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. Author manuscript; available in PMC: 2025 Aug 13.
Published in final edited form as: J Am Chem Soc. 2025 Jul 3;147(29):26019–26028. doi: 10.1021/jacs.5c09040

Versatile Butenolide Syntheses via a Structure-Oriented C−H Activation Reaction

Yu-Kun Lin 1, Donghyeon Kim 1, Yuxin Ouyang 1, Jin-Quan Yu 1
PMCID: PMC12346113  NIHMSID: NIHMS2100111  PMID: 40609099

Abstract

Despite significant advances in forging a single bond via C−H activation in the past decade, one-step construction of biologically or chemically important scaffolds from abundant feedstock chemicals, namely, structure-oriented C−H activation, remains a significant challenge. Since feedstocks often contain a single functional group, multiple C(sp3)–H bond functionalizations are often necessary towards the assembly of densely functionalized scaffolds. As classic pharmacophores and versatile synthetic intermediates, butenolides have received extensive attention from the pharmaceutical industry and synthetic chemists. Here, we report the development of a palladium catalyst that enables one-step conversion of aliphatic acids into ubiquitous butenolides involving triple functionalizations of methylene and methine C−H bonds with tert-butyl hydroperoxide (TBHP) as the sole oxidant. The unprecedented triazole-pyridone ligand is essential for realizing this “butenolide-oriented” C−H activation reaction. The availability of diverse aliphatic acids allows rapid access to unexplored but medicinally interesting chemical space of butenolides. Improved syntheses of a wide range of bioactive natural products and drug molecules were achieved using this reaction, including anticancer and anti-HIV compounds. As low as 1 mol% catalyst loading, ready scalability, and product purification through a simple aqueous wash represent rare practical advantages for C–H activation reactions.

Graphical Abstract

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INTRODUCTION

Butenolides represent an important class of unsaturated four-carbon heterocyclic rings that are found in 11873 natural products1–7. As classic bioactive scaffolds, butenolides are present in 11 FDA (Food and Drug Administration)-approved drugs, 7030 drug candidates, and 2 families of phytohormones1–5,7. These include 15 anticancer clinical candidates, 1 anti-HIV (human immunodeficiency virus) clinical candidate, and 2 clinical candidates for Alzheimer’s disease (Figure 1A) (for the list of bioactive butenolides, see Supporting Information). The ubiquity of butenolides in bioactive compounds stems from their rare ability to engage in various non-covalent and covalent interactions in biology. The lactone motif, double bond, and electron-deficient C–H bond(s) in butenolide serve as a π-system for hydrophobic interactions, as well as hydrogen bond donors and acceptors1,5,6. Additionally, the lactone motif in butenolide can be opened by nucleophiles to form a covalent bond with the active site of the target protein7. The densely functionalized structure also imparts rich chemical reactivity. Acting as nucleophiles, electrophiles, dienophiles, and coupling partners, butenolides have been utilized as synthetic intermediates in more than 180 total syntheses of natural products and bioactive compounds8–10 (Figure 1B) (for the full list, see Supporting Information). Notably, in the total synthesis of merrilactone A, two butenolides were used five times in different roles to construct the core structure. Currently, the most common butenolide syntheses involve multi-step pathways: desaturation of lactones or intramolecular olefin metathesis11,12. Several alternative butenolide syntheses, such as CO insertion13, oxidation of furan by singlet oxygen14, and others15, have been developed. Existing methods for butenolide synthesis suffer from limited compatible structures and functional groups, requirements of installation and/or elimination of auxiliary groups, and case-by-case synthesis tactic. Here we report a palladium-catalyzed one-step butenolide synthesis through triple methylene and methine C−H functionalizations enabled by a triazole-pyridone ligand with TBHP as the sole oxidant. Compatibility with different combinations of C(sp3)−H bonds, namely, three methylene, two methylene and one methine, or one methylene and two methine C−H bonds, allows versatile access to butenolides substituted at both α- and γ-positions. Notably, medicinally important spiro-, bridged butenolides and butenolides bearing heterocycles that were challenging to synthesize via previous routes16,17 are readily prepared by this new reaction. Total and formal syntheses of 12 bioactive natural products and drug molecules, including anticancer and anti-HIV compounds, have been accomplished with improved step counts, scalability, diversity, and ideality compared to reported syntheses. Lastly, as low as 1 mol% catalyst loading, ready scalability, and product purification by simple aqueous washing without chromatography are significant and practical advantages (Figure 1D).

Figure 1. Butenolide Syntheses via Triple C(sp3)−H Functionalization.

Figure 1.

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(A) Butenolides as bioactive compounds. HIV is human immunodeficiency virus. (B) Butenolides as versatile building blocks in more than 180 total syntheses. (C) Two challenges in the “butenolide-oriented” C−H activation reaction. (D) Ligand-enabled one-step butenolide syntheses from aliphatic acids (this work).

RESULTS AND DISCUSSIONS

Reaction Development.

The structural comparison between a butenolide and a simple aliphatic acid points to a loss of three C(sp3)−H bonds and a gain of one C−O bond and one double bond. We envision a C−H activation pathway to deliver this unprecedented cascade transformation: β,γ-dehydrogenation and subsequent 5-endo-trig-type cyclization (Figure 1C). However, there are two challenges in achieving this “butenolide-oriented” C−H activation reaction: 1) achieving site-selective β,γ-dehydrogenation versus the typically favored α,β-dehydrogenation; 2) achieving subsequent palladium-catalyzed 5-endo-trig-type cyclization. While β,γ-dehydrogenation has been observed, the necessity for the presence of α-quaternary centers will prevent the formation of the double bond in butenolides (the absence of α-quaternary centers will lead to undesired α,β-dehydrogenation due to the tendency to form a conjugated system)18,19. Transition-metal catalyzed 5-endo-trig-type cyclization (disfavored by Baldwin’s rule) is also highly challenging due to a lack of support, which means that the ligand promoting the dehydrogenation step must also enable the cyclization step. Unsurprisingly, all bidentate pyridone ligands and MPAA ligands developed in our laboratory (Table 1B and Table S14) failed to give the desired butenolide 1a in more than 6% NMR (nuclear magnetic resonance) yield. Hence, the design of a multi-functional ligand and effective catalyst is required to address the two challenges in this triple C−H functionalizations reaction. Because the 2-pyridone serves a critical role as the internal base for C–H cleavage19, we focused on developing pyridone-based bidentate ligands. Prompted by the use of triazoles as directing groups for Pd(II) in C(sp3)−H activation20 and its easy access via click chemistry, we synthesized a class of bidentate ligands bearing a pyridone and a triazole. The triazole scaffold was unprecedented among our bifunctional ligand family. We anticipated that its unique coordination properties—such as bite angle and metal-binding affinity—may offer new reactivity. Encouragingly, triazole-pyridone ligand L1 afforded a substantially improved yield (> 20% NMR yield) with several oxidants, including TBHP and silver salts (Table 1A and Table S11). Since TBHP is an inexpensive and “traceless” oxidant that are friendly for scaling up, we chose TBHP as the sole oxidant and focused on optimizing other reaction components. After identifying optimal bases, additives, and other components (Table 1A, Table S2–S13), we started to modify the triazole-pyridone ligand. Through extensive tuning on the pyridone and triazole, including electronic properties and conformations of the ligands (Table 1B and Table S15), we identified ligand L32 as the optimal ligand, providing butenolide 1a in 97% isolated yield. Control experiments show that this unprecedented triazole-pyridone ligand is essential for both the β,γ-selective dehydrogenation and the subsequent cyclization leading to butenolides (Figure S11–12).

Table 1. Optimization of the Butenolide Syntheses Reaction.

(A) Reaction optimization (selected). Reaction conditions: aliphatic acid (0.1 mmol), Pd(OAc)2 (10 mol%), L1 (10 mol%), Me4NOAc·H2O (0.5 equiv), KOH (0.5 equiv), duroquinone (BQ1, 2 equiv), TBHP in decane (~ 5.5 M, 2 equiv), HFIP (1.0 mL), at 105 °C under air for 20 hours. The yields were determined by GC-MS using quinoline as the internal standard. (B) Ligand investigation (selected).

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Scope of Butenolides.

Under these optimized conditions, we evaluated the substrate scope of this method for butenolide syntheses (Figure 2A). Aliphatic acids with various substituents are compatible with this method. Substrates with a single α-substituent work well in this reaction in which two methylene and one methine C–H bonds were functionalized. Simple aliphatic acids of different chain lengths (S1a-d, S1ah, S1ai) afforded the butenolide products in good to excellent yields. In the presence of commonly more reactive α-methyl C–H bonds (1e-i, 1t) and α-phenyl C–H bonds (1j)21,22, the preferential functionalizations of the methylene C–H bonds still proceeded to give the desired products. Other potentially chelating functional groups including ester (1e), amide (1f), ether (1k-n, 1aa, 1ag), and ketone (1af) are all compatible. Silyl-protected alcohols (1g, 1q, 1ab, 1aj) and alkyl bromide (1h, 1i) were also tolerated. Butenolides with bulky adamantyl (1r) and tert-butyl (1s) groups at different positions can be synthesized via this method. Heterocycles including piperidines (1t-ac, 1ae) with the nitrogen atom in different positions and pyrrolidine (1ad) are also compatible. This protocol can also be applied in late-stage modification of natural products, such as dihydrojasmonic acid and cholic acid, leading to butenolides 1af and 1ag. While a single diastereomer of butenolide 1ac was formed, a various degree of diastereoselectivity were observed for 1p, 1ad, 1af and 1ag. Although substrates bearing no α-substituent (substrates with three methylene, S1ah-S1aj) are especially challenging owing to the undesired α,β-dehydrogenation pathway as observed by NMR, moderate yields of the butenolides were still obtained. Good mass balances in the reaction were observed with majority of the substrates except those with reactive substituents like alkyl bromide (S1h-S1i). Because of the good mass balances and the acidity of the substrates, we developed a basification and aqueous wash purification of the butenolide products (1a-e, 1t, 1af, 1ag). The use of equally effective but water-soluble benzoquinone (anthraquinone-2,6-disulfonic acid disodium salt, BQ23) as the additive is crucial for this purification as duroquinone (BQ1) is not water-soluble. Practical yields can be maintained with reduced catalyst loading (1–2 mol%), albeit requiring longer reaction time (54 h).

Figure 2. Scope of Butenolides and Large-Scale Reaction.

Figure 2.

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(A) Scope of butenolides. Reaction conditions: aliphatic acid (0.1 mmol), Pd(OAc)2 (10 mol%), L32 (10 mol%), Me4NOAc·H2O (0.83 equiv), KOH (0.17 equiv), MeCN (20 μL), duroquinone (BQ1, 1 equiv), TBHP in decane (~ 5.5 M, 3 equiv), HFIP (0.8 mL), at 105 °C under air for 20 hours. *Pd(OAc)2 (1 mol%), L32 (1 mol%), TBHP in decane (~ 5.5 M, 4 equiv), anthraquinone-2,6-disulfonic acid disodium salt (BQ23, 1 equiv), 54 hours as replacements. Aqueous wash purification. †BQ23 (1 equiv) as a replacement. Aqueous wash purification. ‡Pd(OAc)2 (2 mol%), L32 (2 mol%), TBHP in decane (~ 5.5 M, 4 equiv), BQ23 (1 equiv), 54 hours as replacements. Aqueous wash purification. §Diastereomers. ¶The relative configuration (of the major diastereomer) is not determined. #Relative configuration is shown. dr = diastereomeric ratio. (B) Large-scale reaction. Pd(OAc)2 (2 mol%), L32 (2 mol%), TBHP in decane (~ 5.5 M, 4 equiv), BQ23 (1 equiv), 60 hours as replacements. Aqueous wash purification. **n-Bu4NOAc (1 equiv) as a replacement.

Large-Scale Reaction.

Considering the use of TBHP and potential application of this reaction in large scale, we tested a 20 mmol-scale reaction with S1b using 2 mol% catalyst loading and water-soluble BQ23 as the additive (Figure 2B). Aqueous wash purification gave the butenolide product 1b in 72% yield (see Supporting Information for experimental details) without chromatography. The 0.1 mmol-scale reaction under the same conditions gave 75% yield (1b‡), demonstrating the scalability of this method.

Spiro- and Bridged Butenolides.

Butenolides with various ring systems and topologies are of medicinal interest23,24 but challenging targets via classic methods. Spiro butenolides are present in natural products showing various bioactivities, like securinine23, a GABA receptor antagonist in phase II clinical trials. The compatibility with the substrate bearing γ-methine C–H bond (S1ae) is essential for adopting this method to construct spiro butenolides (2a-i, Figure 3). We found that various spiro butenolides with different spiro ring sizes, including a 5-membered ring (2c), 6-membered ring (2a-f, 2h-i), and macro ring (2g) could be synthesized by our method. Spiro butenolides bearing heterocycles including pyran (2b-d, 2f, 2i) and piperidine (2e-h) were also synthesized. Substrates derived from natural products nootkatone (S2h) and 5α-cholestanone (S2i) were successfully converted to corresponding spiro butenolides with crowded and intriguing 3D structures. The structure of 2h was confirmed by single-crystal x-ray diffraction analysis.

Figure 3. Spiro- and Bridged Butenolides.

Figure 3.

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Reaction conditions: aliphatic acid (0.1 mmol), Pd(OAc)2 (10 mol%), L32 (10 mol%), Me4NOAc·H2O (0.83 equiv), KOH (0.17 equiv), MeCN (20 μL), duroquinone (BQ1, 1 equiv), TBHP in decane (~ 5.5 M, 3 equiv), HFIP (0.8 mL), at 105 °C under air for 20 hours. *Pd(OAc)2 (1 mol%), L32 (1 mol%), TBHP in decane (~ 5.5 M, 4 equiv), anthraquinone-2,6-disulfonic acid disodium salt (BQ23, 1 equiv), 54 hours as replacements. Aqueous wash purification. †BQ23 (1 equiv) as a replacement. Aqueous wash purification. ‡Diastereomers. The major diastereomers is shown. §Diastereomers. The relative configuration of the major diastereomer was not determined. dr = diastereomeric ratio.

Bridged butenolides are another important class of natural products possessing various bioactivities. For example, ovatodiolide, a drug candidate for atopic dermatitis (phase I/IIa) and cancer (preclinical)24, is a butenolide bridged with a 14-membered ring. Due to the presence of bridgehead double bond in bridged butenolides, construction of such ring systems is challenging (Bredt’s rule). Pleasingly, our triple C–H functionalizations were successfully applied to 14–17 membered macrocyclic acids to afford corresponding bridged butenolides in 72–84% yields (2j-m). The 11-membered cycloundecanecarboxylic acid gave 15% NMR yield due to the ring strain. From the substrate derived from axially chiral BINOL (S2j), a pair of bridged butenolides bearing both axial and central chirality were obtained as a mixture of diastereomers (dr = 3:2). Complex cyclic acid attached to celecoxib was also compatible (S2k). Remarkably, the presence of a chiral center on the macrocyclic acid induced high diastereoselectivity in the butenolide formation through remote (2ma) or proximate (2mb) chiral induction. Notably, heteroatoms (2j, 2k, 2m), aromatic rings (2j, 2m), and ester (2m) embedded in the rings are tolerated, which are valuable for drug discovery.

Syntheses of Bioactive Natural Products and Drug Molecules.

Auxofuran

In the modern era of synthesis, achieving short and scalable syntheses of bioactive compounds is a major pursue25. Auxofuran is a fungal-growth-promoting substance produced by the mycorrhiza helper bacterium Streptomyces Strain AcH 505, with potential applications in the development of antifungal drug. Previous syntheses suffer from lengthy steps involving ring closure of a complex allylic alcohol, cumbersome manipulation of oxidation states, or a harsh Diels-Alder reaction at 260 °C26,27. In contrast, one-step synthesis of butenolide 3d from readily accessible aliphatic acid 3c at 10.8 mmol scale provided abundant precursor to the key intermediate 3e. After a ring-closure of 3e and selective oxidation, the total synthesis of 8.7 mmol (±)-auxofuran was accomplished in 29% yield over 6 steps in 67% ideality28 (In reported synthesis, 0.115 mmol (±)-auxofuran was obtained in 30% yield over 13 steps in 23% ideality26), providing enough materials for biological study.

Incrustoporin

In addition to scalability, the versatility to access a wide range of analogues of bioactive molecules is another highly desirable feature of a method, especially for drug discovery29. Incrustoporin, as a lead compound, isolated from Incrustoporia carneola, possesses antifungal activity against a wide array of pathogenic fungi. SAR (structure–activity relationship) studies indicated that the butenolide ring is crucial for its antifungal activity30. The current synthesis of incrustoporin and its derivatives, relying on desaturation of lactones or CO insertion13,30, is handcuffed when access to diverse analogues is needed for the development of a potent antifungal agent from incrustoporin. We demonstrate (±)-incrustoporin (3h) can be synthesized in one step from commercially available acid (S3h) in 42% yield. Both reported analogues of (±)-incrustoporin (3i, 3j) and new analogues (3k-o) with variation at α- and γ-positions were synthesized. Since the racemic incrustoporin derivatives showed more potent antifungal activity than the enantiopure ones30, our method can be directly applied to medicinal chemistry.

Ancepsenolide

We have also extended our method to the synthesis of a dibutenolide natural product. Marine natural product ancepsenolide possesses various bioactivities including anticancer and antimalarial activities. Its total synthesis was reported several times through desaturation of lactones and olefin metathesis31,32. Using our method, ancepsenolide and two unprecedented symmetric and unsymmetric analogues were synthesized in one step from diacid 3p and isolated, offering tools for optimizing ancepsenolide analogues towards a drug candidate.

Key Synthetic Intermediates

Butenolides are key intermediates in the syntheses of numerous natural products and drug molecules. A family of butenolide polyketides including more than 532 compounds, annonaceous acetogenins, possess a broad range of bioactivities including anticancer activity4. The case study shows that the butenolide is the key scaffold (pharmacophore) for its bioactivity6. Total syntheses of several representative annonaceous acetogenins, chamuvarinin, chatenaytrienin, muridienin, asiminocin, asimin, and bullanin, involve butenolide intermediates (3t-x), which were typically forged by olefin metathesis or desaturation of lactones11,12,33. These intermediates were prepared from commercially available aliphatic acids in two steps using our triple C–H functionalization reaction in racemic form, providing materials to optimize annonaceous acetogenins analogues towards a drug candidate. This reaction was also applied to the synthesis of intermediates for alkaloids pandamarilactone-1 and pandamarine, which were isolated from Pandanus amaryllifolius possessing various bioactivities including antileprosy and antiepileptic activity. Using our method, the reported difuran intermediate 3y34,35 was synthesized in 38% yield and 75% ideality over 4 steps (see Supporting Information for details). Improved syntheses of intermediates (3z, 3aa) for antifungal and anticancer metabolites were also achieved36,37. Finally, one-step synthesis of (±)-HBO-TBS (3ab), a versatile intermediate for drug molecules, including nucleoside analogues for HIV treatment38,39, was accomplished by our method.

Machanistic Studies.

Control experiments show that the β,γ-unsaturated acid is a feasible intermediate. A Pd(II)/Pd(0)/Pd(II)/Pd(0) catalytic cycle was therefore proposed to account for the one-step butenolide formation (Figure 5, Figure S7–10). In the proposed catalytic cycle, the reaction starts with a ligand-enabled β,γ-dehydrogenation to form a Pd(0) species, which is then re-oxidized by TBHP to a Pd(II) species. Subsequently, Pd(II)-catalyzed nucleophilic cyclization of the carboxylate onto the double bond occurs to form a lactone bearing a carbon palladium bond at the β-position. Finally, a site-selective β-hydride elimination provides the butenolide product and a Pd(0) species, which is re-oxidized by TBHP to a Pd(II) species to close the catalytic cycle. Since the increase of yield by BQ is only minor, it is unlikely to be the oxidant, instead, BQ could prevent the formation of Pd black by coordinating to Pd(0), as evidenced by the absence of hydroquinone formation in the reaction and supported by related studies40.

Figure 5. Proposed Mechanism.

Figure 5.

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KOH was chosen as the base as an example. R1, R2, R3 are substituents demonstrated in the substrates scope. ArF = 3,5-bis(trifluoromethyl)phenyl. Bn’ = 4-trifluoromethylbenzyl.

CONCLUSIONS

In conclusion, a triple C–H functionalizations reaction for versatile one-step synthesis of a diverse range of butenolides was achieved through the development of unprecedented triazole-pyridone ligands. Compatibility with different combinations of C(sp3)−H bonds allows versatile access to butenolides substituted at both α- and γ-positions. Medicinally important spiro-, bridged butenolides and butenolides bearing heterocycles that were challenging to synthesize via previous routes are readily prepared by this new reaction. Total and formal syntheses of 12 bioactive natural products and drug molecules, including anticancer and anti-HIV compounds, have been accomplished with improved step counts, scalability, diversity, and ideality compared to reported syntheses. Lastly, the use of TBHP as the sole oxidant, as low as 1 mol% catalyst loading, ready scalability, and product purification by simple aqueous washing without chromatography are significant and practical advantages.

METHODS

General procedure for the butenolide synthesis reaction using BQ1: In a 12 mL reaction tube equipped with a stir bar, the aliphatic acid substrate (0.10 mmol) was added. A solution of Pd(OAc)2 (2.2 mg, 10 mol%) and L32 (5.6 mg, 10 mol%) in HFIP (0.40 mL) was premixed (Pd/L solution), and a solution of Me4NOAc·H2O (12.6 mg, 0.83 equiv), KOH (0.9 mg, 0.17 equiv) and duroquinone (BQ1, 16.4 mg, 1 equiv) in HFIP (0.40 mL) was premixed (bases/BQ solution). Both solutions were stirred under room temperature for 5 min before being added to the reaction tube in a sequence of Pd/L solution and bases/BQ solution. MeCN (20 μL) was added, and the solution was stirred for 5 min under room temperature before TBHP in decane (~ 5.5 M, 54.6 μL, 3 equiv) was added. Subsequently the reaction tube was capped and closed tightly. The reaction mixture was then stirred at the rate of 300 rpm at 105 °C for 20 h. After being allowed to cool to room temperature, the solvent was removed on a rotavap. The residual mixture was purified using column chromatography on silica gel or pTLC to afford butenolide products. See Supporting Information for procedures for butenolide synthesis reaction using BQ23, aqueous wash purification of the butenolide products, and large-scale reaction.

Supplementary Material

si

The Supporting Information is available free of charge on the ACS Publications website at DOI: Full experimental details, mechanistic studies and characterization of new compounds (PDF)

Figure 4. Syntheses of Natural Products and Drug Molecules.

Figure 4.

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(A) Total syntheses of bioactive natural products. LDA = Lithium diisopropylamide. DIBAL-H = Diisobutylaluminium hydride. TBSOTf = tert-Butyldimethylsilyl trifluoromethanesulfonate. DMSO = Dimethyl sulfoxide. *Relative configurations are shown, as the synthesis is racemic. (B) Syntheses of synthetic intermediates for bioactive natural products and drug molecules.

ACKNOWLEDGMENT

We acknowledge The Scripps Research Institute, NIH (NIGMS, 2R01GM084019) for financial support. We thank the X-ray Crystallography Facility (UCSD) for x-ray crystallography. We thank Quynh Nguyen Wong, Brittany Sanchez, and Jason Lee for help with purification and high-resolution mass spectrometry. We thank Scripps CoreService for help with high-resolution mass spectrometry. We thank Clara Wiesler for sharing a substrate and proofreading the manuscript. We thank Chia Yu Chen and Will Burgenson for proofreading the manuscript. We thank Lan Zhou for proofreading the Supporting Information.

Footnotes

Patent application related to this work is pending.

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