Main

At present, the enantioselective synthesis of alkylidenecyclopropanes (ACPs) is limited. Asymmetric metallocarbene additions to allenes7,8,9,10, reductive enantioselective alkylidene transfer11 and chirality transfer12,13,14,15,16 represent the main pathways to these desirable products (Fig. 1a(ii)). The most used method, metallocarbene addition, fails to deliver ACPs with substituents on each cyclopropane carbon as the addition occurs at the terminal alkene, a consequence of both electronic and steric considerations. Although metallocarbenes can be added to electron poor alkenes using cobalt catalysis, this chemistry has not yet been applied to allenes17,18. An enantioselective transformation to overcome these limitations represents a notable advancement in the field.

We sought to use our superbasic19,20,21,22,23,24,25 bifunctional iminophosphorane (BIMP) catalyst26,27,28,29,30,31,32,33 to promote their efficient and enantioselective synthesis by means of a conceptually new strain-relieving, deconjugative34,35, prototropic shift29,36,37 making use of substrates that can be readily prepared from commercially available materials.

Exploitation of the cyclopropene ring’s highly strained character provided the cornerstone for the investigation38,39. Double bond migration from an endo-cyclic to an exo-cyclic position has previously been reported and generates a new tetrahedral-like carbon in the cyclopropane ring40,41,42. This substrate scope limited, non-enantioselective or diastereoselective transformation requires super-stoichiometric (achiral) bases, harsh reaction conditions and, with organic bases, a conjugative driving force (Fig. 1a(iii))40. We recognized that if the cyclopropene in Fig. 1a(iii) contains a prochiral π-bonded carbon atom, a stereogenic centre is generated following the migration of the double bond. Theoretically, a suitable electron withdrawing group attached to the prochiral carbon should allow a suitably strong, chiral Brønsted base to achieve enantioselective proton transfer from the external γ-position to the α-position43,44,45, yielding a more stable chiral ACP. When combined with exquisite catalyst control, this downhill thermodynamic driving force could lead to a new and broad-in-scope strategy to valuable small-ring structures; to this end, here we report our findings (Fig. 1a(iv)).

Test substrate 3a was selected and straightforwardly synthesized for investigation (Fig. 1b)46,47. The first generation BIMP catalysts (C1–C5) featuring a single stereogenic centre were efficient deconjugation promoters, and the desired products were obtained in good to excellent yield (68–98%). Whereas yields were generally good, enantiocontrol pivoted around base strength. Thus, whereas catalyst C4 imparted encouraging enantiocontrol (75% enantiomeric excess (e.e.)), the more basic PCy3-derived iminophosphorane (C3) gave none (0% e.e.). Good enantiocontrol was obtained with both thiourea catalyst C2 (−49% e.e.) and urea derived catalysts C4 and C5 (75% e.e. and 67% e.e., respectively) despite the difference in hydrogen bond donor strength, yields were higher on average with urea-based catalysts.

Fig. 1: Previous art, concept and reaction optimizations.
figure 1

a, Drug molecules and agrochemicals containing cyclopropene rings, state-of-the-art synthetic approaches towards chiral ACPs and strain-relieving concept of cyclopropenes to ACPs: (i) natural products and bioactive compounds; (ii) enantioselective approaches to ACPs; (iii) conjugation approach40 and (iv) enantioselective deconjugation concept. b, Catalyst screening for the enantioselective strain-relieving deconjugation of substrate 3a. c, Conditions for the enantioselective strain-relieving deconjugation of substrate 4a with catalyst C12. In b, e.e. was determined by high-performance liquid chromatography analysis on a chiral stationary phase. Also the reactions were carried out with 0.013 mmol of 3a. aReaction carried out in Et2O (0.05 M). bYield only obtained for the last entry, reactions were carried out in Et2O (0.05 M). cReaction was carried out with 0.10 mmol of substrate. DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; Nap, naphthalenyl; PMP, para-methoxyphenyl; rt, room temperature; temp., temperature; THF, tetrahydrofuran.

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Second-generation (C6–C11) BIMP catalysts bearing an extra α-amino amide moiety distal to the iminophosphorane group were then investigated for improved enantiocontrol. Catalyst C6 possessing a single stereogenic centre imparted low enantioselectivity (−11% e.e.) and moderate yield (52%). However, the introduction of a second stereogenic centre (C7) boosted enantioselectivity (42% e.e.) while maintaining yield (48%). Further improvements to the selectivity were achieved by increasing the steric bulk of R2 at the proximal stereogenic centre. Use of a benzhydryl group (C8) increased the enantioselectivity to −63% e.e. and a moderate increase to 76% e.e. was observed with a Ph group in place (C9). Finally, when R2 was a t-Bu (C10) the enantioselectivity was elevated to 81% e.e. Generally, the stereocentre close to the iminophosphorane moiety dictated the product’s absolute stereochemical configuration, with S providing the R-configured products and vice versa. An exception was noted with catalyst C6 that was probably due to the lack of a secondary stereocentre affecting the catalyst’s reactive conformation. Finally, we reduced the catalyst’s Brønsted basicity with a PPh3-derived iminophosphorane (C11) that, on switching the solvent to Et2O (0.05 M), provided 3b in 96% yield and 95% e.e.

α,β-Unsaturated ketones were also investigated to expand the applicable chemical space of the transformation (Fig. 1c). Substrate 4a presented a new challenge in the control of the enantioselectivity and E/Z geometry of the product. Following extensive investigation (Supplementary Information), catalyst C12, the diastereomer of C11 was identified as an efficient catalyst for the transformation. Substrate 4a was rapidly converted to product 4b within 120 minutes and with excellent diastereocontrol (more than 20:1 d.r.). Unfortunately, enantiocontrol was completely lost (0% e.e.) indicative of catalyst-enabled racemization of the more acidic ketonic system (Supplementary Information). Reduction of the overall reaction time (120 minutes (0% e.e.); 5 minutes (24% e.e.); 0.5 minutes (65% e.e.)) revealed that the enantioselectivity could be rescued. Consequently, we performed the reaction at the reduced temperature of −78 °C and the ACP (4b) rapidly formed (2 hours) in 99% yield, more than 20:1 d.r. and 93% e.e. Single-crystal X-ray diffraction analysis of 4b confirmed the absolute stereochemical configuration as (S) (Fig. 2).

Fig. 2: Reaction scope for the enantioselective strain-relieving deconjugation of cyclopropenes.
figure 2

aReactions were carried out with 0.1 mmol of substrate; all e.e. were determined by high-performance liquid chromatography or supercritical fluid chromatography analysis on chiral stationary phase. bReaction carried out with 0.05 mmol of substrate. cReaction carried out in tetrahydrofuran. d−78 to 0 °C. EWG, electron-withdrawing group; TBS, tert-butyldimethylsilane.

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Next, we proceeded to explore the reaction scope (Fig. 2). Replacement of the cyclohexyl group (3a) with a cyclopentyl ring (5a) had no detrimental effect on reactivity (96%), and the product (5b) was obtained in 94% e.e. within 5 h. Heterocyclic rings were also well tolerated, and the products 6b and 7b were obtained in 95% and 96% e.e., respectively. Furthermore, substrate 8a with an allyl ester was converted easily and with excellent selectivity (75%, 97% e.e.).

Under the control of catalyst C11, substrate 9a, featuring an n-propyl chain and a benzyl ester, was converted to 9b in 30 minutes with remarkable selectivity for the (Z)-isomer (more than 20:1 d.r.), 95% e.e. and 97% yield. Steady racemization of 9b occurred over time under the reaction conditions after near instantaneous product formation due to the acidity of 9b’s α-proton (Supplementary Fig. 1). Single-crystal X-ray diffraction analysis confirmed the absolute stereochemical configuration of 9b as (R). Methyl-ester 10b and iso-butyl ester 11b formed rapidly (2 hours and 3 hours, respectively) with excellent levels of diastereoselectivity (more than 20:1 d.r.) and enantioselectivity (97% e.e. and 94% e.e., respectively).

Next, a selection of functionalized alkyl chains were investigated. At reduced temperature, an alkyl chloride was well tolerated, and 12b was obtained in 79% yield and 94% e.e. as a single diastereomer. O-tert-butyldimethylsilane and Ph were also efficiently converted to their deconjugated products with both n-Pr (13b and 14b, respectively) and n-Et (16b and 17b, respectively) chains. Enantioselectivity generally exceeded 90% and most products were obtained as single diastereomers. A moderate drop in both diastereoselectivity (89:11) and enantioselectivity (86% e.e.) occurred with substrate 16a, probably due to the proximal bulk of the tert-butyldimethylsilane group.

We investigated the effect of substituents attached to the cyclopropene’s bridging methylene carbon. Four ester variations, Et (18a), i-Pr (19a), t-Bu (20a) and Bn (21a) were trialled. In each case deconjugation occurred in excellent yield and, despite the increased bulk at the bridge, enantioselectivity was maintained. Removal of the bridging esters was also possible as demonstrated with substrate 22a. The reaction progressed slowly over 24 h and despite the new gem-dimethyl motif, 22b was obtained in 97% yield and 90% e.e.

We next designed a new substrate featuring a pendant ketone (23a). On exposure to the reaction conditions the prototropic shift proceeded smoothly, and the resulting ACP underwent further transformation to enone 23b. All three stereocentres were formed with excellent control resulting in a single trans configured cyclopropane diastereomer (more than 20:1 d.r) and near-perfect enantiomeric excess (98% e.e.).

Finally, we synthesized substrate 24a that represented an ideal substrate for comparison with our computational studies (vide infra) and featured a methyl-ester and ethyl chain that, under the reaction conditions, transformed into 24b in 99% yield, more than 20:1 d.r. and 90% e.e. in 30 minutes.

Furthermore, a range of amides were tested under the optimized reaction conditions for ester substrates. tert-Butyl amide substrate 25a was converted to 25b in under 1 hour regardless of the reduced acidity of the γ-proton. Despite the amide’s hydrogen bond donating N–H group, 25b was obtained in more than 20:1 d.r. and with complete enantiocontrol (98% e.e.). Similarly, allyl amide ACP 26b formed rapidly (2 hours) under the reaction conditions in 73% yield, more than 20:1 d.r. and 97% e.e. Amide 27a, featuring a cyclopentyl ring was tolerated and the ACP (27b) was obtained in 93% yield and 99% e.e. Single-crystal X-ray analysis of 27b confirmed the absolute stereochemical configuration as R and a supplementary study showed that no racemization occurred over 80 h. Substrate 28a converted to 28b in good yield of 78% with complete enantiocontrol (99% e.e.) under a reduced time-frame (24 h). para-Methoxyphenyl amide (29a) was smoothly converted to 29b in more than 99% yield, more than 20:1 d.r. and 94% e.e. in 1.75 h. With prolonged exposure to the reaction conditions, 29b underwent intramolecular cyclization to provide fused ring system 29c with complete diastereocontrol (more than 20:1 d.r.) and near-perfect enantioselectivity (97% e.e.). As a stand-alone example, a substrate featuring a phosphine oxide (30a) was successfully tested. Compound 30b was obtained in high yield of 95% and 99% e.e. of the main diastereomer succinctly demonstrating the transformation’s broad utility.

Catalyst C12 was then used to investigate the scope of ketone substrates. Replacement of 4a’s n-Pr chain with a cyclopentane ring (31a) was well tolerated and 31b was obtained in 90% yield and 99% e.e. in 4 hours. para-Methoxyphenyl ketone (32a) could also be used albeit with moderately reduced enantioselectivity of 84% e.e. but an excellent yield of 97% and complete diastereocontrol (more than 20:1 d.r.).

As of 2020, pyrethroid insecticides accounted for 25% of global insecticide sales48. Despite the differing biological properties of their stereoisomers, few direct enantioselective methods exist for their synthesis48. Current routes involve chiral auxiliaries49, resolution approaches5 or stoichiometric quantities of chiral reagents50. The development of catalytic enantioselective approaches have been met with limited success51.

Pyrethroids have several common, recurring structural features, most notably their gem-dimethyl cyclopropane, alkene and carbonyl motifs (Fig. 1a). To incorporate these features into our ACP products, a modified strategy was realized. Placement of a suitably protected alcohol at the site of deprotonation would result in the formation of an enol-ether on successful migration of the double bond. Deprotection of the enol-ether would then reveal an aldehyde amenable to further functionalization while allowing two stereocentres to be set in a single step (Fig. 3a). A test substrate 33a containing the required structural features was accordingly synthesized (Supplementary Information).

Fig. 3: Enantioselective synthesis of insecticides and their precursors.
figure 3

a, Enantioselective synthesis of (1R,3R)-cis-permethrin and insecticide cores using catalyst C13. b, Derivatization of product 39b and 22b. In a, reactions were carried out with 0.1 mmol of substrate and all e.e. were determined by high-performance liquid chromatography or supercritical fluid chromatography analysis on chiral stationary phase. aReaction carried out with 0.05 mmol of substrate. bReaction carried out with 0.2 mmol of substrate. OMEM, methoxyethoxymethyl ether.

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Initially, the deconjugation reaction was tested on substrate 33a using catalyst C11. No conversion to the desired product was observed, however, the BIMP’s iminophosphorane could be easily tuned by variation of the triarylphosphine, and the catalyst was quickly re-optimized to suit the new substrate (Supplementary Information). The new catalyst (C13) featured a sterically encumbered triarylphosphine moiety and rapidly formed the desired product 33b (90%) with excellent levels of diastereocontrol (more than 20:1 d.r.) and enantiocontrol (98% e.e.). A deuterium labelling study of 33a was undertaken and a large kinetic isotope effect observed for the transformation (Supplementary Information). An enantioselective synthesis of permethrin was performed using the new catalyst C13 showcasing the synthetic utility of the transformation. Following rapid formation of enol-ether 34b (1 hour), an aqueous acidic work-up provided the crude aldehyde as a single diastereomer that, on being subjected to Corey–Fuchs reaction conditions, formed (1R,3R)-cis-permethrin (2) as a single diastereomer in 98% e.e. completing the route in six steps (longest linear sequence, Supplementary Information).

The scope was expanded to aldehyde-cores of other pyrethroid-type insecticides (Fig. 3a). In each case, C13 performed well, and following an acid work-up, aldehyde-cores to kappa-tefluthrin (35b), dimefluthrin (36b) and kappa-bifenthrin (37b) could all be obtained as single diastereomers in >97% e.e. within 1 h.

C13 was also applicable to substrates that did not feature the pendent ether chain. A spirocyclic cyclopropene with a bridging cyclohexyl group (38a) was synthesized. The desired deconjugated product formed rapidly (2 hours) with high levels of diastereoselectivity (more than 20:1 d.r.) and enantioselectivity (99% e.e.).

Next, to showcase the synthetic potential of the ACPs we proceeded to investigate the derivatization of 39b and 22b (Fig. 3b). 39b was synthesized using C13 in good yield (85%) and with excellent stereocontrol (more than 20:1 d.r., 97% e.e.) and was converted into alcohol 40 using DIBAL-H at reduced temperature. The product (40) was obtained without loss of enantioenrichment (97% e.e.) in good yield (44%). ACP 22b was smoothly converted into spirocycle 41 by means of stereoselective epoxidation with mCPBA providing the desired compound as a single diastereomer (more than 20:1) while maintaining 90% e.e.

Density functional theory (DFT) calculations were performed to elucidate the reaction mechanism and origins of diastereoselectivities and enantioselectivities using the ADF program (Fig. 4)52. The reaction probably proceeds through a two-step catalytic sequence; γ-deprotonation, and enantioselective α-reprotonation. An alternative mechanism, involving a non-selective ring strain-relief sequence followed by ACP desymmetrization, is unlikely as the product racemizes over extended reaction time (Supplementary Fig. 1). Two diastereomeric catalysts were considered in this computational study to provide detailed insight into the transformation.

Fig. 4: DFT study of the reaction pathway with ester-substituted cyclopropene.
figure 4

a, Potential energy surface diagram. b, Transition state structures for reprotonation. Computed potential energy surfaces (ΔG (kcal mol−1)) for the 1,3-prototropic shift of ester 24a computed at COSMO(Et2O)-ZORA-M06-2X/TZ2P//COSMO(Et2O)-ZORA-BLYP-D3(BJ)/DZP. Bond lengths (Å) of the transition state geometries are provided in the inset. All non-essential hydrogen atoms were removed from the three-dimensional molecular geometries for clarity.

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First, we explored the reaction pathway of the cyclopropene esters using 24a as an idealized substrate (Fig. 4). Initially, the catalyst C11 and 24a form a hydrogen-bonded complex Int1. We computed and compared all the possible transition state (TS) conformations for deprotonation and reprotonation processes (Supplementary Figs. 7–10). The lowest-energy transition structure TS1-Z for the initial deprotonation leads to the diastereoselective formation of dienolate intermediate Int2. Although the computed Gibbs free energy difference is slightly underestimated for the second-lowest transition state, TS1-E, the large difference in electronic energies supports a deprotonation process that predominantly occurs through TS1-Z in a diastereoselective manner. Reprotonation occurs through TS2-R or TS2-S, and the lowest energy transition state, TS2-R, forms the (R)-product P-1, in agreement with the reaction’s experimentally confirmed absolute stereochemical outcome (ΔΔG‡ = 4.2 kcal mol−1). The geometry of TS2-R benefits from a complementary fit of 24a in the binding pocket of the catalyst in which intramolecular hydrogen bonding between the S(thiourea)–H(amide) fixes the conformational freedom of the ‘left arm’ of the BIMP catalyst. This creates a three-dimensionally defined pocket that embraces 24a to minimize steric repulsions during the reprotonation step (Supplementary Fig. 11). In addition, there is a network of many intermolecular and intramolecular stabilizing interactions, including hydrogen bonding and CH–π interactions ranging in strength between −0.7 and −139.7 kcal mol−1 as quantified by our energy decomposition analysis (Supplementary Fig. 11)53,54.

We also investigated the reaction pathway for ketone-substituted substrates (Supplementary Scheme 6). Conformational analysis of the transition state structures revealed a preferred pathway that leads to the experimentally confirmed absolute stereochemical outcome. Notably, the rate-determining step shifts between the ester-substituted and ketone-substituted cyclopropenes, probably due to differences in the stability and reactivity of their respective dienolate intermediates.

In conclusion, an efficient, conceptually new and broad-scope method for the synthesis of chiral ACPs and cyclopropanes has been developed. Two BIMP catalysts provided excellent reactivity and selectivity across a broad range of substrates including esters, amides, ketones and a stand-alone phosphine oxide example. Through rational substrate design and retuning of the catalyst’s basic iminophosphorane moiety, the transformation was applied in the total synthesis of (1R,3R)-cis-permethrin, providing a new, enantioselective route to synthetically important insecticide cores. Finally, DFT studies elucidated the mechanism and origin of diastereoselectivities and enantioselectivities with the BIMP catalyst and their respective substrate classes. This powerful BIMP-catalysed transformation has provided access to highly attractive, previously unobtainable, enantioenriched ACPs and cyclopropanes through a strain-relief strategy, whose concept will inspire investigations into further transformations of small-ring carbocycles with BIMP catalysts.