclization not only provide the morphinan framework, but also cause a hydride shift resulting in the introduction of the C-6 oxo functionality present in (À)-naltrexone. The C-14 hydroxyl group is installed by an efficient two-step sequence of Pd-mediated ketone to enone dehydrogenation followed by C–H allylic oxidation using Cu(II) and O2, a method that has not previously been reported either for the synthesis or semi-synthesis of opioids. The longest linear sequence is 17 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. steps, and because the stereogenic centers in the product rely on Sharpless asymmetric dihydroxylation, Received 21st August 2018 the route could be used to access either enantiomer of the natural product, which have disparate Accepted 18th October 2018 biological activities. The route also may be applicable to the preparation of opioid derivatives that could DOI: 10.1039/c8sc03748e not be easily prepared from the more fully elaborated and densely functionalized opioid natural products rsc.li/chemical-science that have traditionally served as the starting inputs. Introduction material. A number of strategies have been developed for exchange of the N-methyl for an N-cyclopropylmethyl group.6 7 This article is licensed under a (À)-Morphine (1) is one of the oldest and most extensively used Hudlicky has extensively investigated this step, including analgesics which led it, along with its congeners (À)-codeine (2) a particularly efficient alkylation and demethylation sequence 7c and (À)-thebaine (3), to garner signicant attention from of the thebaine derivative oripavine to give 9 (Fig. 2). The numerous organic chemists as targets for synthesis (Fig. 1).1 dienol ether functionality present in (À)-thebaine allows for the Open Access Article. Published on 23 October 2018. Downloaded 9/27/2021 12:58:55 PM. Extensive modications to the naturally occurring opioids have straightforward introduction of the C-14 hydroxyl group by also been investigated in endeavors to increase potency and in oxidative methods. For example, in Hudlicky's sequence, the vivo efficacy and have led to the discovery of semi-synthetic dienol ether functionality in 9 was epoxidized followed by in situ opioids such as (À)-ketorfanol (4)2 and the extensively oxirane ring opening to generate enone 10 followed by hydro- 8 prescribed (À)-oxycodone (5).3 However, despite the medical genation to give (À)-naltrexone (Fig. 2). Rice has also reported importance of naturally occurring and semi-synthetic opioid a semi-synthesis of the (+)-enantiomer of naltrexone. His agonists, undesired side effects such as addictive properties and the potential for fatal overdoses are enormous societal prob- lems. Therefore, semi-synthetic opioid antagonists were devel- oped to address these growing problems.4 Naltrexone (6) was rst patented in 1967 (ref. 5) and is currently an important treatment option for opioid abuse and alcohol dependence.4 The C-14 hydroxyl and N-cyclopropylmethyl substituent are essential structural features that are important for (À)-naltrex- one's potency and antagonistic properties.4 The prevalent commercial routes to (À)-naltrexone (6) employ the natural product (À)-thebaine (3) as the starting Department of Chemistry, Yale University, Connecticut, 06520, USA. E-mail: jonathan. [email protected]; Tel: +1-203-432-2647 † Electronic supplementary information (ESI) available. See DOI: Fig. 1 Representative naturally occurring opioids (1–3) and semi- 10.1039/c8sc03748e synthetic opioid agonists (4–5) and an antagonist (6). This journal is © The Royal Society of Chemistry 2019 Chem. Sci.,2019,10, 535–541 | 535 View Article Online Chemical Science Edge Article Fig. 2 Hudlicky's semi-synthesis of (À)-naltrexone.7c synthesis proceeded through (+)-thebaine, which was prepared a Rh(I)-catalysed C–H alkenylation and torquoselective 6-p in ve steps from the natural product (+)-sinomenine as an electrocyclization cascade as a key step in the sequence.12 innovative starting material.9 Herein, we further apply this cascade approach to the synthesis (À)-Thebaine is currently isolated from opium poppies but is of the considerably more complex opioid antagonist only a minor component of opium (0.3–1.5%), and poppy (À)-naltrexone (6) (Scheme 1). Imine 11 is efficiently prepared farming is problematic due to illicit drug activities.10 An alter- from achiral starting materials with catalytic asymmetric dihy- native synthetic route that bypasses (À)-thebaine and starts droxylation used to introduce the stereogenic centers. Intra- Creative Commons Attribution-NonCommercial 3.0 Unported Licence. with commercially available achiral precursors would provide molecular Rh(I)-catalysed alkenylation to give azatriene 12 is novel entry to (À)-naltrexone. Moreover, starting from simple followed by in situ torquoselective electrocyclization to set the inputs should enable the investigation of a variety of analogs desired stereochemistry in bicyclic hexahydroisoquinoline 13, not accessible from more fully elaborated and densely func- which is reduced to obtain 14 as a single diastereomer. Acid tionalized morphinan natural products like (À)-thebaine.11 treatment provides the tetracyclic morphinan 15 by concomi- Recently, we reported the synthesis of the unnatural enan- tant removal of the protecting groups, Grewe cyclization and tiomer of the opioid agonist (+)-ketorfanol (4) (Fig. 1) using redox neutral conversion of the diol to the desired keto group. This article is licensed under a Open Access Article. Published on 23 October 2018. Downloaded 9/27/2021 12:58:55 PM. Scheme 1 Approach to (À)-naltrexone from simple, achiral precursors. 536 | Chem. Sci.,2019,10, 535–541 This journal is © The Royal Society of Chemistry 2019 View Article Online Edge Article Chemical Science The 4-methoxy-3,5-disilyloxy substitution pattern on the phenyl ring of 14 was designed to allow for incorporation of the required aromatic ring oxygen substitution pattern while simultaneously ensuring that Grewe cyclization occurs without the possibility of generating regiosomeric products (vide infra).1f The pentacyclic ether 16 is then obtained from tetracyclic 15 by treatment with Br2 in AcOH according to methods developed for the synthesis of codeine.13 For intermediate 16, installation of the hydroxyl group at C- 14 would most efficiently be accomplished by dehydrogenation to an enone followed by C–H g-hydroxylation. However, in syntheses of morphinan natural products such as morphine and codeine, researchers have found that for the efficient dehydrogenation of 6-keto derivatives to enones the nitrogen must be protected by an electron withdrawing carbamoyl or sulphonamide rather than an N-alkyl group as is present in 16.1q,1u,14 Therefore, to enable dehydrogenation and g-hydroxy- lation of 16 without the protection of the nitrogen, a Pd- Scheme 2 Reactions and conditions: (a) (COCl)2 (1.16 equiv.), DMSO mediated dehydrogenation method and Cu(II)-catalysed O2- (2.2 equiv.), Et3N (5.0 equiv.), CH2Cl2, À78 / 23 C; (b) P(OEt)3, neat, mediated allylic C–H oxidation conditions were developed. 120 C; (c) LiOH$H2O (1.1 equiv.), MS 4 A,˚ THF, reflux; (d) K2OsO4- Alkene hydrogenation with concomitant reductive cleavage of $2H2O (1 mol%), (DHQD)2PHAL (5 mol%), K3Fe(CN)6 (3.00 equiv.), 18 19 both the tri ate and the bromide in gave , which upon K2CO3 (3.00 equiv.), MeSO2NH2 (1.00 equiv.), tBuOH/H2O, 0 C; (e) À 2,2-dimethoxypropane (10 equiv.), TsOH$H2O (10 mol%), CH2Cl2, Creative Commons Attribution-NonCommercial 3.0 Unported Licence. demethylation provided ( )-naltrexone in 17 steps for the longest linear sequence. Because the stereochemistry is set by 0 C; (f) Pd(OAc)2 (5 mol%), XPhos (15 mol%), Cs2CO3 (1.5 equiv.), dioxane, 65 C; (g) DIBAL (4.0 equiv.), THF, À78 C; (h) DMP (1.75 asymmetric catalytic dihydroxylation, the same route could equiv.), pyridine (6.0 equiv.), CH2Cl2,0 C; (i) cyclopropylmethylamine equally be employed to prepare the (+)-enantiomer of (1.2 equiv.), MS 3 A,˚ PhMe, 23 C. naltrexone, which has been reported to have antagonist activity toward Toll-like receptor 4.15 toluene to initiate the Rh(I)-catalysed cascade sequence. This Results and discussion process proceeds by Rh(I)-catalysed C–H activation followed by intramolecular insertion of the alkyne to give azatriene 12, This article is licensed under a 11 The synthesis commenced with the preparation of imine in which in situ undergoes rapid electrocyclization to provide 1,2- seven steps from simple achiral starting materials (Scheme 2). dihydropyridine 13 (Scheme 3). This cascade process not only – – 21 Horner Wadsworth Emmons (HWE) reaction of aldehyde forms the desired bicyclic ring system, but also proceeds with and phosphonate 23 afforded 24 in 67% yield. Based upon Open Access Article. Published on 23 October 2018. Downloaded 9/27/2021 12:58:55 PM. high torquoselectivity as enforced by the isopropylidene pro- 16 a report by Takacs, we found that use of LiOH as the base in 12 ˚ tected diol to provide the desired diastereomer. Without the presence of 4 A molecular sieves minimized competitive isolation, hexahydroisoquinoline 13 was reduced under mild self-condensation of aldehyde 21 and thus provided the most robust and reproducible HWE reaction conditions particularly on larger scales.