Enantioselective Organocopper-Catalyzed Hetero Diels-Alder Reaction Through in situ Oxidation of Ethers into Enol Ethers

Abstract

We disclose a catalytic method for the enantio- and diastereo-selective union of alkyl ethers and hetero dienes. We demonstrate that a chiral Cu–BOX complex catalyzes the efficient oxidation of ethers into enol ethers in the presence of trityl acetate. Then, the organocopper promotes stereoselective hetero Diels-Alder reaction between the in situ generated enol ethers and β,γ-unsaturated ketoesters, allowing for rapid access to an array of dihydropyran derivatives possessing three vicinal stereogenic centers.

Graphical Abstract

Chiral ethers are essential building blocks of various natural products, pharmaceuticals, and polymers.^1–9 Such moieties can be accessed by stereoselective transformations of alkyl enol ethers (e.g., BOX–Cu-catalyzed hetero Diels-Alder reaction with 2,3-dihydrofuran; Figure 1A).^10–29 However, only a limited number of enol ethers are commercially available, and their synthesis and purification are often cumbersome (e.g., partial hydrogenation of alkynyl ethers, Wittig reaction).^30–32 An enabling strategy to obviate these key limitations would be to perform enantioselective transformations of enol ethers that are generated in situ by oxidation of significantly more accessible and otherwise stable alkyl ethers (Figure 1B).^33–40 Such an approach would not only be operationally simple but would generate less waste (vs the processes that demand preformation of enol ethers).^41–70

Figure 1.

Strategies for Enantioselective Synthesis of Ethers.

In contemplating ways to develop a protocol for the enantioselective union of various alkyl ethers 1 and hetero dienes 2, we envisioned using a combination of a chiral Cu-based complex and a trityl-containing compound (Ph₃C–OR, Figure 1B). It has been reported that [Ph₃C]⁺[BF₄]⁻ serves as a recipient of hydride from acetals and ethers.^71–79 Inspired by these studies, we imagined that Ph₃C⁺ (I), generated by the reaction of organocopper and Ph₃C–OR, receives a hydride from an ether (1), leading to the formation of Ph₃C–H and an oxocarbenium ion (II). A Brønsted base would subsequently deprotonate II to furnish enol ether III. An ensuing enantio- and diastereo-selective [4+2] cycloaddition between enol ether III and a β,γ-unsaturated ketoester 2, activated by the chiral organocopper catalyst, would deliver a dihydro-2H-pyran derivative 3. A key advantage of this strategy is that it allows the enantioselective union of otherwise-difficult-to-access enol ethers (vs methods that are limited to relatively simple and readily available dienophiles; e.g., Figure 1A).^{10–12,30–32,80} Thus, a considerable range of dihydro-2H-pyrans 3 comprised of stereogenic centers at the C1, C2, and C3 positions may be prepared. However, to achieve highly enantioselective synthesis of 3, Ph₃C⁺ and the chiral Cu-based Lewis acid must be able to perform their independent roles without overlapping functions; otherwise, Ph₃C⁺ could promote racemic cycloaddition by activating 2, likely resulting in diminished enantioselectivity.⁸¹ Herein, we report an organocopper-based catalyst system which promotes in situ oxidation of acyclic and cyclic ethers into enol ethers, and their enantioselective cycloaddition with hetero dienes.

We set out to identify a combination of a Cu-based complex and a trityl-containing compound that could promote the enantioselective union of (3-methoxypropyl)trimethylsilane 1a and ethyl (E)-2-oxo-4-phenylbut-3-enoate 2a, generating 3a (Table 1). We began by reacting 1a (0.20 mmol) and 2a (0.10 mmol) in the presence of 5.0 mol % [t-BuBOX(L1)–Cu](SbF₆)₂ and 0.10 mmol [Ph₃C]⁺[BF₄]⁻ (CH₂Cl₂, 40 °C, 16 h); this afforded rac-3a in 75% yield (endo:exo = 1.4:1; entry 1). The formation of rac-3a indicates that Ph₃C⁺ not only abstracts a hydride from 1a but also activates 2a and facilitates its reaction with the 1a-derived dienophile (vs the desired cycloaddition catalyzed by [L1–Cu](SbF₆)₂; IV → 3a, Figure 1B). Indeed, [Ph₃C]⁺[BF₄]⁻ was found to mediate the formation of rac-3a in the absence of [L1–Cu](SbF₆)₂ (39% yield, endo:exo = 1.3:1; entry 2). These results suggest the need for a catalyst system that is capable of generating a small concentration of Ph₃C⁺ in situ which rapidly reacts with 1a to afford Ph₃C–H. This may allow the ensuing hetero Diels-Alder reaction to be solely catalyzed by the chiral organocopper complex, thereby resulting in an enantioselective process.

Table 1.

Evaluation of Reaction Parameters ^a,b

			endo-3a + exo-3a
entry	[L–Cu](X)2	Ph3C—Y	yield (%)	endo:exo	er (endo)	er (exo)
1	[L1–Cu](SbF6)2	Ph3C⊕⊖BF4	75	1.4:1	50:50	51:49
2	none	Ph3C⊕⊖BF4	39	1.3:1	–	–
3	[L1–Cu](SbF6)2	Ph3C–OH	<5	ND	ND	ND
4c	[L1–Cu](SbF6)2	Ph3C–OH	60	2.7:1	90:10	87:13
5	[L1–Cu](SbF6)2	Ph3C–OAc	55	1.8:1	96:4	96:4
6	[L2–Cu](SbF6)2	Ph3C–OAc	40	7.0:1	40:60	76:24
7	[L3–Cu](SbF6)2	Ph3C–OAc	21	2.0:1	49:51	50:50
8	[L1–Cu](OTf)2	Ph3C–OAc	0	ND	ND	ND
9	[L1–Cu](CI04)2	Ph3C–OAc	13	1.6:1	86:14	88:12
10d,f	[L1–Cu](SbF6)2	Ph3C–OAc	87	1.5:1	96:4	96:4
11e,f	[L1–Cu](SbF6)2	Ph3C–OAc	>95	1.8:1	96:4	96:4
12	none	Ph3C-OAc	0	ND	–	–
13	[L1–Cu](SbF6)2	none	0	ND	ND	ND

^aConditions: Reactions were performed under N₂ atmosphere. (3-methoxypropyl)trimethylsilane (1a, 0.20 mmol), ethyl (E)-2-oxo-4-phenylbut-3-enoate (2a, 0.10 mmol), [L–Cu](X)₂ (5.0 mol %), Ph₃C–Y (0.10 mmol), CH₂Cl₂ (0.6 mL), 40 °C, 16 h.

^bYield and the ratio of endo and exo products were determined by ¹ H NMR analysis of unpurified reaction mixtures with mesitylene as the internal standard. ND stands for not determined.

^cThe reaction was performed at 60 °C.

^d1a (0.30 mmol) and Ph₃C–OAc (0.20 mmol) were used.

^e2a (0.40 mmol) and Ph₃C–OAc (0.20 mmol) were used.

^fThe solution was allowed to stir for 24 h.

Based on these considerations, we evaluated Ph₃C−OH and its derivatives that might react with the Cu-based Lewis acid to furnish Ph₃C⁺ in a catalytic quantity. As a result, with Ph₃C−OH, no product formation was observed when the reaction mixture was allowed to stir at 40 °C (entry 3); however, at 60 °C, endo-3a (90:10 er) and exo-3a (87:13 er) were produced in 60% overall yield (endo:exo = 2.7:1; entry 4). By using the more Lewis acid-sensitive Ph₃C−OAc, the reaction occurred at 40 °C, giving endo-3a in 35% yield (96:4 er) and exo-3a in 20% yield (96:4 er; entry 5). To investigate the effect of using different ligands, we tested various Cu-based complexes (see the Supporting Information for details); using [PhBOX(L2)–Cu](SbF₆)₂ or [t-BuPyBOX(L3)–Cu](SbF₆)₂, 3a was produced in ≤40% yield (50:50 to 76:24 er; entries 6–7). The catalysts possessing SbF₆ counterions were substantially more reactive than those complexes with OTf or ClO₄ anions (entries 5 vs 8–9). While the use of 0.30 mmol of 1a resulted in the formation of 3a in 87% yield (entry 10), with 0.40 mmol of 1a, 3a could be obtained in nearly quantitative yield (entry 11). There was no formation of 3a in the absence of [L1–Cu](SbF₆)₂ or Ph₃C−OAc (entries 12–13).

An assortment of acyclic and cyclic ethers (1a–1s) could be merged with different β,γ-unsaturated ketoesters (2a, 2b, 2t–2w) to afford the corresponding hetero Diels-Alder products with high enantio- and/or diastereo-selectivity (3a–3j and 3l–3w, Tables 2–3). The reaction between 1a and 2a gave endo-3a as the major product (endo:exo = 1.8:1, 96% overall yield). In contrast, with phthalimide-substituted β,γ-unsaturated ketoester 2b, exo-3b (48% yield, 95:5 er) was formed more predominantly than endo-3b (23% yield, 93:7 er). While the O–CH₂CH₂Ph unit of 2-phenethoxyethyl acetate 1c was efficiently merged with 2a to give 3c in 66% yield (endo:exo = 1:4.0, up to 95:5 er), the O–CH₂CH₂OAc group of 1c remained intact. The union of (2-methoxyethyl)trimethylsilane 1d and 2a was found to proceed through the loss of the TMS group to furnish 3d in 75% yield (endo:exo = 8.5:1, 95:5 er). Dihydro-2H-pyran derivatives possessing benzoate (3e, 75% yield, up to 96:4 er) or phthalimide (3f, 77% yield, up to 92:8 er) moieties were readily prepared. Next, we synthesized the isotopologues of (2-methoxyethyl)benzene (1g and 1g-d₃) and independently reacted them with 2a, which resulted in the formation of 3g (72% yield, endo:exo = 1:4.0, 95:5 er) and 3g-d₃ (68% yield, endo:exo =1:4.0, 97:3 er), respectively. The ¹H NMR analysis of 3g-d₃ revealed that only 4% of the OCD₃ moiety underwent hydrogen isotope exchange. Furthermore, only a trace amount of Ph₃C−D was detected (see the Supporting Information for details). These results indicate that Ph₃C⁺-mediated hydride abstraction occurs selectively at the more electronically accessible OCH₂Bn group of 3g-d₃ (as compared to cleavage within less electron-rich OCD₃ unit).

Table 2.

Enantioselective Hetero Diels-Alder Reactions ^a,b

^aStructure of the major stereoisomer is depicted. Conditions: ether (1, 0.40 mmol), β,γ-unsaturated ketoester (2, 0.10 mmol), [L1–Cu](SbF₆)₂ (5.0 mol %), Ph₃COAc (0.20 mmol), CH₂Cl₂ (0.6 mL), 40 °C, 24 h under N₂ atmosphere.

^bYield of isolated and purified product. The dr values were determined by the ¹H NMR analysis of the unpurified reaction mixture. See the Supporting Information for the determination of the absolute and relative configurations.

^cThe reaction mixtures were allowed to stir at different reaction temperatures for the production of 3c and 3e–3g-d₃ (60 °C), 3h and 3h-d₆ (22 °C), 3d (4 °C), and 3i (–20 °C). The syntheses of 3c and 3e–3g-d₃ used 10 mol % of [L1–Cu](SbF₆)₂, 3e was run in the CHCl₃ as the solvent, and for the production of 3f, 0.30 mmol of Ph₃COAc was used. Cyclic ethers (1h–1j) and Ph₃COAc were added in two batches (0.20 mmol 1h–1j/batch and 0.10 mmol Ph₃COAc/batch). See the Supporting Information for details.

Table 3.

Hetero Diels-Alder Reactions with Enantiopure Ethers ^a,b

^aStructure of the major stereoisomer is depicted. Conditions: Reactions were performed under N₂ atmosphere. Ether (1, 0.20 mmol), β,γ-unsaturated ketoester (2, 0.10 mmol), [L1–Cu](SbF₆)₂ (5.0 mol %), Ph₃C–OAc (0.15 mmol), CH₂Cl₂ (0.6 mL), 60 °C, 24 h.

^bYield of isolated and purified product. The dr values were determined by the ¹H NMR analysis of the unpurified reaction mixtures. See the Supporting Information for determination of the absolute and relative configurations.

^cThe solutions were allowed to stir at 40 °C for the synthesis of 3p, and at 22 °C for 3q. For preparation of 3p, 10 mol % of [L1–Cu](SbF₆)₂ was used; 1p and Ph₃COAc were added in 2 batches (0.20 mmol 1o/batch and 0.10 mmol Ph₃COAc/batch). To prepare 3r and 3s, 0.40 mmol of 1r or 1s and 10 mol % of [(R,R)–L2–Cu](SbF₆)₂ were used; TrOAc was added batchwise. See the Supporting Information for details.

The unions of tetrahydrofuran 1h and its isotopologue (1h-d₈) with 2a were found to give 3h (88% yield, endo:exo = 12:1) and 3h-d₆ (80% yield, endo:exo = 11:1), respectively, with 95:5 er. To determine if the reaction of 1h and 2a proceeds more efficiently than the process involving 1h-d₈, a competition kinetic isotope effect experiment was performed (Figure 2A). The obtained k_H/k_D value of 2.8 is consistent with the mechanistic scenario that the enol ether formation by sequential hydride abstraction and deprotonation is more facile with 1h. 1-Oxaspiro[4.4]nonane 1i was found to be a viable substrate, giving endo-3i (72% yield, 98:2 er). The reaction of tetrahydropyran 1j and 2a was less diastereoselective (3j, 88% yield, endo:exo = 2.8:1, up to 94:6 er) compared to the processes involving 5-membered cyclic ethers (3h–3i). Oxidation of rac-2-phenyl-tetrahydrofuran (rac-1k) was found to occur regioselectively to provide the more substituted enol ether (Figure 2B); its cycloaddition with 2a gave rac-3k in 93% yield (endo:exo = 4.8:1).

Figure 2.

Studies aimed at elucidating the reaction mechanism

We investigated the reversibility of the hetero Diels-Alder reaction (Figures 2C–2D). When a dihydro-2H-pyran derivative 3a was reacted with (S)-2-(chloromethyl)tetrahydrofuran 1l in the presence of [L1–Cu](SbF₆)₂ and Ph₃COAc, we observed the formation of 3l in 20% yield (endo:exo = >20:1). This result implies that an enol ether generated in situ by oxidation of 1l reacts with a transient unsaturated β,γ-unsaturated ketoester resulting from a reversible reaction of 3a under the reaction conditions (Figure 2C, see the Supporting Information for details). Then, we reacted the 2.1:1 mixture of exo-3b and endo-3b with 5.0 mol % [L1–Cu](SbF₆)₂ and allowed the solution in CD₂Cl₂ to stir at 22 °C for 36 hours (Figure 2D). This resulted in the formation of exo-3b (93:7 er) as the major product (endo:exo = 1:12), further supporting the notion that the cycloaddition of 1a-derived enol ether and 2b is reversible. Based on the stereochemistry of the products (3a−3g) resulting from acyclic ethers (R¹ group is cis to OR²), only Z-configured enol ethers appear to participate in the hetero Diels-Alder reactions. We performed a control experiment using a preformed E-enol ether ((E)-4g, Figure 2E) and 2a to find that 3g is formed in 90% yield (endo:exo = 1:4.7). In addition, 1.0 mol % of [L1–Cu](SbF₆)₂ was found to catalyze the isomerization of (E)-4g into (Z)-4g (in CD₂Cl₂ at 60 °C; see the Supporting Information for details). These results suggest that the acyclic ethers may be oxidized into a mixture of E- and Z-configured enol ethers, that can then equilibrate under the reaction conditions.

The endo-selective Diels-Alder reactions between dienophiles generated in situ by oxidation of enantiopure ethers and a range of β,γ-unsaturated ketoesters were carried out in the presence of [(S,S)-L1–Cu](SbF₆)₂ (Table 3). Dihydrofurans possessing chloro (1l), bromo (1m), acetoxy (1n), tosyloxy (1o), alkynyl (1p), and alkyl (1q) moieties could be coupled with 2a to furnish 3l–3q in 55–90% yield (endo:exo = >20:1–11:1). For the production of 3l (90% yield, endo:exo = 11:1), the use of [(S,S)-L1–Cu](SbF₆)₂ was found to be crucial; [(R,R)-L1–Cu](SbF₆)₂ was found to be a mismatched enantiomer of the catalyst as 3l was obtained as a complex mixture of stereoisomers in 55% overall yield (see the Supporting Information for details). The cycloadditions of tetrahydropyran derivatives (1r, 1s) with 2a were found to occur less efficiently; 3r (endo:exo = 1.7:1) and 3s (endo:exo = 1:2.3) were obtained in 86% and 53% yield, respectively. However, a batchwise addition of Ph₃COAc and a longer reaction time were necessary (see the Supporting Information for details). β,γ-Unsaturated ketoesters possessing an allyl acetate moiety (2t), p-bromophenyl (2u), p-methoxyphenyl (2v), or methyl (2w)-substituents could be merged with 1l, affording 3t–3w with endo to exo ratios of 20:1–7.3:1 (58−89 % yield).

In summary, we have developed an enantio- and diastereo-selective method for the transformations of vicinal C–H bonds within various acyclic and cyclic ethers to generate dihydro-2H-pyran derivatives. We found that, by using a blend of [t-BuBOX(L1)–Cu](SbF₆)₂ and Ph₃COAc, it is possible to convert ethers into enol ethers and then promote their enantio- and diastereo-selective reaction with β,γ-unsaturated ketoesters. The catalyst system is tolerant of a variety of Lewis acid-sensitive functional units and allows for rapid access to valuable chiral ether products containing stereogenic centers at the C1, C2, and C3 positions. The principles outlined above demonstrate that the proper combination of a chiral Lewis acid and an in situ generated hydride acceptor may be used for chemo- and enantio-selective functionalization of otherwise stable ether-based molecules. This outcome provides a rational basis for the future development of methods for the stereoselective synthesis of biologically relevant ether-based molecules, as well as their late-stage functionalization. Studies aimed at further pursuing these objectives are currently underway.