Lithium Binaphtholate-Catalyzed Asymmetric Michael Reaction of Acrylamides

Abstract

Chiral lithium binaphtholates prepared from the corresponding binaphthols and lithium tert-butoxide effectively catalyze the asymmetric Michael additions of ketones to poorly reactive acrylamides. The lithium binaphtholate catalyst mediates ketone deprotonation and enantioselective carbon–carbon bond formation to the acrylamide to deliver the Michael adduct in good yield and enantioselectivity. A small excess of lithium tert-butoxide relative to the binaphthol successfully enolizes the ketone in the initial stage of the reaction to promote the Michael reaction. Computational analysis of the transition state suggested that the 3- and 3′-phenyl groups of the binaphtholate catalyst regulate the orientation of the lithium enolate and the subsequent approach of the acrylamide, leading to superior enantioselectivity.

Introduction

The Michael addition reaction is a fundamentally important carbon–carbon bond-forming reaction that is used to synthesize a variety of 1,5-dicarbonyl compounds owing to its highly atom-economical and environmentally benign nature, as demonstrated through numerous examples.^1–9) While the Michael reaction was originally mediated by a base,^10,11) the use of cinchona alkaloids as chiral organocatalysts, as reported by Wynberg in 1975, led to a series of catalytic asymmetric reactions.¹²⁾ Although various catalytic asymmetric reactions have been developed, there appear to be few applications involving less-electrophilic conjugated amides over the past 40 years.¹³⁾ In 2015, Kobayashi and colleagues reported that the asymmetric Michael reaction between two amides proceeds in a highly stereoselective manner using a chiral crown ether and potassium bis(trimethylsilyl)amide.¹⁴⁾ Dixon and colleagues recently demonstrated that chiral quartic acids containing iminophosphorane motifs are effective organocatalysts for the asymmetric Michael additions of thiols to α,β-unsaturated amides.¹⁵⁾ Therefore, reactions that activate poorly electrophilic α,β-unsaturated systems have garnered increasing levels of attention in recent years.^16,17) Our group has developed asymmetric reactions catalyzed by lithium binaphtholates and has shown that lithium binaphtholate-catalyzed Michael addition reactions of acyclic α-alkyl-β-keto esters to vinyl ketones are highly enantioselective.¹⁸⁾ Herein, we report that lithium binaphtholates are effective asymmetric catalysts for Michael addition reactions involving poorly reactive α,β-unsaturated amide substrates to extend the application of the lithium binaphtholate catalysts.

Results and Discussion

We began by investigating the Michael reaction of propiophenone (1a) with N,N-dimethylacrylamide (2a) in tetrahydrofuran (THF) and in the presence of lithium binaphtholate catalyst (S)-4a, which was prepared in situ from (S)-3,3′-diphenyl-1,1′-bi-2-naphthol (Ph₂-BINOL, 3a) (10 mol%) and lithium hydroxide (20 mol%) at room temperature (Table 1, entry 1). Although 5aa was obtained in 2% yield, a promising enantioselectivity (79% enantiomeric excess (ee)) was observed. Replacing lithium hydroxide with n-butyllithium or lithium tert-butoxide led to higher product yields (entries 2 and 3). In particular, the reaction with lithium tert-butoxide afforded Michael adduct 5aa in 59% yield with 82% ee (entry 3). We next examined the number of equivalents (equiv.) of lithium tert-butoxide required to promote this reaction; 15 mol% led to insufficient formation of the dilithium binaphtholate (S)-4a, resulting in a dramatically lower yield (entry 4). In contrast, the use of a small excess of lithium tert-butoxide (30 mol%) relative to (S)-3a improved the yield of 5aa to 64% (entry 5). The use of 40 mol% promoted the formation of double Michael adducts with a concomitant decrease in the chemical yield of 5aa (entry 6). These results indicate that the lithium alkali base reagent promotes the formation of the lithium enolate of ketone 1a while also generating the lithium binaphtholate catalyst (S)-4a. The effect of the solvent was also examined; coordinating ether-type solvents tended to afford higher enantioselectivities, suggesting that these solvents coordinate in the transition state (entries 7 and 8). In contrast, highly polar coordinating solvents, such as dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF), can interfere with the transition state or enolize the optically active product 5aa, leading to lower enantioselectivities (entries 9 and 10). The 3- and 3′-substituents of the BINOL motif were also investigated. The parent BINOL (S)-3b and the iodo derivative (S)-3c did not deliver high enantioselectivities (entries 11 and 12). Although 3-thienyl groups (i.e., (S)-3d) provided similar enantioselectivities to (S)-3a (entry 13), the introduction of steric bulk (i.e., (S)-3e and (S)-3f) led to lower enantioselectivities (entries 14 and 15). The absolute configuration of the Michael adduct 5aa was determined to be S by comparing the retention time and optical rotation of the reduced and subsequently lactonized product with literature values.^19,20) Those of the other compounds were assigned by analogy.

Table 1. Investigating the Reaction Conditions

Entrya)	Alkali base	X, mol%	Solvent	Y	Yield, %	Ee of 5aab)
1	LiOH	20	THF	Ph, 3a	2	79
2	nBuLi	20	THF	Ph, 3a	18	86
3	tBuOLi	20	THF	Ph, 3a	59	82
4	tBuOLi	15	THF	Ph, 3a	29	84
5	tBuOLi	30	THF	Ph, 3a	64	79
6	tBuOLi	40	THF	Ph, 3a	44	73
7	tBuOLi	30	1,4-Dioxane	Ph, 3a	14	59
8	tBuOLi	30	DME	Ph, 3a	42	87
9	tBuOLi	30	DMSO	Ph, 3a	36	0
10	tBuOLi	30	DMF	Ph, 3a	89	30
11	tBuOLi	30	THF	H, 3b	72	21
12	tBuOLi	30	THF	I, 3c	42	48
13	tBuOLi	30	THF	3-Thienyl, 3d	56	78
14	tBuOLi	30	THF	4-Ph-C6H4, 3e	59	67
15	tBuOLi	30	THF	3,5-Ph2-C6H3, 3f	50	57

a) All reactions were carried out by adding a solution of ketone 1a (0.5 mmol) to a solution of amide 2a (1.5 equiv.), an alkali base, and (S)-3 (10 mol%) in a solvent (5 mL), and were quenched using aqueous sat. NH₄Cl (5 mL). b) Determined by HPLC.

Various acrylamides were reacted under the optimized reaction conditions; the results of which are summarized in Table 2. N,N-Diethylamide 2b afforded 5ab with 53% yield and 70% ee (entry 2) which were slightly lower than those of 5aa, whereas 5ac was formed in higher yield from N,N-diphenylamide 2c (entry 3). Therefore, we examined the reaction of N-methyl-N-phenylamide 2d, in which one of the methyl groups in 2a is replaced with a phenyl group, which led to both improved yield and selectivity (entry 4); similar results were also observed for cyclic indolinylamide 2e (entry 5), while Weinreb amide 2f reacted efficiently to afford product 5af with good enantioselectivity (entry 6). N,N-Dimethylcrotonamide and N,N-dimethylmethacrylamide did not react under the optimal conditions.

Table 2. Enantioselective Michael Reactions of 1a with Various Amides 2a–f

^aAll reactions were carried out by adding ketone 1a (0.5 mmol) to a solution of amide 2 (1.5 equiv.), ^tBuOLi (30 mol%), and (S)-3a (10 mol%) in THF (5 mL), and were quenched with aqueous sat. NH₄Cl (5 mL). ^b Determined by HPLC.

We next examined enantioselective Michael reactions of ketones 1 with amide 2d, the results of which are shown in Table 3. Butyrophenone (1b) afforded product 5bd in good yield and high enantioselectivity (entry 2). The electronic nature of the benzene ring appears to have little effect on reactions involving p-bromopropiophenone (1c) and p-methoxypropiophenone (1d), which afforded the desired products 5cd and 5dd in good yields and enantioselectivities (entries 3 and 4). Steric effects were found to significantly affect Michael reactivity, with 2-naphthylketone 1e affording 5ed in good yield and enantioselectivity, while no product was obtained from 1-naphthylketone 1f.

Table 3. Enantioselective Michael Additions of Ketones 1a–f to Amide 2d

Entrya)	Ketone			Product
	1	R1	R2	5	Yield, %	Ee, %b)
1	1a	Ph	Me	5ad	67	84
2	1b	Ph	Et	5bd	73	79
3	1c	4-Br-C6H4	Me	5cd	70	78
4	1d	4-MeO-C6H4	Me	5dd	76	88
5	1e	2-Naphthyl	Me	5ed	89	82
6	1f	1-Naphthyl	Me	5fd	—	—

a)All reactions were carried out by adding a solution of ketone 1 (0.5 mmol) to a solution of amide 2c (1.5 equiv.), ^tBuOLi (30 mol%), and (S)-3a (10 mol%) in THF (5 mL) and were quenched with aqueous sat. NH₄Cl (5 mL). b)Determined by HPLC.

We propose a catalytic cycle for the lithium binaphtholate-catalyzed Michael reaction as shown in Fig. 1. It consists of three steps: (1) formation of the lithium enolate from ketone 1a, (2) enantioselective formation of a carbon–carbon bond to acrylamide 2a, and (3) protonation of the amidate intermediate with formation of the lithium enolate. Lithium tert-butoxide initially deprotonates ketone 1a to form the corresponding (Z)-lithium enolate 1a′,²¹⁾ which then forms a complex A with the lithium binaphtholate catalyst (S)-4a²²⁾; the conformation of this lithium complex would be determined by the steric nature of the phenyl groups attached to the lithium binaphtholate (S)-4a. Acrylamide 2a then approaches the lithium complex A from the Re-face to avoid steric repulsion from the phenyl substituents of the binaphtholate catalyst (S)-4a via an eight-membered cyclic transition state B, resulting in the production of the (S)-amidate intermediate C, which finally deprotonates ketone 1a to afford the Michael adduct (S)-5aa and initiates a subsequent catalytic cycle.²³⁾ The assumed transition states (B_major for generation of (S)-5aa and B_minor for generation of (R)-5aa) for the enantio-determining C–C bond formation step were calculated at the M06-2X/6-31G(d)-SMD(THF) level of theory^24–26) (Fig. 2). The transition structures were first optimized without THF solvation, and explicit THF molecules were then added to the transition structures with conformational search. The resulting solvated structures were further optimized at the same level of theory. Although the activation energy of the minor transition state (ΔG_minor^‡) was smaller than that of the major transition state (ΔG_major^‡), the ΔΔG^‡ value was calculated to be 1.1 kcal/mol. This results in the formation of (S)-5aa with 74% ee as the major enantiomer, in good agreement with the experimental data (Table 2, entry 1).

Fig. 1. Proposed Catalytic Cycle

Fig. 2. Computed Transition Structures (Free Energy Differences in kcal/mol)

Conclusion

We developed facile and enantioselective asymmetric Michael chemistry for acrylamides catalyzed by lithium binaphtholates. Lithium tert-butoxide effectively activates various acrylamides leading to highly enantioselective transformations. Furthermore, the transition state involved in this chemistry was determined using computational chemistry. The energy profile of the entire catalytic cycle is currently under investigation by computational studies.

General

TLC was performed using Merck silica gel plates and visualized using UV light. Optical rotations were recorded using a JASCO P-1010 polarimeter. ¹H- and ¹³C-NMR spectra were acquired in CDCl₃ on JEOL JNM-ECX400 spectrometer. Chemical shifts were reported relative to an internal TMS standard (δ 0.00 for ¹H) or to the CDCl₃ solvent signal (δ 77.0 for ¹³C). IR spectra were recorded on a PerkinElmer, Inc. (U.S.A.). Frontier instrument. Mass spectra were acquired using BRUKER Impact II instruments. HPLC was performed using a JASCO P-2080 instrument fitted with a UV-2075 detector. All reactions were performed under an argon atmosphere using dried glassware equipped with rubber septa and magnetic stirring bars. Column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, neutral, 63–210 µm). Dehydrated stabilizer-free dichloromethane was purchased from Kanto Chemical Co. Inc. (Tokyo, Japan). All other solvents and chemicals were purified using standard procedures or used as received.

Typical Procedure for the Enantioselective Michael Reaction Catalyzed by a Lithium Binaphtholate

(S)-3a (21.9 mg, 0.05 mmol, 10 mol%) was added to a 30-mL round-bottomed flask which was then charged with argon. A 1.0 M solution of LiO^tBu in THF (0.15 mL, 0.15 mmol, 30 mol%) was then introduced at room temperature to prepare the lithium binaphtholate catalyst 4a. A 2.5 M solution of ketone 1a (0.20 mL, 0.50 mmol, 1.0 equiv.) and a 3.75 M solution of amide 2a (0.20 mL, 0.75 mmol, 1.5 equiv.) in THF were added successively to the solution at the same temperature. The reaction mixture was stirred at 24 h until 1a disappeared by TLC monitoring and then quenched using sat. aqueous NH₄Cl (4 mL). The two-layer mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (20 mL) and dried over Na₂SO₄. Filtration and concentration afforded the crude product, which was purified by column chromatography (dichloromethane/acetone = 9/1) to yield 5aa (74.9 mg, 64% yield, 79% ee).

(S)-(+)-N,N,4-Trimethyl-5-oxo-5-phenylpentanamide (5aa)²⁷⁾

TLC: Rf 0.48 (hexane/EtOAc = 1/2). [α]_D²⁵ +31.9 (c 1.10, CHCl₃) for 79% ee. IR (attenuated total reflectance (ATR)): 1680, 1635 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.20 (d, J = 6.8 Hz, 3H), 1.74–1.87 (m, 1H), 2.08–2.28 (m, 2H), 2.32–2.44 (m, 1H), 2.88 (s, 3H), 2.93 (s, 3H), 3.64–3.69 (m, 1H), 7.46 (dd, J = 7.6, 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 204.2, 172.5, 136.4, 133.0, 128.6, 128.3, 39.7, 37.2, 35.3, 30.5, 28.6, 17.6. High resolution (HR)-MS: Calcd for C₁₄H₁₉NNaO₂⁺, 256.1313. Found 256.1304. The enantiomeric excess was determined to be 79% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 9.9 min (R), 10.4 min (S)].

(S)-(+)-N,N-Diethyl-4-methyl-5-oxo-5-phenylpentanamide (5ab)

TLC: Rf 0.63 (hexane/EtOAc = 1/2). [α]_D²⁶ +26.2 (c 1.02, CHCl₃) for 70% ee. IR (ATR): 1680, 1635 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.07 (t, J = 7.6 Hz, 3H), 1.10 (t, J = 7.6 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.81–1.90 (m, 1H), 2.12–2.25 (m, 2H), 2.35–2.42 (m, 1H), 3.18–3.26 (m, 2H), 3.35 (q, J = 6.8 Hz, 2H), 3.63–3.72 (m, 1H), 7.47 (dd, J = 7.0, 7.2 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 8.00 (d, J = 7.2 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 204.3, 171.5, 136.5, 133.0, 128.6, 128.4, 41.9, 40.1, 39.7, 30.3, 28.9, 17.6, 14.2, 13.1. HR-MS: Calcd for C₁₆H₂₃NNaO₂⁺, 284.1626. Found 284.1621. The enantiomeric excess was determined to be 70% ee by chiral HPLC with Daicel Chiralpak AS-H column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 9.4 min (S), 10.9 min (R)].

(S)-(+)-4-Methyl-5-oxo-N,N,5-triphenylpentanamide (5ac)

TLC: Rf 0.26 (hexane/EtOAc = 3/1). [α]_D²⁷ +18.7 (c 1.06, CHCl₃) for 49% ee. IR (ATR): 1669, 1593 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.14 (d, J = 6.8 Hz, 3H), 1.78–1.88 (m, 1H), 2.10–2.36 (m, 3H), 3.64–3.72 (m, 1H), 7.18–7.34 (m, 10H), 7.46 (dd, J = 7.6, 8.0 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 204.1, 172.6, 142.6, 136.5, 133.0, 130–125 (broad signals), 128.6, 128.4, 39.3, 32.5, 29.1, 17.2. HR-MS: Calcd for C₂₄H₂₃NNaO₂⁺, 380.1626. Found 380.1617. The enantiomeric excess was determined to be 49% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 0.75 mL/min; detection: 254 nm; t_R: 32.5 min (R), 38.5 min (S)].

(S)-N,4-Dimethyl-5-oxo-N,5-diphenylpentanamide (5ad)

TLC: Rf 0.30 (hexane/EtOAc = 3/1). [α]²⁷₄₃₅ −1.6 (c 1.20, CHCl₃) for 84% ee. IR (ATR): 1678, 1650, 1594 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.09 (d, J = 6.8 Hz, 3H), 1.67–1.78 (m, 1H), 2.02–2.18 (m, 3H), 3.24 (s, 3H), 3.54–3.60 (m, 1H), 7.04 (d, J = 7.2 Hz, 2H), 7.30–7.36 (m, 3H), 7.46 (dd, J = 7.2, 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 203.9, 172.5, 143.7, 136.4, 132.8, 129.7, 128.5, 128.3, 127.7, 127.0, 39.4, 37.2, 31.3, 29.0, 17.0. HR-MS: Calcd for C₁₉H₂₁NNaO₂⁺, 318.1470 found 318.1466. The enantiomeric excess was determined to be 84% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 0.75 mL/min; detection: 254 nm; t_R: 20.6 min (S), 22.1 min (R)].

(S)-(+)-5-(Indolin-1-yl)-2-methyl-1-phenylpentane-1,5-dione (5ae)

TLC: Rf 0.67 (hexane/EtOAc = 1/2). [α]_D²⁵ +49.0 (c 1.31, CHCl₃) for 74% ee. IR (ATR): 1678, 1655 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.26 (d, J = 6.8 Hz, 3H), 1.92–2.01 (m, 1H), 2.17–2.26 (m, 1H), 2.30–2.38 (m, 1H), 2.47–2.55 (m, 1H), 3.08–3.21 (m, 2H), 3.72–3.79 (m, 1H), 3.85–3.92 (m, 1H), 4.01–4.05 (m, 1H), 7.00 (t, J = 7.4 Hz, 1H), 7.15–7.20 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.55 (dd, J = 7.2, 7.6 Hz, 1H), 8.00 (d, J = 7.2 Hz, 2H), 8.23 (d, J = 8.4 Hz, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 204.1, 170.7, 142.9, 136.4, 133.1, 131.0, 128.7, 128.4, 127.5, 124.5, 123.5, 116.9, 47.9, 39.6, 33.1, 28.1, 27.9, 17.8. HR-MS: Calcd for C₂₀H₂₁NNaO₂⁺, 330.1470. Found 330.1462. The enantiomeric excess was determined to be 74% ee by chiral HPLC with Daicel Chiralpak AS-H column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 16.2 min (S), 18.9 min (R)].

(S)-(+)-N-Methoxy-N,4-dimethyl-5-oxo-5-phenylpentanamide (5af)

TLC: Rf 0.14 (hexane/EtOAc = 3 : 1). [α]_D²³ +24.5 (c 1.76, CHCl₃) for 80% ee. IR (ATR): 1676, 1658 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.22 (d, J = 6.8 Hz, 3H), 1.76–1.85 (m, 1H), 2.13–2.22 (m, 1H), 2.35–2.43 (m, 1H), 2.50–2,57 (m, 1H), 3.16 (s, 3H), 3.60 (s, 3H), 3.62–3.68 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.56 (dd, J = 7.6, 8.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 203.9, 174.0, 136.4, 132.9, 128.6, 128.3, 61.1, 39.6, 32.1, 29.1, 28.0, 17.4. HR-MS: Calcd for C₁₄H₁₉NNaO₃⁺, 272.1263. Found 272.1255. The enantiomeric excess was determined to be 80% ee by chiral HPLC with Daicel Chiralpak AS-H column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 39/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 10.7 min (R), 11.6 min (S)].

(S)-4-Benzoyl-N-methyl-N-phenylhexanamide (5bd)

TLC: Rf 0.24 (hexane/EtOAc = 3 : 1). [α]_D²⁸ −13.7 (c 1.27, CHCl₃) for 79% ee. IR (ATR): 1681, 651, 1595 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 0.83 (t, J = 7.6 Hz, 3H), 1.43–1.51 (m, 1H), 1.65–1.76 (m, 1H), 1.85–2.11 (m, 4H), 3.20 (s, 3H), 3.46–3.49 (m, 1H), 6.95 (d, J = 6.4 Hz, 2H), 7.27–7.31 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 7.56 (dd, J = 7.2, 7.6 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 204.0, 172.4, 143.7, 137.4, 132.8, 129.6, 128.5, 128.2, 127.6, 127.0, 46.2, 37.2, 31.4, 27.2, 25.2, 11.6. HR-MS: Calcd for C₂₀H₂₃NNaO₂⁺, 332.1626. Found 332.1621. The enantiomeric excess was determined to be 79% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 13.1 min (R), 14.7 min (S)].

(S)-5-(4-Bromophenyl)-N,4-dimethyl-5-oxo-N-phenylpentanamide (5cd)

TLC: Rf 0.25 (hexane/EtOAc = 3 : 1) [α]_D²⁷ −12.3 (c 1.13, CHCl₃) for 78% ee. IR (ATR): 1649, 1583 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.08 (d, J = 6.4 Hz, 3H), 1.62–1.73 (m, 1H), 1.97–2.18 (m, 3H), 3.24 (s, 3H), 3.50–3.57 (m, 1H), 7.07 (d, J = 6.8 Hz, 2H), 7.29–7.39 (m, 3H), 7.59 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 202.8, 172.2, 143.7, 135.0, 131.8, 129.9, 129.7, 127.9, 127.7, 127.0, 39.4, 37.2, 31.1, 28.9, 16.7. HR-MS: Calcd for C₁₉H₂₀⁷⁹BrNNaO₂⁺, 396.0575. Found 396.0567. The enantiomeric excess was determined to be 78% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 15.9 min (S), 23.0 min (R)].

(S)-5-(4-Methoxyphenyl)-N,4-dimethyl-5-oxo-N-phenylpentanamide (5dd)

TLC: Rf 0.10 (hexane/EtOAc = 4 : 1). [α]_D²⁷ −12.9 (c 1.08, CHCl₃) for 88% ee. IR (ATR): 1651, 1595, 1573 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.07 (d, J = 6.4 Hz, 3H), 1.64–1.73 (m, 1H), 1.96–2.17 (m, 3H), 3.24 (s, 3H), 3.50–3.55 (m, 1H), 3.88 (s, 3H), 6.94 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 6.8 Hz, 2H), 7.27–7.36 (m, 3H), 7.94 (d, J = 8.6 Hz, 2H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 202.5, 172.6, 163.3, 143.8, 130.6, 129.7, 129.4, 127.7, 127.1, 113.7, 55.4, 39.0, 37.3, 31.4, 29.2, 17.2. HR-MS: Calcd for C₂₀H₂₃NNaO₃⁺, 348.1576. Found 348.1567. The enantiomeric excess was determined to be 88% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 33.8 min (S), 39.3 min (R)].

(S)-N,4-Dimethyl-5-(naphthalen-2-yl)-5-oxo-N-phenylpentanamide (5ed)

TLC: Rf 0.23 (hexane/EtOAc = 4 : 1). [α]_D²⁶ +47.0 (c 1.00, CHCl₃) for 82% ee. IR (neat): 1671, 1650, 1594 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 1.17 (d, J = 6.4 Hz, 3H), 1.79–1.83 (m, 1H), 2.04–2.28 (m, 3H), 3.22 (s, 3H), 3.73–3.76 (m, 1H), 6.97 (d, J = 6.8 Hz, 2H), 7.23–7.30 (m, 3H), 7.55–7.63 (m, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 8.49 (s, 1H). ¹³C{¹H}-NMR (100 MHz, CDCl₃) δ: 203.9, 172.5, 143.8, 135.5, 133.9, 132.6, 129.9, 129.66, 129.63, 128.4, 127.7, 127.6, 127.0, 126.6, 124.2, 39.5, 37.2, 31.4, 29.3, 17.3 (One carbon was overlapped). HR-MS: Calcd for C₂₃H₂₃NNaO₂⁺, 368.1626. Found 368.1618. The enantiomeric excess was determined to be 82% ee by chiral HPLC with Daicel Chiralpak AD-3 column (0.46 cm φ ×25 cm) [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 21.5 min (R), 25.8 min (S)].

Derivatization of Michael Products (S)-5aa to (5S,6S)-5-Methyl-6-phenyltetrahydro-2H-pyran-2-one

Under an argon atmosphere, sodium borohydride (30.1 mg, 0.80 mmol, 3.0 equiv.) was added to a solution of 5aa (61.9 mg, 0.27 mmol, 88% ee) in THF (2 mL) at 0 °C. After stirring for 72 h at room temperature, the reaction was quenched with H₂O (5 mL) at 0 °C. The reaction mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (20 mL) and dried over Na₂SO₄. After filtration and concentration in vacuo, the residue was dissolved in toluene (2 mL) and p-toluenesulfonic acid (120 mg, 0.56 mmol, 2.0 equiv.) was added to the solution. After stirring for 5 h under reflux, the reaction mixture was cool to room temperature. The reaction mixture was then extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (20 mL) and dried over Na₂SO₄. Filtration and concentration afforded the crude product, which was purified by column chromatography (toluene/diethyl ether = 9/1) to give the lactone.^19,20)

(5S,6S)-(−)-5-Methyl-6-phenyltetrahydro-2H-pyran-2-one¹⁹⁾

TLC: Rf 0.13 (hexane/EtOAc = 1 : 1). [α]_D²³ −11.7 (c 1.06, CHCl₃) for 88% ee. [lit. [α]_D²⁰ +17.7 (c 0.29, CHCl₃) for 86% ee (5R,6R)-isomer.]^{19) 1}H-NMR (400 MHz, CDCl₃) δ: 0.86 (d, J = 6.4 Hz, 3H), 1.67–1.74 (m, 1H), 1.96–2.07 (m, 2H), 2.61–2.69 (m, 1H), 2.73–2.81 (m, 1H), 4.85 (d, J = 9.6 Hz, 1H), 7.26–7.40 (m, 5H). The enantiomeric excess was determined to be 88% ee by chiral HPLC with Daicel Chiralpak IC-3 column (0.46 cm φ × 25 cm) [eluent: hexane/IPA = 7/3; flow rate: 1.0 mL/min; detection: 210 nm; t_R: 23.9 min (5R,6R), 27.9 min (5S,6S)].

Acknowledgments

This work was partially supported by the Naito Foundation and JSPS KAKENHI Grant Number 20H0336400 from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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