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DOI: 10.1055/a-2595-1691
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Development of Novel Bioactive Alkaloids Based on Specific Reactions of the 4,5-Epoxymorphinan Framework

Noriki Kutsumura  ∗
a   Department of Chemistry, Institute of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
b   International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
,
Hiroshi Nagase∗
b   International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
› Author Affiliations

This work was partly supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15K16553, 17K13259, 19K05710, 20H04763, and 24K08610 to N.K.; 16H05098 and 20H03361 to H.N.), the Japan Agency for Medical Research and Development (AMED), Moonshot Program (JP21zf0127005), and TORAY Industries, Inc. The International Institute For Integrative Sleep Medicine (IIIS) is also supported by the World Premier International Research Center Initiative (WPI), Japan.
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Abstract

Morphinan alkaloids, such as morphine, codeine, heroin, and thebaine, are referred to as opioids and are pharmacologically important compounds. They are widely known to exhibit diverse pharmacological effects by acting on μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). Naltrexone, a commercially available 4,5-epoxymorphinan alkaloid, is a drug primarily used to manage alcohol and opioid dependence. From a pharmacological perspective, naltrexone is classified as an MOR antagonist. On the other hand, from an organic chemistry perspective, naltrexone contains a wealth of functional groups and possesses four consecutive asymmetric centers within a single molecule, giving rise to its unique chemical reactivity. While this reactivity may not be universally applicable, gaining a clear understanding of it is crucial for researchers working on the organic chemistry of morphinan alkaloids. In this account, we provide a comprehensive overview of our research findings over the past decade, with a particular focus on the specific reactions of the 4,5-epoxymorphinan framework. We hope this account will be useful for both organic synthetic and medicinal chemists.

1 Introduction

2 Influence of the E-Ring in the 4,5-Epoxymorphinane Framework

2.1 Reaction of the C6 Ketone with a Stabilized Sulfur Ylide

2.2 Reaction of the C14 Hydroxy Group with Thionyl Chloride

2.3 Reaction of the C14 Hydroxy Group with Acetic Anhydride

2.4 Reaction of 14-Aminonaltrexone with Acetic Anhydride

2.5 Baeyer–Villiger-Type Oxidation of the 4,5-Epoxymorphinan

2.6 Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan

2.7 Unique Rearrangement of Morphinan Into Arylmorphan

3 Synthesis of Bioactive Compounds Based on 4,5-Epoxymorphinan

3.1 Synthesis of (–)-Galanthamine

3.2 Synthesis of (–)-Homogalanthamine

4 Summary


#

Key words

morphinan - 4,5-epoxymorphinan - bioactive alkaloids - rearrangement - substrate-specific reaction - naltrexone

Biographical Sketches

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Noriki Kutsumura was born in 1977 in Sapporo, Japan. He graduated from Keio University in 2001 and received his Ph.D. from Keio University in 2006 under the direction of Professor Shigeru Nishiyama. He subsequently worked as an assistant professor with Professor Seiji Kosemura, taking charge of chemistry at the Faculty of Law, Keio University. In 2007, he became a postdoctoral research fellow at the University of Pennsylvania (USA), under the supervision of Professor Amos B. Smith III. In 2009, he joined Professor Takao Saito’s group at Tokyo University of Science as an assistant professor. In 2013, he moved to Professor Hiroshi Nagase’s group at the International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, as an associate professor. In 2019, he was promoted to full professor (Co-PI), and from 2022 he has been affiliated with the Department of Chemistry, University of Tsukuba and presides over his own group. His research interests are focused on synthetic organic chemistry and medicinal chemistry.

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Hiroshi Nagase was born in 1947 in Toki, Japan. He received his Ph.D. from Nagoya University in 1978 under the direction of Professor Yoshimasa Hirata. He spent his postdoctoral years (1985–1987) at the University of Minnesota (USA), under the supervision of Professor Philip S. Portoghese. In 2001, he became director of the Pharmaceutical Research Laboratories, Toray Industries, Inc. He subsequently moved to Kitasato University as a full professor in 2004 and then moved to the International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, in 2013. He retired in 2022, the same year he received the title of Professor Emeritus of the University of Tsukuba. His research interests are in the area of medicinal chemistry. He released the first orally active PGI2 derivative, Dorner®, in 1992 and the first selective κ-opioid receptor agonist, Remitch® capsules, in 2009. He designed and synthesized the first orexin-2 receptor agonist YNT-185 in 2015, and the orexin-1 receptor agonist YNT-3708 in 2023, collaborating with Professor Masashi Yanagisawa.

1

Introduction

The morphinan alkaloid framework contains a basic nitrogen atom, a common structural motif found in morphine, codeine, heroin, and thebaine. This framework is generally represented as structure 1 with the rings A–D (Figure [1]). Many alkaloids with this core affect the central nervous system and have been extensively investigated over the past 200 years across various scientific fields. One of the 4,5-epoxymorphinan alkaloids, naltrexone (2), has long been used internationally as a therapeutic agent for opioid addiction and alcohol dependence. It belongs to the class of opioids, a term that broadly refers to substances that bind to opioid receptors. Pharmacologically, 2 is classified as a μ-opioid receptor (MOR) antagonist, meaning it competitively inhibits the binding of opioids such as morphine to MOR. From an organic chemistry perspective, naltrexone (2) possesses a diverse array of functional groups and four consecutive asymmetric centers within its molecular structure, leading to a highly versatile chemical reactivity.[1] In our research, we have utilized commercially available 2 as a synthetic starting material to develop various morphinan alkaloid-based compounds that we have applied to drug discovery research. In this account, we introduce some of the unique reactions specific to the 4,5-epoxymorphinan framework that we have identified through our investigations.

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Figure 1 Structures of morphinan skeleton 1 and naltrexone (2)

# 2

Influence of the E-Ring in the 4,5-Epoxymorphinan Framework

Naltrexone (2) has been utilized as a starting material for the synthesis of bioactive compounds that have been applied in drug discovery research. During these studies, investigators have encountered numerous anomalous reactions. These unexpected reactivities originate from the unique 4,5-epoxymorphinan structure of 2. Specifically, compound 2 possesses four consecutive asymmetric centers and multiple reactive functional groups, including a tertiary amine, a phenolic hydroxy group, a ketone, a tertiary hydroxy group, and a tetrahydrofuran ring (commonly referred to as the 4,5-epoxy ring or E-ring in the morphinan framework). These functional groups are spatially arranged to facilitate intramolecular interactions. Among such interactions, intramolecular hydrogen bonding is particularly important, as it often plays a decisive role in determining molecular conformation—from small organic compounds to supramolecular assemblies.[2] In compound 2, a representative hydrogen bond is observed between the C14 hydroxy group and the lone pair of the 17-nitrogen, contributing to conformational rigidity. In addition to this hydrogen-bonding interaction, the E-ring significantly influences the chemical reactivity of the molecule. It increases the acidity of the hydrogen at the C5 position through the inductive effect of the ring oxygen and rigidly locks the morphinan core into a well-defined three-dimensional conformation. This structural rigidity enhances the planarity of the C-ring (Figure [2]). The effect of this C-ring planarity on reactivity is exemplified by the following transformation: when 2 is treated with acetic anhydride and pyridine at room temperature, the C3 and C14 hydroxy groups are acetylated, and the C6 ketone is converted into its enol acetate, affording compound 3 in quantitative yield.[3] This transformation is attributed to two key factors: (1) the increased basicity of the C14 hydroxy group due to intramolecular interaction with the 17-nitrogen, and (2) the planar environment of the C-ring, which facilitates the enolization of the C6 ketone.

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Figure 2 Characteristic structure of 2 and the acetylated product 3

Thus, in morphinan compounds, the presence or absence of the E-ring can lead to entirely different reaction outcomes under identical reaction conditions. Herein, we describe six specific reaction examples that are unique to the 4,5-epoxymorphinan framework. Furthermore, in contrast to the 4,5-epoxymorphinan framework, in which certain reactions do not proceed, we present an example where a peculiar rearrangement reaction occurs in a morphinan framework lacking the E-ring.

2.1

Reaction of the C6 Ketone with a Stabilized Sulfur Ylide

The first example demonstrates the difference in reactivity of the C6 ketone toward a stabilized sulfur ylide 5. We found that when naltrexone methyl ether (4) was treated with ylide 5, β-epoxide 6 was exclusively formed (Scheme [1]).[4] We propose the following rationale for this selectivity. Initially, ylide 5 attacks the C6 keto group from the sterically less hindered upper face of the C-ring. However, the resulting alkoxide intermediate experiences steric repulsion from the E-ring, as well as electrostatic repulsion between the lone pairs of oxygen atoms. These repulsions cause the intermediate to revert reversibly to the original ketone. Subsequently, the intermediate gradually adjusts to minimize these repulsions, allowing the ylide to attack from the lower face of the C-ring, ultimately leading to the selective formation of 6. In contrast, when the E-ring-deficient substrate 7 was subjected to the same reaction, α-epoxide 8 was initially formed, followed by further transformation into compound 9, which possesses an oxabicyclo[2.2.1]heptane structure. Under these conditions, the formation of β-epoxide 10 was observed in only approximately 10% yield, indicating that the presence or absence of the E-ring results in an inversion of the stereoselectivity of the ylide addition to the C6 ketone.

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Scheme 1 Epoxidations of 4,5-epoxymorphinan 4 and morphinan 7

# 2.2

Reaction of the C14 Hydroxy Group with Thionyl Chloride

The dehydration reaction of the C14 hydroxy group in 4,5-epoxymorphinans to yield 8,14-dehydro derivatives can be achieved using reagents such as benzoyl chloride,[5] methanesulfonyl chloride,[6] or thionyl chloride.[7] For example, when naltrexone derivative 11 was stirred with thionyl chloride at room temperature, the 8,14-dehydro derivative 12 was obtained in 90% yield (Scheme [2]).[8] The dehydration of naltrexone methyl ether (4) with thionyl chloride resulted in the formation of complex mixtures due to intramolecular interactions between the C14 hydroxy and C6 keto groups. In contrast, under the same reaction conditions, compound 13, which lacks an E-ring, produced not only 8,14-dehydro derivative 14 but also iminium salt 15 as an isolable byproduct. Further optimization of the reaction conditions revealed that methanesulfonyl chloride significantly enhanced the yield of iminium salt 16, reaching 93%,[9] which serves as a key precursor in the synthesis of numerous propellane-type compounds that exhibit intriguing binding interactions with opioid receptors.[10]

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Scheme 2 Reactions of 4,5-epoxymorphinan 11 and morphinan 13 under the dehydration conditions

# 2.3

Reaction of the C14 Hydroxy Group with Acetic Anhydride

The difference in reactivity due to the presence or absence of the E-ring is also evident in substrates where the D-ring of the morphinan framework has been removed. Specifically, when compound 17, which retains the E-ring, was heated in acetic anhydride, compound 18, in which the C14 hydroxy group was acetylated, was obtained in quantitative yield (Scheme [3]). In contrast, when compound 19, which lacks the E-ring, was subjected to the same reaction conditions, no product acetylated at the C14 hydroxy group was obtained. Instead, acetylation occurred at the 17-nitrogen, yielding compounds 20 and 21.[11] To better understand this reaction, we conducted a series of investigations using substrate 22, which contains a structurally simpler dimethylamino group. Under optimized conditions, the reaction at 60 ℃ led to the isolation of quaternary ammonium salt 23, which possesses a [4.4.3] propellane framework. Furthermore, the isolation of quaternary ammonium salt 23, along with experiments using a deuterium-labeled derivative of 22, in which the dimethylamino group was deuterated, confirmed that a deuterium shift occurs at the C10 position. These findings indicate that this process proceeds through a retro-ene reaction involving intermediate 23, which serves as the key step in the transformation (Scheme [4]).

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Scheme 3 Reaction of 4,5-epoxymorphinan 17 and morphinan 19 under acetylation conditions
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Scheme 4 Proposed mechanism for the synthesis of compound 20

# 2.4

Reaction of 14-Aminonaltrexone with Acetic Anhydride

The reaction between 4,5-epoxymorphinan compounds substituted with an amino group at the C14 position and acetic anhydride revealed a highly intriguing reactivity. Specifically, when the hydrochloride salt of 14-aminonaltrexone 24 was heated under reflux in acetic anhydride, the novel compound 25 possessing an acetylacetone moiety was obtained in 68% yield. In contrast, when the free amine of 24 was heated under the same conditions, the novel compound 26 with a pyranopyridine framework was formed in 78% yield (Scheme [5]).[12]

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Scheme 5 Conversion reactions of 14-aminonaltrexone 24 with and without hydrochloric acid

Modifying the reaction conditions, analyzing isolated intermediates, and estimating the stable conformations of the initial acetylation using DFT calculations allowed us to propose mechanisms for the formation of the unexpected products 25 and 26. As shown in Scheme [6], the formation of 25 may proceed through the initial generation of acylium ion 27, followed by an intramolecular reaction between the acyl group attached to the 17-nitrogen and the 14-nitrogen to produce amidinium salt 29 via 28. Next, in the reaction system in which chloride and acetate ions coexist, the more nucleophilic chloride ion attacks the C16 position on 29, cleaving the C16–N17 bond to form chloride adduct 30. A similar C16–N17 bond cleavage reaction induced by chloride ions has been previously reported.[13] The chloride adduct 30 may undergo an intramolecular SN2 reaction of the secondary amine, leading to the formation of quaternary ammonium salt 31, which subsequently undergoes successive reactions with acetic anhydride, ultimately yielding 25.[14] To validate the key steps of the proposed mechanism experimentally, particularly the transformation from 29 to 31 via the chloride adduct 30, we conducted a model reaction (Scheme [7]). Heating a mixture of N-Boc-protected 4,5-epoxymorphinan 33 and NaCl as a chloride source in tetrachloroethane afforded the expected cyclic urea 34 in quantitative yield. The reaction mechanism was considered to proceed in a manner similar to that shown in Scheme [6], where nucleophilic attack by chloride at the C16 position of quaternary ammonium salt 35 generates chloride adduct 36, which then undergoes an intramolecular SN2 reaction mediated by the 14-nitrogen, ultimately yielding 34. These experimental results provide strong support for the validity of the proposed mechanism shown in Scheme [6]. In summary, these outcomes clearly demonstrate the remarkable reactivity of the 4,5-epoxymorphinan framework, where compounds such as 24·HCl and 33, which are sufficiently stable in air, can undergo facile skeletal transformation upon simple heating with acetic anhydride or NaCl, resulting in the disappearance of the D-ring in the morphinan framework and the formation of novel molecular scaffolds.

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Scheme 6 Possible mechanism for the formation of 25
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Scheme 7 D-Ring cleavage of 4,5-epoxymorphinan 33 induced by a chloride ion and subsequent intramolecular SN2 cyclization
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Scheme 8 Possible mechanism for the formation of 26

A structural analysis of the reaction intermediates allowed us to investigate the mechanism that formed compound 26. These studies confirmed that the first intermediate to form was N-Ac-protected 4,5-epoxymorphinan 37, which resulted from the acetylation of the free form of 24 (Scheme [8]). After amide 37 had been transformed into active iminium salt 39, intramolecular cyclization in 39 involving the 17-nitrogen atom produced quaternary ammonium salt 40. Subsequently, driven by removal of the proton at the C10 position of 40 by the acetate ion, Grob fragmentation with cleavage of the C9–N17 bond proceeded to form isolable amidine 42.[15] [16] After further acetylation of the imino group in 42, an additional two equivalents of acetic anhydride reacted quickly and a stepwise reaction with the generated 43 formed isolable compound 46. On the basis of the structure determination experiments on the intermediates, the cleavage of the amide bond at the 14-position and the conversion of the acetylacetone moiety into the pyranopyridine skeleton were presumed to be the late-stage transformations. After acetylation of the secondary amine in 46, the amide bond at the 14-position in 47 was cleaved to generate 48. Further intramolecular cyclization and dehydration occurred to form 50 with a 4-pyridone skeleton, and aromatization followed by O-acetylation produced 51, and finally, intramolecular cyclization and dehydration afforded product 26. As inferred from the reaction mechanisms described above, the reaction of 14-aminonaltrexone with acetic anhydride yielded significantly different products depending on whether nucleophilic chloride ions were present in the reaction system. In the presence of chloride ions, nucleophilic attack at the C16 position induced C16–N17 bond cleavage, leading to opening of the D-ring in the 4,5-epoxymorphinan framework. In contrast, in the absence of chloride ions, acetate ions acted as a base, removing the proton at the C10 position, thereby triggering Grob fragmentation, which also resulted in D-ring cleavage. Both reactions were highly specific to the 4,5-epoxymorphinan framework. A key finding was that compound 25 and its analogous derivatives have recently been demonstrated to be valuable compounds in exploring the previously uncharted region above the D-ring of the morphinan scaffold as a pharmacophore interacting with opioid receptors.[12b]


# 2.5

Baeyer–Villiger-Type Oxidation of the 4,5-Epoxymorphinan

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Scheme 9 Reaction of 4,5-epoxymorphinan 52 with KOH in tBuOH under an oxygen atmosphere (balloon)

A novel Baeyer–Villiger-type oxidation of the 4,5-epoxymorphinan skeleton was also discovered. When bicyclo[2.2.2]octenone derivative 52, which was derived from naltrexone methyl ether (4) through four steps,[17] was refluxed in tBuOH under an oxygen atmosphere in the presence of KOH, unexpected cyclopropanecarboxylic acid derivative 53 and ketolactone derivative 54 were obtained (Scheme [9]).[18] This reaction proceeds via seven-membered ring lactone 55, possessing an oxabicyclo[3.2.2]nonene skeleton, which is formed by the insertion of an oxygen atom due to the involvement of oxygen molecules. In the presence of a strong base (KOH), enolate 56 is generated, followed by an Ireland–Claisen rearrangement, leading to the stereospecific formation of compound 53 (Scheme [10], Path A).[19] On the other hand, participation of the lone-pair of electrons of the methoxy group at the C6 position promotes the ring-opening reaction of lactone 55, generating carboxylate 58. Subsequent intramolecular Michael addition via enol lactone 59 ultimately yields ketolactone 54 (Path B). Additionally, the partial conversion of 53 into 54 was observed in the reaction system, suggesting that this transformation also proceeds in parallel via Path C. These rearranged products, 53 and 54, have reactive sites (carboxylic acid and lactone) positioned above the C-ring of the morphinan scaffold. Since it has been reported that the pharmacophore above the C-ring of the morphinan scaffold plays a crucial role in the interaction between the morphinan molecule and the κ-opioid receptor (KOR), compounds 53 and 54 have the potential to serve as ideal synthetic intermediates in the molecular design of KOR agonists. Furthermore, this method differs from oxidation using m-chloroperoxybenzoic acid (mCPBA) in that it does not oxidize the nitrogen at the 17-position, which is a fundamental part of the core structure. This characteristic makes this transformation highly valuable in the field of morphinan-based drug discovery research.

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Scheme 10 Possible mechanisms for the formation of 53 and 54

# 2.6

Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan

A unique Favorskii-type rearrangement of the 4,5-epoxymorphinan skeleton to the C-ring-contracted morphinan skeleton was also discovered. 7-Benzylidene naltrexone (BNTX) (60), obtained via aldol condensation between commercially available naltrexone (2)·HCl and benzaldehyde, is known as a δ-opioid receptor (DOR)-selective antagonist (Scheme [11a]).[20] It has been reported that 60 and its derivatives exhibit antiprotozoal activity against Plasmodium (malaria)[21] and Trichomonas,[22] and an efficient synthetic method for BNTX derivatives has also been established.[22] However, during the course of this study, when 2-pyridinecarboxaldehyde was used in the condensation reaction, no BNTX derivative was obtained. Instead, C-normorphinan compounds 61–63, in which the C-ring of the morphinan skeleton has undergone ring contraction to form a five-membered ring, were generated (Scheme [11b]).[23] This unique C-ring contraction reaction with 2-pyridinecarboxaldehyde or its derivatives was also found to be critically dependent on the presence of the E-ring. For comparison, reactions with naltrexone methyl ether (4) and morphinan 7, which lacks the E-ring, are shown in Scheme [12]. When compound 4 was reacted with 2-pyridinecarboxaldehyde in methanol under sealed-tube conditions at 120 °C in the presence of piperidine, methyl ester 64 and spiro-γ-lactones 65 and 66 were obtained (Scheme [12a]). In contrast, the reaction with 7 did not proceed to completion even after 24 hours, yielding the BNTX derivative 67 and its double-bond-isomerized product 68 (Scheme [12b]).

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Scheme 11 Reactions of 2∙HCl with benzaldehyde and 2-pyridinecarboxaldehyde
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Scheme 12 Reactions of 4,5-epoxymorphinan 4 and morphinan 7 with 2-pyridinecarboxaldehyde

We proposed a mechanism for the formation of these C-normorphinan compounds based on the isolation of the reaction intermediate BNTX derivative 69 and in situ IR measurements of the reaction system using ReactIR (Scheme [13]). Specifically, the initially formed intermediate 69 undergoes deprotonation at the C5 position by a base, generating enolate anion 70, which subsequently rearranges to form the cyclopropanone intermediate 71. At this stage, the 2-pyridylidene moiety is believed to contribute to the stabilization of the anion. Subsequently, when intermediate 71 reacts with an additional molecule of aldehyde, spiro-γ-lactones 62 and 63 are produced via intermediate 72. On the other hand, upon protonation of 71 followed by reaction with methanol (the solvent), methyl ester 61 is obtained. Notably, when the reaction is carried out in acetonitrile instead of methanol, bicyclo[2.2.1]lactone 73 is formed instead of 61. This product is considered to arise from an intramolecular nucleophilic attack of the 14-hydroxy group on the carbonyl group of the cyclopropanone intermediates 71 or 74. To further investigate the reaction mechanism, IR measurements of the reaction system were conducted. A characteristic carbonyl absorption band around 1850 cm– 1 was observed, which is attributed to the presence of the strained cyclopropanone intermediate. This observation strongly suggests that the reaction proceeds via a Favorskii-type intermediate, supporting the proposed reaction mechanism.[23]

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Scheme 13 Possible mechanism for the formation of compounds 61–63 and 73

# 2.7

Unique Rearrangement of Morphinan Into Arylmorphan

The reaction examples discussed thus far may give the impression that the 4,5-epoxymorphinan framework is inherently more reactive than the morphinan framework lacking the E-ring, always leading to anomalous reactions. To address this potential misconception, this section describes a unique rearrangement reaction that proceeds exclusively in the morphinan framework. Specifically, when the morphinan derivative 75 is treated with zinc iodide, the reaction yielded the 5-arylmorphan derivatives 76 and 77 (Scheme [14a]).[24] In contrast, under identical reaction conditions, the structurally more rigid 4,5-epoxymorphinan derivative 78 remained unreactive and was recovered in 94% yield. Notably, compound 79, which shares the same scaffold as 77, underwent conversion into the 5-arylmorphan derivative 81, which shares the same scaffold as 76, under reductive amination conditions via the iminium intermediate 80 (Scheme [14b]).

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Scheme 14 Transformation from 75 into arylmorphans 76 and 77 using ZnI2

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# 3

Synthesis of Bioactive Compounds Based on 4,5-Epoxymorphinan

Our research is centered around drug discovery, with a particular focus on the development of compounds targeting opioid receptors,[10c] [25] orexin receptors,[26] and other related targets.[27] In the preceding section, seven distinct substrate-specific reactions that have been discovered over the past decade during our studies on 4,5-epoxymorphinan compounds were introduced, with an emphasis on reactions that are expected to be of interest to readers. In addition to these findings, knowledge gained from the discovery of novel fundamental reactions and the unique reactivity of the morphinan framework have been leveraged to conduct synthetic studies on natural products and their analogs, including compounds that were not necessarily designed with specific biological activity in mind. Although these synthetic approaches may not always be the most efficient in terms of overall yield or the number of synthetic steps, they represent highly distinctive methodologies that capitalize on the unique chemical properties of the morphinan framework. As such, these strategies provide valuable insights into the anomalous reactivity of this framework, which could be of significant interest to researchers engaged in the total synthesis of morphinan alkaloids and drug discovery efforts based on morphinan derivatives. In this section, the detailed syntheses of the natural product (–)-galanthamine (82)[28] and its structural analog (–)-homogalanthamine (83)[16] are described, utilizing commercially available naltrexone (2) as the starting material (Figure [3]).

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Figure 3 Structures of (–)-galanthamine (82), (–)-homogalanthamine (83), and (–)-naltrexone (2)
3.1

Synthesis of (–)-Galanthamine

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Scheme 15 Synthesis of intermediate 87

(–)-Galanthamine (82) is a bioactive alkaloid isolated from plants of the Amaryllidaceae family. Due to its acetylcholinesterase (AChE) inhibitory activity and allosteric modulation of nicotinic acetylcholine (nACh) receptors, it has been utilized in the treatment of Alzheimer’s disease and various memory disorders.[29] Given the structural similarity between 82 and commercially available naltrexone (2), it was hypothesized that the core structure of 82 could be constructed by formal carbon deletion at the C9 position of 2 (Figure [3]). Initially, the ketone at the C6 position of 2 was reduced to a methylene group over six steps (Scheme [15]). Notably, direct application of Wolff–Kishner reduction conditions to 2 [30] or its derivatives resulted in concomitant cleavage of the E-ring.[31] Consequently, a stepwise approach was adopted to circumvent this issue. Specifically, naltrexone methyl ether (4) was stereoselectively reduced using sodium triacetoxyborohydride, followed by three additional transformations to afford a mixture of 85 and 86 in an approximately 7:1 ratio. This mixture of isomers was then quantitatively converted into 87 via homogeneous hydrogenation employing Wilkinson’s catalyst. It should be noted that hydrogenation using palladium catalysts resulted in cleavage of the E-ring in both the allyl ether 85 and the vinyl ether 86.

The synthesized 4,5-epoxymorphinan 87 was then subjected to Hofmann elimination to quantitatively cleave the D-ring at the C9–N17 bond, affording allyl alcohol 88 (Scheme [16]). Subsequently, Lemieux–Johnson oxidation, carried out under acidified acetic acid conditions, enabled a one-pot transformation to ketoaldehyde 89 via a triol intermediate, with formal removal of the C9 carbon. Notably, performing the reaction in the absence of acetic acid resulted in oxidation of the basic 17-nitrogen, leading to undesired side reactions and increased complexity of the reaction mixture. Finally, the cyclopropylmethyl (CPM) group was replaced with a Troc group, yielding ketoaldehyde 90.

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Scheme 16 Synthesis of ketoaldehyde 90

After temporary protection of the ketone carbonyl in ketoaldehyde 90, deprotection of the Troc group, accompanied by intramolecular cyclization and subsequent removal of the cyclic acetal, afforded ketone 91. Next, β-elimination of the sulfonyl group was utilized to generate the α,β-unsaturated ketone 92. During oxidation of the sulfide to the sulfone using mCPBA, the reaction was performed under acidic conditions with camphorsulfonic acid (CSA) to prevent oxidation of the basic 17-nitrogen. Finally, the major product 93, obtained via Luche reduction, was subjected to Trost’s methodology[32] to complete the total synthesis of (–)-galanthamine (82) (Scheme [17]).[28]

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Scheme 17 Completion of the synthesis of (–)-galanthamine (82)
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Scheme 18 Synthesis of intermediate 99 using Grob fragmentation of 96

# 3.2

Synthesis of (–)-Homogalanthamine

We expected to achieve the synthesis of (–)-homogalanthamine (83), which contains one additional carbon compared to (–)-galanthamine (82), by utilizing the core structure of naltrexone (2). Accordingly, we selected 4,5-epoxymorphinan 87 as the starting material, a key intermediate in the synthesis of 83 (Scheme [18]). Specifically, acetylation of the C14 hydroxy group of 87, conversion of the CPM group into a Troc group, and subsequent deprotection of both the acetyl and Troc groups afforded the corresponding secondary amine.[33] Treatment with N-chlorosuccinimide (NCS) then yielded N-chloromorphinan 96. Next, Grob fragmentation of 96 cleaved the C9–C14 bond, and subsequent treatment with lithium borohydride produced a mixture of hemiaminal 97 and secondary amine 98. Through extensive optimization studies, we determined that 97 could be efficiently converted into 99 by treatment with methyl chloroformate. Additionally, 98 could also be transformed into 99 via sequential treatment with methyl chloroformate, carbonate hydrolysis, and oxidation of the regenerated secondary hydroxy group. Ultimately, these transformations were performed sequentially in a single reaction system using the mixture of 97 and 98, affording ketone 99 in 70% yield.

Subsequently, conversion of ketone 99 into α,β-unsaturated ketone 100 through a three-step sequence followed the same procedure as described earlier. Luche reduction of 100 then afforded the desired allyl alcohol 101α as the major product. Finally, an allylic rearrangement, conversion of the carbamate moiety into a methyl group, and deprotection of the acetyl group culminated in the total synthesis of (–)-homogalanthamine (83) (Scheme [19]).[16]

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Scheme 19 Completion of the synthesis of (–)-homogalanthamine (83)

#
# 4

Summary

Morphinan alkaloids are well-known for their interactions with opioid receptors in drug discovery research. However, recent studies have also reported their interactions with a variety of GPCRs, including orexin receptors and MRGPRs. Their pharmacological applications extend beyond analgesia to include antitussive effects, treatments for diarrhea and addiction, as well as potential therapeutic applications for depression and anxiety disorders, making them a subject of extensive pharmaceutical research. While morphinan alkaloids are highly intriguing from a pharmacological perspective, they present significant challenges in synthetic organic chemistry due to their unique structural properties. In this account, we have focused on their distinct reactivity, deliberately omitting discussions on their biological activities and side effects to highlight the synthetic challenges associated with the morphinan framework. In particular, we have discussed the reactions and synthetic strategies involving naltrexone (commercially available as its hydrochloride salt) and its derivatives, which are classified as 4,5-epoxymorphinans, with an emphasis on recent studies in this field. We hope that this account will serve as a valuable resource for researchers engaged in the total synthesis of bioactive alkaloids and drug discovery efforts centered on morphinan alkaloids.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank the staff and students of the Nagase/Kutsumura Laboratory, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, for their tireless efforts, which have significantly contributed to the development of the research presented in this account. We are grateful to all the researchers involved in this work.


Corresponding Authors

Noriki Kutsumura
Department of Chemistry, Institute of Pure and Applied Sciences, University of Tsukuba
1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571
Japan   

Hiroshi Nagase
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575
Japan   

Publication History

Received: 31 March 2025

Accepted after revision: 25 April 2025

Accepted Manuscript online:
25 April 2025

Article published online:
17 June 2025

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Figure 1 Structures of morphinan skeleton 1 and naltrexone (2)
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Figure 2 Characteristic structure of 2 and the acetylated product 3
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Scheme 1 Epoxidations of 4,5-epoxymorphinan 4 and morphinan 7
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Scheme 2 Reactions of 4,5-epoxymorphinan 11 and morphinan 13 under the dehydration conditions
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Scheme 3 Reaction of 4,5-epoxymorphinan 17 and morphinan 19 under acetylation conditions
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Scheme 4 Proposed mechanism for the synthesis of compound 20
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Scheme 5 Conversion reactions of 14-aminonaltrexone 24 with and without hydrochloric acid
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Scheme 6 Possible mechanism for the formation of 25
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Scheme 7 D-Ring cleavage of 4,5-epoxymorphinan 33 induced by a chloride ion and subsequent intramolecular SN2 cyclization
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Scheme 8 Possible mechanism for the formation of 26
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Scheme 9 Reaction of 4,5-epoxymorphinan 52 with KOH in tBuOH under an oxygen atmosphere (balloon)
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Scheme 10 Possible mechanisms for the formation of 53 and 54
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Scheme 11 Reactions of 2∙HCl with benzaldehyde and 2-pyridinecarboxaldehyde
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Scheme 12 Reactions of 4,5-epoxymorphinan 4 and morphinan 7 with 2-pyridinecarboxaldehyde
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Scheme 13 Possible mechanism for the formation of compounds 61–63 and 73
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Scheme 14 Transformation from 75 into arylmorphans 76 and 77 using ZnI2
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Figure 3 Structures of (–)-galanthamine (82), (–)-homogalanthamine (83), and (–)-naltrexone (2)
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Scheme 15 Synthesis of intermediate 87
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Scheme 16 Synthesis of ketoaldehyde 90
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Scheme 17 Completion of the synthesis of (–)-galanthamine (82)
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Scheme 18 Synthesis of intermediate 99 using Grob fragmentation of 96
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Scheme 19 Completion of the synthesis of (–)-homogalanthamine (83)