Bifunctional Amine-Squaramides as Organocatalysts in Michael

Article Cite This: J. Org. Chem. 2018, 83, 13111−13120

pubs.acs.org/joc

Bifunctional Amine-Squaramides as Organocatalysts in Michael/ Hemiketalization Reactions of β,γ-Unsaturated α‑Ketoesters and α,βUnsaturated Ketones with 4‑Hydroxycoumarins Viktória Modrocká, Eva Veverková, Mária Mečiarová, and Radovan Š ebesta*

J. Org. Chem. 2018.83:13111-13120. Downloaded from pubs.acs.org by UNIV OF TEXAS AT EL PASO on 11/02/18. For personal use only.

Faculty of Natural Sciences, Department of Organic Chemistry, Comenius University in Bratislava, Mlynska dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia S Supporting Information *

ABSTRACT: The catalytic efficiency of various aminesquaramides was tested in Michael/hemiketalization reactions of 4-hydroxycoumarines with two types of enones. Tertiary amine-squaramide organocatalysts afforded the best results regarding both activity and enantioselectivity when β,γunsaturated α-ketoesters were used as the Michael acceptors (yields up to 98%, enantioselectivities up to 90% ee). On the other hand, the primary amine-squaramides are the best choice for related reactions of 4-hydroxycoumarins with enones. The corresponding pyrano[3,2-c]chromen-5-on products were obtained in high enantiomeric purities (up to 96%). The Michael addition of 4-hydroxycoumarin to 4-phenylbut3-en-2-on directly produced chiral anticoagulant drug (S)warfarin in 92% ee when green solvent 2-MeTHF and catalyst (S,S)-C8 were used. Moreover, an enantiomeric catalyst (R,R)C8 gave (R)-warfarin in >99% ee.

■

quinoline-based 1,2-diamine organocatalysts.18−20 Primary amine organocatalysts were also tagged with suitable ionic groups to ensure their recyclability.21,22 Warfarin synthesis using quinine as a catalyst was also adopted for flow setup.23 Several other efficient asymmetric methods based on primary amine catalysts derived from cinchona and primary amine thiourea catalysts have been introduced for the preparation of (S)-warfarin.24,25 Although bifunctional amine-squaramide organocatalysts were used for activation of related compounds, they were not used in the asymmetric synthesis of warfarin and its analogues. In this context, we studied the applicability of various chiral bifunctional amine-squaramides (Figure 1) in the Michael/ hemiketalization reaction of 4-hydroxycoumarins with β,γunsaturated α-oxo esters. We also extended our study to Michael/hemiketalization reaction of 4-hydroxycoumarins with enones, which leads to warfarin. Furthermore, we would like to improve sustainability profile of these syntheses by evaluating greener solvent alternatives.

INTRODUCTION Bifunctional amine-squaramides are effective hydrogen bond donating catalysts for promoting many asymmetric transformations.1−3 Since pioneering work of Rawal,4 these catalysts were utilized successfully in a wide array of asymmetric Michael reactions, especially when nitroolefins were used as Michael acceptors.5−10 On the other hand, Michael additions to β,γ-unsaturated α-keto esters catalyzed by squaramides have been reported less frequently. Xu and coworkers described the first example of the ketoester activation by a squaramide organocatalyst.11 They presented Michael addition of 4hydroxycoumarins and related 4-hydroxy-6-methyl-2-pyrone to β,γ-unsaturated α-oxoesters catalyzed by cinchona alkaloidbased squaramide. Amine-squaramide activation of α-oxoesters was also used in Michael addition of 2-hydroxy-1,4naphthoquinone12 and cyclic diketones.13 The enantioselective Michael addition of 4-hydroxycoumarin to 4-phenylbut-3-en-2-one leads directly to a chiral drug, (S)-warfarin, which is an effective anticoagulant for preventing thrombosis and embolism. Jørgensen’s group described the first organocatalytic asymmetric Michael addition that afforded warfarin and other Michael adducts in the presence of chiral imidazolidine catalysts.14 Later, Feng and coworkers used chiral amide catalyst derived from proline in warfarin synthesis.15 Primary amine-based organocatalysts were recognized as useful for Michael additions of coumarins.16,17 Mlynarski and recently Zlotin described the synthesis of warfarin in water using (S,S)-diphenylethylenediamine or © 2018 American Chemical Society

■

RESULTS AND DISCUSSION

In the first part of our study, we examined the reaction of 4hydroxycoumarin (1a) to the α-oxoester 2a (Scheme 1). In our previous work, we found that tertiary amine-squaramide Received: July 19, 2018 Published: October 2, 2018 13111

DOI: 10.1021/acs.joc.8b01847 J. Org. Chem. 2018, 83, 13111−13120

Article

The Journal of Organic Chemistry

Figure 1. Applied amine-squaramide organocatalysts.

Scheme 1. Michael Addition of 4-Hydroxycoumarin to 4-Phenyl-2-oxo-3-butenoate Ethyl Ester

catalysts containing trans-cyclohexane-1,2-diamine chiral backbone were highly efficient for asymmetric Michael addition of 4-hydroxycoumarin to nitrostyrenes.26 Therefore, we exploited tertiary amine catalysts C1−C5 (Figure 1) in the reaction of 4hydroxycoumarin (1a) with the α-oxoester 2a. As shown in Table 1, all tested catalysts afforded the target product 3a without the formation of any byproducts. Catalyst C1 displayed high catalytic activity as the reaction was completed within 2 h and afforded the product 3a in 98% yield. Product 3a is formed as a mixture of open (keto-3a) and closed form (ketal-3a), which are in rapid equilibrium, as we observed only one set of signals on HPLC. Keto and ketal

isomers can, however, be observed by NMR. With catalyst C1, only moderate enantiomeric purity (66% ee) of 3a was observed (Table 1, entry 1). In our previous works, catalyst C2 exhibited high stereocontrol in related Michael additions.8,10 However, catalyst C2 showed only moderate enantioselectivity in the reaction of 4-hydroxycoumarin (1a) with oxoester 2a (Table 1, entry 2, 50% ee). Interestingly, catalyst C3 showed much higher stereocontrol (90% ee) in this transformation (Table 1, entry 3). The decrease of the catalyst loading to 2.5 mol % did not affect enantioselectivity, but the yield decreased, so the reaction time had to be prolonged (Table 1, entry 4). Chiral catalyst C4 possessing binaphthol moiety afforded the product 3a as opposite (R)-enantiomer in 60% yield and low enantiomeric purity (Table 1, entry 5). To compare the effects of the configuration of the piperidinocyclohexylamine moiety on the studied reaction, we investigated the catalyst C5 with both (S,R,R)- and (S,S,S)-configurations (Table 1, cf. entries 6 and 7). Catalyst C8, bearing primary amine functionality, afforded product 3a in only low enantiomeric purity (Table 1, entry 8). Solvents and reaction temperatures were assessed in the reaction of 4-hydroxycoumarin (1a) with oxoester 2a using catalyst C3 (Table 2). This screening showed that the reaction works best in dichloromethane at 20 °C (Table 2, entry 1). Catalysts and conditions evaluation revealed that the reaction of hydroxycoumarins 1 with oxoesters 2 proceeds most efficiently in dichloromethane at room temperature using squaramide catalyst C3. Under the optimized reaction conditions, the scope of the Michael addition/hemiketalization was extended (Scheme 2). The reaction performed with

Table 1. Screening of Catalysts in the Michael Reaction of 1a and 2aa entry

catalyst

time (h)

yield of 3a (%)c

ee (%)d

1 2 3 4 5 6 7 8

C1 C2 C3 C3b (S,S,S)-C4 (S,R,R)-C5 (S,S,S)-C5 C8

2 2 1.5 4 4 2 2 4

98 98 95 80 60 92 87 77

66 (S) 50 (S) 90 (S) 90 (S) 46 (R) 82 (S) 76 (R) 33 (S)

a Unless noted otherwise, the reactions were carried out with 1a (0.2 mmol) and 2a (0.2 mmol) in the presence of a catalyst (10 mol %) in DCM (1.0 mL) at ambient temperature for the time indicated. b2.5 mol % of catalyst was used. cYield of isolated product. dDetermined by HPLC analysis.

13112


Article

The Journal of Organic Chemistry Table 2. Screening of Solvents and Temperatures in the Reaction of 1a with 2a Using Catalyst C3

entry

solvent

time (h)

temp (°C)

yield of 3a (%)a

ee (%)b

1 2 3 4 5 6 7 8

DCM DCM DCM dioxane MeCN THF toluene tBuOMe

1.5 1.5 1.5 2 3 2 4 4

20 30 0 20 30 30 30 30

95 94 36 70 58 98 20 10

90 90 86 76 84 84 60 n.d.

a

Yield of isolated product. bDetermined by HPLC analysis.

Scheme 2. Substrate Scope of the Asymmetric Reaction of Coumarines 1 with α-Oxoesters 2

catalyst C3 provided the corresponding products 3b−g in nearly quantitative yields (Scheme 2). It appears that the electronic properties of substituents do not affect the efficiency of this reaction. In case of selectivity, no difference was observed with an electron donor and electron acceptor substituents on the 4-hydroxycoumarin skeleton of products 3b and 3c. On the other hand, both derivatives of β,γunsaturated α-oxoesters resulted in a decrease of enantioselectivity of the process. While the electron accepting chloro substituent caused only a slight decrease of enantiomeric excess (88% for 3d and 75% for 3f), the electron donating methoxy group led to a significant decrease of enantiomeric purities (58% ee for 3e, and 34% ee for 3g). It appears that higher electron density in the β,γ-unsaturated α-keto ester 2e has a negative effect on the enantioselectivity of the process. Because of swift action and high stereoselectivity of tertiarysquaramide catalysts tested above, we also wanted to exploit them in Michael addition of 4-hydroxycoumarin (1a) to benzylideneacetone (4a), a reaction that affords important

anticoagulant, warfarin (5a). This type of Michael addition can also afford anticoagulant rodenticide coumachlor (5d). Catalysts C1 and C2 were either inactive or gave product 5a in racemic form (Table 3, entries 1 and 2). We tried to enhance the reactivity of benzylidene acetone by covalent activation, imine formation with (S)-proline as cocatalyst (Table 3, entries 3 and 4). Under these conditions, both catalysts (S,S,S)-C4 as well as (S,R,R)-C5 afforded product 5a in good yields (79 and 70%, respectively) but only in moderate enantiomeric purity (24 and 14% ee, respectively). Unsatisfactory results achieved with tertiary amine-squaramide organocatalysts prompted us to investigate catalysts having ancillary secondary or primary amino groups. Secondary amine-squaramide catalyst C6 afforded racemic warfarin (5a). Addition of basic additive led to a slight increase of enantioselectivity (Table 3, cf entries 5 and 6). It was reported that 4-hydroxycoumarin can be activated by LiClO4 as a Lewis acid, so we applied it in the reaction with enones.27 We also replaced dichloromethane/methanol mixture with an aprotic solvent dioxane/acetonitrile because of the possible 13113


Article

The Journal of Organic Chemistry Table 3. Screening of Catalysts and Optimization of Conditions in Warfarin Synthesisa

entry

catalyst

1 2 3 4 5 6 7 8 9

C1 C2 (S,S,S)-C4b (S,R,R)-C5b C6 C6 C6 C7 C8

additivec

solvent

time (d)

yield of 5ad (%)

ee (%)e

5 3 3 3 5 5 5 4 5

52

rac

NaOAc LiClO4 LiClO4 LiClO4

DCM/MeOH dioxane DCM/MeOH DCM/MeOH DCM/MeOH DCM/MeOH dioxane/MeCN dioxane/MeCN dioxane/MeCN

79 70 26 60 44 23 86

24 (S) 14 (R) rac 16 (R) 24 (R) 40 (R) 90 (R)

a

Unless noted otherwise, the reactions were carried out with 1a (0.25 mmol) and 4a (0.3 mmol) in the presence of catalyst (10 mol %) in solvent (1.0 mL) at ambient temperature for the time indicated. b10 mol % of (S)-proline was added. c10 mol % of additive was used. dYield of isolated product. eDetermined by HPLC analysis.

Table 4. Green Solvent Screening in Warfarin Synthesisa

adverse effect of MeOH on the enantioselectivity of the process. However, product 5a was still obtained in low yield and enantiomeric purity (Table 3, entry 7). Interestingly, use of primary amine catalyst C7 resulted in increased enantioselectivity of the reaction to 40% ee (Table 3, entry 8). This result encouraged us to use another primary amine catalyst C8 with somewhat less rigid structure in comparison to catalyst C7. We were pleased to observe that catalyst C8 afforded warfarin (5a) in 86% yield and high enantiomeric purity (90% ee) (Table 3, entry 9). Reaction solvent often dramatically influences reaction rate, yield, selectivity, and health and environmental impact of the reaction.28 Therefore, we screened several “green solvents” in the asymmetric Michael addition of 4-hydroxycoumarin 1a to enone 4a. Owing to the low solubility of starting material and catalysts in common organic solvents, we started our study with ionic liquids and deep eutectic solvents (DESs). Room temperature ionic liquids are excellent alternatives for traditional volatile organic solvents. Synthesis of warfarin proceeded in 1-ethyl-3methylimidazolium methyl sulfate ([Emim]OSO3Me) with 56% yield and 40% ee. Slightly better results (65% yield and 72% ee) were obtained in 1-butyl-3-methylpyridinium bis(trifluormethylsulfonyl)imide ([Bmpy]NTf2). The reaction in 1-ethyl-3-methylimidazolium 2-(2-methoxyethoxy)ethylsulfate gave a product with 49% yield in racemic form (Table 4, entries 1−3). Some other ionic liquids (see Supporting Information) were tested, but they were not applicable for this reaction. DESs exhibit properties similar to those of ionic liquids while being cheaper, easier to obtain, and having components often obtained from natural sources.29 When the reaction of 4hydroxycoumarin (1a) with ketone 4a was carried out in choline chloride/glycerol (1:2) mixture, product 5a was obtained in 23% yield but with only 35% ee. The reaction in choline chloride/urea (1:2) and choline chloride/urea/water (1:2:4) failed, and only traces of warfarin were detected in the reaction mixture (Table 4, entries 4 and 5). Ethyl lactate is an environmentally benign solvent with properties and applicability comparable to those of petroleum-based solvents.30 The reaction in chiral (−)-L-ethyl lactate afforded the product 5a in

entry 1 2 3 4 5 6 7 8 9 10 11 12h

solvent d

[Emim]OSO3Me [Bmpy]NTf2e [Emim]OSO3Etf choline chloride/glycerol (1:2) choline chloride/urea (1:2) (−)-L-ethyl lactate ethylene glycol PEG 600 1,2-dimethoxyethane cyclopentyl(methyl)ether 2-methyltetrahydrofurang 2-methyltetrahydrofuran

time (d)

yield of 5a (%)b

ee (%)c

7 7 7 7

56 65 49 23

40 (R) 72 (R) rac 35 (R)

7 7 7 7 5 5 5 5

traces 51 26 40 78 56 81 84

n.d. 76 (R) 34 (R) 97 (R) 88 (R) 90 (R) >99 (R) 92 (S)

a The reactions were carried out with 1a (0.25 mmol) and 4a (0.3 mmol) in the presence of catalyst (R,R)-C8 (10 mol %) and LiClO4 (10 mol %) at ambient temperature for the time indicated. bYield of isolated product. cDetermined by HPLC analysis. d1-Ethyl-3methylimidazolium methyl sulfate. e1-Butyl-3-methylpyridinium bis(trifluormethylsulfonyl)imide. f1-Ethyl-3-methylimidazolium 2-(2methoxyethoxy) ethyl sulfate. gFor comparison, the reaction in THF afforded product in 66% yield and 92% ee. hCatalyst (S,S)-C8 was used.

51% yield and reasonable optical purity of 76% ee (Table 4, entry 6). Polyethyleneglycols (PEG) as well as glymes (glycol diethers) are nontoxic, inexpensive, thermally stable, and recoverable media for organic reactions.31,32 Synthesis of warfarin in ethylene glycol did not proceed well as the product was isolated only in 26% yield and 34% ee. The yield increased to 40% in PEG 600, and warfarin was obtained with excellent enantiomeric purity (97% ee). Interestingly, monoglyme was one of the best solvents considering yield as well as enantiomeric purity. The reaction led to warfarin in 78% yield and 88% ee (Table 4, entries 7−9). Cyclopentyl(methyl)ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF) are greener alternatives to other ethereal solvents for many types of organic syntheses. Low peroxide formation, stability under acidic and basic conditions, high boiling point, and low heat of vaporization are their main positive features.33 Furthermore, 213114


Article

The Journal of Organic Chemistry Scheme 3. Substrate Scope of the Asymmetric Reaction of Coumarin Derivatives 1 with α,β-Unsaturated Ketones 4

Figure 2. CD spectra for (S)-3a (green line) and (R)-5a (red line).

MeTHF is derived from renewable resources.34 Warfarin synthesis proceeded in CPME with 56% yield and 90% ee (Table 4, entry 10). The best solvent for organocatalytic warfarin synthesis was 2-MeTHF with regard to the yield (81%) as well as enantioselectivity (99% ee) (Table 4, entry 11). Optimized reaction conditions for the Michael addition/ hemiketalization of hydroxycoumarins 1 to enones 4 comprise 2-methyltetrahydrofuran as a solvent, room temperature, LiClO4 as an additive, and primary-amine squaramide catalyst C8. We also extended the scope of Michael addition reaction to various 4-hydroxycoumarines 1 and derivatives of

benzylideneacetone 4 (Scheme 3). The electronic properties of substituents on 4-hydroxycoumarin did not affect the enantioselectivities of products 5b−i in comparison with product 5a. For benzylidene acetone with a substituted benzene ring, electron-withdrawing substituent led to high enantioselectivities (5d, 5f, and 5h). Electron-donating substituent caused a slight decrease in enantioselectivity of product 5g (72% ee), and the yield dropped as well (5e). Absolute configuration of product (S)-3a, which was obtained with catalyst C3, was determined by comparison of the order of peaks of enantiomers of 3a in chiral HPLC and sign of optical rotation with literature values.11,13,35 Absolute 13115


Article


Figure 3. Stereochemical model for Michael addition of coumarin 1a to oxoester 2a (Figure 3a) and to enone 4a (Figure 3b); 3D-renderings obtained by DFT at the ωB97XD/6-31G* level.

configuration of compound (R)-5a (warfarin), which was synthesized using catalyst (R,R)-C8, was determined by comparison of its optical rotation and circular dichroism data with literature.36 Opposite absolute configuration of products 3a and 5a was unequivocally ascertained by CD spectroscopy (Figure 2), which also strengthened assignment of series 3. Configurations of other derivatives 3b−e and 5b−e were confirmed by CD spectroscopy too (see Supporting Information for more details). With the help of quantum-chemical calculations, we devised a stereomodel for the Michael additions. The reaction of coumarin 1a with ketoester 2a was catalyzed by derivative C3. On the other hand, in the reaction of coumarin 1a with enone 4a, the most effective primary amine C8 was examined. DFT calculations were performed with dispersion corrected ωB97XD functional using 6-31G* basis set. Calculations support the notion that the reaction of coumarin 1a with ketoester 2a is catalyzed via a hydrogen-bond-donating activation of catalyst C3. In this case, major (S)-configured products 3 would originate via Si-attack of the coumarin to ketoester (Figure 3a). On the other hand, in the reaction of enones 4, primary amine catalyst C8 promotes the reaction via an iminium activation of the enone and concomitant hydrogen-bond activation of the coumarin moiety. Here, Re-attack would afford (R)-5 as the major enantiomer (Figure 3b).

adducts in high yields and enantioselectivities (up to 99% ee) when 2-methyltetrahydrofuran was used as a green solvent.

■

EXPERIMENTAL SECTION

General Information. The solvents were purified by standard methods. NMR spectra were recorded on NMR System 300 and 600 instruments (300 or 600 MHz for 1H, 151 MHz for 13C). Chemical shifts (δ) are given in ppm relative to tetramethylsilane. Specific optical rotations were measured on Jasco P-2000 instrument and are given in deg cm3 g−1 dm−1. Column chromatography was performed on Merck silica gel 60. Thin-layer chromatography was performed on Merck TLC-plates silica gel 60, F-254. Enantiomeric excesses were determined by HPLC using Chiralpak IA, IB (Daicel Chemical Industries) columns using n-hexane/propan-2-ol as a mobile phase and detected by UV at 254 and 308 nm. HRMS spectra were recorded on a hybrid ion trap/orbitrap mass spectrometer using HESI (heated electrospray ionization) in positive mode. The squaramide organocatalysts C1,37 C2,38 C3,39 C4,40 C5,26 C6,41 C7,37 and C842 were synthesized according to literature procedures. General Procedure for Asymmetric Michael/Hemiketalization Reaction of 4-Hydroxycoumarins and (E)-Ethyl 2-oxo-4phenylbut-3-enoates. To a solution of 4-hydroxycoumarin (1, 0.2 mmol) and (E)-ethyl 2-oxo-4-arylbut-3-enoate (2, 0.2 mmol) in DCM (1 mL) was added the catalyst C3 (0.02 mmol). The solution was stirred at room temperature for 1.5 h. Then, the solvent was removed in vacuo, and the crude product was purified by column chromatography on silica gel, eluted by hexane−EtOAc (5:1−3:1). (4S)-Ethyl 4-Phenyl-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-carboxylate (3a). 70 mg (95%), white solid, mp 166−168 °C; [α]D20 +6.0 (c = 0.93, CHCl3); lit35 [α]D25 −40.8 (c 0.93, CHCl3 for (R)-enantiomer). 1H NMR (600 MHz, CDCl3) δ: 7.79 (dd, J = 7.9, 1.4 Hz, 1 H), 7.57−7.51 (m, 1 H), 7.33−7.20 (m, 7 H), 4.64 (s, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.25 (t, J = 7.8 Hz, 1 H), 2.61−2.43 (m, 2 H); 1.35 (t, J = 7.1 Hz, 3 H). Spectral data are consistent with those in the literature.11 Enantiomeric excess 90% ee determined by HPLC (Chiralpak IB, hexane/iPrOH 80:20, flow rate 1 mL/min, λ = 254 nm): tR(minor) = 14.33 min, tR(major) = 26.57 min. (4S)-Ethyl 9-Bromo-4-phenyl-2-hydroxy-5-oxo-2,3,4,5tetrahydropyrano[3,2-c]chromene-2-carboxylate (3b). 86 mg (96%), white solid, mp 193−195 °C; [α]D20 +15.0 (c = 0.3, CHCl3). The product was found to exist in rapid equilibrium with a

■

CONCLUSION In conclusion, a series of chiral tertiary amine-squaramide catalysts containing trans-cyclohexane-1,2-diamine chiral backbone was successfully applied to catalysis of the Michael/ hemiketalization reaction of 4-hydroxycoumarins with β,γunsaturated α-oxoesters in excellent yields (up to 98%) and enantioselectivities (up to 90%). We found that primary amine-squaramides are highly effective catalysts for Michael/ hemiketalization reaction of 4-hydroxycoumarins with enones. Furthermore, we developed an environmentally friendly Michael reaction affording warfarin and related Michael 13116


Article


those in the literature.27 Enantiomeric excess 58% ee determined by HPLC (Chiralpak IB, Hexane/iPrOH 80:20, flow rate 1.0 mL/min, λ = 254 nm): tR(minor) = 9.96 min, tR(major) = 14.26 min. (4S)-Ethyl 4-(4-Chlorophenyl)-2-hydroxy-9-methyl-5-oxo-2,3,4,5tetrahydropyrano[3,2-c]chromene-2-carboxylate (3f). 61 mg (98%), white solid, mp 204−206 °C; [α]D20 +49,2 (c = 1, CHCl3). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 8.09 (s, 0,2 H, ArH), 7.56 (d, J = 27.7 Hz, 1 H, ArH), 7.36(ddd, J = 22.4 Hz, 8.5 Hz, 1.8 Hz, 1 H, ArH), 7.29−7.26 (m, 1.5 H, ArH), 7.25−7.23 (m, 0.8 H, ArH), 7.20−7.17 (m, 2.5 H, ArH), 4.71 (s, 0.6 H, OH ketal), 4.55 (s, 0.4 H, OH keto), 4.40−4.37 (m, 2 H, CH2 ketal), 4.29 (dd, J = 7.5, 2.8 Hz; 0.4 H, CH ketal), 4.17 (dd, J = 11.6, 7.0 Hz, 0.6 H, CH ketal), 2.80 (dd, J = 13.5, 6.8 Hz, 0.4 H, CH2 ketal), 2.47−2.40 (m, 3.6 H, CH2 and CH3 ketal), 1.37 (td, J = 7.1, 2.6 Hz, 3 H, CH3 ketal and keto) ppm. 13C NMR (151 MHz, CDCl3) δ: 168.5, 168.4, 161.7, 160.7, 158.5, 158.2, 151.0, 151.0, 141.1, 140.3, 133.8, 133.6, 133.2, 133.0, 132.4, 132.3, 129.5, 128.9, 128.5, 128.4, 122.4, 116.5, 116.4, 114.8, 114.6, 104.4, 102.4, 95.7, 95.2, 63.7, 37.9, 35.1, 34.1, 33.1, 30.6, 29.7, 29.0, 24.0, 22.9, 20.9, 14.0. HRMS (ESI) m/z: [M + H]+ calcd for C22H20ClO6 415.0943; found 415.0944. IR (ATR): 3442, 2923, 1720, 1630, 1586, 1489, 1410, 1364, 1026, 920. Enantiomeric excess 75% ee determined by HPLC (Chiralpak IB, Hexane/iPrOH 85:15, flow rate 0,8 mL/min, λ = 254 nm): tR(minor) = 12.28 min, tR(major) = 17.78 min. (4S)-Ethyl 2-Hydroxy-4-(4-methoxyphenyl)-9-methyl-5-oxo2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-carboxylate (3g). 54 mg (87%), white solid, mp 182−184 °C; [α]D20 36,8 (c = 1, CHCl3). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 8.09 (s, 0,3 H, ArH), 7.57 (d, J = 34.9 Hz, 1 H, ArH), 7.36 (dd, J = 8.5 Hz, 1.7 Hz, 0.6 H, ArH), 7.32 (d, J = 10.4 Hz, 0.4 H, ArH), 7.24 (s, 0.3 H, ArH), 7.19− 7.16 (m, 2.4 H, ArH), 6.86−6.81 (m, 2 H, ArH), 4.73 (s, 0.6 H, OH ketal), 4.53 (s, 0.4 H, OH keto), 4.39−4.31 (m, 2.3 H, CH2 ketal and keto, CH ketal), 4.15 (t, J = 9.2 Hz, 0.7 H, CH ketal), 3.78 (s, 1.8 H, CH3 ketal), 3.76 (s, 1 H, CH3 keto), 2.76 (dd, J = 14.9, 6.7 Hz, 0.5 H, CH2 ketal), 2.49 (dd, J = 14.3, 3.0 Hz, 0.5 H, CH2 ketal), 2.43−2.41 (m, 3.6 H, CH2 and CH3 ketal), 1.35 (td, J = 7.1 Hz, 3.2 Hz, 3 H, CH3 keto and ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 168.6, 168.5, 165.9, 161.8, 160.8, 158.3, 158.2, 157.8, 151.0, 150.9, 134.5, 134.2, 133.7, 133.6, 133.5, 133.0, 132.8, 129.5, 128.4, 128.1, 122.5, 122.3, 116.4, 116.3, 115.3, 114.7, 114.1, 113.9, 105.0, 103.0, 96.0, 95.3, 67.8, 63.5, 55.2, 38.9, 38.2, 35.5, 33.8, 32.8, 30.6, 29.7, 29.0, 24.0, 23.0, 20.9, 14.0. HRMS (ESI) m/z: [M + H]+ calcd for C23H23O7 411.1438; found 411.1436. IR (ATR): 3442, 2926, 1721, 1631, 1585, 1243, 1222, 1189, 1100, 1020. Enantiomeric excess 34% ee determined by HPLC (Chiralpak IB, Hexane/iPrOH 80:20, flow rate 1 mL/min, λ = 254 nm): tR(minor) = 29.83 min, tR(major) = 45.63 min. General Procedure for Asymmetric Michael/Hemiketalization Reaction of 4-Hydroxycoumarins and (E)-4-Arylbut-3-en2-one. To a solution of 4-arylbut-3-en-2-one (4, 0.3 mmol) in 2MeTHF (1 mL) was added the catalyst C8 (13 mg, 0.025 mmol), and mixture was stirred at room temperature 5 min. Then, 4hydroxycoumarin (1, 0.25 mmol) and LiClO4 (2.7 mg, 0,025 mmol) were added. The reaction mixture was stirred at room temperature for 4 d. Then, the solution was loaded onto silica gel column to purify the desired product by using hexane/EtOAc (3:1) eluent system. From other green solvents, the product was isolated after extraction to DCM or EtOAc and purification by column chromatography with eluent hexanes/EtOAc. (4R)-4-Phenyl-2-hydroxy-2-methyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5a). 63 mg (81%), white solid, mp 160−161 °C; [α]D20 +10.0 (c 0.6, CH3CN); lit.43 [α]D20 +9.9 (c 0.46, CH2Cl2). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium

pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 7.93 (d, J = 2.4 Hz, 0.3 H, ArH), 7.88 (d, J = 2.4 Hz, 0.7 H, ArH), 7.67−7.59 (m, 1H, ArH), 7.38−7.28 (m, 2.5 H, ArH), 7.25−7.16 (m, 3.5 H, ArH), 4.89 (s, 0.7 H, OH ketal), 4.63 (s, 0.3 H, OH keto), 4.42−4.30 (m, 2.3 H, CH2 ketal and keto, CH ketal), 4.22−4.16 (m, 0.7 H; CH2 keto), 2.80 (ddd, J = 14.3, 7.4, 1.2 Hz, 0.4 H, CH2 ketal), 2.52 (dd, J = 14.3, 3.3 Hz, 0.4 H, CH2 ketal), 2.44 (d, J = 8.8 Hz, 1.3 H, CH2 ketal), 1.45 (t, J = 7.1 Hz, 0.3 H, CH3 keto), 1.36 (dt, J = 7.1 3.3 Hz, 2.8 H, CH3 keto and ketal). 13C NMR (151 MHz, CDCl3) δ: 168.3, 160.9, 160.0, 157.4, 156.9, 151.7, 142.0, 141.2, 134.9, 134.6, 129.2, 128.9, 128.7, 128.4, 127.4, 127.1, 126.9, 126.8, 125.5, 125.4, 118.4, 118.3, 116.9, 116.6, 105.9, 103.9, 96.2, 95.6, 63.7, 38.0, 35.4, 34.7, 33.8, 14.0. HRMS (ESI) m/z: [M + H]+ calcd for C21H18BrO6 445.0288; found 445.0299. Enantiomeric excess 90% ee determined by HPLC (Chiralpak IB, Hexane/iPrOH 75:25, flow rate 1 mL/min, λ = 254 nm): tR(minor) = 11.85 min, tR(major) = 34.13 min. (4S)-Ethyl 4-Fenyl-2-hydroxy-9-methyl-5-oxo-2,3,4,5tetrahydropyrano[3,2-c]chromene-2-carboxylate (3c). 71 mg (94%), white solid, mp 191−193 °C; [α]D20 +23.6 (c 1.03, CHCl3); lit.35 [α]D25 −42.7 (c 1.03, CHCl3 for (R)-enantiomer). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 7.60 (s, 0.4 H), 7.55 (s, 0.6 H, ArH); 7.38−7.27 (m, 3 H, ArH), 7.25−7.22 (m, 2 H, ArH), 7.19 (d, J = 8.4 Hz, 1 H, ArH), 4.68 (s, 0.7 H, OH ketal), 4.48 (s, 0.3 H, OH keto), 4.41−4.31 (m, 2.3 H, CH2 ketal and keto, CH ketal), 4.21−4.18 (m, 0.7 H, CH2 keto), 2.80 (dd, J = 13.2, 7.5 Hz, 0.4 H, CH2 ketal), 2.53 (dd, J = 14.3, 3.1 Hz, 0.4 H, CH2 ketal), 2.45−2.42 (m, 4 H, CH2 and CH3 ketal), 1.37−1.34 (m, 3 H, CH3 keto and ketal). Spectral data are consistent with those in the literature.11 Enantiomeric excess 90% ee determined by HPLC (Chiralpak IB, Hexane/iPrOH 75:25, flow rate 1 mL/min, λ = 254 nm): tR(minor) = 4.90 min, tR(major) = 18.49 min. (4S)-Ethyl 2-Hydroxy-4-(4-chlorophenyl)-5-oxo-2,3,4,5tetrahydropyrano[3,2-c]chromene-2-carboxylate (3d). 78 mg (98%), white solid, mp 200−202 °C; [α]D20 +30.8 (c 1.07, CHCl3); lit.35 [α]D25 −51.7 (c 1.07, CHCl3 for (R)-enantiomer). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 7.79 (ddd, J = 13.3, 7.9, 1.5 Hz, 1 H, ArH), 7.56 (m, 1 H, ArH), 7.38−7.27 (m, 3.5 H, ArH), 7.20 (dt, J = 5.7, 4.5 Hz, 2.5 H, ArH), 4.73 (s, 0.6 H, OH ketal), 4.56 (s, 0.4 H, OH keto), 4.38 (q, J = 7.1 Hz, 2 H, CH2 ketal), 4.31 (dd, J = 7.5, 2.7 Hz; 0.4 H, CH ketal), 4.18 (dd, J = 11.0, 7.6 Hz, 0.7 H, CH ketal), 2.80 (dd, J = 14.3, 7.5 Hz, 0.5 H, CH2 ketal), 2.50− 2.38 (m, 1.7 H, CH2 ketal), 1.36 (td, J = 7.1, 2.6 Hz, 3 H, CH3 ketal and keto). Spectral data are consistent with those in the literature.27 Enantiomeric excess 88% ee determined by HPLC (Chiralpak IB, Hexane/iPrOH 85:15, flow rate 0.7 mL/min, λ = 254 nm): tR(minor) = 26.87 min, tR(major) = 37.04 min. (4S)-Ethyl 2-Hydroxy-4-(4-metoxyphenyl)-5-oxo-2,3,4,5tetrahydropyrano[3,2-c]chromene-2-carboxylate (3e). 77 mg (97%), white solid, mp 164−166 °C; [α]D20 +35.6 (c 1.2, CHCl3); lit.35 [α]D25 −45.0 (c 1.2, CHCl3 for (R)-enantiomer). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 7.80 (ddd, J = 16.7, 7.9, 1.5 Hz, 1 H, ArH), 7.59−7.50 (m, 1 H, ArH), 7.37−7.25 (m, 2 H, ArH), 7.18 (d, J = 8.5 Hz, 2 H, ArH), 6.87−6.81 (m, 2 H, ArH), 4.73 (s, 0.6 H, OH ketal), 4.54 (s, 0.4 H, OH keto), 4.40−4.29 (m, 2.4 H, CH2 ketal and keto, CH ketal), 4.16 (t, J = 9.2 Hz, 0.7 H, CH ketal), 3.78 (s, 1.9 H, CH3 ketal), 3.77 (s, 1.1 H, CH3 keto), 2.78 (dd, J = 14.3, 7.3 Hz, 0.5 H, CH2 ketal), 2.50 (dd, J = 14.3, 3.0 Hz, 0.5 H, CH2 ketal), 2.43 (d, J = 9,3 Hz, 1.3 H, CH2 ketal), 1.35 (t, J = 7.1 Hz, 2.8 H, CH3 ketal), 1.25 (t, J = 7.1 Hz, 0.2 H, CH3 keto). Spectral data are consistent with 13117


Article


Hz, 1.4 Hz, 0.6 H, ArH), 7.57−7.51 (m, 1 H, ArH), 7.36−7.16 (m, 6 H, ArH), 4.64 (d, J = 8.3 Hz, 0.2 H, CH keto); 4,21 (dd, J = 7,0 Hz, 2.5 Hz, 0.4 H, CH ketal), 4.14 (dd, J = 13.7 Hz, 6.8 Hz, 0.6 H, CH ketal), 3.88−3.83 (m, 0.2 H, CH2 keto), 3.27 (d, J = 19.5 Hz, 0.2 H, CH2 keto), 2.99 (d, J = 42.3 Hz, 1 H, CH2 keto), 2.48−2.39 (m, 1.7 H, CH2 keto), 2.30 (s, 0.5 H, CH3 ketal), 2.04 (s, 0.3 H, CH2 ketal), 1.98−1.94 (m, 0.7 H, CH2 ketal), 1.75 (s, 1.8 H, CH3 ketal), 1.70 (s, 1.2 H, CH3 ketal) ppm. Spectral data are consistent with those in the literature.27 Enantiomeric excess 99% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.8 mL/min, λ = 308 nm): tR(major) = 18.85 min, tR(minor) = 52.11 min. (4R)-4-(4-Methoxyphenyl-2-hydroxy-2-methyl-3,4dihydropyrano[3,2-c]chromene-5(2H)-one (5e). 41 mg (48%), white solid, mp 167−169 °C (lit. 164−166 °C), [α]D25 +18.9 (c 1.0, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.41 (s, 0.2 H), 7.86 (dd, J = 24.0 Hz, 7.4 Hz, 1 H, ArH), 7.59−7.48 (m, 1 H, ArH), 7.37− 7.13 (m, 4 H, ArH), 6.88−6.80 (m, 2 H, ArH), 4.65 (dd, J = 10.0 Hz; 2.1 Hz, 0.3 H, CH keto), 4.26 (dd, J = 6.6 Hz, 2.8 Hz, 0.5 H, CH ketal), 4.12 (dd, J = 11.3 Hz, 6.8 Hz, 0.6 H, CH ketal), 3.78 (s, 1.3 H, CH3 ketal), 3.77 (s, 1.7 H, CH3 keto), 3.26 (s, 0.5 H, CH2 keto), 3.09 (d, J = 1.9 Hz, 0.5 H, CH2 keto), 2.57−2.37 (m, 1.7 H, CH2 keto), 2.29 (s, 0.5 H, CH3 ketal), 2.04−1.96 (m, 0.7 H, CH2 ketal), 1.72 (s, 1.5 H, CH3 ketal), 1.68 (s, 1.5 H, CH3 ketal) ppm. Spectral data are consistent with those in the literature.27 Enantiomeric excess 84% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.6 mL/min, λ = 308 nm): tR(major) = 26.77 min, tR(minor) = 59.69 min. (4R) -4-(4-Chlorophenyl)-2-hydroxy-2,9-dimethyl-3,4dihydropyrano[3,2-c]chromene-5(2H)-one (5f). 37 mg (69%), yellow solid, mp 181−183 °C, [α]D25 +14.3 (c 0.6, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) 9.49 (s, 0.2 H), 7.72 (s, 1 H, ArH), 7.66 (s, 0.5 H, ArH), 7.60 (s, 0.5 H, ArH), 7.54−7.52 (m, 1 H, ArH), 7.38−7.32 (m, 1 H, ArH), 7.23−7.15 (m, 3 H, ArH), 4.63 (d, J = 10.2 Hz, 0.2 H, CH keto), 4.29 (d, J = 6.8 Hz, 1 H, CH ketal), 4.22−4.20 (m, 0.5 H, CH keto), 4.15 (dd, J = 11.5 Hz, 6.8 Hz, 0.5 H, CH keto), 3.85 (dd, J = 19.2 Hz, 10.5 Hz, 0.3 H, CH2 keto), 3.00 (s, 0.6 H, CH2 keto), 2.94 (s, 0.4 H, CH2 ketal), 2.47−2.40 (m, 4 H, CH2 and CH3 keto), 2.30 (s, 0.5 H, CH3 ketal), 1.75 (s, 1.7 H, CH3 ketal), 1.70 (s, 1.3 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.5, 167.7, 162.1, 159.5, 158.8, 151.1, 151.1, 141.8, 140.5, 133.7, 133.4, 133.1, 132.7, 132.1, 130.9, 129.4, 129.0, 128.8, 128.6, 128.4, 128.2, 127.9, 127.2, 127.0, 126.9, 126.5, 122.6, 122.3, 116.5, 116.3, 103.7, 101.0, 100.7, 98.7, 66.2, 65.9, 45.2, 42.3, 39.9, 36.5, 34.9, 34.0, 28.3, 27.9, 20.9. HRMS (ESI): m/z 357.0888 calcd for C20H18ClO4 [M + H]+; found 357.0888. IR (ATR): 3375, 2927, 1678, 1617, 1571, 1488, 1376, 1110, 815, 782. Enantiomeric excess 86% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.6 mL/ min, λ = 308 nm): tR(major) = 10.36 min, tR(minor) = 41.59 min. (4R)-2-Hydroxy-4-(4-methoxyphenyl)-2,9-dimethyl-3,4dihydropyrano[3,2-c]chromene-5(2H)-one (5g). 44 mg (83%), yellow solid, mp 186−188 °C, [α]D20 +5.3 (c 1, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.34 (s, 0.2 H), 7.72 (s, 1.6 H, ArH), 7.6 (s, 0.4 H, ArH), 7.54−7.52 (m, 1.6H, ArH), 7.22−7.18 (m, 1.4H), 6,87−6,80 (m, 2H, ArH), 4.64 (dd, J = 9.9 Hz, 2.5 Hz, 0.2 H, CH keto), 4.31−4,28 (m, 1.8 H, CH ketal and CH keto), 4.13−4.10 (m, 0.5 H, CH2 ketal), 3.86 (m, 0.2 H, CH2 keto), 3.78 (s, 1.2 H, CH3 ketal), 3.77 (s, 1.8 H, CH3 keto), 3.23 (s, 0.5 H, CH2 keto), 2.53 (dd, J = 14.2 Hz, 2.9 Hz, 0.5 H, CH2 keto), 2.48− 2.39 (m, 3,6 H, CH2 and CH3 ketal), 2.28 (s, 0.4 H, CH3 ketal), 2.04−1.99 (m, 0.6 H, CH2 ketal), 1.73 (s, 1.6 H, CH3 ketal), 1.68 (s, 1.4 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.6,

is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.45 (s, 0.2 H), 7.94 (dd, J = 8.0, 1.4 Hz; 0.2 H, ArH), 7.89 (dd, J = 8.0, 1.4 Hz, 0.5 H, ArH), 7.81 (dd, J = 8.2, 1.1 Hz, 0.5 H, ArH), 7.56 (ddd, J = 8.6, 7.3, 1.6 Hz, 0.5 H, ArH), 7.50−7.46 (m, 0.6 H, ArH), 7.36−7.20 (m, 7 H, ArH), 4.70 (dd, J = 10.0, 2.4 Hz, 0.2 H, CH keto), 4.28 (dd, J = 6.8, 3.3 Hz, 0.5 H, CH ketal), 4.16 (dd, J = 11.4, 6.9 Hz, 0.6 H, CH ketal), 3.86 (dd, J = 19.4, 10.1 Hz, 0.3 H, CH2 keto), 3.34 (d, J = 2.3 Hz, 0.1 H, CH2 keto), 3.28−3.25 (m, 0.6 H, CH2 keto), 3.20 (s, 0.5 H, CH2 ketal), 2.57−2.38 (m, 1.7 H, CH2 keto), 2.29 (s, 0.5 H, CH3 ketal); 2.05−1.97 (m, 0.7 H, CH2 ketal), 1.71(s, 1.6 H, CH3 ketal), 1.67 (s, 1.4 H, CH3 ketal). Spectral data are consistent with those in the literature.44 Enantiomeric excess 99% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 1 mL/min, λ = 308 nm): tR(major) = 15.76 min, tR(minor) = 49.29 min. (4R)-9-Bromo-2-hydroxy-2-methyl-4-phenyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5b). 68 mg (70%), white solid, mp 181−183 °C, [α]D25 +28.6 (c 1.0, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.63 (s, 0.2 H), 7.97 (dd, J = 47.9 Hz, 1.8 Hz, 1 H, ArH), 7.81 (dd, J = 8.6 Hz, 1.6 Hz, 0.5 H, ArH), 7.65 (dd, J = 8.7 Hz, 2.0 Hz, 0.5 H, ArH), 7.34−7.15 (m, 6 H, ArH), 4.68 (d, J = 9.9 Hz, 0.2 H, CH keto), 4.28 (dd, J = 6.6 Hz, 2.7 Hz, 0.5 H, CH ketal), 4.15 (dd, J = 11.4 Hz, 6.9 Hz, 0.7 H, CH ketal), 3.84 (dd, J = 15.6 Hz, 8.6 Hz, 0.3 H, CH2 keto), 3.32 (d, J = 20.1 Hz, 0.2 H, CH2 keto), 3.17 (s, 1 H, CH2 ketal), 2.56−2.39 (m, 1.7 H, CH2 keto), 2.30 (s, 0.5 H, CH3 ketal), 2.04−1.98 (m, 0.8 H, CH2 ketal), 1.74 (s, 1.6 H, CH3 ketal), 1.69 (s, 1.4 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 161.4, 160.5, 158.4, 157.4, 151.8, 151.7, 142.7, 141.1, 134.8, 134.3, 129.2, 128.7, 127.3, 127.0, 126.9, 126.6, 125.7, 125.3, 118.4, 118.3, 117.4, 116.8, 116.4, 105.3, 102.1, 100.8, 99.2, 42.3, 39.8, 35.4, 34.1, 28.3, 27.8. HRMS (ESI): m/z 387.0233 calcd for C19H16BrO4 [M + H]+; found 387.0230. IR (ATR): 3363, 1683, 1609, 1558, 1479, 1412, 1373, 1066, 878, 780. Enantiomeric excess 94% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 75:25, flow rate 0.5 mL/min, λ = 308 nm): tR(major) = 20.74 min, tR(minor) = 50.29 min. (4R)-2-Hydroxy-2,9-dimethyl-4-phenyl-3,4-dihydropyrano[3,2c]chromene-5(2H)-one (5c). 72 mg (90%), white solid, mp 178−181 °C, [α]D25 +12.3 (c = 1.0, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.41 (s, 0.2 H), 7.64 (d, J = 47.4 Hz, 1 H, ArH), 7.37−7.11 (m, 7 H, ArH), 4.70 (d, J = 10.1 Hz, 0.2 H, CH keto), 4.28 (dd, J = 6.9 Hz, 3.2 Hz, 0.5 H, CH ketal), 4.15 (dd, J = 11.3 Hz, 6.9 Hz, 0.5 H, CH ketal), 3.86 (dd, J = 19.4 Hz, 10.1 Hz, 0.2 H, CH2 keto), 3.31 (dd, J = 19.4 Hz, 2.4 Hz, 0.2 H, CH2 keto), 3.19 (d, J = 13.3 Hz, 1 H, CH2 ketal), 2.54 (dd, J = 14.2 Hz, 3.3 Hz, 0.5 H, CH2 keto), 2.49− 2.39 (m, 4 H, CH2 and CH3 keto), 2.29 (s, 0.5 H, CH3 ketal), 2.04− 1.98 (m, 0.6 H, CH2 ketal), 1.72 (s, 1.5 H, CH3 ketal), 1.68 (s, 1.5 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.6, 177.9, 162.3, 161.4, 159.6, 158.6, 151.1, 151.1, 143.2, 141.5, 133.6, 133.3, 133.0, 132.5, 129.2, 128.6, 128.1, 127.9, 127.2, 127.0, 126.9, 126.5, 122.7, 122.3, 116.4, 116.3, 104.0, 101.0, 100.4, 98.9, 45.2, 42.5, 40,0, 35.3, 34.9, 34.1, 30.0, 28.3, 27.7, 20.9. HRMS (ESI): m/z 323.1279 calcd for C20H19O4 [M + H]+; found 323.1280. IR (ATR): 3428, 2926, 1687, 1610, 1577, 1492, 1379, 1064, 997, 764. Enantiomeric excess 96% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 75:25, flow rate 1 mL/min, λ = 308 nm): tR(major) = 7.37 min, tR(minor) = 22.31 min. (4R)-4-(4-Chlorophenyl)-2-hydroxy-2-methyl-3,4dihydropyrano[3,2-c]chromene-5(2H)-one (5d). 40 mg (47%), white solid, mp 177−179 °C (lit. 174−176 °C), [α]D25 +15.6 (c = 1.0, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.55 (s, 0.2 H), 7.88 (dd, J = 7.9 Hz, 1.4 Hz, 0.4 H, ArH), 7.82 (dd, J = 7.9 13118



■

167.7, 162.3, 159.4, 158.7, 158.1, 151.1, 151.1, 135.1, 133.6, 133.3, 132.9, 132.5, 130.9, 129.0, 128.8, 128.0, 123.5, 122.7, 122.3, 116.4, 116.3, 114.7, 114.1, 104.3, 101.2, 100.4, 98.9, 66.2, 65.9, 55.3, 45.5, 42.5, 39.8, 36.6, 36.5, 34.3, 33.1, 32.5, 29.2, 27.9, 26.8, 23.0, 20.9. HRMS (ESI): m/z 353.1384 calcd for C21H21O5 [M + H]+; found 353.1382. IR (ATR): 3386, 2930, 1681, 1607, 1575, 1376, 1248, 1113, 815, 784. Enantiomeric excess 72% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.6 mL/min, λ = 308 nm): tR(major) = 12.90 min, tR(minor) = 38.19 min. (4R)-9-Bromo-4-(4-chlorophenyl)-2-hydroxy-2-methyl-3,4dihydropyrano[3,2-c]chromene-5(2H)-one (5h). 61 mg (97%), yellow solid, mp 215−217 °C, [α]D20 +24.6 (c 0.5, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.68 (s, 0.3 H), 8.09 (s, 0.3 H, ArH), 7.96 (dd, J = 38.5 Hz, 2.3 Hz, 1 H, ArH), 7.65 (dd, J = 11.0 Hz, 2.2 Hz, 0.4 H, ArH), 7.60 (dd, J = 8.8 Hz, 2.4 Hz, 0.6 H, ArH), 7.28−7.27 (m, 1.2 H, ArH), 7.25−7.14 (m, 3.5 H, ArH), 4.62 (dd, J = 10.0 Hz; 1.8 Hz, 0.2 H, CH keto), 4.28−4.19 (m, 0.8 H, CH ketal), 4.13 (dd, J = 11.8 Hz, 6.8 Hz, 0.7 H, CH ketal), 3.84 (dd, J = 19.3 Hz, 10.6 Hz, 0.3 H, CH ketal), 3.06 (s, 0.6 H, CH2 keto), 2.96 (s, 0.4 H, CH2 keto), 2.48−2.38 (m, 1.6 H, CH2 keto), 2.31 (s, 0.5 H, CH3 ketal), 2.04−1.92 (m, 1 H, CH2 ketal), 1.76 (s, 1.7 H, CH3 ketal), 1.71 (s, 1.3 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 161.3, 160.4, 158.4, 157.6, 141.3, 140.1, 134.9, 134.5, 132.3, 129.5, 129.0, 128.8, 128.6, 128.4, 128.3, 126.6, 125.6, 118.5, 118.3, 117.3, 117.0, 116.8, 116.5, 104.8, 102.1, 100.5, 99.2, 42.1, 39.7, 38.9, 34.9, 34.4, 34.1, 30.0, 29.7, 29.0, 28.3, 28.0. HRMS (ESI): m/z 420.9837 calcd for C19H15BrClO4 [M + H]+; found 420.9836. IR (ATR): 3351, 2928, 1678, 1610, 1560, 1480, 1411, 1373, 1066, 878. Enantiomeric excess > 99% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 75:25, flow rate 0.8 mL/min, λ = 308 nm): tR(major) = 25.74 min, tR(minor) = 74.03 min. (4R)-9-Bromo-2-hydroxy-4-(4-methoxyphenyl)-2-methyl-3,4dihydropyrano[3,2-c]chromen-5(2H)-one (5i). 43 mg (69%), white solid, mp 78−80 °C, [α]D20 +21.3 (c 0.5, CH3CN). The product was found to exist in rapid equilibrium with a pseudodiastereomeric hemiketal form in solution. The equilibrium is very rapid; therefore, no pseudodiastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 9.60 (s, 0.2 H), 8.09 (s, 0.2 H, ArH), 8.05 (s, 0,1 H, ArH), 7.94 (dd, J = 61.0 Hz, 2.3 Hz, 0.7 H, ArH), 7.63 (dd, J = 8.5 Hz, 6.1 Hz, 0.4 H, ArH), 7.53 (dd, J = 8.7 Hz, 2.3 Hz, 0.6 H, ArH), 7.18 (dd, J = 20.0 Hz, 8.7 Hz, 1.5 H, ArH), 7.10 (dd, J = 19.8 Hz, 9.9 Hz, 1.5 H, ArH), 6.85−6.80 (m, 2 H, ArH), 4.62 (dd, J = 9.7 Hz; 1.8 Hz, 0.2 H, CH keto), 4.27−4.20 (m, 0.8 H, CH ketal), 4.11 (dd, J = 15.9 Hz, 8.7 Hz, 0.8 H, CH ketal), 3.77 (s, 1.6 H, CH3 ketal), 3.76 (s, 1.4 H, CH3 keto), 3.45 (s, 0.5 H, CH2 keto), 3.27 (dd, J = 19.4 Hz, 2.2 Hz, 0.3 H, CH2 keto), 2.52−2.35 (m, 1.7 H, CH2 keto), 2.28 (s, 0.5 H, CH3 ketal), 2.04−1.94 (m, 1 H, CH2 ketal), 1.68 (s, 1.6 H, CH3 ketal), 1.66 (s, 1.4 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.7, 166.0, 161.6, 160.7, 158.7, 158.4, 158.2, 157.5, 151.7, 151.6, 151.1, 134.8, 134.7, 134.2, 132.8, 129.5, 129.1, 128.0, 125.7, 125.3, 118.3, 118.2, 117.5, 117.1, 116.8, 116.4, 114.6, 114.1, 105.4, 102.4, 100.9, 99.5, 67.8, 60.4, 55.2, 45.4, 42.5, 39.8, 38.9, 34.6, 33.4, 30.5, 29.0, 28.0, 27.7, 24.0, 23.0. HRMS (ESI): m/z 417.0332 calcd for C20H18BrO5 [M + H]+; found 417.0332. IR (ATR): 3356, 2926, 1687, 1611, 1561, 1479, 1374, 1230, 1071, 877. Enantiomeric excess 86% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 90:10, flow rate 1.0 mL/min, λ = 308 nm): tR(major) = 18.65 min, tR(minor) = 36.47 min.

■

Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Tel.: +421 2 60296208. ORCID

Radovan Š ebesta: 0000-0002-7975-3608 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the Slovak Grant Agency VEGA, Grant VEGA 1/0414/16. This publication is the result of the project implementation 262401200025 supported by the Research & Development Operational Programme funded by the ERDF.

■

REFERENCES

(1) Zhao, B.-L.; Li, J.-H.; Du, D.-M. Squaramide-Catalyzed Asymmetric Reactions. Chem. Rec. 2017, 17, 994−1018. (2) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional Amine-Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions. Adv. Synth. Catal. 2015, 357, 253−281. (3) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem. - Eur. J. 2011, 17, 6890−6899. (4) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130, 14416−14417. (5) Min, C.; Han, X.; Liao, Z.; Wu, X.; Zhou, H.-B.; Dong, C. C3Symmetrical Cinchonine-Squaramide as New Highly Efficient, and Recyclable Organocatalyst for Enantioselective Michael Addition. Adv. Synth. Catal. 2011, 353, 2715−2720. (6) Yang, W.; Du, D.-M. Chiral Squaramide-Catalyzed Highly Enantioselective Michael Addition of 2-Hydroxy-1,4-naphthoquinones to Nitroalkenes. Adv. Synth. Catal. 2011, 353, 1241−1246. (7) Dong, Z.; Qiu, G.; Zhou, H.-B.; Dong, C. Chiral squaramide as multiple H-bond donor organocatalysts for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroolefins. Tetrahedron: Asymmetry 2012, 23, 1550−1556. (8) Baran, R.; Veverková, E.; Š kvorcová, A.; Š ebesta, R. Enantioselective Michael addition of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides - a key step in the synthesis of pregabalin. Org. Biomol. Chem. 2013, 11, 7705−7711. (9) Işık, M.; Unver, M. Y.; Tanyeli, C. Modularly Evolved 2AminoDMAP/Squaramides as Highly Active Bifunctional Organocatalysts in Michael Addition. J. Org. Chem. 2015, 80, 828−835. (10) Veverková, E.; Bilka, S.; Baran, R.; Š ebesta, R. SquaramideCatalyzed Michael Addition as a Key Step for the Direct Synthesis of GABAergic Drugs. Synthesis 2016, 48, 1474−1482. (11) Xu, D.-Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chiral Squaramides as Highly Enantioselective Catalysts for Michael Addition Reactions of 4-Hydroxycoumarins and 4-Hydroxypyrone to β,γ-Unsaturated α-Keto Esters. Chem. - Eur. J. 2010, 16, 4177−4180. (12) Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhang, G.-C.; Xia, A.-B.; Xu, X.-S.; Xu, D.-Q. Highly Enantioselective Organocatalytic Michael Addition of 2-Hydroxy- 1,4-naphthoquinone to β,γ-Unsaturated αOxo Esters. Eur. J. Org. Chem. 2010, 2010, 4981−4985. (13) Wang, Y.-F.; Wang, K.; Zhang, W.; Zhang, B.-B.; Zhang, C.-X.; Xu, D.-Q. Enantioselective Asymmetric Michael Addition of Cyclic Diketones to β,γ-Unsaturated α-Keto Esters. Eur. J. Org. Chem. 2012, 2012, 3691−3696. (14) Halland, N.; Hansen, T.; Jørgensen, K. A. Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated KetonesA Highly Atom-Economic Catalytic

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01847. Pictures of 1H and 13C NMR spectra, HPLC chromatograms, ECD spectra, and DFT computational details (PDF) 13119


Article

The Journal of Organic Chemistry One-Step Formation of Optically Active Warfarin Anticoagulant. Angew. Chem., Int. Ed. 2003, 42, 4955−4957. (15) Dong, Z.; Wang, L.; Chen, X.; Liu, X.; Lin, L.; Feng, X. Organocatalytic Enantioselective Michael Addition of 4-Hydroxycoumarin to α,β-Unsaturated Ketones: A Simple Synthesis of Warfarin. Eur. J. Org. Chem. 2009, 2009, 5192−5197. (16) Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Enantioselective Synthesis of Polycyclic Coumarin Derivatives Catalyzed by an in Situ Formed Primary Amine-Imine Catalyst. Org. Lett. 2011, 13, 4382−4385. (17) Zhu, L.; Zhang, L.; Luo, S. Catalytic Asymmetric β-C−H Functionalizations of Ketones via Enamine Oxidation. Org. Lett. 2018, 20, 1672−1675. (18) Kucherenko, A. S.; Kostenko, A. A.; Zhdankina, G. M.; Kuznetsova, O. Y.; Zlotin, S. G. Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinolinederived 1,2-diamines. Green Chem. 2018, 20, 754−759. (19) Rogozińska-Szymczak, M.; Mlynarski, J. Asymmetric synthesis of warfarin and its analogues on water. Tetrahedron: Asymmetry 2014, 25, 813−820. (20) Rogozińska, M.; Adamkiewicz, A.; Mlynarski, J. Efficient “on water” organocatalytic protocol for the synthesis of optically pure warfarin anticoagulant. Green Chem. 2011, 13, 1155−1157. (21) Kucherenko, A. S.; Siyutkin, D. E.; Nigmatov, A. G.; Chizhov, A. O.; Zlotin, S. G. Chiral Primary Amine Tagged to Ionic Group as Reusable Organocatalyst for Asymmetric Michael Reactions of CNucleophiles with α,β-Unsaturated Ketones. Adv. Synth. Catal. 2012, 354, 3078−3086. (22) Kucherenko, A. S.; Lisnyak, V. G.; Chizhov, A. O.; Zlotin, S. G. Primary Amine Attached to an N-(Carboxyalkyl)imidazolium Cation: A Recyclable Organocatalyst for the Asymmetric Michael Reaction. Eur. J. Org. Chem. 2014, 2014, 3808−3813. (23) Porta, R.; Benaglia, M.; Coccia, F.; Rossi, S.; Puglisi, A. Enantioselective Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S)-Pregabalin Precursor and (S)-Warfarin. Symmetry 2015, 7, 1395. (24) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Highly Enantioselective Michael Addition of Cyclic 1,3Dicarbonyl Compounds to α,β-Unsaturated Ketones. Org. Lett. 2007, 9, 413−415. (25) Mei, R.-Q.; Xu, X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X. Highly effective and enantioselective Michael addition of 4hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011, 52, 1566−1568. (26) Modrocká, V.; Veverková, E.; Baran, R.; Š ebesta, R. Enantioselective Synthesis of 2,3-Dihydrofurocoumarins by Squaramide-Catalyzed Michael Addition/Cyclization of 4-Hydroxycoumarins with β-Nitrostyrenes. ChemistrySelect 2018, 3, 1466−1471. (27) Yang, H.-M.; Li, L.; Jiang, K.-Z.; Jiang, J.-X.; Lai, G.-Q.; Xu, L.W. Highly enantioselective synthesis of warfarin and its analogs by means of cooperative LiClO4/DPEN-catalyzed Michael reaction: enantioselectivity enhancement and mechanism. Tetrahedron 2010, 66, 9708−9713. (28) Clarke, C. J.; Tu, W.-C.; Levers, O.; Bröhl, A.; Hallett, J. P. Green and Sustainable Solvents in Chemical Processes. Chem. Rev. 2018, 118, 747−800. (29) Zhang, Q.; De Oliveira Vigier, K.; Royer, S.; Jerome, F. Deep eutectic solvents: syntheses, properties and applications. Chem. Soc. Rev. 2012, 41, 7108−7146. (30) Pereira, C. S. M.; Silva, V. M. T. M.; Rodrigues, A. E. Ethyl lactate as a solvent: Properties, applications and production processes - a review. Green Chem. 2011, 13, 2658−2671. (31) Pires, M. J. D.; Purificaçaõ , S. I.; Santos, A. S.; Marques, M. M. B. The Role of PEG on Pd- and Cu-Catalyzed Cross-Coupling Reactions. Synthesis 2017, 49, 2337−2350. (32) Tang, S.; Zhao, H. Glymes as versatile solvents for chemical reactions and processes: from the laboratory to industry. RSC Adv. 2014, 4, 11251−11287.

(33) Shanab, K.; Neudorfer, C.; Spreitzer, H. Green Solvents in Organic Synthesis: An Overview II. Curr. Org. Chem. 2016, 20, 1576− 1583. (34) Pace, V.; Hoyos, P.; Castoldi, L.; Domínguez de María, P.; Alcántara, A. R. 2-Methyltetrahydrofuran (2-MeTHF): A BiomassDerived Solvent with Broad Application in Organic Chemistry. ChemSusChem 2012, 5, 1369−1379. (35) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Enantioselective Synthesis of Coumarins Catalyzed by a Bifunctional Amine−Thiourea Catalyst. Chem. - Eur. J. 2010, 16, 13068−13071. (36) Regalado, E. L.; Sherer, E. C.; Green, M. D.; Henderson, D. W.; Thomas, W. R.; Joyce, L. A.; Welch, C. J. Chromatographic Separation and Assignment of Absolute Configuration of Hydroxywarfarin Isomers. Chirality 2014, 26, 95−101. (37) Mailhol, D.; Duque, M. d. M. S.; Raimondi, W.; Bonne, D.; Constantieux, T.; Coquerel, Y.; Rodriguez, J. Enantioselective Organocatalytic Michael Addition of Cyclobutanones to Nitroalkenes. Adv. Synth. Catal. 2012, 354, 3523−3532. (38) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H. Squaramide-catalyzed enantioselective Friedel-Crafts reaction of indoles with imines. Chem. Commun. 2010, 46, 3004−3006. (39) Kasaplar, P.; Riente, P.; Hartmann, C.; Pericàs, M. A. A Polystyrene-Supported, Highly Recyclable Squaramide Organocatalyst for the Enantioselective Michael Addition of 1,3-Dicarbonyl Compounds to β-Nitrostyrenes. Adv. Synth. Catal. 2012, 354, 2905− 2910. (40) Vargová, D.; Baran, R.; Š ebesta, R. Stereoselective synthesis of 4-methylpregabalin via organocatalytic Michael addition to a racemic nitroalkene. Beilstein J. Org. Chem. 2018, 14, 553−559. (41) Albrecht, Ł.; Dickmeiss, G.; Acosta, F. C.; Rodríguez-Escrich, C.; Davis, R. L.; Jørgensen, K. A. Asymmetric Organocatalytic Formal [2 + 2]-Cycloadditions via Bifunctional H-Bond Directing Dienamine Catalysis. J. Am. Chem. Soc. 2012, 134, 2543−2546. (42) Liu, Y.; Lu, A.; Hu, K.; Wang, Y.; Song, H.; Zhou, Z.; Tang, C. Bifunctional Primary Amine-Squaramide Catalyzed Enantioselective Intramolecular Michael Addition of Keto-enones: A Convenient Process to the Stereocontrolled Construction of trans-Dihydrobenzofuran Skeletons. Eur. J. Org. Chem. 2013, 2013, 4836−4843. (43) Liu, Y.; Liu, X.; Wang, M.; He, P.; Lin, L.; Feng, X. Enantioselective Synthesis of 3,4-Dihydropyran Derivatives via Organocatalytic Michael Reaction of α,β-Unsaturated Enones. J. Org. Chem. 2012, 77, 4136−4142. (44) Dong, J.; Du, D.-M. Highly enantioselective synthesis of Warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalysts. Org. Biomol. Chem. 2012, 10, 8125−8131.

13120


Bifunctional Amine-Squaramides as Organocatalysts in Michael

Recommend Documents