Asymmetric synthesis of bis-spiro cyclopropane skeletons via bifunctional phosphonium salt-catalyzed [2 + 1] annulation

Abstract

A new approach for constructing enantiopure spiro[cyclopropane-oxindole] and bispiro[oxindole-cyclopropane-cyclohexone] skeletons featuring three vicinal stereocenters was developed. In this approach, 3-alkenyl-oxindoles and α-bromoketones served as substrates for an asymmetric [2 + 1] cyclopropanation using a chiral bifunctional phosphonium salt catalyst. The reaction afforded the desired products in high yields (up to 97%) and with excellent stereoselectivities (up to 97% ee and >20 : 1 dr).

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Introduction

The cyclopropane ring, a unique motif among carbocycles, has garnered significant scientific interest within the organic chemistry community due to its distinctive bonding and inherent ring strain.^1,2 It is also prevalent in biologically active compounds and natural products.³ Spirocyclopropanes represent a significant class of derivatives within the cyclopropane framework, showing considerable promise for drug discovery applications.⁴ For instance, CFI-400945 and its derivatives containing the spirocyclopropane-oxindole skeleton are pioneering selective inhibitors of polo-like kinase 4 (PLK4) in advanced solid tumors.⁵ Illudin M and Illudin S, which bear the spiro-cyclopropane-cyclohexanone motif, have been reported to exhibit preferential cytotoxicity in vitro against various human tumor cell lines (Scheme 1a).⁶ The frequent occurrence of chiral spirocyclopropyl ring systems in drug molecules has driven advancements in sophisticated synthetic methodologies to prepare highly enantiopure complex spirocyclopropane skeletons. Asymmetric catalytic synthesis of chiral monospirocyclopropanes, such as chiral spiro[cyclopropane-oxindoles], has been extensively documented,⁷ whereas reports on the synthesis of chiral bispirocyclopropanes remain relatively scarce.⁸ Du et al. reported squaramide-catalyzed asymmetric [2 + 1] cyclopropanation for synthesizing bispiro[oxindole-cyclopropane-thiazolone] and bispiro[oxindole-cyclopropane-pyrazolone] derivatives.^8e,f Lei and co-workers developed the diastereo- and enantioselective synthesis of novel bispiro[indanedione-oxindole-cyclopropanes].^8g In 2020, our group devised an efficient method for constructing optically active bispiro-cyclopropane-pyrazolone derivatives.^8h However, existing reports primarily focus on five-membered heterocycles with fused bispirocyclopropane units, whereas reports on chiral bispirocyclopropane frameworks incorporating six-membered rings, which hold considerable promise for future drug development, are very limited (Scheme 1b).^8a Therefore, developing an efficient method to prepare novel chiral bispirocyclopropane frameworks, especially those featuring a spiro six-membered ring, is highly desirable.

Scheme 1 Asymmetric synthesis of (bis)spirocyclopropane skeletons and our strategy.

Bifunctional phosphonium salt (BPS) catalysts constitute a pivotal category in ion-pairing catalysis,⁹ demonstrating excellent catalytic activity in various asymmetric reactions since their inception.¹⁰ By harnessing this catalytic system, we have achieved substantial advancements in synthesizing diverse chiral heterocycles and bridged ring frameworks via annulation reactions.¹¹ Our objective is to achieve the selective synthesis of six-membered rings containing bispirocyclopropane frameworks through systematic substrate design and optimal reaction conditions. Here, we describe a highly efficient formal [2 + 1] annulation reaction between 3-alkenyl-oxindoles and α-bromoketones, yielding multi-substituted spirocyclopropane and bispirocyclopropane frameworks in high yields with exceptional diastereo- and enantioselectivities (Scheme 1c). Furthermore, mechanistic studies have revealed that hydrogen bonding interactions between the catalyst and substrate critically influence stereocontrol.

Results and discussion

Initially, the model reaction employed N-Boc-3-alkenyl-oxindole 1a and α-bromoketone 2a in CHCl₃ at room temperature with cesium carbonate using bifunctional phosphonium salts as catalysts (Table 1). We observed that BPS catalysts with different backbones efficiently facilitated the cyclopropanation reaction, yielding the desired [2 + 1] adducts exclusively. As detailed in Table 1, when L-Val-derived phosphonium iodides (P1–P4) featuring amide, thiourea, or dipeptide scaffolds were used as chiral organocatalysts, cycloaddition adduct 3a was obtained in good yields. Notably, bifunctional phosphonium salt P4, incorporating an amide moiety, emerged as the optimal scaffold for further enhancement of both diastereoselectivity and stereoselectivity (entries 1–4). Subsequent investigations focused on modifying the electronic and steric effects of amide-functionalized PPS catalysts (P5–P8) by varying amino acid residues or adjusting benzyl groups at the active P-center (entries 5–8). Ultimately, P8 was identified as the most effective organocatalyst, achieving outstanding results in this cyclization process with high efficiency (88% yield), excellent diastereoselectivity (92 : 8 dr), and good enantioselectivity (87% ee) at room temperature. Further optimization included evaluating the influence of solvents on reaction conditions (entries 9 and 10), revealing that CHCl₃ provided superior catalytic performance to other solvents. Fine-tuning of other reaction parameters, such as base equivalents, chiral catalyst loading, and temperature, pinpointed the optimal conditions (entry 14: −20 °C, 10 mol% of chiral catalyst P8, and 1.5 equivalents of Cs₂CO₃ in CHCl₃ for 24 hours), resulting in the best outcome (96% yield, 98 : 2 dr, and 90% ee; additional details can be found in Tables S1–S6 in the ESI†).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	dr	Yield^b (%)	eemajor, eeminor (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (10 mol%) and Cs2CO3 (4.0 equiv.) in solvent (1.5 mL) were stirred at room temperature for 24 h, and the dr values were determined by ^1H NMR. b Isolated total yields, and the ee values were determined by chiral HPLC. c Cs2CO3 (1.5 equiv.). d Cs2CO3 (6.0 equiv.). e The catalyst loading was 5 mol%. f At −20 °C.
1	P1	CHCl3	85 : 15	85	38, 16
2	P2	CHCl3	88 : 12	87	11, 8
3	P3	CHCl3	15 : 85	73	6, 20
4	P4	CHCl3	90 : 10	85	55, 30
5	P5	CHCl3	67 : 33	81	58, 42
6	P6	CHCl3	75 : 25	80	58, 52
7	P7	CHCl3	61 : 39	88	75, 71
8	P8	CHCl3	92 : 8	88	86, 80
9	P8	Toluene	88 : 12	85	86, 81
10	P8	Et2O	87 : 13	72	68, 53
11^c	P8	CHCl3	94 : 6	90	86, 80
12^d	P8	CHCl3	50 : 50	69	80, 76
13^c^,^e	P8	CHCl3	97 : 3	84	82, —
14^c^,^f	P8	CHCl3	98 : 2	96	90, —

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Having established the optimized conditions for the [2 + 1] cyclopropanation of 3-alkenyl-oxindoles and α-bromoketones, we explored the scope of the reaction to construct structurally diverse chiral (bis)spirocyclopropanes. Initially, we investigated the tolerance of 3-alkenyl-oxindoles 1 under the optimized conditions using α-bromoketone 2a as the cyclization partner (Table 2). Remarkably, substrates with electron-donating, neutral, or electron-withdrawing substituents on the phenyl rings of 3-alkenyl-oxindoles afforded the desired products 3a–3g in good yields with excellent diastereoselectivities (mostly >20 : 1 dr) and good to excellent enantioselectivities (81–95% ee). Subsequently, we explored the compatibility of non-cyclic α-bromoketone 2. As shown in Table 2, α-bromoketones bearing various substituted aryl groups and heteroaryl groups reacted under standard conditions, yielding the desired monospirocyclopropanes with moderate diastereoselectivities and enantioselectivities (3h–3l). Notably, replacing the oxindole's ester group with a benzoyl group resulted in the formation of spirocyclic product 3m with high diastereoselectivity (>20 : 1 dr) and moderate enantioselectivity (51% ee). The absolute configuration of product 3m was determined by comparing its optical rotation and retention time in HPLC with literature values, while other spiro products were assigned by analogy (see Tables S1–S3 in the ESI† for details).^7e

Table 2 Synthesis of spiro[cyclopropane-oxindole] scaffolds^a,b

a Standard conditions I: 1 (0.2 mmol), 2 (0.3 mmol), P8 (10 mol%) and Cs₂CO₃ (1.5 equiv.) in CHCl₃ (3.0 mL) were stirred at −20 °C for 36 h. b Isolated yields; the dr values were determined by ¹H NMR and the ee values were determined by chiral HPLC. c In toluene (3.0 mL) and at room temperature for 48 h. d At 0 °C.

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Given the promising potential of novel spirocyclopropane scaffolds in drug development, we undertook the challenge of constructing bispiro[oxindole-cyclopropane-cyclohexanone] compounds featuring two quaternary centers using 3-alkenyl-oxindoles and cyclic α-bromoketones (Table 3). Gratifyingly, a series of target molecules bearing these novel bispirocyclopropane scaffolds (3n–3v) were readily synthesized under such a BPS catalysis system, consistently achieving excellent enantio- and diastereo-selectivities (up to 97% ee and >20 : 1 dr). Additionally, compounds incorporating heterocyclohexanone groups (3w–3x) could also be efficiently prepared with notable ee values. It is worth noting that the reaction can still proceed smoothly by changing the size of the ring system in cyclic bromoketone, affording novel bispiro compounds (3y and 3z) in moderate yields with 67–75% ee. The observed non-ideal diastereoselectivities in some cases may be attributed to significant steric hindrance around the cyclohexyl group. However, it is noteworthy that the diastereomers could be effectively separated to obtain optically pure products through straightforward column chromatography. Besides, when alkyl bromoketones are used as reaction partners, this cyclization reaction is unable to proceed for providing the expected products (3aa and 3ab). Moreover, to assess the synthetic applicability of this methodology, we conducted a scale-up reaction of 3c. Using substrates 1c and 2a under standard conditions, we obtained the desired product 3c in 91% yield (233 mg), with a diastereomeric ratio of 98 : 2 and 92% enantiomeric excess (ee). Furthermore, treatment of 3c with boron trifluoride diethyl ether facilitated a hydrolysis and reduction process, yielding compound 4 in a moderate isolated yield with a slight decrease in enantiomeric purity (Scheme 2a).

Scheme 2 Synthetic applications and mechanistic studies.

Table 3 Synthesis of bis-spiro[cyclopropane-oxindole] scaffolds^a,b

a Standard conditions II: 1 (0.2 mmol), 2 (0.3 mmol), P8 (20 mol%) and Cs₂CO₃ (1.5 equiv.) in toluene (3.0 mL) were stirred at room temperature for 48 h. b Isolated yields; the dr values were determined by ¹H NMR and the ee values were determined by chiral HPLC.

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Building on our prior investigations into bi-/multifunctional phosphonium salt-catalyzed transformations, it is evident that hydrogen-bonding interactions, coupled with ion-pair activation, significantly contribute to asymmetric induction (Scheme 2b). Consequently, catalysts P8-1, featuring an amide-NH group protected by a methyl group, were synthesized and employed in the catalytic reaction under standard conditions, replacing P8. Predictably, both the yield and enantiomeric excess (ee) dropped markedly with P8-1 (entries 1 and 2). Of note, substituting polar methanol for CHCl₃ as the solvent resulted in no product formation. Furthermore, replacing the Boc group on the indole with a methyl group led to a dramatic reduction in enantioselectivity in the catalytic reaction, indicating that the steric effect of the protecting group on the indole moiety positively influences stereocontrol (entries 3 and 4). Accordingly, a proposed transition state model, crucial for understanding the asymmetric annulation process, was developed based on these comprehensive mechanistic experiments (Scheme 2c).

Conclusions

In conclusion, we have developed an efficient chiral bifunctional phosphonium salt-catalyzed asymmetric [2 + 1] annulation of 3-alkenyl-oxindoles with two types of α-bromoketones, yielding a series of multi-substituted spirocyclopropyloxindoles and bispiro[oxindole-cyclopropane-cyclohexanones] with excellent stereoselectivities and high diastereoselectivities (up to 97% ee and up to 99 : 1 dr). These novel bispirocyclopropane scaffolds are expected to facilitate the discovery and development of new chiral drugs. Further exploration of the biological activities of these products is currently underway in our laboratory.

Data availability

The data supporting this article have been included as part of the ESI.†

All data included in this study are available upon request by contact with the corresponding author (i.e. Prof. Tianli Wang, email: wangtl@scu.edu.cn).

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (22222109, 21921002 and 22101189), the Science and Technology Strategic Cooperation Project of Luzhou Municipal People's Government-Southwest Medical University (2020LZXNYDJ49), the National Key R&D Program of China (2018YFA0903500), the Beijing National Laboratory for Molecular Sciences (BNLMS202101), the Sichuan Science Foundation for Distinguished Young Scholars (2023NSFSC1921), the Sichuan Provincial Natural Science Foundation (2022NSFSC1181 and 24NSFSC6590), Fundamental Research Funds from Sichuan University (2020SCUNL108) and Fundamental Research Funds for the Central Universities.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01424c

‡ These authors contributed equally to this work.

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