Probing Regio- and Enantioselectivity in the Formal [2 + 2] Cycloaddition of C(1)-Alkyl Ammonium Enolates with β- and α,β-Substituted Trifluoromethylenones

The isothiourea-catalyzed regio- and enantioselective formal [2 + 2] cycloaddition of C(1)-alkyl and C(1)-unsubstituted ammonium enolates with β- and α,β-substituted trifluoromethylenones has been developed. In all cases, preferential [2 + 2]-cycloaddition over the alternative [4 + 2]-cycloaddition is observed, giving β-lactones with excellent diastereo- and enantioselectivity (34 examples, up to >95:5 dr, >99:1 er). The regioselectivity of the process was dictated by the nature of the substituents on both reaction components. Solely [2 + 2] cycloaddition products are observed when using α,β-substituted trifluoromethylenones or α-trialkylsilyl acetic acid derivatives; both [2 + 2] and [4 + 2] cycloaddition products are observed when using β-substituted trifluoromethylenones and α-alkyl-α-trialkylsilyl acetic acids as reactants, with the [2 + 2] cycloaddition as the major reaction product. The beneficial role of the α-silyl substituent within the acid component in this protocol has been demonstrated by control experiments.


■ INTRODUCTION
The asymmetric synthesis of β-lactones has attracted considerable interest in organic chemistry due to their versatility as synthetic intermediates as well as their prevalence in a wide range of biologically active molecules. 1 Enantioenriched β-lactones can be accessed in a number of ways, with Lewis acid-or Lewis base-catalyzed formal cycloadditions being the most common. 2,3 Lewis base-catalyzed approaches typically proceed through the formal [2 + 2] cycloaddition of ammonium enolates with ketenes, aldehydes, or highly reactive ketones. 4−8 In related Lewis base-catalyzed processes, trifluoromethylenones have been extensively explored as electrophiles in formal [4 + 2] cycloadditions such as the isothiourea-catalyzed reaction of trifluoromethylenones with arylacetic acid derivatives (Scheme 1a). 9,10 In this case, exclusive formation of [4 + 2]-products was observed, giving C(6)-trifluoromethyldihydropyranones in high yields and excellent enantioselectivity. However, use of 2-(pyrrol-1yl)acetic acid in this protocol notably gave a 50:50 ratio of products arising from formal [4 + 2] and [2 + 2] cycloaddition reactions (Scheme 1b), 11 indicating that regioselective reaction directly with the carbonyl of the α,β-unsaturated system to generate the corresponding β-lactone is feasible and is dependent upon the C(1)-substitution of the ammonium enolate. Intrigued by this observation, in this manuscript we report the regio-and enantioselective addition of a range of C(1)-alkyl substituted or unsubstituted ammonium enolates, prepared through a recently reported desilylation process, 12 to trifluoromethylenones.
Systematic variation of the substituents within both the trifluoromethylenone and the C(1)-alkyl substituted or unsubstituted ammonium enolate provide preferential, and in some cases exclusive, access to highly functionalized β-lactones with high enantioselectivity.

Investigation of Optimal Reaction
Conditions. An initial trial was performed using α-trimethylsilyl acetic acid 1 as a C(1)-ammonium enolate precursor with β-phenyl trifluoromethylenone 2 ( Table 1). Treatment of acid 1 with pivaloyl chloride (3 equiv) in MTBE to generate the corresponding mixed anhydride, followed by addition of (2S,3R)-HyperBTM 4 (5 mol %) and enone 2 at room temperature, gave exclusively the formal [2 + 2]-cycloaddition product, β-lactone 3, in high yield (75%) and excellent enantioselectivity (92:8 er). Attempted optimization varied a range of reaction parameters, including solvent, catalyst, temperature, auxiliary base, and acid chloride. A range of polar and nonpolar solvents were tested, but in all cases led to reduced yield and enantioselectivity compared with MTBE (see SI). Using (R)-BTM 5 gave significantly reduced conversion to the product, giving 12% isolated yield of 3 in 75:25 er (entry 2), while (S)tetramisole 6 gave no conversion to the product (entry 3). Further variation of base showed that using triethylamine instead of N,N-diisopropylethylamine did not affect the enantioselectivity, but gave significantly decreased yield (entry 4), while inorganic bases Cs 2 CO 3 and NaHCO 3 led to poor reactivity (entries 5−6). Using benzoyl chloride and para-nitrobenzoyl chloride to generate the corresponding mixed anhydride resulted in reduced product yields and enantioselectivity (entries 7−8). The use of 1 equiv of acid 1 led to reduced product conversion (entry 9) while reducing the temperature to 0°C gave the product with slightly reduced er (entry 10).
Further mechanistic studies were conducted by using enantiomerically enriched acid (R)-51 with 10 mol % of each enantiomer of HyperBTM 4 separately under standard conditions (Table 5a). 13 Consistent with our previous observations, 12 the relative rates of product formation with enantiomeric catalysts differed significantly, although identical levels of product diastereo-and enantioselectivity were observed throughout these processes. In the mismatched case, treatment of the anhydride generated from (R)-51 with (2R,3S)-HyperBTM 4 led to relatively slow conversion (35% by 19 F NMR after 480 min) to product β-lactone 15 (88:12 dr, 96:4 er, [2 + 2]:[4 + 2] = 85:15). In the matched case, treatment of the anhydride generated from (R)-51 with (2S,3R)-HyperBTM 4 led to the same stereo-and regioselectivity, but with significantly enhanced conversion (70% by 19    Kinetic analysis using racemic acid 51 and 2 as the electrophile catalyzed by 10 mol % of (2S,3R)-HyperBTM 4 was monitored using 19 F NMR under standard reaction conditions (Table 5b). The rate of formation of product 15 and the rate The Journal of Organic Chemistry pubs.acs.org/joc Article of consumption of enone 2 both demonstrated linear profiles consistent with a pseudo-zero-order reaction, with identical ratios of β-lactone 15 and [4 + 2] cycloaddition product 56 observed throughout the experiment, consistent with the regioselectivity being kinetically controlled rather than through product interconversion. Building upon these observations and our previous work, the proposed mechanistic cycle involves initial N-acylation of HyperBTM with the in situ generated mixed anhydride to generate the corresponding acyl ammonium ion pair in a kinetic resolution process. 12 Subsequent desilylation generates the C(1)-ammonium enolate that can undergo either concerted asynchronous [2 + 2] cycloaddition or [4 + 2] cycloaddition with the trifluoromethylenone. 14 The regioselectivity of this process is dictated by steric factors within both reaction components. When α-substituted-β-aryl trifluoromethylenones are used, exclusive [2 + 2] cycloaddition to give the β-lactone products is observed. When α-unsubstituted-β-aryl trifluoromethylenone and α-alkyl-α-silyl acids are used, the C(1)-ammonium enolate can undergo both concerted asynchronous [2 + 2] cycloaddition and [4 + 2] cycloaddition, furnishing β-lactones as the major product accompanied by [4 + 2] cycloaddition as the minor product. Key to the observed stereochemical outcome is a stabilizing 1,5-O···S chalcogen bonding interaction (n O to σ* S−C ). 15−18 This provides a conformational bias and ensures coplanarity between the 1,5-O-and S-atoms within the (Z)-enolate, with preferential addition anti-to the stereodirecting phenyl substituent within the catalyst.

■ CONCLUSION
To conclude, a protocol for the diastereo-, enantio-, and regioselective [2 + 2] cycloaddition of β-aryl trifluoromethylenones with α-silyl carboxylic acids catalyzed by the isothiourea HyperBTM under mild and operationally simple conditions has been developed. A broad substrate scope of enantiomerically enriched β-lactone products (34 examples, up to >95:5 dr and >99:1 er) and significantly extended reactivity of C(1)-ammonium enolates has been demonstrated. Control experiments indicate that the α-substituents of the trifluoromethylenone and the α-silyl carboxylic acid play a crucial role in dictating the regioselectivity of this transformation. Solely [2 + 2] cycloaddition was observed when α-silyl acetic acids and α-methyl or α-phenyl substituted β-aryl trifluoromethylenones were used. Both [2 + 2] cycloaddition and Michael additionlactonization reactions were observed when α-substituted-αsilyl carboxylic acids were used in conjunction with β-aryl trifluoromethylenones lacking a second α-substituent. The bench stable β-lactones are readily derivatized through ringopening or can be transformed into the corresponding oxetanes without compromising stereochemical integrity. ■ EXPERIMENTAL SECTION General Information. Reactions involving moisture sensitive reagents were carried out in flame-dried glassware under a nitrogen atmosphere using standard vacuum line techniques and using anhydrous solvents. HyperBTM 4 and benzotetramisole (BTM) 5 were synthesized in house. Tetramisole·HCl 6 was obtained from Sigma-Aldrich. Anhydrous solvents (CH 2 Cl 2 , PhMe) was obtained after passing through an alumina column (Mbraun SPS-800). Anhydrous MTBE and MeCN was obtained by treatment with activated 4 Å molecular sieves. Petrol is defined as petroleum ether 40−60°C. All other solvents and commercial reagents were used as supplied without further purification unless otherwise stated. EtOAc,   19 diisopropylamine (9.6 mmol, 2.1 equiv) was dissolved in THF (10 mL) under an N 2 -atmosphere. The solution was cooled to −78°C and n-BuLi (9.6 mmol, 2.1 equiv) was added. The mixture was warmed to r.t. for 15 min before being cooled to −78°C again. 2-(Trimethylsilyl) acetic acid (4.5 mmol, 1.0 equiv) was added and the mixture was stirred at 0°C for 1 h, followed by 1.5 h at r.t. Subsequently the specified halide (4.7 mmol, 1.05 equiv) was added at 0°C and the mixture was stirred additional 30 min at 0°C. Then the reaction was quenched by the addition of HCl (1 M) and the pH adjusted to 2. The aqueous layer was extracted with Et 2 O (3 × 15 mL). The combined organic layers were dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure. The crude residue was triturated from pentane to give the desired product.
General Experimental Procedure B: Synthesis of Alternative α-Silyl Acids. According to a procedure reported by Becker et al., 20 to an oven-dried round-bottomed flask (250 mL) equipped with a magnetic stirring bar were added diisopropylamine (24.0 mmol, 1.15 equiv) and anhydrous THF (40 mL). The mixture was cooled to −78°C, and then n-BuLi 1.6 M (24.0 mmol, 1.15 equiv) was added dropwise. The mixture was warmed to r.t. for 15 min and cooled again to −78°C . Trimethylsilyl acetate (CH 3 CO 2 SiMe 3 ) (21.0 mmol, 1.0 equiv) was added dropwise to the cooled solution of LDA over 15 min and the reaction mixture was stirred for 2 h at −78°C. Then chlorosilane (24.0 mmol, 1.15 equiv) in anhydrous THF (5 mL) was added dropwise to the solution over 10 min. The reaction mixture was then stirred at −78°C for 2 additional hours and allowed to reach room temperature overnight. A solution of saturated aqueous NaCl solution (30 mL) was added, and the pH was adjusted to 3 using 1 M aqueous HCl. The aqueous layer was extracted with Et 2 O (3 × 30 mL) and the combined organic extracts were washed with water, dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residual crude product was dissolved in THF (30 mL) and saturated aqueous NH 4 Cl solution (20 mL) was added. The reaction mixture was then stirred at room temperature for 1 h. Afterward, the aqueous layer was extracted with Et 2 O (3 × 30 mL) and the combined organic extracts were washed with water (30 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude residue was crystallized from hexane to give the desired product.
General Experimental Procedure C: Synthesis of Trifluoromethylenones. According to a procedure reported by Davies et al., 9b the requisite aldehyde (1.0 equiv), piperidine (1.0 equiv), and acetic acid (1.5 equiv) were dissolved in toluene (0.5 M) at 0°C. A solution of trifluoromethyl ketone (2.0−4.0 equiv) in toluene (2−4 M) was added and the reaction was stirred for 2 h at 0°C, followed by heating at 50°C for 16 h. The reaction was cooled to r.t. and quenched with saturated aqueous NH 4 Cl solution. The organic layer was washed with water, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to leave the crude product, which was purified by flash column chromatography on silica.
General Experimental Procedure D: Synthesis of β-Lactones. In a flame-dried Schlenk tube under an N 2 atmosphere, N,N-diisopropylethylamine (3.0 equiv) and pivaloyl chloride (3.0 equiv) were added sequentially to a solution of appropriate acid (2.0 equiv) in anhydrous MTBE (0.1 M) at 0°C. The mixture was allowed to stir for 15 min at 0°C, followed by the sequential addition of the specified ketone (1.0 equiv), (2S,3R)-HyperBTM (5 mol %), and N,N-diisopropylethylamine (1.0 equiv). The mixture was allowed to stir for the specified time at r.t. The solvent was then removed under reduced pressure, and the crude residue purified by Biotage automated column chromatography in the stated solvent system to give the desired product.