Catalytic Asymmetric Intramolecular Darzens Reaction of 2-Halomalonate Derivatives

Abstract

A catalytic asymmetric intramolecular Darzens reaction of 2-halomalonate derivatives was developed for the enantioselective preparation of chiral building blocks for epoxide-containing natural products. Among the screened catalysts, some phase-transfer catalysts gave the desired epoxide in moderate enantioselectivity, albeit in low yield. The epoxide product would be useful as versatile chiral building blocks for natural product synthesis.

Keywords

Darzens reaction asymmetric synthesis asymmetric catalyst organocatalyst intramolecular reaction

Since its discovery over a century ago,¹ the Darzens reaction has been widely recognized as a reliable, robust method for constructing the epoxide functionality, which is ubiquitous in bioactive molecules^2
-4 and can be used as a highly reactive functionality in organic synthesis.⁵ However, to our knowledge, the Darzens reaction is poorly studied compared with the corresponding aldol reaction⁶ because the stereoselectivity in the Darzens reaction is complicated due to its reaction mechanism, which consists of aldol addition and subsequent epoxide formation.^7,8 Nevertheless, the Darzens reaction is very important for epoxide formation from carbonyl compounds, along with the Corey-Chaykovsky reaction.^9,10

Recently, our research group has been intrigued by the unique molecular structures of epoxide-containing bioactive natural products, such as epolactaene,¹¹ L-755,807,¹² fusarin C,¹³ and euvesperin A¹⁴ (Figure 1).

Figure 1

Structures of epolactaene, L-755,807, fusarin C, and euvesperin A.

During synthetic studies of these natural products, we developed a highly syn-selective Darzens reaction between optically active α-alkylsilyloxy aldehyde 1 and di-tert-butyl 2-bromomalonate to obtain epoxide 2 in high yield,¹⁵ and we applied the reaction to the first total synthesis of L-755,807^16,17 (Scheme 1).

Scheme 1

syn-Selective Darzens reaction.

We envisioned that an enantioselective version of Darzens reaction would be more valuable in our system.¹⁸ Thus, we investigated a catalytic asymmetric intramolecular Darzens reaction of 2-halomalonate derivative 3 to obtain versatile epoxide-containing intermediate 4 as a chiral building block for natural product synthesis (Scheme 2).

Scheme 2

Proposed asymmetric intramolecular Darzens reaction.

This paper describes the asymmetric intramolecular Darzens reaction of 2-halomalonate derivatives with chiral organocatalysts.

Initially, substrates 8 and 13 for the intramolecular Darzens reaction were prepared (Scheme 3). According to the literature,¹⁹ a commercially available mono-tert-butyl malonate (5) was reacted with allyl bromide and cesium carbonate to give allyl ester 6 in 81% yield. Treatment of product 6 with bromine and lithium cyclohexyl(isopropyl)amide afforded mono bromomalonate 7 in 49% yield.²⁰ Finally, ozonolysis of olefin 7 gave aldehyde 8 for the Darzens reaction.

Scheme 3

Synthesis of aldehydes 8 and 13 for intramolecular Darzens reaction.

Weinreb amide 13 was synthesized as follows. Meldrum’s acid (9) was subjected to a ring-opening reaction to produce Weinreb amide 10 (97%),²¹ which was then allylated to give allyl ester 11 in 72% yield. After bromination of 11 to 12 (54%), the terminal olefin was converted to a formyl group by ozonolysis to furnish aldehyde 13 in 74% yield.

With substrates 8 and 13 in hand, we attempted asymmetric intramolecular Darzens reactions using various organocatalysts (Table 1). In the initial experiments, tetrabutylammonium bromide (TBAB) was employed as an achiral catalyst for the reaction of tert-butyl ester 8 (Table 1, entries 1-4). Bases and solvents were screened, and only a trace amount of desired lactone 14 was obtained when Cs₂CO₃ was used as a base (entries 1 and 2). Chiral catalysts (S)-(–)-1,1′-bi-2-naphthol (BINOL) and (–)-4,5-bis[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolane (TADDOL) did not work effectively in this reaction (entries 5-7). Next, we tried several bases and solvents with chiral phase-transfer catalyst PTC-1,²² but desired lactone 14 was not produced (entries 8-12).

Table 1

Intramolecular Darzens Reaction Using Organocatalysts.


Entry	Substrate	Base (1.3 equiv)	Solvent	Catalyst (0.1 equiv)	ee (%)^a	Yield (%)
1	8	Cs₂CO₃	Toluene	TBAB	-	Trace
2	8	Cs₂CO₃	Toluene/H₂O	TBAB	-	Trace
3	8	AcONa	Toluene	TBAB	-	No reaction
4	8	Na₂HPO₄	Toluene	TBAB	-	No reaction
5	8	AcONa	Toluene	BINOL	-	No reaction
6	8	Cs₂CO₃	Toluene	TADDOL	-	0
7	8	Na₂HPO₄	Toluene	TADDOL	-	No reaction
8	8	LiOH·H₂O	Bu₂O	PTC-1	-	0
9	8	50% KOH	Toluene	PTC-1	-	0
10	8	CsOH·H₂O	CH₂Cl₂	PTC-1	-	0
11	8	CsOH·H₂O	CH₂Cl₂	PTC-1	-	0
12	8	50% KOH	Toluene	PTC-1	-	0
13^b	13	50% KOH	Toluene	PTC-1	-	0
14^c	13	t-BuOK	CH₂Cl₂	PTC-1	-	0
15	13	Cs₂CO₃	CH₂Cl₂	TBAB	-	0
16^b	13	Cs₂CO₃	CH₂Cl₂	PTC-2	0	30
17	13	Cs₂CO₃	CH₂Cl₂	PTC-2	-	0
18^b	13	Cs₂CO₃	CH₂Cl₂	PTC-1	0	31
19	13	KF	CH₂Cl₂	PTC-1	12	47
20	13	KF	CH₂Cl₂	PTC-2	7	61
21	13	KF	CH₂Cl₂	PTC-3	0	17
22	13	KF	CH₂Cl₂	TADDOL	0	19
23	13	KF	CH₂Cl₂	16	0	19
24	13	KF	CH₂Cl₂	Quinidine	-	Trace
25	13	1 M KOH, KF	CH₂Cl₂	PTC-3	2	28
26	13	LiOH·H₂O	CH₂Cl₂	PTC-3	44	Trace

^aDetermined by chiral high-performance liquid chromatography.

^bThe reaction was carried out at 0°C.

^cThe reaction was carried out at –78°C.

With Weinreb amide 13, combinations of bases, solvents, and catalysts were examined (entries 13-26). Under the reaction conditions in entries 13 to 15, lactone 15 was not produced. To our delight, the reaction of 13 with Cs₂CO₃ and PTC-2 ^23,24 in CH₂Cl₂ at 0°C gave the desired lactone 15 in 30% yield, but 15 was found to be racemic (entry 16). With the aim of achieving asymmetric induction, the same reaction was carried out at –78°C, but lactone 15 was not obtained (entry 17). Catalyst PTC-1 at 0°C gave a result similar to that with PTC-2 (entry 18). A slight improvement in asymmetric induction was observed with some chiral catalysts and KF as a base instead of Cs₂CO₃ (entries 19-24). Although PTC-3 ²⁵ (entry 21), TADDOL (entry 22), and Rawal’s squaramide catalyst^21,26 (entry 23) gave racemic lactone 15 in low yield, PTC-1 (entry 19) and PTC-2 (entry 20) afforded a moderate yield of the product with some asymmetric induction. The yield and enantioselectivity were still low with 1 M KOH/KF and PTC-3 (entry 25), and modest enantioselectivity (44% ee) was obtained with LiOH as the base, although the yield was poor (entry 26).

In conclusion, we demonstrated the intramolecular Darzens reaction of 2-halomalonate derivatives with chiral organocatalysts. The absolute configuration of the products and a plausible transition state for the present Darzens reaction will be reported in future work. The asymmetric induction was insufficient, although we believe this work is a promising starting point for development of a catalytic asymmetric intramolecular Darzens reaction. Structural optimization of the substrate to achieve high enantioselectivity is necessary, and this work is currently underway in our laboratory.

Experimental

¹H NMR spectra were recorded on a JEOL JNM-AL300 (300 MHz) or JEOL JNM-ECS400 (400 MHz) spectrometer. The chemical shifts are expressed in ppm relative to tetramethylsilane (δ = 0) as an internal standard (CDCl₃ solution). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; and br, broad peak. ¹³C NMR spectra were recorded on a 100 MHz instrument (JNM-ECS400, JEOL). The chemical shifts are reported in ppm relative to the central line of the triplet at 77.0 ppm for CDCl₃. Infrared (IR) spectra were measured on an IR spectrometer (VALOR-III, JASCO) and are reported in wavenumbers (cm⁻¹). Both low-resolution mass spectra (MS) and high-resolution mass spectra (HRMS) were obtained using a double-focusing mass spectrometer (JMS 700, JEOL) in electron impact ionization (EI) or fast atom bombardment (FAB) mode with a direct inlet system. Column chromatography was performed on silica gel (40-100 mesh). Analytical thin-layer chromatography was conducted using 0.25 mm silica gel 60 F plates. Chiral high-performance liquid chromatography (HPLC) was performed on a Shimadzu HPLC with CHIRALPAK IC column (4.6 mmϕ × 250 mm, 5 µm particle size, 1.0 mL/min flow rate) equipped with a guard, employing a mixture of EtOH and n-hexane.

Allyl tert-Butyl Malonate (6)

Cesium carbonate (3.42 g, 10.5 mmol) and allyl bromide (0.90 mL, 11 mmol) were added to a stirred solution of mono-tert-butyl malonate (5) (1.5 mL, 10.1 mmol) in N,N-dimethylformamide (DMF) (20 mL) at room temperature. The reaction mixture was stirred for 3 hours, and the reaction was quenched by the addition of brine (5 mL) and H₂O (5 mL). The resulting mixture was extracted with EtOAc (10 mL, three times). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 39:1) to afford allyl ester 6 (1.61 g, 81% yield) as a colorless oil.

Rf: 0.25 (n-hexane/EtOAc, 19:1).

IR (NaCl): 3087, 2980, 1748, 1732, 1650, 1145, 994 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 1.47 (9H, s, t-Bu), 3.32 (2H, s, CH₂), 4.65 (2H, dt, J = 5.7, 1.5 Hz, OCH₂), 5.27 (1H, dq, J = 10.5, 1.2 Hz, C=CHH), 5.37 (1H, dq, J = 17.4, 1.5 Hz, C=CHH), 5.91 (1H, ddt, J = 10.5, 17.4, 6.0 Hz, CH=CH₂).

¹³C NMR (100 MHz, CDCl₃): 27.9 (CH₃ × 3), 42.8 (CH₂), 65.8 (CH₂), 82.1 (C), 118.6 (CH₂), 131.6 (CH), 165.6 (C=O), 166.6 (C=O).

MS (EI, 70 eV): m/z = 200 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₁₀H₁₆O₄: 200.1049; found: 200.1054.

1-Allyl 3-(tert-Butyl) 2-Bromomalonate (7)

n-BuLi (1.6 M solution in n-hexane, 1.2 mL, 1.95 mmol) was slowly added to a stirred solution of N-isopropylcyclohexylamine (0.32 mL, 2.0 mmol) at −40°C. After stirring for 30 minutes at the same temperature, 6 (488 mg, 2.44 mmol) was added dropwise to the reaction mixture. The resultant mixture was stirred for 10 minutes and warmed to 0°C.

The solution prepared above in tetrahydrofuran (THF) (5 mL) was added to a stirred solution of bromine (0.10 mL, 2.0 mmol) in THF (10 mL) at −78°C. After stirring for 2 hours at the same temperature, the reaction was quenched by the addition of 0.3 M HCl (30 mL). The resultant mixture was extracted with CH₂Cl₂ (30 mL, twice). The combined organic layers were washed with saturated aqueous NaHCO₃ (75 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 39:1) to afford bromide 7 (268 mg, 49% yield) as a colorless oil.

Rf: 0.3 (n-hexane/EtOAc, 19:1).

IR (NaCl): 3089, 2982, 1763, 1742, 1650, 1371, 1140 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 1.49 (9H, s, t-Bu), 4.71 (2H, dt, J = 5.7, 1.2 Hz, CH₂), 4.78 (1H, s, CHBr), 5.30 (1H, dq, J = 10.2, 1.2 Hz, C=CHH) 5.40 (1H, dq, J = 17.1, 1.5 Hz, C=CHH), 5.92 (1H, ddt, J = 10.2, 16.8, 6.0 Hz, CH=CH₂).

¹³C NMR (100 MHz, CDCl₃): 27.6 (CH₃ × 3), 43.7 (CH), 67.3 (CH₂), 84.4 (C), 119.4 (CH₂), 130.8 (CH), 163.2 (C=O), 164.7 (C=O).

MS (EI, 70 eV): m/z = 280, 278 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₁₀H₁₅BrO₄: 278.1054; found: 278.1048.

1-(tert-Butyl) 3-(2-Oxoethyl)-2-Bromomalonate (8)

Ozone was bubbled through a stirred solution of 7 (100 mg, 0.358 mmol) in CH₂Cl₂ (3.6 mL) at −78°C for 30 minutes. Then, argon was bubbled until the blue color of the reaction mixture disappeared. Me₂S (0.13 mL, 1.8 mmol) was added, and the resultant mixture was warmed to room temperature and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 1:1). The combined fractions containing 8 were concentrated in vacuo, and the residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 11:9) to afford aldehyde 8 (78.7 mg, 78% yield) as a colorless oil.

Rf: 0.3 (n-hexane/EtOAc, 1:1).

IR (NaCl): 3492, 2981, 1739, 1731, 1302, 1257, 1140, 845 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 1.52 (9H, s, t-Bu), 4.79 (2H, s, OCH₂), 4.89 (1H, s, CHBr), 9.62 (1H, s, CHO).

¹³C NMR (100 MHz, CDCl₃): 27.6 (CH₃ × 3), 42.9 (CH), 70.0 (CH₂), 85.0 (C), 162.9 (C=O), 164.6 (C=O), 194.1 (C=O).

MS (FAB, 10 kV): m/z = 283, 281 [M+H⁺].

HRMS-FAB: m/z [M+H⁺] calcd for C₉H₁₃BrO₅: 281.0025; found: 281.0020.

3-(Methoxy(methyl)amino)-3-Oxopropanoic Acid (10)

Meldrum’s acid (9) (5.00 g, 34.7 mmol) and N(OMe)Me·HCl (13.5 g, 139 mmol) were added to a stirred solution of NaOH (5.55 g, 139 mmol) in water (17 mL) at 0°C. After stirring for 10 minutes at the same temperature, the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction was quenched by the addition of conc. HCl (8.5 mL), and the resultant mixture was extracted with CHCl₃ (20 mL, 20 times). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 4:1 then CH₂Cl₂/MeOH, 9:1) to afford acid 10 (4.94 g, 97% yield) as a colorless oil.

Rf: 0.25 (CHCl₃/MeOH/AcOH, 95:5:3).

IR (NaCl): 3449, 1736, 1633, 1392, 1177 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 3.28 (3H, s, NMe), 3.55 (2H, s, CH₂), 3.75 (3H, s, OMe).

¹³C NMR (100 MHz, CDCl₃): 32.1 (CH₃), 36.7 (CH₂), 61.5 (CH₃), 168.9 (C=O), 169.2 (C=O).

MS (EI, 70 eV): m/z = 147 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₅H₉NO₄: 147.0532; found: 147.0531.

Allyl 3-(Methoxy(methyl)amino)-3-Oxopropanoate (11)

Cesium carbonate (5.13 g, 15.8 mmol) and allyl bromide (1.4 mL, 16.5 mmol) were added to a stirred solution of 10 (2.20 g, 15.0 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred for 16 hours, and the reaction was quenched by the addition of brine (10 mL) and H₂O (10 mL). The resulting mixture was extracted with EtOAc (10 mL, three times). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 3:2) to afford allyl ester 11 (2.01 g, 72% yield) as a colorless oil.

Rf: 0.3 (n-hexane/EtOAc, 3:2).

IR (NaCl): 3087, 1742, 1670, 1249, 1160, 992 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 3.22 (3H, s, NMe), 3.53 (2H, s, CH₂), 3.71 (3H, s, OMe), 4.65 (2H, dt, J = 5.7, 1.5 Hz, OCH₂), 5.25 (1H, dq, J = 10.5, 1.2 Hz, C=CHH), 5.35 (1H, dq, J = 17.1, 1.5 Hz, C=CHH), 5.93 (1H, ddt, J = 10.2, 16.8, 6.0 Hz, CH=CH₂).

¹³C NMR (100 MHz, CDCl₃): 32.1 (CH₃), 40.0 (CH₂), 61.3 (CH₃), 65.8 (CH₂), 118.6 (CH₂), 131.6 (CH), 167.09 (C=O), 167.10 (C=O).

MS (EI, 70 eV): m/z = 187 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₈H₁₃NO₄: 187.0845; found: 187.0844.

Allyl 2-Bromo-3-(Methoxy(methyl)amino)-3-Oxopropanoate (12)

n-BuLi (1.6 M solution in n-hexane, 1.7 mL, 2.7 mmol) was slowly added to a stirred solution of N-isopropylcyclohexylamine (0.45 mL, 2.7 mmol) at −40°C. After stirring for 30 minutes at the same temperature, 11 (500 mg, 2.67 mmol) was added dropwise to the reaction mixture. The resultant mixture was stirred for 10 minutes and warmed to 0°C.

The solution prepared above in THF (5 mL) was added to a stirred solution of bromine (0.15 mL, 2.9 mmol) in THF (5 mL) at −78°C. After stirring for 1.5 hours at the same temperature, the reaction was quenched by the addition of 0.3 M HCl (30 mL). The resultant mixture was extracted with CH₂Cl₂ (30 mL, three times). The combined organic layers were washed with saturated aqueous NaHCO₃ (75 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 7:3). The combined fractions containing 12 were concentrated in vacuo, and the residue was purified via flash chromatography on silica gel (benzene/EtOAc, 9:1) to afford bromide 12 (383 mg, 54% yield) as a colorless oil.

Rf: 0.4 (n-hexane/EtOAc, 3:2).

IR (NaCl): 3087, 2943, 1764, 1744, 1673, 1151, 989 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 3.26 (3H, s, NMe), 3.77 (3H, s, OMe), 4.68 (1H, ddt, J = 6.0, 12.9, 1.5 Hz, CHH), 4.73 (1H, ddt, J = 5.7, 12.9, 1.5 Hz, CHH), 5.26 (1H, s, CHBr), 5.28 (1H, dq, J = 10.5, 1.5 Hz, C=CHH), 5.38 (1H, dq, J = 17.1, 1.5 Hz, C=CHH), 5.92 (1H, ddt, J = 10.5, 17.1, 5.7 Hz, CH=CH₂).

¹³C NMR (100 MHz, CDCl₃): 33.0 (CH₃), 42.6 (CH), 61.5 (CH₃), 67.3 (CH₂), 119.3 (CH₂), 131.0 (CH), 164.5 (C=O), 166.6 (C=O).

MS (EI, 70 eV): m/z = 267, 265 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₈H₁₂BrNO₄: 264.9950; found: 264.9944.

2-Oxoethyl 2-Bromo-3-(Methoxy(methyl)amino)-3-Oxopropanoate (13)

Ozone was bubbled through a stirred solution of 12 (100 mg, 0.376 mmol) in CH₂Cl₂ (3.8 mL) at −78°C for 3 hours. Then, argon was bubbled until the blue color of the reaction mixture disappeared. Me₂S (0.14 mL, 1.9 mmol) was added, and the resultant mixture was warmed to room temperature and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc, 3:2 then 1:4) to afford aldehyde 13 (74.7 mg, 74% yield) as a colorless oil.

Rf: 0.3 (n-hexane/EtOAc, 1:4).

IR (NaCl): 3417, 2985, 1766, 1747, 1667, 1155, 994 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): 3.27 (3H, s, NMe), 3.81 (3H, s, OMe), 4.74 (1H, d, J = 17.1 Hz, CHH), 4.81 (1H, d, J = 17.1 Hz, CHH), 5.38 (1H, s, CHBr), 9.62 (1H, s, CHO).

¹³C NMR (100 MHz, CDCl₃): 32.9 (CH₃), 41.5 (CH), 61.7 (CH₃), 70.0 (CH₂), 163.7 (C=O), 164.4 (C=O), 194.6 (C=O).

MS (EI, 70 eV): m/z = 269, 267 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₇H₁₀BrNO₅: 266.9742; found: 266.9747.

General Procedure for the Intramolecular Darzens Reaction

A base (1.3 equiv) and an organocatalyst (0.1 equiv) were added to a stirred solution of the substrate (1 equiv) in the solvent (c = 0.1 M), and the resultant mixture was stirred at room temperature. After full consumption of the starting material, the reaction was quenched with saturated aqueous NH₄Cl, and the resultant mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (n-hexane/EtOAc) to afford the desired epoxide.

N-Methoxy-N-Methyl-2-Oxo-3,6-Dioxabicyclo[3.1.0]Hexane-1-Carboxamide (15)

Rf: 0.5 (CHCl₃/MeOH, 19:1).

IR (NaCl): 2918, 1786, 1685, 1462, 1246, 1064 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): 3.29 (3H, s, NMe), 3.75 (3H, s, OMe), 4.37 (1H, br s, CH), 4.38 (1H, dd, J = 1.2, 11.2 Hz, CHH), 4.50 (1H, d, J = 11.2 Hz, CHH).

¹³C NMR (100 MHz, CDCl₃): 32.2 (CH₃), 60.0 (CH), 61.3 (CH₃), 67.4 (CH₂), 77.2 (C), 161.3 (C=O), 167.4 (C=O).

MS (EI, 70 eV): m/z = 187 [M⁺].

HRMS-EI: m/z [M⁺] calcd for C₇H₉NO₅: 187.0481; found: 187.0480.

Chiral HPLC analysis (CHRALPAK IC, EtOH:n-hexane = 50/50, flow rate = 1.0 mL/min, λ = 220 nm), t _r (minor) = 6.9 minutes, t _r (major) = 10.1 minutes.

Footnotes

Authors’ Note

This paper is dedicated to Professor Chiaki Kuroda on the occasion of his 65th birthday.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by JSPS KAKENHI Grant number 17K08227 and partially supported by a grant from the Dementia Drug Resource Development Center, Project S1511016, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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