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DOI: 10.1055/a-2524-9014
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Small Molecules in Medicinal Chemistry

A Concise Account on Organocatalyzed Asymmetric Synthesis of Epoxide and Aziridine Derivatives from α,β-Unsaturated Carbonyl Compounds

Alice K. de A. Martinez
,
Penina S. Mourão
,
Arlene G. Corrêa  ∗

The authors gratefully acknowledge Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grants 2021/12394-0 and 2024/05518-2), GlaxoSmithKline, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Finance Code 001), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; grant 303973/2023-4) for funding and fellowships.
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Abstract

Epoxides and aziridines are important pharmacologically active compounds that are found in many drugs. These three-membered rings are also employed in the synthesis of a wide range of other heterocycles. In this account, we highlight the contributions of our research group to the organocatalyzed asymmetric synthesis of epoxides and aziridines from α,β-unsaturated carbonyl compounds, followed by multicomponent reactions that afford novel peptidomimetics. Additionally, these scaffolds have been employed in the synthesis of lactones, lactams, and hydantoins, showcasing their versatility in drug development and synthetic chemistry.

1 Introduction

2 Epoxides

2.1 γ-Lactones

3 Aziridines

3.1 γ-Lactams

3.2 Hydantoins

4 Conclusion


#

Key words

epoxide - aziridine γ-lactams - γ-lactones - hydantoins - cathepsins - organocatalysis

Biographical Sketches

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Alice K. A. Martinez received her B.Sc. (2024) from the Federal University of São Carlos (Brazil), conducting undergraduate research with Professor Arlene G. Corrêa and remains under her supervision as a Ph.D. student at the Centre of Excellence for Research in Sustainable Chemistry (CERSusChem).

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Penina S. Mourão received her licentiate degree (2020) and M.Sc. (2022) degrees from the State University of Piauí – UESPI (Brazil), conducting undergraduate research with Professor Francisco das Chagas Alves Lima and Master’s research with Professor Valdiléia Teixeira Uchôa. She is currently a PhD student being supervised by Professor Arlene G. Corrêa at the Federal University of São Carlos.

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Arlene G. Corrêa received her B.Sc. (1985) and M.Sc. (1988) degrees from the Federal University of São Carlos - UFSCar (Brazil), conducting undergraduate research with Professor Ursula Brocksom. After spending two years as a postgraduate student in the group of Professor Andrew E. Greene at the University of Grenoble (France), she received her Ph.D. degree in 1991 under the supervision of Professor Timothy J. Brocksom at UFSCar, where she became an Assistant Professor in 1992 and Full Professor in 2014. She joined the group of Professor Paul A. Wender at Stanford University (USA) as a visiting scholar in 1996. She is the Director of the Centre of Excellence for Research in Sustainable Chemistry (CERSusChem).

1

Introduction

N-Heterocycles are undoubtedly the most important class of bioactive natural or synthetic compounds, and, among them, the three-membered rings are highlighted. For example, the anticancer drugs carfilzomib,[1] mitomycin C,[2] and azinomycin B,[3] contain epoxide and aziridine rings (Figure [1]).

Many pathological conditions in humans and animals are linked to malfunctioning proteases; as a result, they are seen as attractive targets for drug discovery. Proteases are named by the nature of their active site catalytic residues, such as the cysteine proteases.[4] [5] The epoxysuccinyl derivative E-64, isolated from Aspergillus japonicus TPR-64,[6] is an irreversible inhibitor of cysteine proteases, inactivating the enzymes by alkylation of the active-site cysteine residues.[7]

One of the subfamilies of the cysteine proteases is the lysosomal cathepsins, which are responsible for a number of physiological processes, including cellular protein degradation and protein and lipid metabolism.[8] Therefore, the cathepsins are a target for drug development to treat several diseases, such as osteoporosis and arthritis,[9] cystic fibrosis,[10] and cancer.[11]

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Figure 1 Synthetic and natural bioactive compounds containing epoxide and aziridine moieties

Due to their relevant pharmacological properties, greener synthetic methods have been reported that allow epoxides and aziridines to be obtained,[12] and, in this context, asymmetric organocatalysis plays a key role.[13] Several factors have contributed significantly to the widespread success of chiral organic scaffolds as catalysts, including biodegradability, insensitivity to oxygen and moisture, availability from natural sources, and generally lower cost compared to enzymes or transition metals.[14] Epoxides and aziridines are also quite important as intermediates to achieve other N-heterocycles via ring-expansion reactions,[15] [16] [17] thus producing lactones, lactams, and hydantoins, for example.

In this account, the contributions of our research group to the asymmetric organocatalyzed synthesis of epoxide and aziridine derivatives are reviewed. Moreover, their ring expansion reactions to afford five-membered heterocycles are also discussed.


# 2

Epoxides

Several organocatalyzed asymmetric synthetic methods to obtain epoxides have been reported.[18] [19] The pioneering work by Shi allows the synthesis of epoxides from alkenes using a fructose-derived organocatalyst with Oxone as oxidant (Scheme [1]).[20] High enantioselectivity has been obtained for a wide variety of trans and trisubstituted olefins, as well as a number of cis olefins, with encouragingly high enantiomeric excesses (ee) for some terminal olefins.[20] Page et al. described in 2016 the use of octahydrobinaphthyl iminium salts for asymmetric epoxidation of di- and trisubstituted alkenes, also using Oxone as the oxidant.[21]

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Scheme 1 Synthesis of epoxides from alkenes using a fructose-derived organocatalyst with Oxone as oxidant

The group of Jørgensen reported, in 2005, the first asymmetric organocatalytic epoxidation of α,β-unsaturated aldehydes using a chiral bis-aryl–silyl-protected pyrrolidine and hydrogen peroxide as oxidation agent.[22] [23] The reaction scope was demonstrated by the formation of optically active α,β-epoxy aldehydes in high yields and enantioselectivities >94% ee (Scheme [2], conditions a). Following this work, McMillan and Lee reported the use of an imidazolidinone derivative as organocatalyst and hypervalent iodine reagents for the enantioselective formation of oxiranes, also from α,β-unsaturated aldehydes. Under the optimized conditions, good to excellent levels of reaction efficiency and enantiocontrol have been accomplished (Scheme [2], conditions b).[24] Later, this class of organocatalyst was employed in singly occupied molecular orbital (SOMO) activation leading to the enantioselective production of terminal epoxides.[25]

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Scheme 2 Jørgensen[22] (a) and McMillan[24] (b) organocatalyzed asymmetric epoxidation of α,β-unsaturated aldehydes

Jurczak and co-workers in 2020 described a protocol for the highly enantioselective epoxidation of α,β-unsaturated ketones using amide-based cinchona alkaloids as hybrid phase-transfer catalysts.[26] A series of chiral epoxides were obtained with excellent yields (up to 99%) and enantioselectivities (88–99% ee) and low catalyst loading (0.5 mol%), short reaction times, and catalyst reuse in up to 10 cycles (Scheme [3]).

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Scheme 3 Epoxidation of α,β-unsaturated ketones using amide-based cinchona alkaloids[26]

He and co-workers described a simple asymmetric epoxidation method using a cinchona-derived amine-thiourea dual catalysis.[27] By using TBHP as oxidant and KOH, the epoxides were obtained in 19–90% yield and enantiomeric excess of 31–96% (Scheme [4]).

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Scheme 4 Synthesis of asymmetric α-carbonyl epoxides catalyzed by dual amino-thiourea activation

A new organocatalyst was prepared by Bica-Schroder and co-workers using accessible chiral diamines and sterically flexible phosphoric acids.[28] This catalyst showed high catalytic activities and excellent steric control for the epoxidation of cyclic enones, obtaining a wide range of products with yields of 51–79% and enantiomeric excesses up to 98% ee (Scheme [5]).

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Scheme 5 Synthesis of asymmetric epoxides catalyzed by the combination of chiral diamines and phosphoric acids

Although quite efficient, most of these protocols use toxic solvents such as dichloromethane, toluene, and dioxane. Thus, looking for greener reaction conditions, in 2012, we synthesized new organocatalysts from l-proline,[29] [30] in three steps, using a Grignard reagent, followed by deprotection of the amine and protection of the alcohol (Scheme [6]).[29–33] The organocatalysts were then evaluated in the asymmetric synthesis of α,β-unsaturated aldehydes with hydrogen peroxide as oxidant. The best results were obtained with catalyst 6d; under the optimized conditions, in a 3:1 mixture of EtOH/H2O as the solvent at room temperature (Scheme [7]), the epoxides were obtained in 40–92% yield, with good to excellent diastereoisomeric ratio (dr), and 78–99% ee.[29]

To add more structural complexity to these compounds, the three-component Passerini reaction (Passerini-3CR) was carried out. Notably, this approach was performed in a tandem protocol (Scheme [8]). As a result, it was possible to obtain six examples of compounds 9 with 53–75% overall yield and 52:48 to 69:31 dr.[29]

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Scheme 6 Synthesis of new organocatalysts from proline
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Scheme 7 Organocatalyzed asymmetric epoxidation using green solvents

These epoxy-α-acyloxycarboxamides 9 (Scheme [8]) were evaluated against cathepsins V, K, and L. Of this set of compounds, none appeared to be active against catV; compounds LSPN422 and LSPN423 showed inhibition against catK, with IC50 = 12.47 and 5.72 μM, respectively; and LSPN423 was the most potent and selective against catL (K i = 1.33 μM). Based on these results, the library of compounds was expanded with 11 more examples (Scheme [9]), and compound LSPN437 showed a tight binding uncompetitive inhibition of catL with IC50 = 8.55 μM.[34]

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Scheme 8 Synthesis of epoxy-α-acylaminocarboxamides via organocatalyzed epoxidation/Passerini reactions
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Scheme 9 Synthesis of new epoxy-α-acyloxycarboxamides

Moreover, five new epoxypeptidomimetics were efficiently synthesized using the organocatalyzed asymmetric epoxidation, followed by the Ugi reaction, in 22–67% overall yield (Scheme [10]). The compounds were evaluated against cathepsins K and L and showed selectivity. Investigation of the mechanism of action carried out for compound LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding of the interactions of inhibitors with the enzyme.[35]

In addition, both enantiomers of organocatalyst 6d were efficiently employed in the asymmetric synthesis of (R,R)- and (S,S)-epoxyalcohols 11 from trans-pentenal with good yields (79 and 81%), excellent diastereoisomeric ratio (anti/syn, 93:7) and enantiomeric excesses (95 and 96%, respectively) followed by reduction with NaBH4 in situ (Scheme [11]). These epoxyalcohols were then employed in the total synthesis of (S,R)- and (R,S)-3,4-epoxy-Z6,Z9-heneicosadiene (12), which are possible components of the sex pheromone of the brown caterpillar Thyrinteina arnobia, an important insect pest in Eucalyptus plantations.[36]

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Scheme 10 Synthesis of epoxy-α-acylaminocarboxamides via organocatalyzed epoxidation/Ugi MCR
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Scheme 11 Synthesis of (R,R)- and (S,S)-epoxyalcohols 11 as intermediates for the synthesis of (S,R)- and (R,S)-3,4-epoxy-Z6,Z9-heneicosadiene
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Scheme 12 Synthesis of γ-butenolides from chalcones
2.1

γ-Lactones

The γ-lactone moiety is found in many compounds possessing, for example, anticancer, antimicrobial, anti-HIV-1,[37] antibacterial,[38] antioxidant, and anti-inflammatory[39] activities.[40] Because of these important properties, the asymmetric syntheses of γ-lactones and γ-butelonides have been intensively investigated.[41]

Among the methods, the organocatalyzed vinylogous Mukaiyama aldol reaction of silyloxyfurans as well as the direct vinylogous aldol reaction of 2(5H)-furanone derivatives stand out.[37] [42] The organocatalytic Baeyer–Villiger oxidation of butanones has also been explored.[43]

In 2017, we developed a new method for the synthesis of γ-butenolides from chalcones.[44] Different cinchona-derived phase-transfer catalysts[45] [46] [47] [48] [49] were evaluated for the enantioselective epoxidation of chalcones. After the optimization study using a range of oxidants and bases, the epoxidation reaction using the organocatalyst 13 provided the desired products 15 in good yields and high enantiomeric excess (Scheme [12]).

The epoxychalcones were then subjected to the Horner–Wadsworth–Emmons (HWE) reaction, with triethyl phosphonoacetate and sodium hydride in dry THF under reflux for 3 h, followed by hydrolysis of the epoxyester and cyclization with 15% w/w montmorillonite clay K10 (MK-10), with ethanol as solvent, for 7 h at room temperature. Moreover, when this method was carried out under microwave irradiation, the reaction time was reduced to 1 h (30 min each step) and afforded γ-butenolides 16 with similar or even higher yields than with the conventional procedure (Scheme [12]).

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Scheme 13 First asymmetric aziridination reaction
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Scheme 14 Pioneering asymmetric organocatalytic aziridination

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# 3

Aziridines

In the last decade, 82% of newly FDA-approved drugs contain a nitrogen heterocycle.[50] Among the N-heterocycles, the aziridine moiety is one of the most important three-membered ring functionalities in organic synthesis,[51] [52] especially as building blocks for the synthesis of more complex organic molecules.[53] Because of their tendency to undergo ring-opening reactions with nucleophiles, aziridines are in general regarded as good alkylating agents, possessing mutagenic and toxic activities, that could lead to cancer chemotherapeutic agents.[54] Consequently, studies towards the asymmetric synthesis and biological evaluation of this class of compounds has attract the attention of the scientific community.[53] [55]

There are many reported procedures for the synthesis of aziridines. The main approaches can be broadly classified as: (1) cyclization of 2-aminoalcohols, (2) addition of nitrenes or nitrenoids to alkenes, and (3) reactions of sulfur ylides or carbenes/carbenoids with imines.[55] The first organocatalyzed aziridination reaction was performed with acrylate derivatives using cinchona salt derivatives under phase-transfer catalysis conditions (Scheme [13]). The reaction of different hydroxamic acids afforded the expected aziridines in low to moderate yield and ee.[56]

Córdova et al. reported in 2007 a pioneer work on asymmetric organocatalytic aziridination employing simple enals and a nitrene equivalent as starting material in the presence of the Jørgensen–Hayashi catalyst (17) and chloroform as solvent. In total, 10 examples were prepared in 54–78% yield and 84–99 ee (Scheme [14]).[57]

Following such initial outstanding outcomes, several other groups focused on improving the organocatalyzed asymmetric aziridination reaction of α,β-unsaturated carbonyl compounds; however, most of them still employ toxic solvents such as chloroform and toluene.[58] [59]

In this context, we turned our efforts to a greener and more efficient alternative, using the organocatalyst 6d to promote the aziridination reaction, followed by a one-pot Passerini MCR.[60] The optimization started with a telescope method, because using sodium acetate in the aziridination reaction, one of the byproducts would be acetic acid, which might compete with the MCR acid in a one-pot procedure. To avoid this problem, sodium carbonate (Na2CO3) was employed as base in the aziridination, once the carbonic acid decomposes into CO2 and water, allowing the Passerini reaction. Thus, the desired products 19 were obtained in 31–73% yield and moderate to good stereoselectivity (Scheme [15]).

3.1

γ-Lactams

The γ-lactams are a very important scaffold, presenting antibiotic, anti-inflammatory, cytotoxic, and antitumor activities.[61] Several synthetic approaches have been developed to achieve the γ-lactam moiety, such as cyclization by amide formation between a carboxylic group and an amine or an amine precursor,[62] ring-closing an aliphatic amide either by N-alkylation or by C–C bond formation,[63] (3+2) cyclization,[64] and ring opening.[65] In the last decade, the aziridine moiety has been reported to be involved in several ring-opening reactions, allowing domino and one-pot methods.[66] Capitta et al. synthesized optically active 4-substituted 5-hydroxy-γ-lactams from cyclobutanones with nitrosobenzene promoted by proline.[67]

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Scheme 15 Asymmetric synthesis of aziridines and one-pot functionalization via Passerini MCR
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Scheme 16 Organocatalyzed azidirination of chalcones followed by HWE reaction to obtain γ-lactams

In 2023, our group developed a straightforward synthesis of γ-lactams from ketoaziridines 20, that were obtained from α,β-unsaturated ketones or chalcones with 37–94% yields (Scheme [16]).[68] Based on our previous results, the aziridines were submitted to the Horner–Wadsworth–Emmons reaction, followed by one-pot ring-opening leading directly to the γ-lactams 21. The scope and limitations study afforded 17 examples in 14–88% yield.

The organocatalyzed asymmetric version of this method was achieved by using a quaternary ammonium salt between 9-epi-aminoquinine and d-Boc-phenylglycine (22). The chalcone was submitted to these conditions (Scheme [17]) and the ketoaziridine 20a was obtained in 75% yield and 70% ee, after the TBAF-mediated deprotection. The enantiomerically enriched aziridine 20a was then submitted to the HWE reaction and the corresponding γ-lactam 21a was efficiently obtained in 73% yield and 72% ee. This γ-lactam could lead, for example, to the total synthesis of the natural product (–)-clausamide, an antidementia drug candidate.[69]


# 3.2

Hydantoins

Hydantoin is an important structural motif found in many natural products and drugs with various pharmacological activities, such as antiandrogen, antidiabetic, anticonvulsant and anticancer action.[70] The usual method to synthesize this range of compounds is via the Bucherer–Bergs reaction, in which the aldehyde or ketone is heated in aqueous ethanol, with KCN and ammonium carbonate.[71] This MCR has been explored using enabling technologies such as continuous-flow regime,[72] microwave irradiation,[73] and mechanochemistry.[74]

The synthesis of aziridine-fused reduced hydantoins has also been reported.[75] [76] Thus, based on these works, our research group has reported the synthesis of aziridine-fused reduced hydantoin via a [3+2] cycloaddition reaction with isocyanates and asymmetric formyl aziridines, in a two-step procedure.[77]

Initially, the 2-formyl aziridines 23a–d were synthesized using the Jørgensen–Hayashi catalyst 17, as described by Vesely et al., the pioneers in this organocatalyzed reaction, who used dichloromethane as solvent. Alternative solvents were tested and ethyl acetate showed the best result, delivering excellent ee and dr (Scheme [18]).

After the Boc deprotection, the aziridine dimer 24 was submitted to the [3+2] cycloaddition reaction with isocyanates without further purification, using an 8:2 mixture of hexafluorisopropanol (HFIP) and water as solvent. The scope and limitation study was carried out with different isocyanates, affording the corresponding reduced hydantoins 25 in 40–59% overall yields (Scheme [19]).

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Scheme 17 Asymmetric version of the aziridination of chalcones
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Scheme 18 Synthesis of the asymmetric ketoaziridines
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Scheme 19 Aziridine-fused reduced hydantoin synthesis

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# 4

Conclusion

Herein, we present our studies on asymmetric organocatalyzed synthesis of epoxides and aziridines carried out over the last decade. To achieve this, new catalysts such as proline and cinchona derivatives were synthesized, allowing excellent diastereoselectivity and enantiomeric excess, using environmentally friendly solvents. The enantiomerically enriched epoxides and aziridines were applied in one-pot multicomponent reactions leading to new peptidomimetics that were found to be potent and selective inhibitors of different cathepsins. These important three-membered rings were efficiently employed in the synthesis of new five-membered heterocycles, demonstrating the potential of these scaffolds for the asymmetric synthesis of bioactive compounds. More recently, significant advances in photochemical transformations have led to increased interest in visible-light-assisted synthesis and ring-opening of epoxides and aziridines.[78] This approach is expanding the toolbox of available methods to obtain heterocyclic derivatives.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Arlene G. Corrêa
Center of Excellence for Research on Sustainable Chemistry, Department of Chemistry, Federal University of São Carlos
São Carlos, 13565-905, SP
Brazil   

Publication History

Received: 18 November 2024

Accepted after revision: 24 January 2025

Accepted Manuscript online:
24 January 2025

Article published online:
12 March 2025

© 2025. Thieme. All rights reserved

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Figure 1 Synthetic and natural bioactive compounds containing epoxide and aziridine moieties
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Scheme 1 Synthesis of epoxides from alkenes using a fructose-derived organocatalyst with Oxone as oxidant
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Scheme 2 Jørgensen[22] (a) and McMillan[24] (b) organocatalyzed asymmetric epoxidation of α,β-unsaturated aldehydes
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Scheme 3 Epoxidation of α,β-unsaturated ketones using amide-based cinchona alkaloids[26]
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Scheme 4 Synthesis of asymmetric α-carbonyl epoxides catalyzed by dual amino-thiourea activation
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Scheme 5 Synthesis of asymmetric epoxides catalyzed by the combination of chiral diamines and phosphoric acids
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Scheme 6 Synthesis of new organocatalysts from proline
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Scheme 7 Organocatalyzed asymmetric epoxidation using green solvents
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Scheme 8 Synthesis of epoxy-α-acylaminocarboxamides via organocatalyzed epoxidation/Passerini reactions
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Scheme 9 Synthesis of new epoxy-α-acyloxycarboxamides
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Scheme 10 Synthesis of epoxy-α-acylaminocarboxamides via organocatalyzed epoxidation/Ugi MCR
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Scheme 11 Synthesis of (R,R)- and (S,S)-epoxyalcohols 11 as intermediates for the synthesis of (S,R)- and (R,S)-3,4-epoxy-Z6,Z9-heneicosadiene
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Scheme 12 Synthesis of γ-butenolides from chalcones
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Scheme 13 First asymmetric aziridination reaction
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Scheme 14 Pioneering asymmetric organocatalytic aziridination
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Scheme 15 Asymmetric synthesis of aziridines and one-pot functionalization via Passerini MCR
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Scheme 16 Organocatalyzed azidirination of chalcones followed by HWE reaction to obtain γ-lactams
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Scheme 17 Asymmetric version of the aziridination of chalcones
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Scheme 18 Synthesis of the asymmetric ketoaziridines
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Scheme 19 Aziridine-fused reduced hydantoin synthesis