Isothiourea‐Catalysed Acylative Kinetic and Dynamic Kinetic Resolution of Planar Chiral Paracyclophanols

Zhanyu Zhou; Kevin Kasten; Dr Aidan P McKay; Dr David B Cordes; Prof Dr Andrew D Smith

doi:10.1002/anie.202507126

. 2025 Jun 23;64(31):e202507126. doi: 10.1002/anie.202507126

Isothiourea‐Catalysed Acylative Kinetic and Dynamic Kinetic Resolution of Planar Chiral Paracyclophanols

Zhanyu Zhou ¹, Kevin Kasten ¹, Aidan P McKay ¹, David B Cordes ¹, Andrew D Smith ^1,^✉

PMCID: PMC12304874 PMID: 40392605

Abstract

The development of synthetic methods for the catalytic enantioselective preparation of planar chiral paracyclophane derivatives is of considerable interest to the synthetic community. To date, relatively few successful and effective organocatalytic approaches to this molecular class have been reported. This manuscript describes effective isothiourea catalysed acylative kinetic (KR) and dynamic kinetic resolution (DKR) approaches to the generation of a range of planar chiral paracyclophane macrocycles with excellent levels of enantioselectivity. Effective KR of configurationally stable planar chiral paracyclophanols with 12‐ and 13‐membered ansa‐chains is demonstrated (6 examples, s = up to 50) using 5 mol% of the isothiourea (R)‐BTM and isobutyric anhydride. Application to configurationally labile macrocyclic phenols with 14 to 18‐membered ansa‐chains allows their effective acylative DKR, generating the desired products with excellent enantioselectivity (25 examples, up to 95% yield and 98:2 er).

Keywords: Dynamic kinetic resolution, Isothiourea, Kinetic resolution, Macrocycles, Paracyclophane

The highly selective acylative (dynamic) kinetic resolution of racemic paracyclophanols catalysed by a chiral isothiourea (5 mol%) is described (up to s = 50 at 49% conversion or up to 98:2 er and 96% yield in 30 examples). Rotational barriers were analysed for paracyclophanols and selected ester products.

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Introduction

Planar chirality describes stereoisomerism that results from the arrangement of out‐of‐plane groups in relation to a reference plane (Figure 1a).^[ ¹ , ² ^] A range of molecular types that encompass macrocycles, such as cyclophanes and bridged annulenes, as well as cycloalkenes and metallocenes, have been prepared that demonstrate this configurational phenomenon. Such species are of significant interest from a synthetic,^[ ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ ^] structural,^[ ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ ^] and chiroptical perspective.^[ ²⁹ ^] In addition, planar chiral macrocycles are found within natural products^[ ³⁰ , ³¹ , ³² ^] and bioactive species^[ ⁷ , ¹³ , ¹⁴ , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ ^] such as Fijiolides.^[ ⁶⁹ ^] Within this class, a cyclophane can be defined as a macrocycle that is made up of aromatic units connected by chain linkers.^[ ⁷⁰ ^] In mancude‐ring systems (such as benzene) that are bridged by a linker, the so‐called ansa‐chain is constrained to lie over one face of the ring, with asymmetric substitution of the arene leading to the formation of chiral products. In such structures, configurational stability arises due to restricted rotation of the aromatic ring, with substituents needing to pass through the ansa‐chain to interconvert enantiomers. Because of their structural interest and dynamic behaviour, several methods have been developed for the asymmetric synthesis of planar chiral cyclophanes (Figure 1b).^[ ⁵ , ⁶ , ¹⁰ , ¹⁶ , ¹⁷ , ²¹ ^] These include elegant methods for the construction of either the ansa‐chain,^[ ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² ^] the arene within the chiral plane,^[ ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ ^] or stereoselective transformation of the chiral plane employing chiral auxiliaries^[ ⁴² , ⁸⁸ , ⁸⁹ , ⁹⁰ , ⁹¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ ^] and reagents,^[ ⁹⁶ , ⁹⁷ ^] as well as enantioselective desymmetrisation^[ ⁹⁸ , ⁹⁹ , ¹⁰⁰ ^] or (dynamic) kinetic resolution [(D)KR] processes.^[ ⁹⁸ , ¹⁰¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ , ¹⁰⁹ , ¹¹⁰ , ¹¹¹ , ¹¹² , ¹¹³ , ¹¹⁴ , ¹¹⁵ ^] In the latter area, the rate of enantiomerization is dependent upon size and position of arene substituents within the plane, as well as ansa‐chain length and its constitution (Figure 1c).^[ ⁵ , ¹⁶ , ¹⁷ , ²¹ , ¹¹⁶ , ¹¹⁷ , ¹¹⁸ ^] Either reducing the size of the ansa‐chain or increasing the size of the substituents within the chiral plane can lead to configurationally stable products. Several methods that allow modification of the arene in this manner encompass asymmetric Sonagashira coupling,^[ ¹⁰¹ ^] or lithiation‐trapping approaches,^[ ⁹⁸ ^] as well as C─H‐activation‐olefination or ‐arylation using transition metal based catalysts.^[ ¹⁰⁵ , ¹¹² ^] To date, limited organocatalytic (D)KR approaches have been demonstrated in this area to generate chiral paracyclophanes.^[ ¹⁰² , ¹⁰³ , ¹⁰⁷ , ¹¹⁵ ^] The current state‐of‐the‐art methods utilise a direct electrophilic arene substitution process via either CPA‐promoted electrophilic amination^[ ¹⁰⁴ ^] or Lewis base‐catalysed electrophilic sulfenylation of arenes.^[ ¹¹¹ ^] Alternatively, functionalisation of a macrocyclic aldehyde via either NHC‐catalysed oxidative esterification (that requires a stoichiometric oxidant)^[ ¹⁰⁹ ^] or chiral phosphoric acid (CPA) catalysed transfer hydrogenation to promote reductive amination^[ ¹⁰⁶ ^] has been achieved (Figure 1d).

a) Planar chirality: cyclophane, metallocene, alkene, and natural product. b) Synthetic strategies towards chiral paracyclophanes. c) Mode of enantiomerization. d) Current state‐of‐the‐art organocatalytic cyclophane modification strategies. e) Previous isothiourea‐catalysed KR of [2.2]paracyclophan‐4‐ol. f) This work: isothiourea‐catalysed acylative KR/DKR of paracyclophanols.

The acylative KR and DKR of racemic alcohols is a strategy that has been widely adopted by both industry and academia to deliver enantiomerically pure products.^[ ¹¹⁹ , ¹²⁰ ^] The use of nitrogen‐centred Lewis base catalysts has been widely described in this area,^[ ¹²¹ , ¹²² , ¹²³ , ¹²⁴ ^] with the use of isothiourea catalysts having been applied to the KR of a range of primary,^[ ¹²⁵ ^] secondary,^[ ¹²⁶ , ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ ^] and tertiary^[ ¹³² ^] point chiral alcohols since the first demonstration of their utility in KR by Birman and co‐workers.^[ ¹³³ ^] Application to the KR of 2,6‐dihydroxybiaryls,^[ ¹³⁴ ^] as well as desymmetrisation of 2‐hydroxybiaryls^[ ¹³⁵ ^] has extended their utility to the development of molecules with a chiral axis. Deployment of isothiourea‐catalysed enantioselective acylation to planar chiral molecules is in its infancy, with Waser and co‐workers having demonstrated a single example of an acylative KR of [2.2]paracyclophan‐4‐ol with promising but modest selectivity (up to s = 20, Figure 1e).^[ ¹¹⁵ ^] In this context, the catalytic acylative DKR of planar chiral alcohols represents an underdeveloped area in the field. This manuscript describes the isothiourea‐catalysed acylative KR and DKR of a range of planar chiral paracyclophanols (Figure 1f). At the onset of this study, the following key challenges were recognised. 1) For an effective DKR, the rate of enantioselective acylation must couple with enantiomerization of the racemic planar chiral paracyclophanol, with the assumption that the increased steric hinderance generated upon esterification would prohibit product racemisation. 2) Differentiation of the two paracyclophanol enantiomers using an isothiourea catalyst is a previously underexplored challenge that would require distinguishing between the two potential ether linkage recognition motifs within the substrate. 3) Variation of the ansa‐chain length in such macrocycles is known to markedly affect their configurational stability,^[ ⁵ , ¹⁶ , ¹⁷ , ²¹ , ¹¹⁶ , ¹¹⁷ , ¹¹⁸ ^] potentially allowing for both KR and DKR processes to be developed. Herein, we describe the successful realisation of this strategy that utilises a commercially available isothiourea catalyst (R)‐BTM and common anhydride reagents to promote effective catalytic acylative KR and DKR of a range of planar chiral paracyclophanols (KR, s = 50 at 49% conversion; DKR up to 96% yield and 98:2 er).^[ ¹³⁶ ^]

Results and Discussion

Acylative Kinetic Resolution of Configurationally Stable Planar Chiral Paracyclophanols

To initially verify the feasibility of this enantioselective acylation process, the kinetic resolution (KR) of a configurationally stable racemic macrocyclic phenol 1 with a 12‐membered ansa‐chain was explored as a model substrate. Using 5 mol% of the chiral isothiourea catalyst (2S,3R)‐HyperBTM 3 and isobutyric anhydride as the acyl source in CHCl₃ or toluene with ⁱ Pr₂NEt as the co‐base led to effective acylation but moderate selectivity (s = 5) (entries 1 and 2, Table 1). Changing to the alternative isothiourea catalyst (R)‐BTM 4 in CHCl₃ led to increased selectivity (s = 14, entry 3). Exploration of several co‐bases showed that the use of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) led to poor selectivity (s = 2, entry 4), while lutidine, 2,6‐di‐tert‐butyl pyridine (2,6‐DTBP) and quinaldine all lead to useful levels of selectivity (s = 16) at 47%–52% conversion (entries 5–7). Using quinaldine, decreasing the catalyst loading showed that both 5% and 2.5 mol% of (R)‐BTM 4 gave equivalent conversion and selectivity (entries 8–9). Optimal selectivity was observed using toluene as the reaction solvent and quinaldine as the base, leading to effective KR of 1 (c = 49, s = 50), allowing isolation of alcohol (S _p)‐1 in 38% yield and 93:7 er, as well as the generation of ester (R _p)‐2 in 48% yield and 95:5 er (entry 10).

Table 1.

Optimisation of Acylative Kinetic Resolution Process.


Entry	Catalyst (y mol%)	Base	Solvent	c ^a)	s ^a)
1	3 (10)	ⁱ Pr₂NEt	PhMe	51	5
2	3 (10)	ⁱ Pr₂NEt	CHCl₃	56	3
3	4 (10)	ⁱ Pr₂NEt	CHCl₃	56	14
4	4 (10)	DBU	CHCl₃	57	2
5	4 (10)	Lutidine	CHCl₃	48	16
6	4 (10)	2,6‐DTBP	CHCl₃	47	16
7	4 (10)	Quinaldine	CHCl₃	52	16
8	4 (5)	Quinaldine	CHCl₃	55	16
9	4 (2.5)	Quinaldine	CHCl₃	52	16
10	4 (5)	Quinaldine	PhMe	49	50

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^{^a)}

Conversion (c) and selectivity factor (s) calculated using the enantiomeric ratios of alcohol and ester as measured by HPLC analysis on a chiral stationary phase.^[ ¹¹⁹ , ¹²⁰ , ¹³⁷ ^]

s values rounded according to estimated errors.^[ ¹³⁸ ^]

With optimised conditions for the KR developed, the scope and limitations of this process were investigated through variation of the aryl substitution pattern and macrocycle ring size (Scheme 1). With a 12‐membered ansa‐chain (n = 1), incorporation of bromine, phenyl, and 3‐pyridyl substituents led to consistently excellent selectivity in this acylative KR (2, 5, 6, s = 50, 37, and 41, respectively) at 49%–57% conversion. Employing sterically less encumbered acetic anhydride was also feasible, albeit with decreased selectivity (7, s = 21 at 49% conversion). Further extension to a 13‐membered ansa‐chain (n = 2) also gave efficient KR, giving bromine‐bearing macrocycle 8 (c = 53, s = 31) and phenyl‐substituted analogue 9 (c = 53, s = 20). The configurational stability of paracyclophanol 8 (96:4 er) was probed via heating in toluene at 60 °C for >24 h, but no change of the enantiomeric ratio was observed. However, upon heating in toluene at 100 °C, a linear decrease in er with time was observed (to 82:18 er after 43 h), consistent with k_rac = 2.0 × 10⁻⁶ s⁻¹, ΔG₃₇₃ = 32.6 kcal mol⁻¹ (see SI for details).^[ ¹³⁶ ^]

Scheme 1 — a) Conversion (c) and selectivity factor (s) calculated using the enantiomeric ratios of recovered alcohol and ester as measured by HPLC analysis on a chiral stationary phase.^[ ¹¹⁹ , ¹²⁰ , ¹³⁷ ^] s values rounded according to estimated errors.^[ ¹³⁸ ^] b) Isobutyric anhydride used; c) Acetic anhydride used; d) Following KR, the phenol and ester products could not be separated, but were resolved on HPLC, yield determined by NMR ratio of the mixture.

Acylative Dynamic Kinetic Resolution of Configurationally Labile Planar Chiral Paracyclophanols

Further investigation considered that increasing the ansa‐chain length would allow starting material enantiomerization to occur on a timescale compatible with enantioselective acylation, facilitating an acylative DKR process (Table 2). This process was predicated on the increased steric encumbrance of the ester effectively increasing the barrier to enantiomerization under the reaction conditions. Using paracyclophanol 10 with a 14‐membered ansa‐chain as a model system, screening for the potential DKR process was followed. Using 10 mol% of the chiral isothiourea catalyst (2S,3R)‐HyperBTM 3 and isobutyric anhydride as the acyl source in toluene with ⁱ Pr₂NEt as the co‐base led to effective acylation but poor selectivity (96% yield, 63:37 er, entry 1, Table 1). Using isothiourea catalyst (R)‐BTM 4 under these conditions led to significantly increased selectivity (96% yield, 96:4 er, entry 2). Using (R)‐BTM 4, variation in solvent was tested (entries 3–5), with CHCl₃ and Et₂O giving reduced but acceptable selectivity and MeCN leading to significantly reduced product enantiocontrol (54:46 er). Variation of the base was also trialled, with Na₂CO₃, quinaldine, 2,6‐lutidine, and 1,4‐diazabicylo[2.2.2]octane (DABCO) all leading to good to excellent product enantiocontrol but reduced product yields (entries 6–9). As the use of ⁱ Pr₂NEt in toluene led to optimal balance between yield and enantiocontrol, reduction in catalyst loading to 5 and 2.5 mol% using this combination was also tested (entries 10 and 11). While good conversion and high product er were observed using 2.5 mol% catalyst, the optimal reaction conditions were considered to use 5 mol% catalyst, leading to 11 in 92% yield and 97:3 er. Under these reaction conditions, the use of isobutyryl chloride as acylating agent also proved successful, giving (R _P)‐11 in 82% yield and 92:8 er (entry 12). The use of propionic and benzoic anhydrides also worked well, giving the corresponding esters in good yields and enantioselectivity (88% yield, 92:8 er; 83% yield, 97:3 er, respectively; see SI for further information).

Table 2.

Optimisation of Acylative Dynamic Kinetic Resolution Process.


Entry	Catalyst (mol%)	Base	Solvent	Yield ^a)	er ^b)
1	3 (10)	ⁱ Pr₂NEt	PhMe	96	63:37
2	4 (10)	ⁱ Pr₂NEt	PhMe	96	96:4
3	4 (10)	ⁱ Pr₂NEt	CHCl₃	92	88:12
4	4 (10)	ⁱ Pr₂NEt	Et₂O	80	93:7
5	4 (10)	ⁱ Pr₂NEt	MeCN	92	54:46
6	4 (10)	Na₂CO₃	PhMe	81	95:5
7	4 (10)	quinaldine	PhMe	78	98:2
8	4 (10)	2,6‐lutidine	PhMe	80	97:3
9	4 (10)	DABCO	PhMe	85	93:7
10	4 (5)	ⁱ Pr₂NEt	PhMe	92	97:3
11	4 (2.5)	ⁱ Pr₂NEt	PhMe	87	96:4
12 ^c)	4 (5)	ⁱ Pr₂NEt	PhMe	82	92:8

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^{^a)}

Isolated yield.

^{^b)}

Measured by HPLC analysis on a chiral stationary phase.

^{^c)}

Isobutyryl chloride used as acylating agent.

Under the developed DKR conditions, the scope and limitations of this process were identified. With a 14‐membered ansa‐chain, variation of the R¹‐substituent was probed (Scheme 2a). Incorporation of a bromine substituent was tolerated, giving 12 in 96% yield and 93:7 er. The incorporation of a vinyl substituent was also tested, giving 13 with excellent stereoselectivity (88%, 95:5 er) with the reaction conditions requiring a N₂ atmosphere to avoid competitive oxidation of the paracyclophanol starting material to the quinone (see SI for further information). The incorporation of aryl and heteroaryl substituents at R¹ was extensively tested, with the incorporation of electron‐rich 4‐MeOC₆H₄ and electron‐deficient 4‐F₃CC₆H₄ substituents tolerated, giving 14 and 15 in good yield and selectivity (94% yield, 97:3 er and 87% yield, 97:3 er, respectively). Incorporation of a 2‐MeOC₆H₄ substituent gave 16 in 77% yield (96:4 er). The incorporation of 1‐ and 2‐naphthyl substituents led to 17 and 18 with excellent stereocontrol (90% yield, 95:5 er and 88% yield, 97:3 er, respectively), although for optimal yield and selectivity, 17 had to be generated under N₂ to avoid competitive paracyclophanol oxidation. Rotamers for ester 17 were observed on the NMR time scale at 20 °C, but product er could be assessed by HPLC at 30 °C (see SI for details), emphasising the dynamic complexity of this molecular class.

Heteroaromatic substituent variation was also trialled, with 3‐pyridyl, 2‐furyl, and 3‐thienyl 19–21 generated with excellent stereoselectivity (81% yield, 97:3 er;93% yield, 96:4 er; 89% yield, 97:3 er, respectively). The absolute configuration within 2‐furyl derivative 20 was unambiguously assigned as (R _P) by single crystal X‐ray diffraction,^[ ¹³⁹ ^] with all other structures assigned by analogy. The functionalised N‐Boc‐protected indole variant was also tolerated, giving 22 with reduced stereocontrol (89%, 85:15 er), while the incorporation of a pyrene substituent gave 23 in 93% yield (96:4 er). Similarly to 17, rotamers were also observed for 23 on the NMR time scale at 20 °C but not via HPLC at 30 °C. The incorporation of a naphthoquinol substituent derivative was also tested, giving 24 with excellent stereoselectivity (95%, 98:2 er), with a protective N₂ atmosphere again required to minimise alcohol oxidation and achieve high product yield. The incorporation of an alkyl R¹‐substituent was also explored, giving ⁿ Bu substituted ester 25 with excellent enantioselectivity (87% yield, 96:4 er). Maintaining the length of the ansa‐chain but incorporating two oxygen atoms within the linkage was also tolerated, giving 26 in 91% yield and 97:3 er. Interestingly, the paracyclophanol precursor to 26 was not resolved at 30 °C, consistent with enantiomerization being faster than the HPLC timescale. As a comparison, the corresponding starting material to 12 bearing an all hydrocarbon CH₂ linker showed enantiomer interconversion through dynamic HPLC at 30 °C, consistent with enantiomerization occurring at the HPLC timescale. This emphasises the importance of chain constituents with regard to conformational flexibility and configurational stability. Further variation probed the effect of extension to the ansa‐chain length (from 15 to 18 atoms) as well as the incorporation of amide linkages within the chain (Scheme 2b). Chain extension to a 15‐membered ansa‐chain with the inclusion of either a bromo‐ or phenyl substituent proved successful, giving 27 (88% yield, 96:4 er) and 28 (88% yield, 98:2 er), respectively. Notably, a further single carbon extension to give a 16‐membered ansa‐chain showed that incorporation of a bromo‐substituent gave product 29 in 92% yield that could not be resolved on the HPLC timescale, consistent with configurational instability as observed in other literature examples.^[ ⁷⁶ , ⁸¹ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁹ , ¹¹¹ ^] However, with a 16‐membered ansa‐chain chain length and the incorporation of a phenyl substituent, effective DKR was observed, giving ester 30 in 86% yield and 98:2 er. The incorporation of amide linkages within a 16‐membered ansa‐chain length was probed, with a bromo‐substituent giving ester product 31. Notably, ester 31 showed enantiomer interconversion through dynamic HPLC, in contrast to that observed for 29 (only a single broad peak displayed, consistent with enantiomerization being faster than the HPLC timescale) despite containing the same ansa‐chain length and Br substituent. This is consistent with an increased barrier to rotation and enantiomerization for 31 over 29, consistent with the inclusion of partial double bond character increasing the conformational rigidity of the ansa‐chain (k _rac = 3.92 × 10⁻³ s⁻¹, ΔG₃₀₃ = 21.9 kcal mol⁻¹). With R¹ = phenyl effective acylative DKR gave 32 in 93% yield and 90:10 er, while the incorporation of a catechol‐containing linkage gave 33 in 83% yield but moderate enantioselectivity (68:32 er). Further chain extension to the incorporation of 17‐ and 18‐membered ansa‐chains with a R¹ phenyl substituent also showed effective DKR, generating 34 and 35 with high stereoselectivity (88% yield, 97:3 er and 87% yield, 96:4 er, respectively). The configurational stability of a range of paracyclophanol starting materials with a 14‐membered ansa‐chain were assessed using dynamic HPLC with the corresponding phenols of esters 11–23 giving k_rac values in the range of 0.78–1.95 × 10⁻³ s⁻¹, equating to ΔG₃₀₃ = 22.4–22.9 kcal mol⁻¹ (see SI for full details).^[ ¹³⁶ ^] Notably, the incorporation of a naphthoquinol substituent derivative within 36 led to increased k_rac (5.71 × 10⁻³ s⁻¹, ΔG₃₀₃ = 21.4 kcal mol⁻¹). Interestingly, for the ester product (R _p)‐12 with a 14‐membered ansa‐chain, no enantiomerization was observed after heating in toluene at 100 °C for 2 days, indicating that the rotational barrier within 12 is sufficiently large to prevent racemization. Increasing the ansa‐chain to a 15‐atom linkage as within 27 led to enantiomerization upon heating in toluene at 100 °C, consistent with k_rac = 4.4 × 10⁻⁵ s⁻¹, ΔG₃₇₃ = 30.3 kcal mol⁻¹.

Scheme 2 — All quoted yields are isolated yields; all ers determined by HPLC analysis on a chiral stationary phase. ^a) Reaction performed under an N₂ atmosphere, ^b) Rotamers were observed for 17 and 23 by ¹H NMR spectroscopy at RT in CDCl₃ and were confirmed by 1D‐NOESY; product er was assessed by HPLC analysis at 30 °C (see SI for further information). ^c) Enantiomers were not resolved by HPLC at 30 °C due to fast interconversion within the HPLC timescale. ^d) Dynamic HPLC observed consistent with enantiomerization within the HPLC timescale (k _rac = 3.92 × 10⁻³ s⁻¹, ΔG₃₀₃ = 21.9 kcal mol⁻¹).

A postulated mechanistic scheme for this acylative DKR process is indicated in Scheme 3. Acylation of the isothiourea (R)‐BTM 4 with isobutyric anhydride generates an intermediate acyl isothiouronium carboxylate ion pair 37. For the configurationally labile macrocyclic phenols with 14 to 18‐membered ansa‐chains, substrate enantiomerization is fast with respect to acylation, resulting in selective DKR upon acylation. Following the established model developed in previous KR work by ourselves and others,^[ ¹³⁴ , ¹⁴⁰ , ¹⁴¹ , ¹⁴² , ¹⁴³ , ¹⁴⁴ , ¹⁴⁵ , ¹⁴⁶ , ¹⁴⁷ , ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ , ¹⁵¹ , ¹⁵² ^] preferential reaction of this acyl isothiouronium intermediate with the (R _P)‐enantiomer of the paracyclophanol in the stereodetermining step will preferentially generate the enantioenriched ester products. Subsequent reaction of 38 with ⁱ Pr₂NEt regenerates the free isothiourea BTM catalyst.

By analogy to previous computational studies, the observed selectivity in this acylation can be rationalised using the proposed transition state assembly 39. This is predicated upon the inclusion of a 1,5‐chalcogen bond (n_O → σ*_S‐C) O•••S interaction between the acyl oxygen and the isothiourea catalyst sulphur that acts as a conformational lock.^[ ¹⁵³ , ¹⁵⁴ , ¹⁵⁵ ^] The isobutyrate counterion deprotonates the phenol, activating it to acylation, while participating in non‐classical H‐bonding to the acylated catalyst's benzylic hydrogen.^[ ¹⁴³ , ¹⁴⁴ , ¹⁵⁶ , ¹⁵⁷ , ¹⁵⁸ , ¹⁵⁹ , ¹⁶⁰ ^] To deliver high enantioselectivity, a donor substrate motif is needed to promote enantiorecognition through interaction with the positively charged acylated isothiouronium intermediate 38.^[ ⁷⁰ ^] Recognised enantiorecognition motifs in isothiourea‐catalyzed acylations include aryl,^[ ¹⁶¹ , ¹⁶² , ¹⁶³ , ¹⁶⁴ , ¹⁶⁵ ^] heteroaryl,^[ ¹⁴¹ ^] alkenyl,^[ ¹⁶³ ^] alkynyl,^[ ¹⁶⁴ ^] heteroatom,^[ ¹⁵¹ ^] C═O,^[ ¹⁴⁵ , ¹⁶⁶ ^] CF₂,^[ ¹⁴⁹ ^] and P═O substituents.^[ ¹⁴⁶ ^] Utilising the O‐atom adjacent to the phenol within the cyclophane in this capacity (blue dotted line) directs the ansa‐chain away from the stereodirecting unit of the acylated catalyst, leading to the observed selectivity.

Conclusion

In this manuscript, an effective isothiourea [(R)‐BTM)] catalysed acylative kinetic (KR) and dynamic kinetic resolution (DKR) approach that leads to the efficient synthesis of a range of planar chiral paracyclophanols with excellent levels of enantioselectivity is demonstrated. Efficient KR of stable planar chiral macrocyclic paracyclophanols with 12‐ and 13‐membered ansa‐chains is demonstrated (6 examples, s = up to 50). Extension of the ansa‐chain to include 14 to 18‐membered substituted substrates allows their effective acylative DKR, generating the desired products with excellent enantioselectivity (25 examples, up to 95% yield and 98:2 er). In a wider context, the configurational lability of the starting materials and products has been systematically evaluated, with the effect of ansa‐chain length and constitution investigated. Furthermore, esterification of the paracyclophanol starting material leads to a significant increase in the barrier to enantiomerization resulting in enhanced configurational stability of the ester products. The simplicity of this synthetic approach significantly broadens the methods available of the preparation of these valuable materials. The further application of this methodology to alternative planar chiral substrates and bioactive natural products is currently underway within our laboratory.

Supporting Information

The authors have cited additional references within the Supporting Information.^[ ¹⁶⁷ , ¹⁶⁸ , ¹⁶⁹ , ¹⁷⁰ , ¹⁷¹ , ¹⁷² , ¹⁷³ , ¹⁷⁴ , ¹⁷⁵ , ¹⁷⁶ , ¹⁷⁷ , ¹⁷⁸ , ¹⁷⁹ , ¹⁸⁰ , ¹⁸¹ , ¹⁸² , ¹⁸³ , ¹⁸⁴ , ¹⁸⁵ , ¹⁸⁶ , ¹⁸⁷ , ¹⁸⁸ , ¹⁸⁹ , ¹⁹⁰ ^]

Conflict of Interests

The authors declare no conflict of interest.

Supporting information

Supporting Information

ANIE-64-e202507126-s002.pdf^{(35.2MB, pdf)}

Supporting Information

ANIE-64-e202507126-s001.cif^{(1.4MB, cif)}

Acknowledgements

A.D.S. and K.K. thank the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support. To meet institutional and research funder open access requirements, any accepted manuscript arising shall be open access under a Creative Commons Attribution (CC‐BY) reuse licence with zero embargo.

Zhou Z., Kasten K., McKay A. P., Cordes D. B., Smith A. D., Angew. Chem. Int. Ed.. 2025, 64, e202507126. 10.1002/anie.202507126

Data Availability Statement

The research data supporting this publication can be accessed from “Isothiourea‐Catalysed Acylative Kinetic and Dynamic Resolution of Planar Chiral Macrocycles”. Pure ID: 316 046 332. University of St Andrews Research Portal: https://doi.org/10.17630/70b47d2f‐941b‐40b6‐9645‐036d99456577.

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Data Availability Statement

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PERMALINK

Isothiourea‐Catalysed Acylative Kinetic and Dynamic Kinetic Resolution of Planar Chiral Paracyclophanols

Zhanyu Zhou

Kevin Kasten

Dr Aidan P McKay

Dr David B Cordes

Prof Dr Andrew D Smith

Abstract

Introduction

Figure 1.

Results and Discussion

Acylative Kinetic Resolution of Configurationally Stable Planar Chiral Paracyclophanols

Table 1.

Scheme 1.

Acylative Dynamic Kinetic Resolution of Configurationally Labile Planar Chiral Paracyclophanols

Table 2.

Scheme 2.

Scheme 3.

Conclusion

Supporting Information

Conflict of Interests

Supporting information

Acknowledgements

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Isothiourea‐Catalysed Acylative Kinetic and Dynamic Kinetic Resolution of Planar Chiral Paracyclophanols

Zhanyu Zhou

Kevin Kasten

Dr Aidan P McKay

Dr David B Cordes

Prof Dr Andrew D Smith

Abstract

Introduction

Figure 1.

Results and Discussion

Acylative Kinetic Resolution of Configurationally Stable Planar Chiral Paracyclophanols

Table 1.

Scheme 1.

Acylative Dynamic Kinetic Resolution of Configurationally Labile Planar Chiral Paracyclophanols

Table 2.

Scheme 2.

Scheme 3.

Conclusion

Supporting Information

Conflict of Interests

Supporting information

Acknowledgements

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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