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. 2023 Apr 12;145(16):8788–8793. doi: 10.1021/jacs.3c01404

A Catalytic Asymmetric Hydrolactonization

Rajat Maji †, Santanu Ghosh †, Oleg Grossmann †, Pinglu Zhang †, Markus Leutzsch †, Nobuya Tsuji ‡, Benjamin List †,‡,*
PMCID: PMC10141295  PMID: 37043821

Abstract

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Despite recent advancements in the development of catalytic asymmetric electrophile induced lactonization reactions of olefinic carboxylic acids, the archetypical hydrolactonization has long remained an unsolved and well-recognized challenge. Here, we report the realization of a catalytic asymmetric hydrolactonization using a confined imidodiphosphorimidate (IDPi) Brønsted acid catalyst. The method is operationally simple, scalable, and compatible with a wide variety of substrates. Its potential is showcased with concise syntheses of the sesquiterpenes (−)-boivinianin A and (+)-gossonorol. Through in-depth physicochemical and DFT analyses, we derive a nuanced picture of the mechanism and enantioselectivity of this reaction.

With an estimated one-third of all drugs and natural products featuring lactones,1 the development of lactonization strategies continues to garner considerable attention.2 Especially, lactones that are formally derived from stereogenic, methyl-substituted tertiary alcohols, for simplicity called “tertiary lactones” here, exemplify biological significance.3 These structures are privileged not only due to their presence in a vast array of natural products and drugs (Figure 1a) but also as valuable synthetic intermediates for elaboration into numerous bioactives. A catalytic asymmetric hydrolactonization of unsaturated carboxylic acids would arguably provide an elegant and straightforward solution to this problem. However, contemporary asymmetric electrophilic lactonization methods typically introduce an electrophile other than the proton, i.e. a halide and related functional groups (Figure 1b).4 While a reductive replacement of such a group can be realized, a direct hydrolactonization procedure would evidently provide the desired motifs in a more atom- and step-economical manner (Figure 1c). We now report a general catalytic asymmetric hydrolactonization of readily available γ,δ-unsaturated carboxylic acids using a confined imidodiphosphorimidate (IDPi) catalyst.

Figure 1.

Figure 1

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(a) Bioactives containing lactones with methyl-substituted stereocenters. (b) Current strategy and limitations. (c) Our design.

Since their discovery in 1883,5 electrophilic lactonizations have continually served as workhorse organic transformations, and numerous such variants have been developed in recent years.6 Despite significant effort, however, the catalytic asymmetric hydrolactonization still remains in its infancy.7 A phosphonium salt and an iridium complex have previously been utilized, albeit with limited substrate scope.8,9 Constructing enantiomerically enriched tertiary lactones upon direct hydrofunctionalization remains a challenging problem. Recognizing these limitations and inspired by our recent success in activating unbiased olefins toward hydrofunctionlizations,10 we sought to design a suitable chiral organocatalyst capable of imparting stereocontrol on the process. Two critical factors were central to the design of such a catalyst: first, enabling substrate reactivity via activating the alkene;11 and second, providing an environment conducive to facial discrimination during cyclization, rendering the process stereoselective.12

In earlier studies, we established that fine-tuning different substituents of IDPi catalysts can significantly enhance their acidity, enabling protonation of unactivated olefins.10 Additionally, these catalysts contain small enzyme-like substrate-binding cavities that provide tunable microenvironments, enabling controlled stereodifferentiation.13 We therefore envisioned that IDPi catalysts possess all the requisite characteristics to position them for successful application in the proposed transformation.

With the foregoing mechanistic blueprint in hand, we set out to investigate the desired transformation using γ,δ-unsaturated acid 4a as substrate. Consistent with our initial hypothesis, moderately acidic and unconfined Brønsted acids were ineffective in promoting the desired transformation (see the Supporting Information (SI), Table S1). We surmised that the optimized conditions for our recently disclosed catalytic enantioselective hydroalkoxylation might be an appropriate starting point for further investigation.11a However, to our disappointment, all efforts with the previous optimal catalyst 7a proved futile (Table 1, entry 1), with no observable reaction. We reasoned that the moderate acidity of IDPi 7a—featuring aryl sulfonyl groups—might be insufficient to trigger transformation of olefin 4a, and upon turning to the more acidic triflyl-based catalyst 7b, we were indeed pleased to find reactivity, albeit with modest conversion and enantioselectivity (Table 1, entry 2). Changing the solvent from cyclohexane (CyH) to CHCl3 significantly improved conversion and even allowed us to reduce the temperature to boost selectivity (Table 1, entries 2, 3, and 8). Encouraged by these results, we decided to fine-tune the acidity and active site topography of the catalyst by judicially varying 3,3′-positions of BINOLs and inner core sulfonyl groups. Screening of a number of 3,3′-substituents showed that 4-tBu-C6H4 performed best (Table 1, entries 4–8). When altering the inner core sulfonyl groups, a significant increase in enantioselectivity was observed upon switching from triflyl (7b) to the pentafluorophenylsulfonyl group (7g; Table 1, entries 8, 9). Similarly, catalyst 7h, with an even bulkier perfluoronaphthalene-2-sulfonyl group, gave excellent enantioselectivity (Table 1, entry 10), which was further increased by lowering temperature and concentration (Table 1, entries 11, 12) leading to an e.r. of 96.5:3.5. Comprehensive solvent screening (see SI) revealed that both CHCl3 and toluene could lead to high stereoselectivity, while the conversion was generally better in CHCl3.

Table 1. Reaction Developmenta.

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Entry IDPi T (°C) Solvent Conv. (%)b e.r.c
1 7a 60 CyH 0 –
2 7b 60 CyH 45 67:33
3 7b 60 CHCl3 >95 68.32
4d 7c 40 CHCl3 >95 50.5:49.5
5d 7d 40 CHCl3 >95 51.5:48.5
6d 7e 40 CHCl3 >95 53:47
7d 7f 40 CHCl3 >95 55:45
8d 7b 40 CHCl3 >95 75.5:24.5
9d 7g 40 CHCl3 >95 93:7
10d 7h 40 CHCl3 >95 95:5
11 7h 40 CHCl3 >95 95.5:4.5
12e 7h 20 CHCl3 87 96.5:3.5
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a

Unless otherwise noted, reactions used 0.05 mmol of substrate at 0.2 M concentration.

b

Conversion to 6a was determined by 1H NMR with anisole as internal standard.

c

Enantiomeric ratio (e.r.) of 6a was determined by chiral HPLC.

d

At 0.5 M concentration.

e

For 5 d.

Having optimized the reaction conditions, we next evaluated the substrate scope (Figure 2a). A broad range of aromatic groups was well tolerated, with varied substitution patterns and electronic properties, affording tertiary lactones 6a–m in good to excellent yields with consistently high enantioselectivity. Remarkably, catalyst 7h was proficient in handling sterically demanding ortho-substituted aromatics (6l, 6m) at slightly elevated temperature. To test robustness, operational simplicity, and practicality of our method, conversion of olefin 4j to lactone 6j was performed on a gram scale without any deterioration in enantioselectivity, recovering the catalyst (95%) by column chromatography. Substrates bearing polyaromatic (4n) and heterocyclic (4o) groups also proved compatible, leading to the desired lactones 6n and 6o with high yield and enantioselectivity. An initial attempt to extend this methodology to the synthesis of six-membered tertiary lactones (6p) was also successful.

Figure 2.

Figure 2

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(A) Scope of hydrolactonization, showing isolated yields. Enantiomeric ratios (e.r.) were measured by HPLC, and absolute configurations were determined by literature comparison. aUnless otherwise stated, reactions were carried out with substrate 4 (0.10 mmol) and IDPi 7h (5 mol %) in CHCl3 (0.2 M) at 20 °C for 5 days. bIDPi 7h (2.5 mol %). cIDPi 7h (10 mol %). dCHCl3 (0.1 M). eCyclohexane (0.1 M). f0 °C. g10 °C. h40 °C. iToluene (0.2 M). jToluene (0.5 M). k2 days. l3 days. m4 days. n8 days. o14 days. p17 days. qIDPi 7g (10 mol %) was used. (B) Synthesis of natural products (see SI for exact procedures).

Next, we tested our catalyst with aliphatic substrates and were pleased to observe excellent reactivity and enantioselectivity for benzyl- and phenethyl-substituted lactones (6q, 6r). Even completely unbiased aliphatic substrates with cyclohexyl (4s) and butyl (4t) groups furnished the corresponding lactones 6s and 6t, in good to moderate yield and with excellent enantioselectivity. However, these conditions were not compatible with higher (tri- and tetra-substituted) olefin substrates, highlighting a present limitation of this new methodology.

The utility of our approach is illustrated by an efficient route to the antioxidant (−)-boivinianin A 3a (Figure 2b), which was accessed directly in excellent yield and with high enantioselectivity by subjecting γ-alkenoic acid 4u to our optimized conditions. Subsequent one-pot functionalization of this natural product completed a concise total synthesis of the sesquiterpene (−)-gossonorol 8 in 86% yield. Notably, the stereoselective synthesis of both natural products using our method was achieved in three steps from inexpensive carboxylic acid 9, thereby representing a more direct and economically viable alternative to existing routes.14 Moreover, (−)-gossonorol has found utility as a synthetic precursor to other natural products including boivinianin B 10 and the antimalarial compound yingzhaosu C 11 (Figure 2b),14a,14e further emphasizing the potential of the described hydrolactonization methodology.

Keen to understand the mechanism of our catalytic hydrolactonization, we performed a series of kinetic and spectroscopic studies. The reaction orders of catalyst 7g and substrate 4u were investigated using variable time normalization analysis (VTNA) of concentration profiles obtained from 1H NMR at 50 °C. The normalized curves overlapped best when assuming first-order dependence on both catalyst and substrate (Figure 3A1). The steady-state approximation agreed with NMR analysis over the reaction course, suggesting that the free catalyst is the resting state (Figure S16). To elucidate the nature of the transition state, we performed a Hammett analysis with different para-substituents of aryl substituted γ-alkenoic acids (Figure 3A2). Plotting log(kX/kH) against σp+ revealed a negative linear correlation. The nature of the observed linear free-energy relationship (ρ+ = −2.6 ± 0.2) indicates significant positive charge accumulation at the reaction center during the rate-determining step. Eyring analysis of the decay rate of 4u over the temperature range from 30 to 60 °C allowed us to determine the activation enthalpy ΔH‡ (15.5 ± 0.3 kcal mol–1), activation entropy ΔS‡ (−20.7 ± 1.0 cal mol–1K–1), and free energy ΔG‡ (22.0 ± 0.5 kcal mol–1) of the reaction (Figure 3A3).

Figure 3.

Figure 3

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(A) Mechanistic study of the hydrolactonization reaction using catalyst 7g and substrate 4u. (A1) The overall reaction orders of the individual components were determined using VTNA. (A2) The nature of the reaction intermediate using a Hammett study. (A3) The thermodynamic parameters using catalyst 7g and substrate 4u determined by Eyring analysis. (B) Computational analysis of the hydrolactonization reaction. (B1) Computed free energy profile of asymmetric hydrolactonization at the [B3LYP-D3/def2-TZVP+C-PCM-(chloroform)//PBE-D3/def2-SVP+C-PCM-(chloroform)] level at 313.15 K. (B2) TS structure leading to the major enantiomer of 6a.

For further molecular-level insight into these processes, we undertook density functional theory (DFT) calculations using substrate 4a and IDPi catalyst 7g. Previous studies on electrophilic lactonizations have suggested two distinct mechanistic pathways: (i) stepwise protonation and subsequent stereoselective cyclization,15 or (ii) concerted stereoselective cyclization.16 Comprehensive analysis of both putative reaction pathways revealed that this reaction follows an asynchronous concerted mechanism (Figure 3B1, also Figure S19) where alkene protonation (C–H: 1.18 Å) precedes ring closure (C–O: 2.33 Å; Figure 3B2).17 This marked asynchronicity leads to a net accumulation of positive charge at the electrophilic carbon center (+0.26e), consistent with the Hammett study, and the computed energetic span is in qualitative agreement with that of the experiment.18 Furthermore, the hydrogen bond established early in molecular recognition between the substrate carboxylic acid group and the sulfone moiety of the catalyst (OH···O interaction) is conserved along the entire reaction pathway. We next looked to rationalize the stereochemical outcome of the transformation, noting that the DFT-computed selectivity of 94.5:5.5 (ΔΔG‡ = 1.81 kcal mol–1) between the two stereodetermining TS structures (Figure S13) was in excellent agreement with experimental observations (93:7; ΔΔG‡ = 1.7 kcal mol–1). To trace its origins, we employed distortion/interaction analysis,19 which considers the energy penalty for distortion of the substrate into the transition state conformation as the key driver behind selectivity.20 Finally, we challenged our computational model to rationalize the substrate scope limitation in the presence of tri- and tetra-substituted olefins (see Figure S6 in the SI). Based on the computed TS structure, the methylene group of the substrate protrudes into the binding pocket to accept a proton from the sulfonamide group of the catalyst. This pocket is just adequate to accommodate a methylene group but not any higher-substituted alkene (Figure S21) resulting in enzyme-like substrate specificity observed in this case.

To summarize, we have described an organocatalytic asymmetric hydrolactonization that efficiently generates enantiomerically enriched tertiary lactones. Using a confined IDPi catalyst, we realized this transformation under mild conditions for a diverse array of substrates with good to excellent enantioselectivities, while suppressing competing alkene isomerization. The utility of our method was further demonstrated by concise total syntheses of (−)-boivinianin A (3a) and (+)-gossonorol (8), further establishing formal syntheses of boivinianin B (10) and yingzhaosu C (11). Experimental and computational analyses deconstructed the reaction mechanism and its underlying stereoselectivity. The new methodology fills a long-standing gap in the asymmetric electrophilic lactonization literature and recapitulates many features of enzymatic catalysis. We believe that the principles underlying the present study will enable a leap forward in designing other elusive alkene hydrofunctionalizations.

Acknowledgments

Generous support from the Deutsche Forschungsgemeinschaft (Leibniz Award to B.L.), the European Research Council (Advanced Grant “C–H Acids for Organic Synthesis, CHAOS”), and the Horizon 2020 Marie-Sklodowska-Curie Postdoctoral Fellowship (to R.M., Grant agreement No. 897130) is gratefully acknowledged. We also thank the technicians of our group and the members of our NMR, MS, and chromatography groups for their excellent service.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c01404.

  • Experimental, computational, and spectroscopic details (PDF)

Author Contributions

§ S.G. and O.G. contributed equally.

Open access funded by Max Planck Society.

The authors declare the following competing financial interest(s): A patent on the general catalyst class has been filed.

Supplementary Material

ja3c01404_si_001.pdf (7.4MB, pdf)

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