Copper-Catalyzed Enantioselective Alkene Carboetherification for the Synthesis of Saturated Six-Membered Cyclic Ethers

Abstract

The enantioselective copper-catalyzed oxidative coupling of alkenols with styrenes for the construction of dihydropyrans, isochromans, pyrans and morpholines is reported. A concise formal synthesis of a σ₁ receptor ligand using this alkene carboetherification methodology was demonstrated. Ligand, solvent and base all impact reaction efficiency. DFT transition state calculations are presented.

Graphical Abstract

Alkene carboetherification, a reaction that involves the addition of an alcohol and a carbon across an alkene, is an expedient way to build up molecular complexity from readily available and commodity chemicals.^1–5 The carboetherification of alkenols enables the synthesis of saturated cyclic ethers, compounds of significant importance in drug discovery.⁶ Factors such as ring size, regioselectivity and enantioselectivity contribute to the complexity and diversity of the transformation and products thereof. In this regard, while a number of catalytic enantioselective alkene carboetherification methods have enabled the synthesis of enantioenriched five-membered ring ethers such as tetrahydrofurans^7–11 and phthalans,¹² far fewer syntheses of enantioenriched saturated six-membered cyclic ethers have been disclosed using this strategy (e.g. Scheme 1a),^{1, 10, 13, 14} and such reactions have been frequently optimal for quaternary carbon stereocenter formation, where side reactions (e.g. from β-hydride elimination) could be avoided.^{13, 14}

Scheme 1.

Saturated six-membered rings via enantioselective carboetherification

We have reported a strategy for enantioselective synthesis of five-membered saturated cyclic ethers via copper-catalyzed alkene carboetherification involving the oxidative coupling of alkenols with styrenes.^7–8 The synthesis of six-membered rings is less entropically favorable. Additionally, the transannular strain present in the projected eight-membered cyclic cis-oxycupration transition state also contributes to a higher activation energy (Scheme 1b).⁷ The proposed mechanism involves subsequent C-[Cu(II)] homolysis to provide a carbon radical intermediate that can add to a styrene coupling partner.^12,15 Substrates predisposed toward cyclization (ortho-substituted arenes and those containing quaternary carbons in the tether) have enjoyed more success in related metal-catalyzed cyclizations of alkenols.¹⁶ Replacement of a carbon with a heteroatom in the backbone can also facilitate six-membered ring formation.^8,13,17 Herein we report copper-catalyzed enantioselective oxidative coupling of alkenols with styrenes for the synthesis of dihydropyrans, isochromans, pyrans and morpholines (Scheme 1b). Most of these compound classes have not previously been obtained through enantioselective alkene carboetherification couplings.

Our investigation of the oxidative carboetherification coupling began with the synthesis of isochromans 2a and 2b (Table 1) using Cu(OTf)₂ as the pre-catalyst. Labile triflate ligands are important for enabling enantioselectivity in this class of reactions; copper carboxylates and CuCl provide near racemic products in related reactions.^2a When primary alcohol substrate 1a was subjected to copper-catalyzed oxidative coupling with 1,1-diphenylethylene using achiral bis(oxazoline) ligand 3a and MnO₂ (2.6 equiv) as oxidant 30% of isochroman 2a was obtained along with 33% of 2-allylbenzaldehyde (entry 1). Replacing MnO₂ with the milder oxidant, Ag₂CO₃, provided 48% yield of 2a (entry 2). The reaction is a net 2-electron oxidation, so it requires a corresponding amount of oxidizing reagent. Applying the (S,S)-t-Bu-Box ligand 3c under otherwise similar conditions to Table 1, entry 2 resulted in 62% of 2a being formed in 60% ee (entry 3). Changing the solvent to 1,2-dichloroethane (DCE) (at 105 °C) resulted in 2a being formed with notably higher enantioselectivity (86% ee, entry 4). Tertiary alcohol 1b underwent carboetherification using achiral ligand 3a and MnO₂ as oxidant to give isochroman 2b in 47% yield (entry 5). When the (S,S)-i-Pr-Box and (S,S)-t-Bu-Box ligands were applied (PhCF₃ as solvent), 2b was formed in 78% yield (>95% ee) and 64% yield (94% ee), respectively (entries 7 and 8). In PhCF₃, lowering the Cu(OTf)₂ loading to 15 mol % diminished the yield (entry 9). Formation of 2b using (S,S)-t-Bu-Box in DCE also worked well (entry 10). In DCE, lowering the Cu(OTf)₂ loading to 15 mol % did not reduce the yield or enantioselectivity (entry 11), while lowering the Cu(OTf)₂ loading to 10 mol % did (entry 12). Reactions using the (R,R)-Ph-box 3d and (4R,5S)-bis-Ph-box 3e ligands provided the enantiomeric 2b in 84% yield (89% ee) and 81% yield (84% ee), respectively (entries 13 and 14). A solvent effect on enantioselectivity was observed with ligand 3d; isochroman 2b was formed in 78% yield and >95% ee in DCE (compare entries 13 and 12).

Table 1.

Effect of Reaction Conditions^a

Entry	Substrate	Ligand	Yield (%)	ee 2 (%)
1	1a	3a	30b	--
2c	1a	3a	48	--
3c	1a	3c	62	60
4c,d	1a	3c	50	89
5c,d,e	1a	3c	68	71
6	1b	3a	47	--
7	1b	3b	78	>95
8	1b	3c	64	94
9	1b	3c	47	Nd
10d	1b	3c	78	>95
11d,f	1b	3c	75	>95
12d,g	1b	3c	48	Nd
13	1b	3d	84	−89
14	1b	3e	81	−84
15d	1b	3d	78	>−95

^aGeneral conditions: 1 (0.18 mmol), 20 mol% Cu(OTf)₂, 25 mol% 3, PhCF₃ (0.1 M w/r to 1), 120 °C, 24 h, sealed tube, under Argon. MnO₂ (85% by weight, <5 m particle size) was used.

^b30% product 2a along with 30% 1a and 33% of its corresponding aldehyde.

^cAg₂CO₃ (1 equiv) was used instead of MnO₂.

^dReaction run in 1,2-dichloroethane (DCE) at 105 °C.

^eReaction run with 2,6-di-tert-butyl-4-methylpyridine instead of K₂CO₃.

^f15 mol% Cu(OTf)₂ and 19 mol% 3c were used.

^g10 mol% Cu(OTf)₂ and 12.5 mol % 3c were used. Nd = not determined.

Flame-activated 4 Å molecular sieves were applied to minimize adventitious water.

The alkenol scope was next explored (Table 2). Tertiary benzylic alcohols (1) with various alkyl substituents adjacent to the alcohol (Me, Et, cyclohexyl) underwent the copper-catalyzed carboetherification coupling with 1,1-diphenylethylene, providing isochromans 2c-2f in good yields and excellent enantioselectivities (Table 2). Electron-donating (OMe) and withdrawing (CF₃) substituents on the arene of 1 were compatible, providing 2d and 2e. Cyclohexyl-substituted isochroman 2d was formed with higher enantioselectivity when the (S,S)-i-Pr-Box ligand 3b is applied, perhaps due to more complementary sterics. Formation of dihydropyran 4a, which lacks the backbone arene, occurred sluggishly under standard enantioselective conditions (ca. 8% yield). Changing the solvent to DCE, which aids in catalyst solubility, and changing to the more organic soluble 2,6-di-t-butyl-4-methylpyridine base, enabled formation of 41% of 4a in 71% ee using ligand 3c. When ligand 3e was applied, product 4a was obtained in 20% ee. The corresponding tertiary alcohol formed 4b in 58% yield and 82% ee (using ligand 3c in PhCF₃).

Table 2.

Alkenol Scope^a

Less conformationally biased substrates underwent cyclization using the generally more reactive [Cu(4R,5S)-(bis-Ph-Box)](OTf)₂ complex, albeit in modest efficiency. When 5-hexenol was subjected to the cyclization, pyran 5a was not produced while 3,3-dimethyl-5-hexenol formed pyran 5b in 23% yield. 3,3-Diphenyl-5-hexenol provided pyran 5c in 40% yield and 20% ee. Isochroman 6 could not be produced via carboetherification of 2-(2-vinylphenyl)ethan-1-ol (trace product formed), likely due to ground state stabilization of the conjugated alkenol.

2-Allylmorpholines 7a-e, bearing different substitution patterns, were formed from 2-(N-allyl)ethanols. Substrates with primary alcohols and geminal backbone substitution were more reactive, giving 7b and 7c in high selectivity, while modest amounts of 7a and 7d were obtained from unsubstituted and tertiary alcohol substrates, respectively. Ligand 3d was required for better yields in these latter two cases. A 2-(N-methallyl)ethanol provided the 2-methyl-2-allylmorpholine 7e.

A brief survey of styrene coupling partners was conducted (Table 3). These reactions were more efficient when 2,6-di-t-butyl-4-methylpyridine was used as base in place of K₂CO₃, possibly due to minimization of acid-catalyzed styrene polymerization. Additionally, highest yields and selectivities were observed using DCE as solvent (8b was formed in 32% yield in PhCF₃ and 70% yield in DCE). 4-Methoxy, 4-methyl and 4-tert-butylstyrenes were all productive coupling partners and isochromans 8a-d and morpholine 9 were produced. Styrene (R² = H) did not undergo the coupling reaction, however.

Table 3.

Styrene Scope^a

We examined the stereochemistry-determining 8-membered cis-oxycupration transition states using density functional theory (DFT) calculations as implemented in the Gaussian 16 software package.¹⁸ The unrestricted B3LYP functional^19,20 was coupled with a def2-SVP basis set²¹ employed for all atoms. To mimic experimental conditions, the SMD solvation model²² was employed with 1,2-dichloroethane (ε = 10.13), and all calculations were carried out at 105 °C. Single point calculations were performed at the M06^23,24/def2-TZVP²¹ level of theory to obtain the molecular properties and calculate the ee. The resulting structures of the pro-S (major) and pro-R (minor) cis-oxycupration transition states for 1a are illustrated in Figure 1. The major transition state was calculated to be 2.06 kcal/mol lower in Gibbs free energy, translating to a predicted ee value of 88% (where 86% ee was experimentally observed, Table 1, entry 4). While no non-bonded interatomic distances of 2.3 Å or less were observed in the major transition state (Figure 1A), one ligand-substrate H-H distance of 2.12 Å and another at 2.27 Å were observed in the minor transition state (Figure 1B). Both transition state conformations can be described as boat-like with respect to the cyclizing substrate backbone. While the ligand-copper complex is largely unstrained and chair-like in the major transition state, in the minor transition state it adopts a distorted boat-like conformation where the oxazoline rings display a butterfly-type conformation with respect to one another. Tetrahedral twist angle measurements indicate the copper center of the major transition state can be characterized as distorted tetrahedral while the minor transition state’s copper center is distorted square planar. Analysis of the major transition state’s Mulliken charges on the alkene, and the Wiberg bond indices^25–27 of the forming bonds support an alkene addition with polar character. Spin analysis indicated the unpaired electron resides mainly on the copper at the transition state. Based on Natural Bond Order²⁸ analysis, the bonding interactions of the major transition state are more favourable, in particular, a bond between one of the ligand’s nitrogens and copper.

Figure 1.

a) Calculated major oxycupration transition state. b) Calculated minor oxycupration transition state. ΔΔG^‡ = 2.06 kcal/mol (88% ee). Calculated at 105 °C in 1,2-dichloroethane (DCE).

The enantioselective copper-catalyzed carboetherification was applied in the synthesis of (R)-12,²⁹ a common synthetic precursor for a family of σ₁ receptor ligands. Treatment of 2-allylbromobenzene with Mg in THF followed by addition of the resulting Grignard to 1-acetyl-4-pyridone provided alkenol 10. Enantioselective copper-catalyzed coupling of 10 and 4-methylstyrene using the (R,R)-i-Pr-Box ligand provided 11 in 58% yield and 96% ee. Alkene oxidation with ozone and in situ reduction with Me₂S followed by treatment of the resulting crude aldehyde with NaBH₄ provided alcohol (S)-12 (70% yield, 2 steps) which compared favorably with the literature data on this compound and confirmed our absolute stereochemical assignment.²⁹ This synthesis of (S)-12 (18% yield over 4 steps) is more efficient than the previously reported enantioselective synthesis (ca. 2% yield over 6 steps).²⁹

In summary, we have demonstrated that enantioselective copper-catalyzed oxidative cyclization / coupling reactions between alkenols and styrenes can be applied for the synthesis of enantioenriched saturated six-membered ring oxygen heterocycles. In most cases MnO₂ could be employed as stoichiometric oxidant, however, primary benzylic and allylic alcohols required Ag₂CO₃ as a milder alternative. Choice of optimal ligand and solvent was also dependent on substrate structure and the organic soluble 2,6-di-t-butyl-4-methylpyridine was superior to K₂CO₃ in cases where side reactions hampered efficient carboetherification. The utility of this enantioselective copper-catalyzed reaction was demonstrated in the formal synthesis of a common intermediate used for σ₁ receptor ligand synthesis.

Scheme 2.

Formal synthesis of a σ₁ receptor ligand.