Enantioselective synthesis of tetrahydrofurans by permanganate-mediated oxidative cyclisation of 1,5-dienes using chiral phase-transfer catalysis

Abstract

Permanganate-mediated oxidative cyclisation of 1,5-dienes under chiral phase transfer catalysis (CPTC) conditions provides 2,5-dihydroxyalkyl substituted tetrahydrofurans (THF-diols) wherein four new C–O bonds are established with excellent control of relative and absolute stereochemistry. Structurally complex THF-containing motifs found in a host of bioactive natural products are accessible by oxidative transformation of simple dienes, which is exemplified by formal syntheses of cis-solamin A. Electron-withdrawing ester or ketone groups in the substrates – conjugated to one alkene of the 1,5-diene system – direct the initial manganation reaction to the electron-deficient alkene, which proceeds with enantiofacial selectivity in the presence of the CPTC. Cinchona alkaloid scaffolds are a convenient platform for chiral quaternary ammoniums with short synthetic routes to anthracenylmethyl and 3,5-bis(trifluoromethylbenzyl) CPTC derivatives realising enantioselectivities up to 89–94% ee for structurally distinct 1,5-diene systems using a readily-available and inexpensive oxidant. DFT calculations provide significant new mechanistic insight into the permanganate-mediated reaction supporting the involvement of a protonated Mn(V) glycolate in THF ring-formation through enhanced electrophilicity of the metal oxo intermediate. Furthermore, calculations identify the interplay between dipole-driven electrostatic stabilisation and cooperative noncovalent interactions in the transition state complex for manganation in the first reaction step, leading to the observed facial selectivity in this powerful synthetic reaction.

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Introduction

Tetrahydrofurans (THFs) are key structural features of numerous bioactive compounds, with prominent examples including polyether ionophore antibiotics and Annonaceous acetogenins.¹ The THF ring systems in these natural products are often substituted with stereo-defined hydroxyalkyl groups at their 2- and 5-positions, rendering such “THF-diol” motifs enduring targets for asymmetric synthesis.^1f,2 Oxidative cyclisation using transition-metal-oxo species such as MnO₄⁻,³ OsO₄,⁴ and RuO₄,⁵ is exceptional in providing direct access to THF-diols 2 from 1,5-dienes 1 with the creation of four new C–O bonds, and up to four new stereocentres in a single reaction (Scheme 1(a)).⁶ Access to enantiomerically enriched THF-diols 4a has been realised by permanganate-mediated oxidative cyclisation of dienoyl systems 3a bearing chiral auxiliaries (Scheme 1(b)).⁷ To date, analogous asymmetric processes using Ru- or Os oxo species have proved elusive, although oxidative cyclisation of enantiomerically-enriched hex-5-ene-1,2-diols 6 has been accomplished using these catalysts and Cr oxo reagents (Scheme 1(c)).^6d,8

Scheme 1 Oxidative cyclisation of 1,5-dienes and enediols using metal oxo species.

We discovered that asymmetric oxidative cyclisation of 2,6-dienones 3b was possible in the presence of a chiral phase-transfer catalyst (CPTC) 5a giving enantioenriched THF diols 4b (Scheme 1(b)),⁹ demonstrating the concept of achieving stereoinduction through chiral ion pairing with permanganate. Subsequently, asymmetric permanganate-promoted dihydroxylation,¹⁰ and oxohydroxylation^10a,11 have been developed under CPTC. Most recently, an asymmetric oxidative cyclisation of 1,4-dienes has been reported using quaternary ammonium CPTC.¹²

Despite the novelty of our original CPTC 1,5-diene oxidative cyclisation, enantioselectivities of up to 75% ee were moderate and the use of aryl-2,6-dienones 3b as substrates restricted flexibility for onwards transformation of the THF products 4b. Accordingly, the potential of this asymmetric process to access valuable THF diol fragments warranted further investigation, particularly given the ability to deliver structural complexity with control over relative and absolute stereochemistry using an inexpensive oxidising agent, benign metal byproducts and easily accessible catalyst. In the present work, we show that oxidative cyclisation of 1- and 2-carboxyaryl-1,5-hexadienes (dienoates) and 1-aroyl-1,5-hexadienes (dienones) of different structural types can be realised under CPTC conditions to afford THF diols with high levels of enantiocontrol (Scheme 1(d)). The utility of the process is illustrated through formal syntheses of the bioactive acetogenin cis-solamin A from two different oxidative cyclisation products, each obtained with >90% ee. DFT calculations are presented to gain understanding of the role of acid in the cyclisation step and the interactions giving rise to the observed enantioinduction in the anionic CPTC-manganation transition state (TS) complexes.

Results and discussion

Optimisation and substrate scope

Asymmetric induction in the THF diol products arising from 1,5-diene oxidative cyclisation is determined during the first reaction step (FRS), namely manganation of the more reactive alkene (Scheme 1d). α,β-Unsaturated ketones and carboxylic acid derivatives are good initiators of permanganate cyclisations due to the activating effect of electron-withdrawing groups on alkene reactivity.^7,9,12–14 In the present optimisation an enoate ester functioned as the initiator group, wherein aryl groups delivered promising levels of asymmetric induction. Aryl esters also facilitate onwards transformations of the resulting THF diols towards bioactive natural products. On this basis the 2-naphthyl dienoate 7a was selected for optimisation using N-anthracenylmethyl cinchonidinium 5a as CPTC (Table 1).^9,15 The racemic THF diol rac-8a was obtained from 7a in 70% yield using Adogen 464 in acetone/AcOH.¹⁶

Table 1 Influence of reaction conditions on yield and enantioselectivity for CPTC oxidative cyclisation of dienoate 7a^a

Entry	Deviation from standard conditions	Yield^a (%)		ee^b (%)
		8a	9a
Reactions conducted on 0.20 mmol scale.a Isolated yields.b ee determined by chiral HPLC analysis.c Diol 9a not observed when AcOH was present.d Starting diene 7a recovered (80%).e Starting diene 7a recovered (20%).
1	None	70	—^c	71
2	CPTC 5a (0 mol%)	15^d	—^c	0
3	CPTC 5a (30 mol%)	60	—^c	75
4	CPTC 5a (5 mol%)	64	—	68
5	–20 → −30 °C	52	—^c	59
6	0 °C	67	—^c	49
7	AcOH (0 equiv.)	—^e	10	70

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The preferred solid-liquid CPTC conditions – finely ground KMnO₄ (1.6 equiv.), catalyst 5a (10 mol%) and AcOH (6.5 equiv.) in CH₂Cl₂ at −60 to −50 °C – afforded the enantioenriched THF diol 8a in 70% yield and 71% ee (entry 1, Table 1). KMnO₄ is insoluble in CH₂Cl₂ and without the CPTC a low yield (15%) of the racemic THF diol 8a was obtained, also recovering unreacted diene (80%, entry 2). The small amount of conversion seen in the absence of CPTC was attributed to solubilisation of MnO₄⁻ taking place during the aqueous work-up.

Increasing the amount of CPTC to 30 mol% offered a modest increase in ee to 75% (entry 3), and a lower loading of 5 mol% led to a small erosion of enantioselectivity (68% ee, entry 4). Temperatures above −50 °C also gave diminished enantioselectivities (entries 5 and 6). Omitting AcOH resulted in incomplete conversion of starting material with formation of the alkenediol 9a in 10% yield with comparable enantioselectivity (ee = 70%, entry 7) to that obtained for the THF diol 8a. The preference for dihydroxylation products from permanganate oxidation of alkenes under neutral or basic conditions is well-established.^10,17 This experiment also confirmed preference for initial reaction of permanganate ion at the electron-poor enoate alkene and that acidic conditions are necessary for cyclisation of the intermediate Mn glycolate.

With promising enantioselectivity (>70% ee) achieved for a dienoate substrate using CPTC 5a, attention turned to the influence of the chiral quaternary ammonium structure (Table 2).¹⁸ Five additional readily accessible dihydrocinchonidinium CPTCs 5b–e, 10d and pseudo-enantiomeric dihydrocinchonium 11d were applied to the oxidative cyclisation of 2-naphthyl ester 7a (Table 2). Pleasingly, all benzyl ether derivatives 5a–e returned THF diols with moderate to high ee values (entries 1–5), with the highest selectivity (89% ee) and yield (78%) realised using the 3,5-bis(trifluoromethylbenzyl)ammonium salt 5d (entry 4). The other fluorinated derivative – 2,3,4-trifluorobenzylammonium 5e – provided the second highest enantioselectivity (81% ee, entry 5) among the cinchonidinium catalysts investigated. The carbinol catalyst 10d performed very poorly both in terms of rates of conversion of 7a and enantioselectivity compared to its benzyl ether 5d (entry 6, Table 2). This finding is consistent with previous proposals that ether substituents may serve as a blocking group in these CPTCs, which – in combination with the N-CH₂Ar group – control ion pairing in the TS complex.¹⁹

Table 2 Influence of CPTC structure on enantioselectivity for oxidation of dienoate 7a

Entry	CPTC	Yield of 8a^a (%)	ee (%)
a Isolated yields.b Unreacted starting material 7a (54%) recovered.c Unreacted starting material 7a (40%) recovered.d ent-8a (2S,5R) is the major enantiomer obtained.
1	5a	70	71
2	5b	37	74
3	5c	70	70
4	5d	78	89
5	5e	6^b	81
6	10d	22^c	10
7	11d	41 (ent-8a)	91^d

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Application of the pseudo-enantiomeric catalyst 11d – obtained in three steps from cinchonine – afforded the enantiomeric THF diol ent-8a with improved 91% ee highlighting the flexibility of the CPTC approach (entry 7, Table 2). The absolute stereochemistry of THF diol ent-8a was determined as (2S,5R) using single crystal X-ray diffraction (Fig. 1).²⁰ On this basis, and corroborated by X-ray structural assignment for 13b below,²⁰ the major enantiomers 8a–k were assigned (2R,5S).

Fig. 1 Absolute stereochemistry of ent-8a (2S,5R) determined using single crystal X-ray diffraction. Thermal ellipsoids shown at 50% probability.

At this juncture, the influence of the aryl ester group on enantioselectivity was investigated for substrates 7b–k (Table 3). Reactions were carried out under the conditions optimised for 7a using two CPTCs, 5a and 5d. In some cases the reactions did not reach completion in 5 h and the starting dienes were recovered (see table footnotes).²¹ With respect to enantioselectivity, the new CPTC 5d out-performed the original N-anthracenylmethyl ammonium 5a for all but one ester substrate where a similar ee value was obtained (entry 5). Aryl esters with ortho-substituents gave enantioselectivities in the range 70–89% ee (entries 4–8) using CPTC 5d. The highest selectivity was observed for the 2-methoxyphenyl ester 7f (89% ee, 76% yield, entry 6) matching that for the 2-naphthyl ester 7a (89% ee, 78% yield, entry 1). Interestingly, the 1-naphthyl ester 7b gave a significantly lower enantioselectivity (68% ee, entry 2) using CPTC 5d compared to its regioisomer 7a (89% ee, entry 1). A notable improvement in the magnitude of the ee for the THF diol ent-8b (78% ee, entry 2) was obtained using the pseudo-enantiomeric CPTC 11d.

Table 3 Enantioselective oxidative cyclisation of aryl dienoates 7

Entry	Ar	Yield 8a–k^a (%) [ee^b (%)]
		Using PTC^c	Using CPTC 5a	Using CPTC 5d
a Isolated yields.b Determined using chiral HPLC.c Adogen 464 (10 mol%), KMnO4 (1.3 equiv.), acetone/AcOH (3 : 2), −30 to −10 °C, 3 h.d Reactions using pseudo-enantiomeric CPTC 11d gave ent-8a (entry 1) and ent-8b (entry 2).e Starting material recovered: 7d (15%); 7e (34%) using CPTC 5a, (25%) using CPTC 5d; 7f (20%); 7h (34%); 7j (72%).
1		53 [rac]	60 [75]	78 [89]
				ent-8a, 41 [91]^d
2		58 [rac]	71 [65]	73 [68]
				ent-8b, 78 [78]^d
3		52 [rac]	58 [45]	56 [74]
4		55 [rac]	—	41 [76]^e
5		56 [rac]	40 [71]^e	18 [70]^e
6		36 [rac]	55 [59]^e	76 [89]
7		88 [rac]	84 [52]	81 [82]
8		70 [rac]	32 [61]	38 [79]^e
9		74 [rac]	—	33 [57]
10		70 [rac]	—	16 [57]^e
11		94 [rac]	73 [62]	58 [72]

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Dienoates 12 containing a pendant trisubstituted alkene were investigated using the optimised conditions (Table 4).²¹ The best performing substrates again proved to be the 2-naphthyl and 2-methoxyphenyl esters 12a and 12f, affording THF diols 13a and 13f in good yields and 84% ee using catalyst 5d. A modest reduction in selectivity – compared to monosubstituted alkenes – may be due to the interaction of the alkenyl group with the catalyst, but some conversion with low selectivity initiated at the trisubstituted alkene cannot be excluded. A crystal structure for the major enantiomer 13b was obtained (see SI),²⁰ affirming the absolute stereochemical assignments for the series.

Table 4 Enantioselective oxidative cyclisation of aryl dienoates 12

Entry	Ar	Yield 13a,b,e,f and h^a (%) [ee^b (%)]
		Using PTC^c	Using CPTC 5a	Using CPTC 5d
a Isolated yields.b Determined using chiral HPLC.c Adogen 464 (10 mol%), KMnO4 (1.3 equiv.), acetone/AcOH (3 : 2), −30 to −10 °C, 3 h.d Primary alcohol acetylated prior to chiral HPLC analysis.e Starting material recovered 12b (4%); 12e (20%).
1	a 2-Naphthyl	70 [rac]	—	68 [84]^d
2	b 1-Naphthyl	51 [rac]	76 [61]^e	88 [71]
3		73 [rac]	60 [69]	40 [70]^e
4	f 2-MeOC6H4	59 [rac]	—	75 [84]
5	h 2-ClC6H4	76 [rac]	—	68 [81]

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2-Naphthyl hepta-2,6-dienoate 14 is a representative model substrate towards polyether and acetogenin natural products (Scheme 2). Pleasingly, oxidative cyclisation of 14 using CPTC 5d afforded the THF diol 15 with 92% ee and 40% yield, demonstrating the potential to achieve highly enantioselectivity in a different substrate type. A lower ee of 75% was obtained using the original (9-anthacenyl)methylammonium catalyst 5a. These results highlight the ability to optimise selectivity within different diene structural types through simple manipulations of a common readily available CPTC scaffold.

Scheme 2 CPTC oxidative cyclisation of hepta-2,6-dienoate 14.

Our original report disclosed the oxidative cyclisation of a relatively small subset of aryl 2,6-dienone substrates under CPTC conditions to give THF diols with ee values 58–75%.⁹ Further investigation of aryl dienones – varying the aryl groups in 16a–c and 18a–d – revealed that highly enantioselective transformations are possible in the presence of CPTC 5a (Tables 5 and 6). Indeed, several THF diol products were obtained with ee values exceeding 90% (Table 5, entry 1 and Table 6, entries 3 and 4). The 1-naphthyl substrate 16a provided excellent selectivity (93% ee, Table 5, entry 1). Phenyl ketone 16b gave the corresponding THF diol 17b with a modest 54% ee (entry 2), while an ortho substituent in 16c increased selectivity (entry 3).

Table 5 Enantioselective oxidative cyclisation of aryl 2,6-dienones 16a–c

Entry	Ar	Yield 19a–e^a (%) [ee]^b (%)
		Using PTC^c	Using CPTC 5a
a Isolated yields.b Determined using chiral HPLC.c Adogen 464 (10 mol%), KMnO4 (1.3 equiv.), AcOH (16 equiv.), acetone, −30 to −10 °C, 1.5 h.
1	a 1-Naphthyl	46 [rac]	42 [93]
2	b Ph	50 [rac]	43 [54]
3	c 2-Tolyl	35 [rac]	34 [71]

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Table 6 Enantioselective oxidative cyclisation of aryl 2,6-dienones 18a–d

Entry	Ar	Yield 19a–d^a (%) [ee^b (%)]
		Using PTC	Using CPTC 5a
a Isolated yields.b Determined using chiral HPLC.c Adogen 464 (10 mol%), KMnO4 (1.3 equiv.), AcOH (16 equiv.), acetone, −30 to −10 °C, 1.5 h.d A complex mixture of products was obtained.e Adogen 464 (10 mol%), KMnO4 (1.3 equiv.), acetone/AcOH (3 : 2), −30 to −10 °C, 1 h.f Reaction conducted at −60 to −50 °C, 6 h.g Using CPTC 5d.
1		5 [rac]^c^,^d	0^d
2		76 [rac]^e	43 [<5]
3		81 [rac]^e	43 [92]
4		66 [rac]^e	42 [94], 55 [90]^f
			40 [39]^g

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Extending the polyaromatic system in the 9-anthracenyl ketone 18a apparently shut down oxidative cyclisation under CPTC conditions, giving a complex mixture of oxidation products (Table 6, entry 1). Oxidation under achiral conditions afforded the racemic THF diol rac-19a in only 5% yield, indicating that steric hindrance of the 9-anthryl group – twisted out of the plane of the carbonyl – impeded initial permanganate addition.

Racemic oxidation of the 2-methoxy substituted 1-naphthyl ketone 18b afforded THF diol rac-19b in 76% yield (entry 2). Under CPTC conditions, however, the yield was substantially reduced to 43% and the enantioselectivity was completely eroded (entry 2; cf. Table 5, entry 1). On the other hand, 4-fluoro-1-naphthyl ketone and the 2,3-dichlorophenyl ketone both gave very high levels of asymmetric induction (92 and 94% ee) with the CPTC catalyst 5a (Table 6, entries 3 and 4). The 3,5-bis(trifluoromethylbenzyl)ammonium CPTC 5d was not effective for enantioselective ketone oxidation, affording the THF diol 18d with a greatly diminished 39% ee (entry 4).

The absolute stereochemistry of the major enantiomeric 4-fluoro-1-naphthyl ketone 19c was established by X-ray diffraction after derivatisation as its mono 3-bromobenzoyl ester 20 (Fig. 2).^20,22 An intriguing observation is that the absolute configuration within the THF diol moiety is reversed for the ketone series compared to the corresponding aryl ester systems (cf. THF diol 15, Scheme 2). The factors contributing to facial selectivity are discussed below.

Fig. 2 Absolute stereochemistry of 3-bromobenzoate derivative 20 determined using single crystal X-ray diffraction. Thermal ellipsoids are shown at 50% probability.

Formal synthesis of cis-solamin A (26)

The value of enantiomerically enriched aryl ketone and aryl ester oxidative cyclisation products obtained from CPTC oxidative cyclisation was highlighted through application to formal syntheses of cis-solamin A (26, Schemes 3 and 4).^23,24 Asymmetric cyclisation of dienone 21 using CPTC catalyst 5a at −40 °C gave the THF diol 22 in 52% yield and 92% ee on a 0.5 g scale (Scheme 3).²⁵ Initial attempts to effect regioselective Baeyer–Villiger oxidation of diol 22 or its diacetate 23 proved fruitless, leading to oxidative cleavage of the side-chain to afford a lactone. Therefore, a three-step oxidative cleavage of the arene system was implemented. Thus, borohydride reduction of ketone 23 afforded a mixture of epimeric carbinols, which underwent Ru-catalysed oxidative cleavage and reaction with O-methyl-N,N′-diisopropylisourea to afford the methyl ester 24.^26,27 Finally, reduction of ester 24 using LiAlH₄ secured the enantiomerically enriched triol 25, which is an intermediate previously used in total syntheses of cis-solamin A.^8d,23d,e,24

Scheme 3 Formal synthesis of cis-solamin A (26) from aryl dienone 21. Reagents and conditions: (a) KMnO₄ (1.6 equiv.), CPTC 5a (10 mol%), AcOH (8 equiv.), CH₂Cl₂, −40 °C, 3 h.; (b) AcCl (5 equiv.), pyr (10 equiv.), DMAP (2.5 equiv.), CH₂Cl₂, 0 °C, 1.5 h; (c) NaBH₄ (1.2 equiv.), MeOH, −10 °C, 25 min; (d) RuCl₃·H₂O (20 mol%), H₅IO₆ (15 equiv.), CH₃CN, CCl₄, H₂O, 3 h; (e) O-methyl-N,N′-diisopropylisourea (1.6 equiv.), THF, reflux, 4 h; (f) LiAlH₄ (5 equiv.), Et₂O, 0 °C, 30 min.

Scheme 4 Formal synthesis of cis-solamin A (26) from dienoate 27. Reagents and conditions: (a) KMnO₄ (1.6 equiv.), CPTC 11d (10 mol%), AcOH (6.5 equiv.), CH₂Cl₂, −60 °C, 5 h.; (b) NaBH₄ (2.0 equiv.), THF/H₂O (3 : 1), −20 to −10 °C, 3 h.

An analogous aryl 2,6-dienoate 27 was also oxidised under CPTC conditions using pseudo-enantiomeric CPTC 11d (Scheme 4), securing THF diol 28 in 21% yield (92% ee). Diene 27 (12%) and an uncyclized α,β-diketoester byproduct (<5%) were also isolated.²⁸ From ester 28 conversion to the cis-solamin A triol 25 was trivial, using borohydride reduction. Comparison of the specific rotation values of the triol 25 samples obtained from dienone and dienoate oxidative cyclisation products 22 and 28 with literature values confirmed their absolute stereochemistry to be the same. This corroborated the reversal of facial selectivity exhibited by the enone and enoate systems, giving rise to the same enantiomeric triols by using pseudo-enantiomers of the CPTC.

Mechanism and stereochemistry

Permanganate oxidative cyclisation is highly diastereoselective for the 2,5-cis-disubstituted THF stereoisomer, with stereospecific vicinal dioxygenation of each alkene by the metal oxo species.²⁹ Based upon the original proposal of Baldwin et al. a plausible step-wise mechanism is shown for a simple dienoate ester 29 (Fig. 3a).^29a The first reaction step involves [3 + 2] cycloaddition of permanganate ion and diene 29 to form the Mn(V) glycolate intermediate 30. As discussed above, the presence of the conjugated electron-withdrawing carbonyl group directs the addition of permanganate to the enoate alkene in the first reaction step. The rate acceleration is consistent with stabilisation of an electron-rich transition state TS1 by the conjugated carbonyl group.¹³ Thus, developing negative charge in the first reaction step TS manifests in an increased interaction between the carbonyl oxygen of the substrate and the chiral quaternary ammonium giving rise to asymmetric induction.⁹ Prior to addressing the factors contributing to enantiofacial selectivity in this first reaction step, computational analysis of the cyclisation using density functional theory (DFT) calculations is provided.

Fig. 3 (a) Proposed mechanism for the oxidative cyclisation of methyl (E)-hepta-2,6-dienoate (29) by MnO₄⁻ in the presence of AcOH. (b) Transition states for anionic and protonated THF ring formation. Free energies are in kcal mol⁻¹.

Although it is reported that reoxidation of the Mn(V) centre in glycolate 30 to Mn(VI) is required for the THF ring-formation to proceed,^29a DFT calculation find comproportionation of 30 with permanganate to be highly unfavourable.^30,31 Furthermore, it is clear from experimental studies that manganate ion (Mn(VI)) actually disproportionates rapidly under acidic conditions, giving hypomanganate (Mn(V)) and permanganate (Mn(VII)).³² Therefore, it is reasonable to conclude that the THF-forming step should proceed through an Mn(V) intermediate under the oxidative cyclisation reaction conditions.

A previous computational study concluded that an intermediate Mn(V) glycolate is able to cyclise onto the pendant alkene leading to the THF diol after hydrolysis.³⁰ However, mildly acidic conditions – CO₂ ebullition or AcOH – are necessary to obtain cyclised products, and in absence of acid vicinal dihydroxylation is the major pathway (see Table 1, entry 7).^10c Therefore, it is plausible that the Mn(V) glycolate 30 undergoes protonation under acid conditions, increasing the electrophilicity of the metal oxo species 30_H to promote reaction with the second alkene via TS2_H.¹³ Indeed, our DFT calculations lend support to this hypothesis, observing a substantially lower barrier of 14.4 kcal mol⁻¹ for cyclisation of the protonated glycolate 30_H→31_H compared to 39.5 kcal mol⁻¹ for the anionic pathway via TS2 (Fig. 3b). Enhanced electrophilicity of the protonated Mn(V) intermediate 30_H is evident from LUMO localisation at the Mn site.

To shed light onto the interactions leading to enantioselectivity, DFT calculations were performed including the CPTC in the first reaction step.^33,34 We sought to reconcile the high and opposing facial selectivity outcomes observed for the ester and ketone substrates (Fig. 4). The 2-naphthyl ester 7a and model 1-naphthyl ketone (33, right) systems were selected for investigation using the cinchonidinium CPTCs 5d and 5a, respectively, as these catalysts provide the highest levels of enantioinduction for the respective substrates.³⁵ Considering the 2-naphthyl ester 7a first, TSs arising from reaction at its Re and Si faces involve asynchronous (3 + 2) cycloaddition of MnO₄⁻ with more advanced development of the C_β–O bond compared to the C_α–O bond (Fig. 5a). The TS_(2R) – consistent with the major enantiomeric product 8a derived from Si face approach – is calculated to be lower in energy than TS_(2S) by 1.52 kcal mol⁻¹. For the aryl ketone substrate model calculations find the TS_(1′S,2R) to be 2.5 kcal mol⁻¹ lower in energy compared to the TS_(1′R,2S) (Fig. 5b). Again, this result is consistent with the observed major product, which is formed from approach of the oxidant from below the plane of the enone as depicted in Fig. 4 and 5.

Fig. 4 Observed facial selectivity outcomes from permanganate oxidation of ester and ketone substrates using cinchonidinium CPTCs 5a and 5d.

Fig. 5 DFT computed transition states for the enantioinduction step involving (3 + 2) cycloaddition of MnO₄⁻ and the electron-deficient alkene for (a) 2-naphthyl dienoate 7a in presence of CPTC 5d and (b) 1-naphthyl 2,6-dienone 33 in presence of CPTC 5a computed at 213.15 K. (c) Intermolecular NCIs calculated using the IGMH method. Energies are in kcal mol⁻¹.

To better understand the computational results we performed distortion/interaction analysis (DIA)³⁶ and calculated intermolecular noncovalent interactions (NCIs) using the independent gradient model based on the Hirschfeld (IGMH) partition of the molecular density (Fig. 5c).^37,38 The DIA calculations for the ester TS_(2R) show a greater stabilisation energy (ΔE_int = −3.0 vs. −0.73 kcal mol⁻¹) and lower total distortion energy (11.05 vs. 13.01 kcal mol⁻¹) compared to TS_(2S), leading to reduce the overall barrier (8.05 vs. 12.28 kcal mol⁻¹). According to NCI analysis, TS_(2R) features strong π–π stacking interactions and cation–π interactions between the naphthyl group of the ester and the CH₂ groups adjacent to the quaternary nitrogen and bis(trifluoromethyl)phenyl (BTFMP) group of CPTC 5d. Crucially, nonclassical C–H⋯O hydrogen bonding between the ester carbonyl oxygen and the same CH₂ groups contributes towards stabilisation. Electrostatic stabilisation of this interaction is enhanced due to charge separation between MnO₄⁻ and the positively charged ammonium and a larger dipole moment (μ = 17.1 D) with greater electron density at the carbonyl oxygen. The TS_(2S) leading to the minor enantiomer maintains strong π–π stacking between the substrate naphthyl and the BTFMP group of the CPTC. However, it lacks the stabilising hydrogen bond between the ester carbonyl and the ammonium CH₂ groups, and instead MnO₄⁻ remains localized near the positively charged region as indicated from the reduced dipole (μ = 13.2 D), contributing to its relatively higher energy.

For dienone oxidations of the 1-naphthyl ketone, TS_(1′S,2R) is more stable than TS_(1′R,2S) by 2.5 kcal mol⁻¹, consistent with the observed enantiofacial selectivity. Although TS_(1′S,2R) exhibits higher distortion (16.21 vs. 11.65 kcal mol⁻¹) and intrinsic activation energies (11.72 vs. 9.62 kcal mol⁻¹), it benefits from more than twice the stabilisation energy of TS_(1′R,2S) (−4.49 vs. −2.03 kcal mol⁻¹). NCI analysis identifies cooperative interactions in TS_(1′S,2R), including naphthyl-anthryl π-π stacking and multiple non-classical H-bonding between Mn–O and C=O oxygens of the bound TS with C(sp²)–H and C(sp³)–H groups of the ammonium catalyst. These interactions stabilise TS_(1′S,2R) while keeping its dipole nearly unchanged (13.3 D vs. 12.8 D) from the pre-TS complex. The TS_(1′R,2S) also features π–π and cation–π interactions, but the carbonyl primarily engages with CH₂ groups of the ammonium, raising the dipole (24.7 D vs. 18.0 D in the pre-TS complex) and reducing net stabilisation. Overall, the stereochemical outcome originates from favourable stabilisation of TS_(1′S,2R) due to a balance of moderate dipole and cooperative noncovalent interactions.

Conclusions

Highly enantioselective oxidative cyclisation of 1,5-dienes to give THF diols has been realised using easily accessible chiral phase-transfer catalysts and inexpensive oxidant. The quaternary ammonium catalyst structure can be readily modified to achieve high levels of enantioinduction (89–94% ee) across different diene types containing initiator enone or enoate groups. Furthermore, the synthetic ultility towards bioactive compounds is highlighted by formal syntheses of the Annonaceous acetogenin natural product cis-solamin A (26). Enantiocontrol is established during the first reaction step due to selective ion pairing between the chiral quaternary ammonium and the anionic manganation TS. DFT calculations identify the interplay between dipole-driven electrostatic stabilisation and cooperative noncovalent interactions in the TS complex, giving rise to the observed facial selectivity. Furthermore, calculations support the proposal that the THF-forming reaction step proceeds through a protonated Mn(V) glycolate intermediate 30_H, extending our mechanistic understanding of this powerful synthetic method.

Author contributions

Nikita Rank: investigation (lead); writing – original draft preparation. Aqeel Hussein: investigation; methodology (computational lead); writing – original draft. Alexander Cecil: investigation. Mark Light: investigation (crystallography). Richard Brown: conceptualisation; supervision; writing – review and editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: NMR spectra, experimental details, crystallographic data, and computational details. See DOI: https://doi.org/10.1039/d6qo00377j.

CCDC 2334832 (ent-8a), 2372158 (13b), 2476423 (20) and 2354449 (11d) contain the supplementary crystallographic data for this paper.^20a–d

Acknowledgements

The authors acknowledge financial support from Savita Rank, Suresh Rank, and Ankita Rank (studentship NR), the office of the Iraqi Prime Minister (HCED/Iraq, studentship AAH) and The Royal Society (University Research Fellowship to RCDB). N. Wells (NMR) and J. Herniman (MS) supported collection of characterisation data through the respective NMR (EP/K039466/1 and EP/W006480/1) and MS (EP/K039466/1 and EP/S033343/1) Facilities. Calculations were performed using the IRIDIS High Performance Computing Facility, and associated support services at the University of Southampton, and the DICC High Performance Computing Facility at Universiti Malaya with support from Prof. A. Ariffin (Universiti Malaya).

References

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