Lithium Binaphtholate-Catalyzed Michael Reaction of Malonates with Maleates and Its Application to the Enantioselective Synthesis of Tricarboxylic Acid Derivatives

Abstract

The Michael reaction of malonates with maleates afforded the corresponding adducts in high yields with high enantioselectivities (up to 98% enantiomeric excess (ee)) by using dilithium 3,3′-dichlorobinaphtholate as a catalyst. The obtained Michael adducts could be converted to optically active tricarboxylic acid (TCA) derivatives via the Krapcho reaction.

Introduction

The Michael reaction of various nucleophiles with acceptors is one of the most versatile tools for the carbon–carbon bond formation reaction.^1–7) Enantioselective Michael reaction has emerged as a key step in the construction of complex natural products. Therefore, an elegant and economical Michael reactions have still attracted considerable attentions. To date, numerous catalytic enantioselective Michael reactions have been demonstrated. Generally, enones,^8–20) maleimides^21,22) and others have been used as Michael acceptors. In contrast, maleates have been used as acceptors to a lesser extent as acceptors. The Michael reaction of malonates to maleates is a typical example of this conjugate addition, which has been previously described even in an early volume of the famous ‘Organic Syntheses.’²³⁾ However, to the best of our knowledge, no reports are available on the enantioselective Michael reactions of malonates to maleates. Our group has reported enantioselective reactions catalyzed by metal binaphtholates.^24–33) Metal binaphtholates,^34–45) which are easily prepared from 2,2′-binaphthols (BINOLs) and metal bases, such as ⁿBuLi or Grignard reagents, act as Brønsted bases to promote asymmetric reactions. Recently, we also reported the first example of the enantioselective Michael reaction of malonates to maleates,⁴⁶⁾ affording tetracarboxylic acid esters as Michael adducts in high yields with high enantioselectivities. Herein, we describe the details of this reaction, including the extension of substrates and the mechanism of lithium binaphtholate-catalyzed Michael reaction of maleates as acceptors. Furthermore, we demonstrate the transformation of obtained product to the tricarboxylic acid (TCA) derivatives, which are often found in biologically active compounds, through decarboxylation.^47,48)

The initial experiment was started with the addition of dibenzyl malonate (1a) to diethyl maleate (2a) in diethyl ether using lithium binaphtholate catalyst (4a), which was prepared from (R)-3,3′-Cl₂-BINOL and ⁿBuLi. The reaction proceeded smoothly,⁴⁹⁾ resulting in the corresponding product 3aa in high yield with moderate selectivity within 0.5 h (Table 1, entry 1). Enantioselectivity decreased using toluene as a solvent, probably owing to the lack of coordination of lithium atom in the solvent (entry 2). Changing the solvent to tert-butyl methyl ether (TBME) and lowering catalyst concentration (0.01 mmol/mL) dramatically improved the enantioselectivity for 3aa to 90% enantiomeric excess (ee) (entry 5). Neither lowering the catalyst concentration below 0.01 mmol/mL nor lowering the temperature (0°C) increased the enantioselectivity of 3aa (entries 6 and 7). When cyclopentyl methyl ether (CPME) was used as an ether solvent, the same effect as TBME was obtained (entry 8). In the case of l,2-dimethoxyethane (DME) (entry 9), the Michael reaction did not proceed at all owing to its high chelation ability.

Table 1. Optimization of Enantioselective Michael Reaction of Malonate 1a with Maleate 2a

Entry	Solvent	c (mol/L) (%)a)	Cat.: X	Conditions	Yield (%)b)	ee (%)c,d)
1	Et2O	0.1	4a: Cl	r.t., 0.5 h	93	45 (R)
2	Toluene	0.1	4a: Cl	r.t., 0.5 h	92	20 (R)
3	THF	0.1	4a: Cl	r.t., 4 h	85	57 (R)
4	TBME	0.1	4a: Cl	r.t., 0.5 h	94	58 (R)
5	TBME	0.01	4a: Cl	r.t., 1 h	94	90 (R)
6	TBME	0.003	4a: Cl	r.t., 1 h	92	90 (R)
7	TBME	0.1	4a: Cl	0°C, 3 h	88	91 (R)
8	CPME	0.01	4a: Cl	r.t., 1 h	87	91 (R)
9	DME	0.01	4a: Cl	r.t., 15 h	N. R.	—
10	TBME	0.01	4b: Br	r.t., 1 h	94	87 (R)
11	TBME	0.01	4c: H	r.t., 24 h	65	20 (R)
12	TBME	0.01	4d: Me	r.t., 24 h	99	25 (R)
13	TBME	0.01	4e: Ph	r.t., 3 h	79	18 (R)

a) Catalyst concentration. b) Isolated yield. c) Determined by HPLC. d) The absolute configuration was determined by the comparison to literature value and authentic sample 3ca prepared from Michael adduct 3aa.

Next, we investigated the effect of the substitution on the 3,3′-position of binaphthols in more detail. The catalyst 4b, prepared from (R)-3,3′-Br₂-BINOL and ⁿBuLi, afforded the Michael adduct in high yield with high enantioselectivity (entry 10), whereas unsubstituted (R)-BINOL-Li₂ (4c), (R)-3,3′-Me₂-BINOL-Li₂ (4d), and (R)-3,3′-Ph₂-BINOL-Li₂ (4e) were ineffective in this Michael reaction (entries 11–13). From these results, it is suggested that the electron deficiency might increase catalytic activity.

Next, the Michael reactions between various malonates and maleates were carried out under optimized reaction conditions (Table 2). As for the Michael acceptors, reduced stereoselectivities were obtained with dimethyl maleate (2b) or dibenzyl maleate (2c), or substituted dibenzyl maleates (2d and 2e) were found to be decreased (entries 2–4). These results indicate that the electronic and steric effects affect for the reaction rate of this reaction. Di-n-propyl maleate (2f) reacted with malonate 1a to give the corresponding Michael adduct 3af, albeit in low enantioselectivity, but diallyl maleate (2g) gave a result similar to that of diethyl maleate (2a). Among the other Michael donors, no alkyl malonate performed better than dibenzyl malonate (1a) (entries 9–11). As the general Michael acceptors, the enantioselectivities of N-phenylmaleimide (2h) and chalcone (2i) were decreased (entries 12, 13). Interestingly, fumarate 2j, the trans-isomer of maleate 2a, gave an almost racemic product 3aa (entry 14), suggesting that the cis geometry of the C–C double bond of 2a allows both carbonyl groups to coordinate with lithium metals. A ketone with a cis geometry (2k)⁵⁰⁾ yielded very low selectivity (entry 15).

Table 2. Michael Reaction of Malonates with Various Acceptors

Entry	Donor	Acceptor	Conditions	Product	Yield (%)a)	ee (%)b)
1	1a: R2  =  Bn	2a (R3  =  Et)	r.t., 1 h	3aa	94	90 (R)c)
2	1a: R2  =  Bn	2b (R3  =  Me)	r.t., 1 h	3ab	94	85 (R)c)
3	1a: R2  =  Bn	2c (R3  =  Bn)	r.t., 1 h	3ac	75	83
4	1a: R2  =  Bn	2d (R3  =  PBB)	r.t., 4 h	3ad	94	78
5d)	1a: R2  =  Bn	2e (R3  =  PMB)	50°C, 24 h	3ae	80	72
6	1a: R2  =  Bn	2f (R3  =  nPr)	r.t., 3 h	3af	66	74
7d)	1a: R2  =  Bn	2g (R3  =  allyl)	r.t., 5 h	3ag	90	91
8	1b: R2  =  Me	2b (R3  =  Me)	r.t., 1 h	3bb	93	85 (R)e)
9	1b: R2  =  Me	2a (R3  =  Et)	r.t., 1 h	3ba	92	77
10	1c: R2  =  Et	2a (R3  =  Et)	r.t., 1 h	3ca	82	88 (R)c)
11	1d: R2  =  tBu	2a (R3  =  Et)	r.t., 1 h	3da	99	55
12	1a: R2  =  Bn	2h	r.t., 2 h	3ah	69	18
13	1a: R2  =  Bn	2i	r.t., 1 h	3ai	78	20
14	1a: R2  =  Bn	2j	r.t., 24 h	3aa	83	−8
15	1a: R2  =  Bn	2k	50°C, 1 h	3ak	79	4

a) Isolated yield. b) Determined by HPLC. c) The absolute configuration was determined by the comparison to literature value and authentic sample 3ca prepared from each Michael adduct. d) (R)-3,3′-Cl₂-BINOL (20 mol%), ⁿBuLi (40 mol%). e) The absolute configuration was determined to be R by the comparison with the literature values of the HPLC retention time [CHIRALPAK AD-H, hexane–2-PrOH (9 : 1), 0.5 mL/min; 23.4 min (S), 24.32 min (R)].⁸⁾

Introduction of an additional substituent, such as a methyl, ethyl, benzyl, isopropyl, and halogen groups on the 2-position of malonates afforded adducts containing quaternary carbon (Table 3).

Table 3. Michael Reaction of Substituted Malonates with Maleates

Entry	Donor	Acceptor	Conditions	Product	Yield (%)a)	ee (%)b)
1	1e: R1  =  Me, R2  =  Me	2a (R3  =  Et)	r.t., 1 h	5ea	91	94
2	1f: R1  =  Me, R2  =  Bn	2a (R3  =  Et)	r.t., 1 h	5fa	93	98 (R)c)
3	1f: R1  =  Me, R2  =  Bn	2d (R3  =  PBB)	r.t., 1 h	5fd	92	93
4	1g: R1  =  Et, R2  =  Bn	2a (R3  =  Et)	r.t., 3 h	5ga	88	92 (R)c)
5d)	1h: R1  =  iPr, R2  =  Bn	2a (R3  =  Et)	50°C, 17 h	5 ha	91	95 (R)c)
6	1i: R1  =  iPr, R2  =  Et	2c (R3  =  Bn)	50°C, 17 h	5ic	79	90
7	1j: R1  =  Bn, R2  =  Bn	2a (R3  =  Et)	r.t., 3 h	5ja	36	86
8	1k: R1  =  Bn, R2  =  Et	2c (R3  =  Bn)	r.t., 87 h	5kc	44	79
9	1l: R1  =  Cl, R2  =  Et	2a (R3  =  Et)	r.t., 17 h	5la	79	74
10	1m: R1  =  F, R2  =  Bn	2a (R3  =  Et)	r.t., 15 h	5ma	91	91 (S)c)
11	1n: R1  =  F, R2  =  Et	2a (R3  =  Et)	r.t., 2 h	5na	74	98

a) Isolated yield. b) Determined by HPLC. c) The absolute configuration was determined by the comparison with authentic samples prepared from the known compound 3aa. d) (R)-Cl₂-BINOL (20 mol%), ⁿBuLi (40 mol%).

2-Alkyl malonate donors prepared the adducts 5ea, fa, fd, ga, ha, ic, ja, and kc with a sterically congested carbons in good yields with high enantioselectivities (entries 1–8), although 2-isopropyl malonates (1h and 1i) required 20 mol% catalyst and heating to 50°C to achieve a smooth reaction. This Michael reaction is not limited to 2-alkylmalonates. In the case of malonate bearing a chlorine atom (1l), the elimination reaction proceeded from the adduct, resulting in a low yield of Michael adduct with moderate enantioselectivity (entry 9). However, 2-fluoro malonates 1m and 1n afforded the corresponding adducts in high yields with high enantioselectivities (entries 10, 11).

The absolute configuration of the Michael adduct 3bb prepared from 1b and 2b (Table 2, entry 8) was found to be R, which was assigned via the comparison with the HPLC data to the literature value.⁸⁾ Furthermore, methyl ester 3bb was converted to ethyl ester 3ca by the transesterification reaction using Ti(OEt)₄ (Chart 1A). The values of HPLC retention time from the two methods, transesterification product and Michael adduct prepared from 1c and 2a were identical. From these experiments, the absolute configuration of the obtained 3ca was determined to be R. Similarly, the absolute configuration of other adducts 3aa and 3ab were found to be R, after conversion to 3ca by transesterification (Chart 1B). As a result, it was found that the adducts 3bb, 3aa, and 3ab, respectively, have the same absolute configuration. It is suggested that the other Michael adducts possess the same configuration. Next, to determine the absolute configuration of compounds 5fa, 5ga, 5 ha, and 5ma, we conducted the functionalization for the known compound 3aa, which was prepared from 1a and 2a (Table 1, entry 1). As shown in Chart 2, compound 5fa could be prepared from the obtained adduct 3aa by reacting with methyl iodide in the presence of base.^51,52) Comparing the HPLC value of this methylated product and Michael adduct from 1f and 2a, the absolute configuration of 5fa was found to be R. Therefore, these results indicate that the adduct synthesized from 2-methyl benzyl malonate (1f) have the same absolute configuration as the adducts from unsubstituted malonate (1a). In addition, the absolute configurations of 5ga and 5ha were determined to be R by the comparison with the values of the HPLC retention time after substitution reactions with appropriate alkyl halides in the presence of bases. Similarly, that of 5ma was determined to be S after fluorination reaction using the Selectfluor.

Chart 1. Determination of the Absolute Configurations of Compounds by Their Introduction into a Known Compound Using Transesterification

Chart 2. Determination of the Absolute Configurations of Compounds Bearing Quaternary Carbon Center

Considering of the absolute configuration of products, the proposed transition state of this reaction is shown in Fig. 1. It is presumed that maleate ester approaches to the catalyst-binding malonates while avoiding steric hindrance caused by the substitution of a catalyst, leading an enantioselective carbon–carbon bond formation.

Fig. 1. Proposed Transition State in the Asymmetric Michael Reaction

Next, to demonstrate the utility of this reaction, the transformation of tetracarboxylic acid ester is accomplished. Optically active tricarboxylic acids (TCA) are widely found in biologically and pharmaceutically active compounds. Important natural compounds such as Fumonisin Bl^53–63) or pharmaceutical compounds such as J-104, 118^64–67) contain tricarboxylic acid moiety and possess bioactivities (Fig. 2).

Fig. 2. Examples of Tricarboxylic Acid in Natural and Bioactive Compounds

For instance, in the reported methods for the synthesis of tricarboxylic acid moiety of Fumonisins or J-104, 118, enantioselective syntheses were achieved by using chiral auxiliary^47,48,58,62) or optical resolution of racemic compound using stoichiometric amount of chiral amines.^64–66) In order to improve the efficiency of the synthesis of such compounds, we envisioned that Michael reaction of malonates to maleates and subsequent decarboxylation would afford the desired tricarboxylic acid derivatives.

Our study for decarboxylation commenced with reaction under acidic media,⁶⁸⁾ but the decarboxylation product was not obtained by heating with aqueous HCl after deprotection of benzyl group (Chart 3A). To improve this transformation, we performed the Krapcho reaction of 3ag in the presence of lithium salt,^69–73) but enantioselectivity of the product 6ag decreased. Finally, we discovered that on heating with water in a sealed tube in the absence of alkali bases⁷⁴⁾ caused the decarboxylation reaction to proceed well, without the loss of remarkable enantioselectivity (Chart 3B). As mentioned above, these tricarboxylic acids and its derivatives are common and versatile structures in biologically active natural products. Our method allows facile access to the optically active tricarboxylic acid derivatives from commercially available materials through base-catalyzed Michael reaction.

Chart 3. Decarboxylation of Tetracarboxylic Acid Ester

In conclusion, we report the first example of enantioselective Michael reaction of malonates to maleates, catalyzed by dilithium 3,3′-dichlorobinaphtholate, affording the tetracarboxylic acid esters with high enantioselectivities. This Michael reaction can accommodate a wide range of donors and acceptors, even producing adducts with quaternary carbon. Furthermore, the resulting adduct can successfully be functionalized to biologically important compounds. Further investigation including the application to other substrates is ongoing in our laboratory.

Experimental

General

All reactions were performed under argon atmosphere using dried glasswares equipped with a rubber septum and a magnetic stirring bar. The column chromatography purifications were performed using Kanto Chemical Silica Gel 60N (spherical, neutral, 63–210 µm). The IR spectra were recorded using a PerkinElmer, Inc. Frontier MIR/NIR. The ¹H- and ¹³C-NMR spectra were recorded in CDCl₃ using a JEOL JNM-ECX-400 spectrometer. The chemical shifts are reported in ppm relative to the internal tetramethylsilane (TMS) standard (δ 0.00 ppm) for the ¹H-NMR spectra and solvent signals (δ 77.0 ppm) for the ¹³C-NMR spectra. The mass spectra were recorded using a JEOL JMS-700MStation mass spectrometer. The HPLC analyses were performed using JASCO P-2080 and UV-2075.

Typical Procedure of Michael Reaction (Table 1, Entry 5)

Under argon atmosphere, n-butyllithium (0.10 mmol, 20 mol%) in hexane (0.15 M, 0.67 mL) was added to a solution of (R)-3,3′-Cl₂-BINOL (17.8 mg, 0.05 mmol, 10 mol%) in TBME (5.0 mL) at 0°C. After stirring for 1 min, dibenzyl malonate (1a) (0.125 mL, 0.5 mmol, 1.0 eq) and diethyl maleate (2a) (0.096 mL, 0.6 mmol, 1.2 eq) was successively added to the mixture at room temperature (r.t.). After 1 h, the reaction was quenched with sat. NH₄Cl aq. (2 mL) and stirred for 0.5 h. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), and dried over Na₂SO₄. After filtration and concentration, the crude product was purified by column chromatography (hexane–EtOAc = 9 : 1, SiO₂: 10 g) to give product 3aa as a colorless oil (214 mg, 94% yield, 90% ee).

(R)-1,1-Dibenzyl 2,3-Diethyl Propane-1,1,2,3-tetracarboxylate (3aa)⁴⁶⁾

Colorless oil. 214 mg. 94% yield. TLC: Rf 0.52 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]²⁷₄₃₅ +11.5 (c = 1.03, CHCl₃) for 90% ee. ¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J = 7.2 Hz), 1.23 (3H, t, J = 7.6 Hz), 2.66 (1H, dd, J = 17.0, 5.2 Hz), 2.79 (1H, dd, J = 17.0, 7.6 Hz), 3.60–3.62 (1H, m), 4.04–4.12 (5H, m), 5.14 (2H, s), 5.15 (2H, s), 7.28–7.37 (10H, m). The enantiomeric excess was determined to be 90% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 22.0 min (R), 23.7 min (S)].

(R)-1,1-Dibenzyl 2,3-Dimethyl Propane-1,1,2,3-tetracarboxylate (3ab)⁴⁶⁾

Colorless oil. 201 mg. 94% yield. TLC: Rf 0.41 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁹₄₃₅ +7.5 (c = 0.88, CHCl₃) for 85% ee. ¹H-NMR (CDCl₃) δ: 2.67 (1H, dd, J = 17.0, 4.8 Hz), 2.80 (1H, dd, J = 17.0, 8.0 Hz), 3.58 (3H, s), 3.60–3.64 (1H, m), 3.65 (3H, s), 4.03 (1H, d, J = 6.8 Hz), 5.15 (2H, s), 5.16 (2H, s), 7.26–7.37 (10H, m). The enantiomeric excess was determined to be 85% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 54.0 min (R), 56.9 min (S)].

(+)-Tetrabenzyl Propane-1,1,2,3-tetracarboxylate (3ac)⁴⁶⁾

Colorless oil. 217 mg. 75% yield. TLC: Rf 0.33 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]³¹₄₃₅ +11.4 (c = 1.15, CHCl₃) for 83% ee. ¹H-NMR (CDCl₃) δ: 2.72 (1H, dd, J = 17.0, 5.2 Hz), 2.88 (1H, dd, J = 17.0, 7.6 Hz), 3.67–3.70 (1H, m), 4.05 (1H, d, J = 6.8 Hz), 5.00–5.08 (8H, m), 7.21–7.34 (20H, m). The enantiomeric excess was determined to be 83% ee by chiral HPLC with Daicel Chiralpak AS-H column [eluent: hexane–IPA = 4 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 11.5 min (minor), 15.0 min (major)].

(+)-1,1-Dibenzyl 2,3-Bis(4-bromobenzyl) Propane-1,1,2,3-tetracarboxylate (3ad)

Pale yellow oil. 346 mg. 94% yield. TLC: Rf 0.47 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]¹⁹₄₃₅ +5.8 (c = 1.2, CHCl₃) for 78% ee. IR (ATR) cm⁻¹: 3035, 1729, 1153. ¹H-NMR (CDCl₃) δ: 2.71 (1H, dd, J = 16.9, 4.6 Hz), 2.86 (1H, dd, J = 16.9, 7.8 Hz), 3.65–3.70 (1H, m), 4.00–4.03 (1H, m), 4.94 (2H, s), 4.98 (2H, s), 5.04 (2H, s), 5.09 (2H, s), 7.07 (2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz), 7.22–7.31 (10H, m), 7.41 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 7.8 Hz). ¹³C-NMR (CDCl₃) δ: 33.2, 40.3, 52.1, 66.4, 65.8, 67.5, 67.6, 122.3, 122.3, 128.2, 128.4, 128.4, 128.5, 129.8, 129.9, 131.6, 131.6, 134.1, 134.5, 134.7, 134.8, 167.1, 167.3, 170.7, 171.1 (two carbons overlapped). FAB-MS m/z: 759.0211 (Calcd for C₃₅H₃₀Br₂O₈Na: 761.0188). MS m/z: 759, 761, 763 (M + Na⁺), 91. The enantiomeric excess was determined to be 78% ee by chiral HPLC with Daicel Chiralcel AS-H column [eluent: hexane–IPA = 4 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 24.3 min (minor), 32.2 min (major)].

(+)-1,1-Dibenzyl 2,3-Bis(4-methoxybenzyl) Propane-1,1,2,3-tetracarboxylate (3ae)

Colorless oil. 256 mg. 80% yield. TLC: Rf 0.44 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]¹⁹₄₃₅ +9.5 (c = 0.92, CHCl₃) for 72% ee. IR (ATR) cm⁻¹: 3034, 1732, 1153. ¹H-NMR (CDCl₃) δ: 2.68 (1H, dd, J = 16.9, 5.0 Hz), 2.83 (1H, dd, J = 16.9, 8.2 Hz), 3.63–3.68 (1H, m), 3.77 (3H, s), 3.80 (3H, s), 4.02 (1H, d, J = 6.9 Hz), 4.93–4.98 (4H, m), 5.02 (2H, s), 5.07 (2H, s), 6.81(2H, d, J = 8.7 Hz), 6.85 (2H, d, J = 8.2 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.21–7.31 (12H, m). ¹³C-NMR (CDCl₃) δ: 33.4, 40.5, 52.2, 55.3, 66.5, 67.1, 67.5, 67.5, 113.8, 113.9, 127.3, 127.7, 128.2, 128.4, 128.5, 130.1, 130.2, 134.9, 135.0, 159.6, 159.6, 167.3, 167.4, 171.0, 171.3 (four carbons overlapped). FAB-MS m/z: 663.2218 (Calcd for C₃₇H₃₆O₁₀Na: 663.2206). MS m/z: 663 (M + Na⁺), 91. The enantiomeric excess was determined to be 72% ee by chiral HPLC with Daicel Chiralcel AD-3 column [eluent: hexane–IPA = 4 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 47.6 min (major), 51.4 min (minor)].

(+)-1,1-Dibenzyl 2,3-Dipropyl Propane-1,1,2,3-tetracarboxylate (3af)

Colorless oil. 160 mg. 66% yield. TLC: Rf 0.26 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁷₄₃₅ +11.5 (c = 1.07, CHCl₃) for 74% ee. IR (ATR) cm⁻¹: 3035, 2967, 1730, 1151. ¹H-NMR (CDCl₃) δ: 0.86 (3H, t, J = 7.4 Hz), 0.91 (3H, t, J = 7.3 Hz), 1.50–1.66 (4H, m), 2.67 (1H, dd, J = 17.0, 4.6 Hz), 2.81 (1H, dd, J = 17.0, 7.8 Hz), 3.60–3.62 (1H, m), 4.04–4.12 (5H, m), 5.14 (2H, s), 5.15 (2H, s), 7.28–7.37 (10H, m) ¹³C-NMR (CDCl₃) δ: 10.2, 10.3, 21.7, 21.8, 33.4, 40.5, 52.3, 66.4, 67.0, 67.5, 128.2, 128.4, 128.4, 128.5, 135.0, 135.0, 167.3, 167.5, 171.1, 171.5 (three carbons overlapped). FAB-MS m/z: 485.2173 (Calcd for C₂₇H₃₃O₈: 485.2175). MS m/z: 485 (M + H⁺), 91. The enantiomeric excess was determined to be 74% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 15.9 min (major), 17.4 min (minor)].

(+)-2,3-Diallyl 1,1-Dibenzyl Propane-1,1,2,3-tetracarboxylate (3ag)

Colorless oil. 216 mg. 90% yield. TLC: Rf 0.47 (hexane–EtOAc = 4 : 1, stained purple with anisaldehyde). [α]¹⁹₄₃₅ +7.8 (c = 0.98, CHCl₃) for 91% ee. IR (ATR) cm⁻¹: 3034, 1731, 1649, 1153. ¹H-NMR (CDCl₃) δ: 2.72 (1H, dd, J = 17.2, 4.6 Hz), 2.85 (1H, dd, J = 17.2, 7.8 Hz), 3.64–3.69 (1H, m), 4.05 (1H, d, J = 6.9 Hz), 4.51 (2H, d, J = 6.0 Hz), 4.55 (2H, d, J = 6.0 Hz), 5.14 (2H, s), 5.15 (2H, s), 5.17–5.32 (4H, m), 5.74–5.91 (2H, m), 7.26–7.32 (10H, m). ¹³C-NMR (CDCl₃) δ: 33.2, 40.4, 52.2, 65.5, 66.1, 67.6, 118.4, 118.6, 128.3, 128.4, 128.4, 128.5, 131.5, 131.8, 134.9, 135.0, 167.3, 167.4, 170.7, 171.1 (three carbons overlapped). FAB-MS m/z: 481.1892 (Calcd for C₂₇H₂₉O₈: 481.1862). MS m/z: 481 (M + H⁺). The enantiomeric excess was determined to be 91% ee by chiral HPLC with Daicel Chiralpak AS-H column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 16.6 min (minor), 21.7 min (major)].

(R)-Tetramethyl Propane-1,1,2,3-tetracarboxylate (3bb)⁸⁾

Colorless oil. 127 mg. 93% yield. TLC: Rf 0.26 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]_D²⁹ +13.4 (c = 0.2, CHCl₃) for 85% ee (R). [(lit⁸⁾: [α]_D²⁵ +5.3, c = 0.2, CHCl₃) for 93% ee (R)]. ¹H-NMR (CDCl₃) δ: 2.72 (1H, dd, J = 17.2, 4.8 Hz), 2.84 (1H, dd, J = 17.2, 7.0 Hz), 3.58–3.63 (1H, m), 3.70 (3H, s), 3.72 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.94 (1H, d, J = 6.8 Hz). The enantiomeric excess was determined to be 85% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 9 : 1; flow rate: 0.5 mL/min; detection: 220 nm; t_R: 23.4 min (S), 24.3 min (R)].

(+)-2,3-Diethyl 1,1-Dimethyl Propane-1,1,2,3-tetracarboxylate (3ba)⁴⁶⁾

Pale yellow oil. 140 mg. 92% yield. TLC: Rf 0.71 (hexane–EtOAc = 1 : 1, stained blue with phosphomolybdic acid). [α]²⁸₄₃₅ +29.6 (c = 1.02, CHCl₃) for 77% ee. ¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J = 7.4 Hz), 1.32 (3H, t, J = 7.4 Hz), 2.69 (1H, dd, J = 16.8, 5.2 Hz), 2.81 (1H, dd, J = 16.8, 8.0 Hz), 3.56–3.61 (1H, m), 3.75 (3H, s), 3.76 (3H, s), 3.94 (1H, d, J = 7.6 Hz), 4.15 (2H, q, J = 7.4 Hz), 4.17 (2H, q, J = 7.4 Hz). The enantiomeric excess was determined to be 77% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 29 : 1; flow rate: 1.0 mL/min; detection: 220 nm; t_R: 27.6 min (minor), 28.6 min (major)].

(+)-Tetraethyl Propane-1,1,2,3-tetracarboxylate (3ca)

Pale yellow oil. 136 mg. 82% yield. TLC: Rf 0.26 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁹₄₃₅ +23.2 (c = 1.01, CHCl₃) for 88% ee. IR (film on NaCl) cm⁻¹: 2983, 1731, 1164. ¹H-NMR (CDCl₃) δ: 1.24–1.29 (12H, m), 2.69 (1H, dd, J = 16.8, 5.2 Hz), 2.81 (1H, dd, J = 16.8, 8.0 Hz), 3.55–3.60 (1H, m), 3.89 (1H, d, J = 7.2 Hz), 4.12–4.25 (8H, m). ¹³C-NMR (CDCl₃) δ: 14.0, 14.1, 33.5, 40.5, 52.4, 60.8, 61.4, 61.8, 167.7, 167.8, 171.2, 171.7 (three carbons overlapped). FAB-MS m/z: 333.1559 (Calcd for C₁₅H₂₅O₈: 333.1549). MS m/z: 333 (M + H⁺), 259. The enantiomeric excess was determined to be 88% ee by chiral HPLC with Daicel Chiralpak AS-H column [eluent: hexane–IPA = 49 : 1; flow rate: 1.0 mL/min; detection: 220 nm; t_R: 17.1 min (minor), 18.7 min (major)].

(+)-1,1-Di-tert-butyl 2,3-Diethyl Propane-1,1,2,3-tetracarboxylate (3da)⁴⁶⁾

Colorless oil. 192 mg. 99% yield. TLC: Rf 0.29 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁹₄₃₅ +11.5 (c = 1.13, CHCl₃) for 55% ee. ¹H-NMR (CDCl₃) δ: 1.23–1.28 (6H, m), 1.46 (18H, s, 18H), 2.69 (1H, dd, J = 16.8, 4.4 Hz), 2.78 (1H, dd, J = 16.8, 8.4 Hz), 3.45–3.50 (1H, m), 3.71 (1H, d, J = 7.2 Hz), 4.14 (2H, q, J = 7.6 Hz), 4.18 (2H, q, J = 7.2 Hz). The enantiomeric excess was determined to be 55% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 29 : 1; flow rate: 1.0 mL/min; detection: 220 nm; t_R: 9.7 min (minor), 11.4 min (major)].

(−)-Dibenzyl 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)malonate (3ah)⁴⁶⁾

Colorless prisms. mp: 90.0–92.0°C. 158 mg. 69% yield. TLC: Rf 0.66 (hexane–EtOAc = 1 : 1, stained blue with phosphomolybdic acid). [α]³⁰₄₃₅ −5.8 (c = 0.94, CHCl₃) for 18% ee. ¹H-NMR (CDCl₃) δ: 2.88–3.00 (2H, m), 3.45–3.51 (1H, m), 4.31 (1H, d, J = 4.0 Hz), 5.18 (2H, s), 5.21 (2H, s), 7.19 (2H, d, J = 7.6 Hz), 7.26–7.45 (13H, m). The enantiomeric excess was determined to be 18% ee by chiral HPLC with Daicel Chiralcel OZ-H column [eluent: hexane–IPA = 1 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 19.5 min (minor), 40.0 min (major)].

(S)-Dibenzyl 2-(3-Oxo-1,3-diphenylpropyl)malonate (3ai)¹⁰⁾

Colorless oil. 192 mg. 78% yield. TLC: Rf 0.51 (hexane–EtOAc = 4 : 1, stained blue with anisaldehyde). [α]_D²⁵ +1.6 (c = 1.0, CHCl₃) for 20% ee. [(lit¹⁰⁾: [α]_D²⁵ +18.4 (c = 1.0, CHCl₃) for 91% ee (S)]. ¹H-NMR (CDCl₃) δ: 3.44 (2H, d, J = 6.8 Hz), 3.94 (1H, d, J = 9.8 Hz), 4.19–4.25 (1H, m), 4.90 (2H, s), 5.12 (1H, d, J = 12.4 Hz), 5.17 (1H, d, J = 12.4 Hz), 7.05–7.07 (2H, m), 7.15–7.34 (13H, m), 7.36–7.43 (2H, m), 7.46–7.55 (1H, m), 7.80 (2H, d, J = 8.2 Hz). The ee was determined to be 20% ee by chiral HPLC with Daicel Chiralpak AS-H column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 19.9 min (R), 23.0 min (S)].

(S)-1,1-Dibenzyl 2,3-Diethyl Propane-1,1,2,3-tetracarboxylate (3aa)⁴⁶⁾

Colorless oil. 189 mg. 83% yield. TLC: Rf 0.52 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]²⁹₄₃₅ −1.1 (c = 1.1, CHCl₃) for −8% ee. The enantiomeric excess was determined to be −8% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 20.8 min (R), 22.2 min (S)].

(S)-Dibenzyl 2-(1,4-Dioxo-1,4-diphenylbutan-2-yl)malonate (3ak)⁵⁰⁾

White prisms. mp: 66.0–68.0°C. 205 mg. 79% yield. TLC: Rf 0.50 (hexane–EtOAc = 4 : 1, stained blue with anisaldehyde). [α]_D²⁴ +1.1 (c = 1.1, CHCl₃) for 4% ee. [(lit⁵⁰⁾: [α]_D²³ −23.4 (c = 0.25, CHCl₃) for 88% ee (R)]; ¹H-NMR (CDCl₃) δ: 3.38 (1H, dd, J = 18.3, 6.3 Hz), 3.54 (1H, dd, J = 18.3, 5.9 Hz), 4.04 (1H, d, J = 8.4 Hz), 4.9–5.13 (5H, m), 7.14–7.28 (10H, m), 7.35–7.44 (4H, m), 7.52–7.58 (2H, m), 7.13 (2H, d, J = 7.6 Hz), 7.32 (2H, d, J = 6.8 Hz). The enantiomeric excess was determined to be 4% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 4 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 51.6 min (R), 54.3 min (S)].

(−)-1,2-Diethyl 3,3-Dimethyl Butane-1,2,3,3-tetracarboxylate (5ea)⁴⁶⁾

Colorless oil. 144 mg. 91% yield. TLC: Rf 0.20 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]_D²⁴ −22.3 (c = 1.01, CHCl₃) for 94% ee. ¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J = 6.8 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.47 (3H, s), 2.57 (1H, dd, J = 16.4, 3.2 Hz), 2.82 (1H, dd, J = 16.4, 10.4 Hz), 3.69–3.72 (1H, m), 3.75 (6H, s), 4.14 (2H, q, J = 6.8 Hz), 4.15 (2H, q, J = 7.2 Hz). The enantiomeric excess was determined to be 94% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 220 nm; t_R: 13.6 min (major), 15.0 min (minor)].

(R)-3,3-Dibenzyl 1,2-Diethyl Butane-1,2,3,3-tetracarboxylate (5fa)⁴⁶⁾

Pale yellow oil. 219 mg. 93% yield. TLC: Rf 0.34 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]_D²⁹ −11.4 (c = 1.0, CHCl₃) for 98% ee. ¹H-NMR (CDCl₃) δ: 1.16 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.6 Hz), 1.50 (3H, s), 2.56 (1H, dd, J = 16.6, 3.2 Hz), 2.77 (1H, dd, J = 16.6, 10.4 Hz), 3.76 (1H, dd, J = 10.4, 3.2 Hz), 4.03 (2H, q, J = 7.2 Hz), 4.10 (2H, q, J = 7.6 Hz), 5.08 (1H, d, J = 12.4 Hz), 5.12 (2H, s), 5.14 (1H, d, J = 12.4 Hz), 7.22–7.25 (4H, m), 7.30–7.32 (6H, m). The enantiomeric excess was determined to be 98% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 29.6 min (S), 30.8 min (R)].

(−)-3,3-Dibenzyl 1,2-Bis(4-bromobenzyl)butane-1,2,3,3-tetracarboxylate (5fd)⁴⁶⁾

Pale yellow oil. 345 mg. 92% yield. TLC: Rf 0.41 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]_D²⁷ −12.8 (c = 0.69, CHCl₃) for 93% ee. ¹H-NMR (CDCl₃) δ: 1.49 (3H, s), 2.62 (1H, dd, J = 16.6, 3.2 Hz), 2.86 (1H, dd, J = 16.6, 11.0 Hz), 3.81 (1H, dd, J = 11.0, 3.2 Hz), 4.83–5.02 (8H, m), 7.08 (2H, d, J = 8.0 Hz), 7.14–7.20 (6H, m), 7.26–7.30 (6H, m), 7.41 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz). The enantiomeric excess was determined to be 93% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 4 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 31.9 min (minor), 40.0 min (major)].

(R)-3,3-Dibenzyl-1,2-diethylpentane-1,2,3,3-tetracarboxylate (5ga)⁴⁶⁾

Colorless oil. 212 mg. 88% yield. TLC: Rf 0.31 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]_D²⁸ +19.5 (c = 0.99, CHCl₃) for 92% ee. ¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J = 7.6 Hz), 1.15 (3H, t, J = 7.6 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.93–2.03 (2H, m), 2.64 (1H, dd, J = 16.6, 2.8 Hz), 2.82 (1H, dd, J = 16.6, 10.8 Hz), 3.62 (1H, dd, J = 10.8, 2.8 Hz), 4.01 (2H, q, J = 7.6 Hz), 4.11 (2H, q, J = 7.2 Hz), 5.07 (2H, d, J = 12.0 Hz), 5.17 (2H, d, J = 12.0 Hz), 7.24–7.27 (2H, m), 7.29–7.32 (8H, m). The ee was determined to be 92% ee by chiral HPLC with Daicel Chiralpak AS-H column [eluent: hexane–IPA = 19/1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 7.7 min (S), 9.6 min (R)].

(R)-3,3-Dibenzyl 1,2-Diethyl 4-Methylpentane-1,2,3,3-tetracarboxylate (5ha)⁴⁶⁾

Pale yellow oil. 226 mg. 91% yield. TLC: Rf 0.37 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]_D²⁶ +23.7 (c = 0.7, CHCl₃) for 95% ee. ¹H-NMR (CDCl₃) δ: 1.01 (3H, d, J = 6.4 Hz), 1.02 (3H, d, J = 6.4 Hz), 1.09 (3H, t, J = 6.8 Hz), 1.24 (3H, t, J = 6.8 Hz), 2.43–2.51 (2H, m), 2.67 (1H, dd, J = 16.4, 11.6 Hz), 3.75 (1H, dd, J = 11.6, 2.0 Hz), 3.91 (2H, q, J = 6.8 Hz), 4.12 (2H, q, J = 6.8 Hz), 5.07 (1H, d, J = 12.4 Hz), 5.13 (1H, d, J = 12.4 Hz), 5.19 (2H, d, J = 12.4 Hz), 7.29–7.32 (10H, m). The ee was determined to be 95% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 20.1 min (R), 22.8 min (S)].

(+)-1,2-Dibenzyl 3,3-Diethyl 4-Methylpentane-1,2,3,3-tetracarboxylate (5ic)⁴⁶⁾

Pale yellow oil. 196 mg. 79% yield. TLC: Rf 0.37 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁴₄₃₅ +11.5 (c = 0.7, CHCl₃) for 90% ee. ¹H-NMR (CDCl₃) δ: 1.01 (3H, d, J = 7.6 Hz), 1.03 (3H, d, J = 7.6 Hz), 1.16 (3H, t, J = 7.6 Hz), 1.22 (3H, t, J = 7.2 Hz), 2.38 (1H, sept, J = 7.6 Hz), 2.58 (1H, dd, J = 17.0, 2.0 Hz), 2.80 (1H, dd, J = 17.0, 11.2 Hz), 3.82 (1H, dd, J = 11.2, 2.0 Hz), 3.95–4.17 (4H, m), 5.01–5.13 (4H, m), 7.26–7.32 (10H, m). The ee was determined to be 90% ee by chiral HPLC with Daicel Chiralcel OD-H column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 10.7 min (minor), 13.4 min (major)].

(+)-3,3-Dibenzyl 1,2-Diethyl 4-Phenylbutane-1,2,3,3-tetracarboxylate (5ja)

Pale yellow oil. 98 mg. 36% yield. TLC: Rf 0.39 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁶₄₃₅ +5.6 (c = 1.3, EtOH) for 86% ee. IR (ATR) cm⁻¹: 3065, 3033, 2981, 1727, 1173. ¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J = 7.6 Hz), 1.21 (3H, t, J = 7.2 Hz), 2.75 (1H, dd, J = 16.8, 2.8 Hz), 2.88 (1H, dd, J = 16.8, 10.8 Hz), 3.33 (2H, s), 3.65 (1H, dd, J = 10.8, 2.8 Hz), 4.06–4.12 (4H, m), 4.96 (2H, s), 5.09 (2H, s), 7.12–7.14 (2H, m), 7.21–7.31 (13H, m). ¹³C-NMR (CDCl₃) δ: 13.7, 14.1, 33.8, 39.6, 45.4, 60.6, 60.8, 61.3, 67.4, 67.5, 127.2, 128.2, 128.3, 128.3, 128.4, 128.4, 128.4, 128.4, 130.5, 134.6, 134.9, 135.4, 168.7, 169.0, 171.8 (one carbon overlapped). FAB-MS m/z: 547.2333 (Calcd for C₃₂H₃₅O₈: 547.2332). MS m/z: 547 (M + H⁺), 455, 91. The ee was determined to be 86% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 33.7 min (major), 38.7 min (minor)].

(−)-1,2-Dibenzyl 3,3-Diethyl 4-Phenylbutane-1,2,3,3-tetracarboxylate (5kc)

Colorless oil. 120 mg. 44% yield. TLC: Rf 0.42 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁴₄₃₅ −5.9 (c = 1.3, MeOH) for 79% ee. IR (ATR) cm⁻¹: 3033, 1728, 1155. ¹H-NMR (CDCl₃) δ: 1.09 (3H, t, J = 6.8 Hz), 1.14 (3H, t, J = 7.2 Hz), 2.84 (1H, dd, J = 16.8, 3.2 Hz), 2.97 (1H, dd, J = 16.8, 11.2 Hz), 3.28 (2H, s) 3.71 (1H, dd, J = 11.2, 3.2 Hz), 3.95–4.08 (4H, m), 4.99–5.15 (4H, m), 7.18–7.22 (5H, m), 7.27–7.37 (10H, m). ¹³C-NMR (CDCl₃) δ: 13.7, 13.8, 25.3, 33.9, 39.5, 45.3, 60.6, 61.6, 66.5, 67.3, 127.0, 128.0, 128.2, 128.3, 128.4, 128.5, 128.6, 130.5, 135.2, 135.6, 135.7, 169.0, 169.1, 171.6 (two carbons overlapped). FAB-MS m/z: 547.2335 (Calcd for C₃₂H₃₅O₈: 547.2332). MS m/z: 547(M + H⁺), 455, 91. The ee was determined to be 79% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 17.2 min (minor), 18.9 min (major)].

(−)-Tetraethyl 1-Chloropropane-1,1,2,3-tetracarboxylate (5la)

Pale yellow oil. 144 mg. 79% yield. TLC: Rf 0.53 (hexane–EtOAc = 4 : 1, stained yellow with phosphomolybdic acid). [α]²⁷₄₃₅ −8.1 (c = 1.07, CHCl₃) for 74% ee. IR (ATR) cm⁻¹: 2984, 1732, 1239, 1199, 1175, 1023. ¹H-NMR (CDCl₃) δ: 1.21–1.33 (12H, m), 2.83 (1H, dd, J = 16.9, 3.2 Hz), 2.94 (1H, dd, J = 16.9, 9.6 Hz), 4.09–4.11 (1H, m), 4.14–4.21 (4H, m), 4.28–4.32 (4H, m). ¹³C-NMR (CDCl₃) δ: 13.7, 13.8, 14.1, 29.7, 33.0, 47.9, 61.0, 61.8, 63.4, 63.5, 71.1, 165.1, 165.6, 169.3, 171.3. FAB-MS m/z: 367.1181 (Calcd for C₁₅H₂₄O₈Cl: 367.1160). MS m/z: 367 (M + H⁺). The ee was determined to be 74% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 220 nm; t_R: 12.0 min (major), 13.9 min (minor)].

(S)-1,1-Dibenzyl 2,3-Diethyl 1-Fluoropropane-1,1,2,3-tetracarboxylate (5ma)

Pale yellow oil. 215 mg. 91% yield. TLC: Rf 0.53 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]_D²⁹ −9.1 (c = 1.0, CHCl₃) for 91% ee. IR (ATR) cm⁻¹: 3067, 1734, 1215, 1024. ¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J = 7.3 Hz), 1.24 (3H, t, J = 6.9 Hz), 2.47 (1H, dd, J = 16.9, 3.7 Hz), 2.83 (1H, dd, J = 16.9, 10.1 Hz), 4.02–4.17 (5H, m), 5.21 (4H, s), 7.28–7.37 (10H, m). ¹³C-NMR (CDCl₃) δ: 13.7, 14.0, 31.1, 31.1, 45.8 (d), 61.5 (d), 68.4 (d), 68.6 (d), 94.3 (d), 128.3, 128.4, 128.6, 128.6, 128.7, 134.1, 134.3, 134.4, 164.2 (d), 164.6 (d), 168.7 (d), 170.6. FAB-MS m/z: 475.1738 (Calcd for C₂₅H₂₈O₈F: 475.1768). MS m/z: 475 (M + H⁺), 91. The ee was determined to be 91% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 9 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 22.9 min (S), 27.8 min (R)].

(−)-Tetraethyl 1-Fluoropropane-1,1,2,3-tetracarboxylate (5na)

Pale yellow oil. 129 mg. 74% yield. TLC: Rf 0.26 (hexane–EtOAc = 4 : 1, stained white with anisaldehyde). [α]_D²⁹ −10.3 (c = 0.88, CHCl₃) for 98% ee. IR (ATR) cm⁻¹: 2985, 1735, 1231. ¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.33 (3H, t, J = 7.3 Hz), 1.33 (3H, t, J = 7.3 Hz), 2.57 (1H, dd, J = 16.5, 3.7 Hz), 2.88 (1H, dd, J = 16.5, 10.1 Hz), 4.04 (1H, ddd, J = 26.8, 10.1, 3.7 Hz), 4.14–4.20 (4H, m), 4.29–4.35 (4H, m). ¹³C-NMR (CDCl₃) δ: 13.7, 14.0, 29.5, 31.1, 45.6 (d), 61.4 (d), 63.0 (d), 93.0 (d), 164.4 (d), 164.7 (d), 168.7, 170.7 (three carbons overlapped). FAB-MS m/z: 351.1463 (Calcd for C₁₅H₂₄O₈F: 351.1455). MS m/z: 351 (M + H⁺). The ee was determined to be 98% ee by chiral HPLC with Daicel Chiralpak AD-H column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 220 nm; t_R: 14.5 min (major), 15.5 min (minor)].

Typical Procedure of Transesterification (Chart 1)

Under argon atmosphere, Ti(OEt)₄ (0.21 mL, 1.0 mmol, 4.0 eq) in EtOH (2 mL) was added Michael adduct 3bb (69.0 mg, 0.25 mmol) in EtOH (1 mL). After refluxing for 14 h, the reaction was quenched with sat. NH₄Cl aq. (2 mL) and stirred for 0.5 h. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), and dried over Na₂SO₄. After filtration and concentration, the crude product was purified by column chromatography (hexane–EtOAc = 9 : 1, SiO₂: 5 g) to give product 3ca as a pale yellow oil (76 mg, 91% yield, 81% ee).

Typical Procedure of Alkylation of Michael Adduct 3aa (Chart 2)

Under argon atmosphere, methyl iodide (0.024 mL, 0.4 mmol, 4.0 eq) was added to a solution of Cs₂CO₃ (45.6 mg, 0.14 mmol, 1.4 eq) and Michael adduct 3aa (45.6 mg, 0.1 mmol, 1.0 eq) in DMF (1 mL) at r.t. After 14 h, the reaction was quenched with water (2 mL) and stirred for 0.5 h. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), and dried over Na₂SO₄. After filtration and concentration, the crude product was purified by column chromatography (hexane–EtOAc = 9 : 1, SiO₂: 5 g) to give product 5fa as a pale yellow oil (24 mg, 50% yield, 89% ee).

Procedure of Fluorination of Michael Adduct 3aa (Chart 2)

Under argon atmosphere, solution of Michael adduct 3aa (68.4 mg, 0.15 mmol, 1.0 eq) in DMF (3 mL) was added NaH (7.2 mg, 0.18 mmol, 1.2 eq content; 60% by weight in oil) at 0°C and stirred for 0.5 h. Then Selectfluor^® (69.1 mg, 0.20 mmol, 1.3 eq) was added to the reaction mixture and stirred 14 h at r.t. The reaction solution was poured into ice water (5 mL). The aqueous layer was extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with brine (20 mL), and dried over Na₂SO₄. After filtration and concentration, the crude product was purified by column chromatography (hexane–EtOAc = 9 : 1, SiO₂: 5 g) to give product 5ma as a yellow oil (64 mg, 90% yield, 88% ee).

Procedure of Krapcho Reaction (Chart 3)

Michael adduct 3ag (160 mg, 0.3 mmol) and H₂O (0.16 mL, 9.0 mmol, 30 eq were stirred at 150°C. After 40 h, the crude product was loaded directly onto column chromatography and purified (hexane–EtOAc = 12 : 1, SiO₂: 10 g) to give product 6ag as a colorless oil (78.9 mg, 76% yield, 90% ee).

(−)-1,2-Diallyl 3-Benzyl-propane-1,2,3-tricarboxylate (6ag)

Colorless oil. 78.9 mg. 76% yield. TLC: Rf 0.47 (hexane–EtOAc = 4 : 1, stained blue with phosphomolybdic acid). [α]²⁰₄₃₅ −5.2 (c = 1.05, CHCl₃) for 90% ee. IR (ATR) cm⁻¹: 3034, 1729, 1649, 1152. ¹H-NMR (CDCl₃) δ: 2.62–2.71 (2H, m), 2.79–2.88 (2H, m), 3.30–3.35 (1H, m), 4.57 (4H, t, J = 5.5 Hz), 5.13 (2H, s), 5.20–5.33 (4H, m), 5.80–5.93 (2H, m), 7.33–7.39 (5H, m). ¹³C-NMR (CDCl₃) δ: 35.2, 35.2, 37.4, 65.5, 65.7, 66.6, 118.4, 118.5, 128.3, 128.3, 128.5, 131.8, 131.8, 135.6, 170.9, 171.1, 172.7. FAB-MS m/z: 347.1533 (Calcd for C₁₉H₂₃O₆: 347.1495). MS m/z: 347 (M + H⁺). The ee was determined to be 90% ee by chiral HPLC with Daicel Chiralpak AD-3 column [eluent: hexane–IPA = 19 : 1; flow rate: 1.0 mL/min; detection: 254 nm; t_R: 18.5 min (major), 19.7 min (minor)].

Acknowledgments

This work was partially supported by Naito Foundation and the Ministry of Education, Science and Culture of Japan.

Conflict of Interest

The authors declare no conflict of interest.

References and Notes

• 1) Christoffers J., Koripelly G., Rosiak A., Rössle M., Synthesis, 2007, 1279–1300 (2007).
• 2) Tsogoeva S. B., Eur. J. Org. Chem., 2007, 1701–1716 (2007).
• 3) Almaşi D., Alonso D. A., Nájera C., Tetrahedron Asymmetry, 18, 299–365 (2007).
• 4) Zhang Y., Wang W., Catal. Sci. Technol., 2, 42–53 (2012).
• 5) Matsunaga S., “Comprehensive Chirality,” Vol. 5, ed. by Carreira E. M., Yamamoto H., Elsevier, Amsterdam, 2012, pp. 243–292.
• 6) Takemoto Y., Stadler M., “Comprehensive Chirality,” Vol. 6, ed. by Carreira E. M., Yamamoto H., Elsevier, Amsterdam, 2012, pp. 37–68.
• 7) Zheng K., Liu X., Feng X., Chem. Rev., 118, 7586–7656 (2018).
• 8) Evans D. A., Rovis T., Kozlowski M. C., Downey C. W., Tedrow J. S., J. Am. Chem. Soc., 122, 9134–9142 (2000).
• 9) Ooi T., Ohara D., Fukumoto K., Maruoka K., Org. Lett., 7, 3195–3197 (2005).
• 10) Wang J., Li H., Zu L., Jiang W., Xie H., Duan W., Wang W., J. Am. Chem. Soc., 128, 12652–12653 (2006).
• 11) Naka H., Kanase N., Ueno M., Kondo Y., Chem. Eur. J., 14, 5267–5274 (2008).
• 12) Agostinho M., Kobayashi S., J. Am. Chem. Soc., 130, 2430–2431 (2008).
• 13) Wascholowski V., Knudsen K. R., Mitchell C. E. T., Ley S. V., Chem. Eur. J., 14, 6155–6165 (2008).
• 14) Chen D., Chen Z., Xiao X., Yang Z., Lin L., Liu X., Feng X., Chem. Eur. J., 15, 6807–6810 (2009).
• 15) Mase N., Fukasawa M., Kitagawa N., Shibagaki F., Noshiro N., Takabe K., Synlett, 2010, 2340–2344 (2010).
• 16) Mao Z., Jia Y., Li W., Wang R., J. Org. Chem., 75, 7428–7430 (2010).
• 17) Yoshida M., Narita M., Hara S., J. Org. Chem., 76, 8513–8517 (2011).
• 18) Espinosa M., Blay G., Cardona L., Pedro J. R., Chem. Eur. J., 19, 14861–14866 (2013).
• 19) Tsubo T., Yamada T., Synlett, 26, 1111–1115 (2015).
• 20) Lippur K., Kaabel S., Järving I., Rissanen K., Kanger T., J. Org. Chem., 80, 6336–6341 (2015).
• 21) Ye W., Jiang Z., Zhao Y., Goh S. L. M., Leow D., Soh Y.-T., Tan C.-H., Adv. Synth. Catal., 349, 2454–2458 (2007).
• 22) Gómez-Torres E., Alonso D. A., Gómez-Bengoa E., Nájera C., Org. Lett., 13, 6106–6109 (2011).
• 23) Clarke H. T., Murray T. F. Org. Synth., Coll., I, 272–273 (1941).
• 24) Tanaka K., Kukita K., Ichibakase T., Kotani S., Nakajima M., Chem. Commun., 47, 5614–5616 (2011).
• 25) Ichibakase T., Nakatsu M., Nakajima M., Molecules, 16, 5008–5019 (2011).
• 26) Ichibakase T., Nakajima M., Org. Lett., 13, 1579–1581 (2011).
• 27) Ichibakase T., Nakajima M., Synthesis, 44, 3145–3151 (2012).
• 28) Ichibakase T., Kaneko T., Orito Y., Kotani S., Nakajima M., Tetrahedron, 68, 4210–4224 (2012).
• 29) Kotani S., Kukita K., Tanaka K., Ichibakase T., Nakajima M., J. Org. Chem., 79, 4817–4825 (2014).
• 30) Kotani S., Moritani M., Nakajima M. Asian, J. Org. Chem., 4, 616–618 (2015).
• 31) Osakama K., Nakajima M., Org. Lett., 18, 236–239 (2016).
• 32) Kotani S., Asano T., Moritani M., Nakajima M., Tetrahedron Lett., 57, 4217–4219 (2016).
• 33) Nakajima M., Watanabe R., Osakama K., Sakamoto M., Takemoto D., Kukita K., Heterocycles, in press.10.3987/COM-18-S(T)63
• 34) Selected reports for the catalytic asymmetric Michael reactions using alkali metal salts of binaphthol derivatives: Tamai Y., Kamifuku A., Koshiishi E., Miyano S., Chem. Lett., 24, 957–958 (1995).
• 35) Kim Y. S., Matsunaga S., Das J., Sekine A., Ohshima T., Shibasaki M., J. Am. Chem. Soc., 122, 6506–6507 (2000).
• 36) Belokon Y. N., Gugkaeva Z. T., Maleev V. I., Moskalenko M. A., Tsaloev A. T., Khrustalev V. N., Hakobyan K. V., Tetrahedron Asymmetry, 22, 167–172 (2011).
• 37) Otani T., Sugawara A., Tamai Y., Tetrahedron Lett., 55, 4923–4926 (2014).
• 38) Samoilichenko Y., Kondratenko V., Ezernitskaya M., Lyssenko K., Peregudov A., Khrustalev V., Maleev V., Moskalenko M., North M., Tsaloev A., Gugkaeva Z. T., Belokon Y., Catal. Sci. Technol., 7, 90–101 (2017).
• 39) Selected examples of lithium binaphtholate-catalyzed asymmetric reactions: Schiffers R., Kagan H. B., Synlett, 1175–1178 (1997).
• 40) Loog O., Mäeorg U., Tetrahedron Asymmetry, 10, 2411–2415 (1999).
• 41) Holmes I. P., Kagan H. B., Tetrahedron Lett., 41, 7453–7456 (2000).
• 42) Holmes I. P., Kagan H. B., Tetrahedron Lett., 41, 7457–7460 (2000).
• 43) Hatano M., Ikeno T., Miyamoto T., Ishihara K., J. Am. Chem. Soc., 127, 10776–10777 (2005).
• 44) Hatano M., Ishihara K., Synthesis, 3785–3801 (2010).
• 45) Hatano M., Horibe T., Ishihara K., J. Am. Chem. Soc., 132, 56–57 (2010).
• 46) Sakamoto M., Kaneko T., Orito Y., Nakajima M., Synlett, 27, 2477–2480 (2016).
• 47) Hanessian S., Gomtsyan A., Payne A., Herve Y., Beaudoin S., J. Org. Chem., 58, 5032–5034 (1993).
• 48) Harmat N. J. S., Mangani S., Perrotta E., Giannotti D., Nannicini R., Altamura M., Tetrahedron Lett., 41, 1261–1264 (2000).
• 49) Lithium salt prepared from the (R)-3,3′-Cl₂-BINOL (10 mol%) and lithium hydroxide (20 mol%) gave lesser result (68% yield, 75% ee). Mono-lithium salt prepared from (R)-3,3′-Cl₂-BINOL (10 mol%) and ⁿBuLi (10 mol%) afforded lesser result (76% yield, 74% ee).
• 50) Žari S., Kailas T., Kudrjashova M., Öeren M., Järving I., Tamm T., Lopp M., Kanger T., Beilstein J. Org. Chem., 8, 1452–1457 (2012).
• 51) Hale J., Lynch C., Caldwell C., Willoughby C., Kim D., Shen D., Mills S., Chapman K., Chen L., Gentry A., MacCoss M., Konteatis Z., US20020094989.
• 52) Li H., Gao X., Liu R., Wang Y., Zhang M., Fu Z., Mi Y., Wang Y., Yao Z., Gao Q., Eur. J. Med. Chem., 101, 400–408 (2015).
• 53) Fumonisins are common contaminant of corn: Bezuidenhout S. C., Gelderblom W. C. A., Gorst-Allman C. P., Horak R. M., Marasas W. F. O., Spiteller G., Vleggaar R., J. Chem. Soc., Chem. Commun., 743–745 (1988).
• 54) Gelderblom W. C. A., Jaskiewicz K., Marasas W. F. O., Thiel P. G., Horak R. M., Vleggaar R., Kriek N. P., Appl. Environ. Microbiol., 54, 1806–1811 (1988).
• 55) Rheeder J. P., Marasas W. F. O., Thiel P. G., Sydenham E. W., Shephard G. S., van Schalkwyk D. J., Phytopathology, 82, 353–357 (1992).
• 56) Hoye T. R., Jiménez J. I., Shier W. T., J. Am. Chem. Soc., 116, 9409–9410 (1994).
• 57) Boyle C. D., Kishi Y., Tetrahedron Lett., 36, 4579–4582 (1995).
• 58) Shi Y., Peng L. F., Kishi Y., J. Org. Chem., 62, 5666–5667 (1997).
• 59) Humpf H.-U., Schmelz E.-M., Meredith F. I., Vesper H., Vales T. R., Wang E., Menaldino D. S., Liotta D. C., Merrill A. H. Jr., J. Biol. Chem., 273, 19060–19064 (1998).
• 60) Sadler T. W., Merrill A. H., Stevens V. L., Sullards M. C., Wang E., Wang P., Teratology, 66, 169–176 (2002).
• 61) Hendricks K., Epidemiology, 10, 198–200 (1999).
• 62) Pereira C. L., Chen Y.-H., McDonald F. E., J. Am. Chem. Soc., 131, 6066–6067 (2009).
• 63) McDonald F. E., Pereira C. L., Chen Y.-H., Pure Appl. Chem., 83, 445–459 (2011).
• 64) J-104 118 inhibits squalene synthase: Iwasawa Y., Hayashi M., Nomoto T., Shibata J., Mitsuya M., Hirota K., Yonemoto M., Kamei T., Miura K., Tomimoto K., Bioorg. Med. Chem. Lett., 5, 1989–1994 (1995).
• 65) Iwasawa Y., Shibata J., Nonoshita K., Arai S., Masaki H., Tomimoto K., Tetrahedron, 52, 13881–13894 (1996).
• 66) Iwasawa Y., Nonoshita K., Tomimoto K., Tetrahedron Lett., 36, 7459–7462 (1995).
• 67) Iwasawa Y., Shibata J., Mitsuya M., Masaki H., Hayashi M., Kanno T., Sawasaki Y., Hisaka A., Kamei T., Tomimoto K., Bioorg. Med. Chem. Lett., 6, 463–466 (1996).
• 68) The procedure of acidic condition: Under H₂ atmosphere, Pd-C (31.9 mg, 0.03 mmol, 10% of the weight of the substrate) in EtOH (1.0 mL) was added Michael product 3aa (160 mg, 0.3 mmol) in EtOH (3.0 mL). After stirring for 0.5 h, the reaction mixture was filtered using a celite cake and the filtrate was concentrated in vacuo. The crude product 2-(1,4-diethoxy-1,4-dioxobutan-2-yl)malonic acid was used without further purification. A solution of obtained dicarboxylic acid in HCl (5.0 mL, 35% in weight) was refluxed for 5 h.
• 69) The procedure of standard Krapcho reaction: Michael adduct 3ag (160 mg, 0.3 mmol), H₂O (0.05 mL. 3.0 mmol, 10 eq and LiCl (0.6 mmol, 2.0 eq were stirred at 150°C in DMSO. After 11 h, the crude product was loaded directly onto column chromatography and purified (hexane–EtOAc = 12 : 1, SiO₂: 10 g) to give product 6ag as a colorless oil (27.0 mg, 26% yield, 87% ee).
• 70) Krapcho A. P., Synthesis, 1982, 805–822 (1982).
• 71) Krapcho A. P., Synthesis, 1982, 893–914 (1982).
• 72) Poon P. S., Banerjee A. K., Laya M. S., J. Chem. Res., 35, 67–73 (2011).
• 73) Krapcho A. P., ARKIVOC, 1–53 (2007).
• 74) Evans D. A., Scheidt K. A., Downey C. W., Org. Lett., 3, 3009–3012 (2001).