Stereoselective access to furan-fused [5.5.0] bicyclic heterocycles enabled by gold-catalyzed asymmetric [8 + 4] cycloaddition

Abstract

The construction of fused [5.5.0] bicyclic heterocycles with precise regio-, stereo-, and enantioselective control remains a significant challenge in asymmetric catalysis. In this work, we introduce a novel gold-catalyzed asymmetric [8 + 4] cycloaddition reaction of 1-(1-alkynyl)cyclopropyl ketones with simple tropones, yielding highly functionalized cyclohepta[b]furo[3,4-d]oxepine derivatives with excellent diastereo- and enantioselectivity (38 examples, all >20 : 1 dr, up to 95% ee). Additionally, an efficient kinetic resolution (KR) process is achieved (s factor up to 104). The gram-scale synthesis and subsequent synthetic transformations of the cycloadducts further demonstrate the synthetic potential of this method. Furthermore, the cycloadduct can undergo a [1,5]-H shift under acid catalysis, adding another dimension to the structural diversity.

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Introduction

Medium-sized rings are privileged structural motifs in various natural products and exhibit wide applications in chemical synthesis and the pharmaceutical industry.¹ Fused [5.5.0] bicyclic heterocycles, in particular, are prevalent in bioactive molecules, such as psiguadial A (anti-HIV), colchicine (antitubulin), daphnillonin B (anti-cancer), and daphnicyclidin A (Scheme 1a).² Despite the structural diversity, intriguing architectures, and potential utility of these core scaffolds, general synthetic strategies from simple precursors with high efficiency and excellent stereocontrol remain elusive.³ To date, two principal approaches have been adopted for constructing this scaffold: intramolecular and intermolecular reactions (Scheme 1b). For instance, intramolecular reactions include methods such as intramolecular Michael addition,^4a ring-closing metathesis,^4b [4 + 3] cycloaddition,^4c ring expansion, etc.^4d These reactions often require meticulous substrate design, typically involving extensive synthetic procedures, and usually result in racemic mixtures. In 2009, the Mukai group disclosed rhodium(I)-catalyzed intramolecular [5 + 2] cycloaddition of alkyne-allenylcyclopropanes, reporting two elegant examples of bicyclo[5.5.0]dodecatrienes in racemic form (Scheme 1c, left).⁵ To resolve the above problems, intermolecular cycloaddition reactions offer a significant advantage for the efficient construction of such frameworks from simple building blocks. Most of these elegant examples have focused on the use of commercially available tropones through asymmetric [8 + n] cycloaddition approaches.^6,7 Nevertheless, progress in intermolecular asymmetric high-order cycloadditions in this field remains significantly limited. In 2020, the pioneering work by Zhao, Shao, and colleagues made a notable advance by demonstrating a palladium-catalyzed [8 + 4] cycloaddition of γ-methylidene-δ-valerolactones with tropones, enabling the assembly of fused [5.5.0] bicyclic structures (Scheme 1c, right).⁸ While this work represents a significant breakthrough, only one chiral example was achieved (49% yield, 82% ee), highlighting the challenges in asymmetric synthesis of these frameworks. Thus, there is an urgent need to develop novel asymmetric intermolecular strategies that can achieve facile construction of enantioenriched fused [5.5.0] bicyclic skeletons, thereby enhancing their potential applications in drug discovery and development.

Scheme 1 The strategy for the construction of fused [5.5.0] bicyclic scaffolds.

Given the intricate challenge of preparing chiral fused [5.5.0] bicyclic heterocycles and the significance of fury structures⁹ in medicinal chemistry, we explored whether gold-catalyzed stereoselective [8 + 4] cycloadditions of tropones with Au-fury 1,4-dipoles could provide a convenient route to synthesize these valuable skeletons.^10,11 However, this strategy faces several challenges. First, it is uncertain whether tropone and 1,4-dipolar species are sufficiently reactive to match, and there is a potential for competitive [6 + 4] cycloaddition reactions to occur. Additionally, for the unique [5.5.0] bicyclic heterocyclic core, it remains unclear whether diastereoselectivity and enantioselectivity can be effectively controlled during the cycloaddition process to overcome the inherent unfavorable entropy and enthalpy factors. Building on this concept, we report the first gold-catalyzed, highly diastereo- and enantioselective [8 + 4] cycloaddition of 1-(1-alkynyl)cyclopropyl ketones with tropones. This approach provides a straightforward method to synthesize polycyclic functionalized cyclohepta[b]furo[3,4-d]oxepine derivatives bearing furan/pyrrole-fused moieties (38 examples, all >20 : 1 dr, up to 95% ee), enabled by a chiral gold catalyst (Scheme 1d). This method also facilitates the efficient kinetic resolution¹² of 1-(1-alkynyl)-cyclopropyl ketones, leading to the synthesis of two optically active furan/pyrrole-fused ring systems with high enantioselectivity. Moreover, the cycloadduct undergoes a [1,5]-H shift under acid catalysis, further enhancing structural diversity.

Results and discussion

Initially, racemic cyclopropyl ketone 1a and tropone 2a were selected as model compounds to investigate the asymmetric [8 + 4] cycloaddition, where both cycloaddition products and chiral cyclopropyl ketones were obtained concurrently via the kinetic resolution process (Table 1). Preliminary screening of various reaction parameters revealed that chiral bidentate phosphine ligands were crucial in enhancing the efficiency of this cycloaddition (see the ESI† for details). Focusing our optimization efforts on chiral gold complexes, we were pleased to observe that the asymmetric [8 + 4] cycloaddition proceeded smoothly with L1(AuCl)₂, yielding the desired cycloadduct 3a in 35% yield with 73% ee (entry 1). When (S)-DTBM-SEGPHOS was employed, the enantioselectivity increased to 85% ee, although the yield decreased significantly to just 15% (entry 2). Fortunately, switching to the L3 ligand improved the yield of product 3a to 31% while maintaining high enantioselectivity (entry 3).¹³ In addition, the choice of additive also had a substantial impact on the reaction's reactivity. Replacing the silver salt with NaBAr^F resulted in a marked improvement, yielding the desired product 3a in 40% yield with 81% ee (entries 4 and 5). Further temperature optimization (entries 6 and 7) identified −20 °C as the optimal reaction temperature, allowing cycloadduct 3a to be obtained in 40% yield with 89% ee (s factor is 51).

Table 1 Reaction optimization^a

Entry	Ligand	Additive	Yield^b	ee^c	s
a Unless otherwise indicated, all reactions were performed with 1a (0.1 mmol) and 2a (0.08 mmol) in the presence of Ln(AuCl)2 (3.0 mol%) and an additive (12.0 mol%) in a solvent (1.0 mL) at 0 °C or −10 °C or −20 °C under a nitrogen atmosphere. b Isolated yields. c Determined by HPLC analysis. d Selectivity (s) values were calculated using the equation s = ln [(1 − C) (1 − ee1a)]/ln [(1 − C) (1 + ee1a)], where C is the conversion; C = ee1a/(ee1a + ee3a). e The reaction temperature was −10 °C. f The reaction temperature was −20 °C. NaBAr^F: sodium tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate.
1	L1	AgPF6	35%	73%	17
2	L2	AgPF6	15%	85%	11
3	L3	AgPF6	31%	85%	20
4	L3	AgOTf	36%	81%	18
5	L3	NaBAr^F	40%	81%	37
6^e	L3	NaBAr^F	41%	83%	38
7^f	L3	NaBAr^F	40%	89%	51

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With the optimal reaction conditions in hand, we examined the substrate scope of the gold-catalyzed asymmetric [8 + 4] cycloaddition (Table 2). Encouragingly, all cycloadducts exhibited excellent exo-diastereoselectivity (all dr > 20 : 1). First, we investigated the scope of cyclopropyl ketones 1 with commercially available tropone 2a as the model substrate (Table 2A). For the R² substituent of cyclopropyl ketones 1, a range of racemic substrates (1a–1f) with different substituents at various positions of the benzene ring were well-tolerated, delivering the desired products 3a–3f in 36–42% yields with 85–92% ee, along with the corresponding chiral cyclopropyl ketones 1a–1f in 38–43% yields with 88–97% ee. Cyclopropyl ketones bearing 3-thiophenyl (1g) and 1-naphthalyl (1h) groups also performed well, affording products 3g and 3h in 42% yield with 80% ee and 42% yield with 82% ee, respectively. In addition, the asymmetric [8 + 4] cycloadditions proceeded smoothly regardless of the electronic and steric properties of the R¹ substituents on the phenyl ring, whether at the ortho-, meta- or para-position. These reactions provided a series of furan-fused chiral [5.5.0] bicyclic heterocycles 3i–3u with good yields and stereoselectivities (s factor up to 103, up to 40% yield, up to 94% ee, all >20 : 1 dr). Substrates bearing 1-naphthyl groups (1v) led to the cycloadduct 3v in 44% yield with 80% ee and the corresponding chiral cyclopropyl ketone 1v in 35% yield with 98% ee. Notably, substrate 1w, containing a cyclohexenyl group, also reacted smoothly, yielding cycloadduct 3w in 34% yield with >20 : 1 dr and 35% ee. Pyrroles, being ubiquitous in natural products and displaying diverse biological activities, have garnered considerable interest for the construction of complex molecules incorporating these heterocyclic scaffolds, which are essential for advancing biological research.¹⁴ We were particularly pleased to observe that the oxime-containing substrate 1x performed well under the optimized conditions, generating the chiral [5.5.0] bicyclic compound with a pyrrole moiety (3x) in 31% yield and 73% ee. Next, the scope of various tropones 2 was explored (Table 2B). When 2-chloro-substituted tropone 2b was employed, the reaction proceeded smoothly, affording the desired cycloadducts 4a–4c in good yields and enantioselectivities with high stereoselectivity (31%–35% yields, dr > 20 : 1, 88–94% ee), irrespective of the substituents’ electronic nature. For 2-benzyl-substituted tropones 2c–2k, the cycloaddition displayed good versatility, performing well with both electron-poor and electron-rich groups at different positions, yielding chiral bicyclic heterocycles (4d–4l) with good results (s factor up to 104, up to 38% yield, up to 95% ee). Notably, a variety of functional groups, such as F, Cl, Br, Me, ester, CF₃, and nitro moieties, showed good compatibility. Additionally, the substrate with 1-naphthyl (1h) substitution reacted well, providing the desired product 4m in 31% yield with 89% ee. The absolute configuration of 3k was determined as 5R, 11S by X-ray crystallographic analysis.¹⁵

Table 2 Reaction scope of the asymmetric [8 + 4] cycloaddition^a

a All reactions were performed with 1 (0.2 mmol) and 2 (0.16 mmol) in the presence of L3(AuCl)₂ (3.0 mol%) and NaBAr^F (12 mol%) in DCM at −20 °C. b The solvent was DCM/PhCF₃ (in 1 : 1 ratio).

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To further demonstrate the synthetic utility of this methodology, a gram-scale synthesis of chiral cyclohepta[b]furo[3,4-d]oxepine 3b was successfully achieved (Scheme 2A), maintaining both high efficiency and excellent stereochemical control (40% yield, >20 : 1 dr, 92% ee). Several synthetic transformations were then explored. Interestingly, the product underwent a 1,5-H shift process with p-toluenesulfonic acid (PTSA) at room temperature, yielding a more stable isomer (Scheme 2B).¹⁶ Using different substituents, we obtained products 5a–5d in 61%–71% yields with 80%–88% ee. Additionally, the treatment of 4b with Pd/C under a hydrogen atmosphere (H₂ balloon) afforded the corresponding hydrogenated product 6 in 82% yield with 91% ee (Scheme 2C). Moreover, product 4b participated in a stereoselective [4 + 2] cycloaddition with in situ generated benzyne, resulting in a 75% yield of the O-bridged polycyclic compound 7.

Scheme 2 Synthetic transformations and the proposed reaction mechanism.

Based on previous studies,¹⁰ a plausible reaction pathway for the gold(I)-catalyzed asymmetric [8 + 4] cycloadditions is shown in Scheme 2D. Initially, the chiral gold complex facilitates the interaction between the alkyne and the carbonyl group of racemic 1-(1-alkynyl)cyclopropyl ketone 1, leading to the formation of intermediates I and I′. These intermediates undergo intramolecular ring closure at different rates due to the varying reactivities of the diastereomeric complexes. Specifically, the more reactive diastereomer I reacts faster, primarily forming intermediate II while preserving the enantiomeric purity of (1S,2R)-1 with good enantioselectivity. Guided by the chiral environment of the gold catalyst, tropone 2 undergoes SN2 addition with intermediate II to generate intermediate III. Finally, this is followed by intramolecular cyclization, yielding the desired cycloadduct 3, while regenerating the chiral gold catalyst.

Conclusions

In conclusion, we have developed a chiral gold-catalyzed stereoselective [8 + 4] cycloaddition of cyclopropyl ketones with simple tropones under mild reaction conditions. This method provides straightforward access to highly functionalized polycyclic cyclohepta[b]furo[3,4-d]oxepine derivatives featuring furan- and pyrrole-fused moieties from readily available starting materials, with good yields and excellent stereoselectivities. These derivatives can be readily transformed into another class of chiral fused [5.5.0] skeletons via a [1,5]-H shift process. This novel strategy not only offers a powerful tool for the asymmetric synthesis of synthetically challenging fused [5.5.0] bicyclic scaffolds, but also expands the repertoire of asymmetric intermolecular higher-order cycloaddition methodologies, with potential applications in drug discovery.

Author contributions

X. Li designed the project. X. Wang performed the experiments. X. Wang and J. Wang analyzed the data. X. Li, J. Wang and X. Wang wrote the paper.

Data availability

The data supporting this article have been included as part of the ESI.† Data for this work, including optimization tables, general experimental procedures, characterization data (NMR and HPLC spectra) for all new compounds and X-ray data, are provided in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the financial support for this work from the National Natural Science Foundation of China (21901142), the Natural Science Foundation of Jiangsu Province (BK20220097), the Natural Science Foundation of Shandong Province (ZR2024MB004), and the Fundamental Research Funds of Shandong University (2020QNQT007 and 2020QNQT009).

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13. See the ESI† for details.
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15. Deposition number CCDC 2382467 (3k) contains the supplementary crystallographic data for this paper.†.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 2382467. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01841a

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