Asymmetric Michael/hemiketalization of 5-hydroxy-2-methyl-4H-pyran-4-one to β,γ-unsaturated α-ketoesters catalyzed by a bifunctional rosin–indane amine thiourea catalyst

Abstract

A highly efficient asymmetric cascade reaction namely Michael-hemiketalization of 5-hydroxy-2-methyl-4H-pyran-4one to β,γ-unsaturated α-ketoesters has been developed using a chiral bifunctional rosin–indane amine thiourea catalyst. The products are obtained in excellent yields with a high degree of enantiomeric excess (up to 99% ee), in a short reaction time with low catalyst loading of 2.5 mol%.

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Introduction

Kojic acid (a fungal metabolite) is used as an additive in cosmetics to lighten the skin color and is known to inhibit the copper containing enzyme tyrosinase that causes melanization in humans (Fig. 1).¹ It is also found to exhibit a wide range of biological activities such as antifungal,² anti-neoplastic,³ anti-proliferative,⁴ anti-HIV,⁵ anti-convulsant,⁶ anti-inflammatory,⁷ antioxidative,⁸ anti-bacterial⁹ and tyrosinase inhibitory activity.¹⁰

Fig. 1 Kojic acid and its derivatives.

In this context, 5-hydroxy-2-methyl-4H-pyran-4one 1 (allomaltol) is used for the treatment of pigmentation disorders, sunburn prevention and also useful as an antioxidant for oils and fats.¹¹ In view of the significance of kojic acid and its derivatives in the field of medicinal chemistry (Fig. 1), the development of efficient approaches to generate pharmaceutical relevant scaffolds are still a challenging task for the synthetic chemists. Recently, organocatalytic Michael reaction has been recognized as one of the most elegant approaches for carbon–carbon bond forming reactions.¹² In this prospect, a bifunctional thiourea-amine catalyzed conjugate addition has extensively been investigated over the past decade due to their extensive H-bonding ability to induce the chirality.¹³ In particular, β,γ-unsaturated α-ketoesters act as effective Michael acceptors in asymmetric conjugate addition reactions.¹⁴ However, a few methods are reported on Michael addition/heketalization of β,γ-unsaturated α-ketoesters with different nucleophiles^15–20 including cyclic 1,3-dicarbonyls and 2-hydroxy-1,4-naphtha-quinones using chiral metal complexes or organocatalysts such as thioureas or squaramides. Nevertheless, there are still some drawbacks in these procedures, such as high catalyst loading, low temperature and long reaction time for high enantioselectivity.

Therefore, still there is a demand for efficient catalytic systems in exploring β,γ-unsaturated α-ketoesters as Michael acceptors. Recently, we have successfully demonstrated a novel bifunctional rosin–indane amine thiourea catalyzed asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone and 1,3-dicarbonyl compounds to β-nitroalkenes to produce the chiral molecules in good yields with excellent enantioselectivity.²¹ Inspired by the unique catalytic performance of rosin–indane amine thiourea organocatalysis²² for synthesizing chiral molecules, we attempted a novel asymmetric cascade reaction of allomaltol with β,γ-unsaturated α-ketoesters to produce the chiral tetrahydro pyrano[3,2-b]pyran scaffolds.

To evaluate the efficacy of thiourea catalysts, we performed the conjugate addition of 5-hydroxy-2-methyl-4H-pyran-4-one to (E)-ethyl 2-oxo-4-phenylbut-3-enoate using a series of bifunctional thiourea and squaramide catalysts bearing different chiral diamines I–XI (Fig. 2). Allomaltol was prepared from the commercially available kojic acid in two-steps according to the procedure reported in literature.²³ In a model reaction, 5-hydroxy-2-methyl-4H-pyran-4-one was treated with (E)-ethyl 2-oxo-4-phenylbut-3-enoate in the presence of 10 mol% of catalyst in DCM at 25 °C (Table 1).

Fig. 2 Bifunctional thiourea catalysts.

Table 1 Screening of catalysts in the formation of 3a^a

Entry	Catalyst	Solvent	T °C	Time (h)	Yield^b (%)	ee^c (%)
a Unless noted the reaction was carried out with 1 (0.2 mmol), 2a (0.22 mmol) in the presence of mol% organocatalyst.b Isolated yields after column chromatography.c Determined by chiral HPLC.d 2.5 mol% catalyst used.
a	I	CH2Cl2	25	4	96	87
b	II	CH2Cl2	25	6	93	82
c	III	CH2Cl2	25	8	96	−80
d	IV	CH2Cl2	25	5	95	78
e	V	CH2Cl2	25	5	94	88
f	VI	CH2Cl2	25	6	95	90
g	VII	CH2Cl2	25	6	94	−83
h	VIII	CH2Cl2	25	12	93	77
i	IX	CH2Cl2	25	12	96	71
j	X	CH2Cl2	25	6	92	81
k	XI	CH2Cl2	25	15	68	36
l	VI	CH2Cl2	0	12	96	97
m	VI	CH2Cl2	0	12	96	97^d
n	V	CH2Cl2	0	12	97	92^d
o	VI	CH2Cl2	−20	24	90	75
p	VI	PhCH3	25	7	92	73
q	VI	DCE	25	7	91	76
r	VI	o-xylene	25	7	88	45
s	VI	CH3CN	25	7	84	64
t	VI	i-PrOH	25	7	76	37

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The corresponding Michael adduct was found to exist in a rapid equilibrium between the cyclic hemiketal 3a and acyclic Michael adduct 3a′ in a ratio of 1.5 : 1 as shown in Scheme 1 revealed by ¹H and ¹³C NMR spectra.²⁴

Scheme 1 Equilibrium of the product 3a and 3a′.

As shown in Table 1, the 9-epi-dihydroquinine-derived thiourea catalyst I afforded the desired Michael adduct reasonably in good yield and enantioselectivity (87% ee, Table 1, entry a). Using quinine-derived catalyst II, there was a drop in enantioselectivity (82% ee, Table 1, entry b) compared to catalyst I. Moreover, a slight decrease in enantioselectivity with an opposite sense of asymmetric induction was observed using psuedodiastereomeric dihdroquininidine-derived thiourea III catalyst (−80% ee, Table 1, entry c). By using indane-thiourea catalysts IV and V,²⁵ the desired product was obtained with 78% and 88% ee respectively (Table 1, entries d and e). Gratifyingly, the rosin–indane amine thiourea catalyst VI shows a remarkable catalytic effect in this reaction affording the desired Michael adduct in 95% yield with 90% ee (Table 1, entry f). However, a significant decrease in enantioselectivity was observed with catalyst X derived from (1R,2R)-amino-1,2-indanol bearing a sugar moiety (81% ee, Table 1, entry j). Similarly, indane-derived squaramides VII and IX bearing mono- or bis-trifluoromethyl groups also showed a detrimental effect in terms of enantioselectivity (77% ee and 71% ee, Table 1, entries h and i). Furthermore, a poor enantio-selectivity was observed even with aminoindanol based thiourea catalyst XI (36% ee, Table 1, entry k).

After several experiments, the catalyst VI was found to be optimal for this reaction in terms of enantioselectivity. With the best catalyst in hand, we next focused our attention towards the screening of different solvents, catalyst loading and effect of temperature. Among various solvents tested, high conversions and good enantioselectivity were achieved in dichloromethane (Table 1, entry f), whereas moderate enantioselectivity was observed in non-polar solvents like toluene and o-xylene (Table 1, entries p and r). Polar solvents like acetonitrile and iPrOH gave poor enantioslectivity due to their interference in H-bonding catalysis (64% and 37% ee, Table 1, entries s and t). Furthermore, the reaction temperature was found to have a significant influence on the enantioselectivity of this reaction. By lowering the temperature to, the enantio selectivity was remarkedly increased to 97% ee (Table 1, entry l) while a slight deterioration and longer time were observed when the reaction was carried out at −20 °C (87% ee, Table 1, entry o). Furthermore, retention of the enantioselectivity was observed with similar yield when the catalyst loading was decreased to 2.5 mol% at 0 °C (97% ee, Table 1, entry m). The superiorty of catalyst VI over V was further confirmed by performing the model reaction using 2.5 mol% of V at 0 °C. However, the desired Michael adduct was obtained with 92% ee with catalyst V, which is lower compared to 97% ee that was obtained from catalyst VI (Table 1, entries m and n). These results clearly indicate that VI is the better catalyst in term of enantioselectivity than catalyst V (entries m and n, Table 1). Thus, the best optimal reaction conditions for this Michael addition were determined to be 0.2 mmol of 5-hydroxy-2-methyl-4H-pyran-4-one (1), 0.22 mmol of (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) with 2.5 mol% of catalyst VI in 2 mL DCM at 0 °C for 12 h.

With a set of optimized reaction conditions in hand, we then investigated the scope of this asymmetric Michael reaction with a range of β,γ-unsaturated α-ketoesters. The results are summarized in Table 2. In general, the substituents present on aromatic ring of the β,γ-unsaturated α-ketoesters are well tolerated under the reaction conditions (Table 2, entries a–o). As shown in Table 2, the desired (4R)-ethyl 4-(phenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate derivatives (3a–o) were obtained in 88–95% yields with 86 to >99% ee (Table 2, entries a–o). However, the electronic properties and position of the substituent on aromatic ring of the β,γ-unsaturated α-ketoesters didnot show significant influence on the outcome of the reaction. Notably, disubstituted aromatic substrates, naphthalen-2-yl and heteroaromatic alkenes also participated well to give the corresponding products in excellent yields and enantioselectivity (95% ee, >99% ee and 93% ee, Table 2, entries h, i, j and l). The crystal structures of 3i and 5c were elucidated by single crystal X-ray diffraction (Fig. 3). The absolute configuration of the 5c was confirmed by unambiguous refinement of the absolute structure parameter.²⁶

Table 2 Asymmetric Michael/hemiketalization reaction using thiourea catalyst VI^a

Entry	R^1	R^2	Product	Yield^b (%)	ee^c (%)	Config.
a Reaction was carried out with 1 (0.2 mmol), 2a (0.22 mmol) in 2 mL of DCM.b Isolated yields after column chromatography.c Determined by chiral HPLC.
a	C6H5	Et	3a	93	97	R
b	4-BrC6H4	Et	3b	95	96	R
c	4-ClC6H4	Et	3c	94	95	R
d	4-FC6H4	Et	3d	95	94	R
e	4-MeC6H4	Et	3e	95	95	R
f	3-ClC6H4	Et	3f	93	86	R
g	3-FC6H4	Et	3g	91	96	R
h	2,4-Cl2C6H3	Et	3h	92	95	R
i	2-Napthyl	Et	3i	94	>99	R
j	2-Thienyl	Et	3j	96	93	R
k	4-MeOC6H4	Me	3k	90	90	R
l	2-Furyl	Me	3l	90	>99	R
m	C6H5	Me	3m	95	99	R
n	C6H5	iPr	3n	91	88	R
o	C6H5	tBu	3o	88	90	R

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Fig. 3 A view of 3i and 5c, showing the atom-labelling scheme.

In Fig. 3, displacement ellipsoids are drawn at the 30% probability level and H atoms are represented by circles of arbitrary radii. Minor disordered components (O4′/O5′/C21′/C22′) of 3i have been omitted for clarity.

Encouraged by the above results, we extended this process to different kojic acid derivatives. In general, the reaction proceeded smoothly with TBS protected kojic acid (4a), chloro-kojic acid (4b) and thio-kojic acid (4c) to afford the Michael adducts (5a–5d) in good yields (93–95%) and excellent enantioselectivity (92–95%) (Table 3).

Table 3 Asymmetric Michae/hemiketalizationl addtion of kojic acid derivatives (4a,b,c)^a

Entry	R^1	R^2	Product	Yield^b (%)	ee^c (%)
a Reaction was carried out with 4 (0.2 mmol), 2a (0.22 mmol) in the presence of 2.5 mol% organocatalyst.b Isolated yields.c Determined by chiral HPLC.
a	C6H5	OTBS	5a	93	92(R)
b	4-BrC6H4	OTBS	5b	95	94(R)
c	C6H5	CI	5c	94	95(R)
d	C6H5	4-CIC6H4S	5d	95	95(R)

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In order to show its practicality, the reaction was performed in gram quantities (Scheme 2). The desired Michael adduct 3b was still obtained in excellent yield and enantioselectivity (1.67 g, 89% yield, 94% ee) using 2.5 mol% of the organocatalyst VI (Scheme 2).

Scheme 2 Asymmertic Michael/hemiketalization reaction in gram scale.

On the basis of previous mechanistic aspects, we imagined that a ternary complex of thiourea catalyst VI, 5-hydroxy-2-methyl-4H-pyran-4one and (E)-ethyl 2-oxo-4-phenylbut-3-enoate is involved in the transition state. In the plausible transition state, as shown in Fig. 4, the thiourea moiety of the catalyst VI activates the (E)-ethyl-2-oxo-4-phenylbut-3-enoate (2a) through hydrogen bonding, while tertiary amine activates the 5-hydroxy-2-methyl-4H-pyran-4one (1). With these synergistic interactions, the nucleophile attacks from the Si face leading to the formation (R)-enantiomer as a major stereoisomer.

Fig. 4 A ternary complex.

Conclusion

In conclusion, we have successfully demonstrated a rosin–indane amine thiourea catalyzed first asymmetric Michael addition of 5-hydroxy-2-methyl-4H-pyran-4one to β,γ-unsaturated α-keto esters. This asymmetric cascade reaction provides the Michael adducts in high yields (upto 98%) and excellent enantiomeric excess (upto >99% ee) under mild conditions with lower catalyst loading (2.5 mol%). Further investigation of the application of this organocatalyst is in progress in our group.

Experimental

General remarks

All the solvents were purchased from commercial source and dried prior to use. All the enantioselective Michael reactions were performed in an oven-dried Schlenk flask under an inert atmosphere of argon. All products were purified by column chromatography on silica gel 60–120 mesh using a mixture of ethyl acetate–hexane as eluents. Progress of the reaction was monitored by Thin Layer Chromatography. ¹H NMR spectra were recorded in CDCl₃ using 300 MHz or 500 MHz spectrometers. ¹³C NMR spectra were recorded in CDCl₃ using 75 MHz and 125 MHz NMR spectrometers. The chemical shifts (δ) were reported in parts per million (ppm) with respect to TMS as an internal standard. The coupling constants (J) are quoted in Hertz (Hz). Mass spectra were recorded on mass spectrometer by electrospray ionization (ESI) technique. HPLC analysis was carried out in a Shimadzu LC-20 using chiral columns. A mixture of hexane-isopropyl alcohol was used as eluent. Optical rotations of the products were recorded on Digipol-781 M6U Polarimeter.

Catalyst I was directly used from Sigma Aldrich. Catalysts II and III were prepared according to the procedures reported in literature.²⁷ Catalysts IV, V and XI were prepared according to the procedures reported in literature.²⁵

General procedure for preparing thiourea catalysts VI and VII

To a stirred solution of chiral aminoindane (2 mmol) in dichloromethane (8 mL) was added a solution of dehydroabiethyl isothiocyanate (2.4 mmol) in dichloromethane (12 mL) dropwise under nitrogen atmosphere. After completion, the resulting mixture was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel (hexane/EtOAc = 1 : 1) to give the thiourea catalyst as a white solid.

Spectral data for ligand VI. 1-(((1R,4aS,10aR)-7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methyl)-3-(1-(piperidin-1-yl)-2,3-dihydro-1H-inden-2-yl)thiourea: white solid, yield 85%, m.p. = 132–134 °C; [α]²⁸_D = −86.9 (c = 0.5, in CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ 1.05 (s, 3H), 1.15–1.27 (m, 9H), 1.29–1.50 (m, 4H), 1.53–1.89 (m, 9H), 2.33 (d, J = 13.0 Hz, 1H) 2.45–2.61 (m, 4H), 2.77–3.01 (m, 4H), 3.01–3.21 (m, 1H), 3.50 (brs, 1H, NH), 6.33 (brs, 1H, NH), 6.92 (s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 7.16–7.30 (m, 5H), 7.38 (d, J = 6.9 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 17.7, 18.4, 19.3, 23.9, 24.0, 25.2, 30.0, 33.4, 37.4, 38.2, 38.4, 50.7, 73.2, 123.7, 124.3, 125.0, 126.8, 127.4, 129.1, 134.8, 145.6, 147.1, 182.9. IR (KBr): υ 3273, 2928, 2857, 1545, 1453, 1376, 1269, 1114, 886, 752 cm⁻¹; MS (ESI) m/z 544 [M + H]⁺; HRMS (ESI): exact mass calcd for C₃₅H₅₀N₃S 544.37200. Found: 544.37236.

Spectral data for ligand VII. Off white solid, yield 78%, m.p. = 128–130 °C; [α]²⁸_D = +84.04 (c = 0.5, in CHCl₃). MS (ESI) m/z 544 [M + H]⁺; HRMS (ESI): exact mass calcd for C₃₅H₅₀N₃S 544.37200. Found: 544.37232.

General procedure for the preparation of thiourea catalyst X

To a stirred solution of chiral aminoindane (4 mmol) in dichloromethane (10 mL) was added a solution of glycosyl isothiocyanate (4.4 mmol) in dichloromethane (15 mL) dropwise manner under nitrogen atmosphere. The resulting mixture was stirred at room temperature until total consumption of the isothiocyanate (monitored by TLC). After removal of the solvent, the residue was purified through column chromatography on silica gel (EtOAc/MeOH = 85/15) to give the thiourea catalyst as a off-white solid.

Spectral data for ligand X. Off White solid, yield 86%, m.p. = 101–103 °C; [α]²⁸_D = −40.8 (c = 0.25, in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ 1.53–1.90 (m, 6H), 2.01–2.11 (m, 12H), 2.56–2.75 (s, 4H), 2.93 (dd, J = 8.9, 15.9 Hz, 1H), 3.20 (dd, J = 7.9, 15.9 Hz, 1H), 3.52 (q, J = 7.9, 15.9 Hz, 1H) 3.93 (d, J = 8.9 Hz, 1H), 4.14 (d, J = 10.9 Hz, 1H), 4.37 (dd, J = 3.9, 11.9 Hz, 1H), 5.00 (t, J = 4.9 Hz, 1H), 5.07–5.17 (m, 2H), 5.37–5.44 (m, 1H), 6.10 (t, J = 8.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 7.20–7.34 (m, 4H), 10.48 (d, J = 7.9 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 20.6, 20.7, 24.2, 25.8, 26.3, 50.6, 61.7, 62.4, 68.2, 71.7, 72.9, 73.9, 74.6, 84.8, 123.7, 125.4, 127.5, 129.1, 138.0, 141.0, 169.6, 169.8, 170.5. IR (KBr): υ 3354, 2937, 1752, 1541, 1373, 1373, 1225, 1038, 909, 752 cm⁻¹; MS (ESI) m/z 606 [M + H]⁺; HRMS (ESI): exact mass calcd for C₂₉H₄₀O₉N₃S 606.24798. Found: 606.24919.

General procedure for the preparation of squaramide catalysts VIII and IX

To a solution of 3,4-dimethoxy-3-cyclobutane-1,2-dione (2.0 g, 14.1 mmol) in MeOH (20 mL) was added 3,5-bis(trifluoromethyl)aniline (15.5 mmol, 1.1 equiv.) or 4-trifluoromethylaniline (15.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 days. The reaction mixture was filtered and washed with MeOH. The resulting yellow solids were dried in vacuo to give the mono-aminoaryl squaramide in good yields. A solution of (1S,2S)-aminoindane (2.0 mmol) in 10 mL CH₂Cl₂ was added to the mono-aminoaryl squaramide (2.0 mmol). The resulting mixture was stirred at room temperature until total consumption of precursors (monitored by TLC). The crude products VII or IX were obtained as white solids after filtration. Removal of the solvent followed by purification through column chromatography on silica gel (EtOAc/MeOH = 85/15) gave the thiourea catalysts VII or IX as off-white solids.

Spectral data for ligand VIII. White solid, yield 74%, m.p. = 290–292 °C; [α]²⁸_D = −73.5 (c = 0.5, in CHCl₃). ¹H NMR (300 MHz, DMSO-d₆): δ 1.40–1.76 (m, 6H), 2.56–2.80 (m, 4H), 3.43–3.28 (m, 3H), 5.83 (brs, 1H), 7.37–7.08 (m, 4H), 7.41 (s, 1H), 8. 16–7.84 (m, 2H), 8.04 (m, 3H), 9.86 (brs, NH, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 23.2, 24.9, 30.3, 50.4, 59.2, 74.1, 113.7, 116.8, 122.9, 123.9, 125.0, 125.9, 127.4, 130.9, 131.3, 138.8, 139.8, 140.1, 161.7, 168.4, 179.4, 183.2; IR (KBr): υ 3257, 2939, 1793, 1686, 1606, 1560, 1442, 1379, 1279, 1177, 1133, 883, 745 cm⁻¹; MS (ESI) m/z 524 [M + H]⁺; HRMS (ESI): exact mass calcd for C₂₆H₂₄F₆N₃O₂ 524.17672. Found: 524.17600.

Spectral data for ligand IX. White solid, yield 71%, m.p. = 270–272 °C; [α]²⁸_D = −71.2 (c = 0.5, in CHCl₃). ¹H NMR (300 MHz, DMSO-d₆): δ 1.37–1.77 (m, 6H), 2.48–2.77 (m, 4H), 2.91–2.38 (m, 3H), 5.75–5.91 (m, 1H), 7.14–7.38 (m, 3H), 7.49–7.74 (m, 5H), 7.92 (d, J = 8.3 Hz, 1H), 9.51 (brs, NH, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 22.9, 24.6, 30.0, 50.0, 58.8, 73.8, 116.5, 122.7, 123.6, 125.0, 125.6, 127.0, 138.5, 139.7, 141.1, 161.9, 167.9, 178.9, 182.9; IR (KBr): υ 3167, 2933, 1795, 1682, 1613 1554, 1446, 1323, 1118, 1015, 840, 748, 671 cm⁻¹; MS (ESI) m/z 456 [M + H]⁺; HRMS (ESI): exact mass calcd for C₂₅H₂₅F₃N₃O₂ 456.18934. Found: 456.18833.

General procedure for the enantioselective Michael/hemeketalization addition reaction

A mixture of organocatalyst IV (2.5 mol%) and (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) (0.22 mmol) in dry DCM (1 mL) was stirred for 10 min at room temperature. The reaction mixture was cooled to 0 °C and then 5-hydroxy-2-methyl-4H-pyran-4-one 1 (0.2 mmol) was added. The resulting mixture was stirred for 12 h at the same temperature. After completion of the reaction, the mixture was concentrated in vacuo and the resulting residue was purified by column chromatography on silica gel (hexane/acetone) to afford the corresponding optically active Michael adduct.

(4R)-Ethyl 2-hydroxy-6-methyl-8-oxo-4-phenyl-2,3,4,8-tetrahydro pyrano[3,2-b]pyran-2-carboxylate (3a). Brown solid; m.p. 156–158 °C; [α]²⁷_D = −85.4 (c = 0.5, CHCl₃); yield: 93%. The product was found to exist in rapid equilibrium with its acyclic form and hemiketal 3a form in solution. The equilibrium is very rapid and therefore one pair of enantiomers are observed during HPLC analysis. The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 0.80 mL min⁻¹, 254 nm; t_minor = 31.1 min, t_major = 38.2 min (97% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.41–7.30 (m, 4.2H), 7.27–7.20 (m, 1.7H), 6.19 (d, J = 8.2 Hz, 1H), 5.18 (brs, 0.5H) 4.78 (dd, J = 6.4, 8.9 Hz, 0.5H), 4.36–4.25 (m, 2.3H), 3.82 (dd, J = 8.9, 18.6 Hz, 0.5H), 3.53 (dd, J = 6.4, 18.8 Hz, 0.5H), 2.49 (t, J = 13.6 Hz, 0.7H), 2.40 (dd, J = 6.7, 13.6 Hz, 0.9H), 2.33–2.28 (m, 2.5H), 1.37–1.30 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 191.3, 173.9, 173.2, 168.2, 165.4, 164.2, 160.4, 150.5, 149.1, 140.7, 139.3, 139.1, 138.5, 128.8, 128.0, 128.1, 127.6, 127.4, 113.4, 110.4, 94.0, 62.9, 62.6, 41.7, 39.6, 37.9, 37.4, 19.9, 19.4, 13.8; IR (KBr): 3070, 2932, 2851, 1751, 1652, 1607, 1447, 1384, 1227, 1151, 1021, 949, 982, 701 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₉O₆: 331.11761, found: 331.11722.

(4R)-Ethyl 4-(4-bromophenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetr-ahydropyrano[3,2-b]pyran-2-carboxylate (3b). Brown solid; m.p. 146–148 °C; yield: 95%; [α]²⁷_D = −83.2 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 21.2 min, t_major = 27.3 min (96% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.51 (d, J = 7.9 Hz, 1.2H), 7.45 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1.4H), 6.18 (d, J = 9.0 Hz, 1H), 4.99 (brs, 0.4H), 4.74 (t, J = 7.2 Hz, 0.5H), 4.37–4.25 (m, 3H), 3.77 (dd, J = 8.6, 18.8 Hz, 0.5H), 3.52 (dd, J = 6.4, 18.8 Hz, 0.5H), 2.45 (t, J = 13.2 Hz, 0.6H), 2.37 (dd, J = 6.8, 13.9 Hz, 0.7H), 2.28 (s, 1.4H), 2.10 (s, 2.5H), 1.39–1.28 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃): 191.1, 173.2, 168.1, 164.3, 160.4, 149.3, 148.8, 139.4, 138.1, 137.7, 137.6, 131.9, 129.8, 121.4, 113.5, 110.5, 94.0, 63.0, 41.9, 39.0, 37.5, 37.2, 19.5, 13.8; IR (KBr): 3072, 2982, 2929, 1652, 1608, 1451, 1347, 1226, 1152, 1019, 981, 821, 738 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₇O₆BrNa: 431.01007, found: 431.00930.

(4R)-Ethyl 4-(4-chlorophenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetrahydro pyrano[3,2-b]pyran-2-carboxylate (3c). Off-white solid; m.p. 120–122 °C; yield: 94%; [α]²⁷_D = −79.1 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 20.1 min, t_major = 26.1 min (95% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.39–7.27 (m, 0.6H), 7.24–7.18 (m, 1.1H), 7.11–6.97 (m, 2H), 6.18 (s, 1H), 5.10 (brs, 0.19H), 4.77 (t, J = 7.2 Hz, 0.3H), 4.39–4.22 (m, 2.7H), 3.77 (dd, J = 8.2, 16.9 Hz, 0.27H), 3.52 (dd, J = 6.4, 18.5 Hz, 0.39H), 2.46 (t, J = 13.3 Hz, 0.3H), 2.38 (dd, J = 6.6, 13.6 Hz, 0.27H), 2.28 (s, 1.3H), 2.09 (s, 3H), 1.38–1.29 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃): 190.9, 173.9, 173.2, 168.1, 165.5, 164.4, 160.3, 149.3, 148.4, 140.5, 139.4, 137.8, 134.6, 130.1, 128, 127.8, 126.4, 126.0, 113.5, 110.5, 94.0, 63.0, 62.7, 41.5, 39.2, 37.7, 37.2, 29.6, 19.5, 13.8; IR (KBr): 3418, 3075, 1750, 1651, 1608, 1452, 1426, 1347, 1226, 1153, 1110, 1025, 981, 690 cm⁻¹. HRMS (ESI) calcd for C₁₈H₁₈O₆Cl: 365.07864, found: 365.07884.

(4R)-Ethyl 4-(4-fluorophenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetra hydropyrano[3,2-b]pyran-2-carboxylate (3d). Brown solid; m.p. 116–118 °C; yield: 95%; [α]²⁷_D = −75.6 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 18.6 min, t_major = 24.1 min (94% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.57–7.39 (m, 2H), 7.33–7.18 (m, 1H), 7.12 (d, J = 7.3 Hz, 1H), 6.27–6.14 (m, 1H), 5.29 (brs, 0.3H), 4.75 (t, J = 7.2 Hz, 0.3H), 4.41–4.18 (m, 2.4H), 3.78 (dd, J = 9.1, 18.7 Hz, 0.3H), 3.53 (dd, J = 9.1, 18.7 Hz, 0.3H), 2.51–2.34 (m, 0.6H), 2.28 (s, 1.3H), 2.10 (s, 2.5H), 1.40–1.19 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃): 191.0, 173.2, 168.1, 165.4, 160.3, 149.3, 148.7, 139.3, 138.1, 137.5, 132.0, 129.8, 121.1, 113.5, 110.5, 94.0, 63.0, 62.8, 41.5, 39.1, 37.5, 37.2, 20.0, 19.5, 13.8; IR (KBr): 3517, 3278, 2991, 2848, 2585, 1743, 1650, 1619, 1511, 1451, 1294, 1213, 1165, 1026, 853, 699 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₈O₆F: 349.10819, found: 349.10782.

(4R)-Ethyl 2-hydroxy-6-methyl-8-oxo-4-(p-tolyl)-2,3,4,8-tetrahydro pyrano[3,2-b]pyran-2-carboxylate (3e). Off-white solid; m.p. 152–154 °C; yield: 95%; [α]²⁷_D = −75.4 (c = 0.75, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 15.8 min, t_major = 20.2 min (95% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.24 (d, J = 7.5 Hz, 0.7H), 7.18 (d, J = 7.5 Hz, 1.3H), 7.16–7.10 (m, 2.4H), 6.17 (s, 1.3H), 4.98 (brs, 0.4H), 4.74 (t, J = 7.0 Hz, 0.4H), 4.37–4.23 (m, 3.2H), 3.79 (dd, J = 9.0, 18.6 Hz, 1.3H), 3.50 (dd, J = 6.4, 18.6 Hz, 0.4H), 2.47 (t, J = 13.5 Hz, 0.7H), 2.40–2.22 (m, 7.3H), 1.37–1.29 (m, 3.3H); ¹³C-NMR (75 MHz, CDCl₃): 191.3, 173.9, 173.2, 168.2, 165.3, 164.1, 160.4, 150.2, 149.4, 140.6, 139.2, 137.1, 136.0, 135.4, 129.4, 127.5, 113.3, 110.4, 94.1, 62.8, 62.5, 41.7, 39.1, 37.5, 20.9, 19.9, 19.4, 13.8; IR (KBr): 3251, 2929, 2855, 1652, 1630, 1589, 1553, 1455, 1378, 1253, 1215, 1081, 843, 782 cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₁O₆: 345.13326, found: 345.13298.

(4R)-Ethyl 4-(3-chlorophenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetra hydropyrano[3,2-b]pyran-2-carboxylate (3f). White solid; m.p. 118–120 °C; yield: 93%; [α]²⁷_D = −80.9 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 15.8 min, t_major = 20.7 min (86% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.38–7.19 (m, 3H),7.12 (s, 1H), 6.18 (s, 1H), 5.47 (brs, 0.3H), 4.75 (t, J = 7.4 Hz, 0.3H), 4.40–4.21 (m, 3H), 3.80 (dd, J = 8.7, 18.3 Hz, 0.3H), 3.52 (dd, J = 6.5, 18.3 Hz, 0.3H), 2.48–2.38 (m, 1H), 2.32–2.24 (m, 1.3H), 2.17 (s, 3H), 1.39–1.28 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃ + DMSO-d₆): 191.0, 173.9, 173.2, 168.1, 165.5, 164.9, 149.3, 148.4, 140.5, 139.4, 134.6, 130.1, 128.3, 127.8, 126.4, 126.0, 113.5, 110.5, 94.0, 63.0, 62.7, 41.4, 39.2, 37.7, 37.2, 29.6, 20.0, 19.5, 13.8; IR (KBr): 3424, 3077, 1755, 1654, 1609, 1453, 1426, 1347, 1225, 1153, 1111, 1020, 981, 690 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₈O₆Cl: 365.07864, found: 365.07879.

(4R)-Ethyl 4-(3-fluorophenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetra hydropyrano[3,2-b]pyran-2-carboxylate (3g). Brown solid; m.p. 116–118 °C; yield: 91%; [α]²⁷_D = −82.1 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 14.3 min, t_major = 18.3 min (96% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.39–7.27 (m, 0.5H), 7.14 (d, J = 7.5 Hz, 1H), 7.09–7.00 (m, 2H), 7.00–6.92 (m, 1.3H), 6.24–6.16 (m, 1.4H), 5.12 (brs, 0.3H), 4.78 (t, J = 7.5 Hz, 0.5H), 4.38–4.23 (m, 2.6H), 3.79 (dd, J = 8.5, 18.6 Hz, 0.5H), 3.53 (dd, J = 6.4, 18.6 Hz, 0.6H), 2.47 (t, J = 13.6 Hz, 0.5H), 2.40 (dd, J = 6.6, 13.6 Hz, 0.6H), 2.29 (s, 1.5H), 2.10 (s, 2.8H), 1.38–1.28 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃): 191.0, 173.9, 173.2, 168.0, 165.5, 164.3, 163.9, 161.9, 149.3, 148.5, 141.0, 139.4, 130.5, 123.9, 123.5, 115.2, 115.0, 114.7, 114.5, 113.5, 110.5, 94.0, 63.1, 62.7, 41.5, 39.2, 37.8, 37.1, 20.0, 19.5, 13.8; IR (KBr): 3256, 2955, 2932, 2858, 1653, 1630, 1590, 1552, 1451, 1378, 1251, 1085, 841, 781, 704 cm⁻¹. HRMS (ESI) calcd for C₁₈H₁₈O₆F: 349.10819 found: 349.10826.

(4R)-Ethyl 4-(2,4-dichlorophenyl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate (3h). Brown solid; m.p. 128–130 °C; yield: 92%; [α]²⁷_D = −58.6 (c = 0.5, CHCl₃). The ee was determined by HPLC using a DaicelChiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 13.8 min, t_major = 28.1 min (95% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.41–7.18 (m, 3.7H),7.14 (s, 0.5H), 6.18 (s, 1H), 5.19 (brs, 0.5H), 4.74 (t, J = 7.4 Hz, 0.4H), 4.40–4.17 (m, 2.8H), 3.81 (dd, J = 8.5, 18.7 Hz, 0.4H), 3.52 (dd, J = 5.6, 18.3 Hz, 0.3H), 2.54–2.33 (m, 0.9H), 2.11 (s, 3H), 1.34 (t, J = 7.4 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃): 190.9, 173.9, 173.2, 168.1, 165.5, 164.4, 160.3, 149.3, 148.4, 140.5, 139.4, 137.8, 134.6, 130.1, 128.3, 127.8, 126.4, 126.0, 113.5, 110.5, 94.0, 63.0, 62.7, 41.5, 39.2, 37.7, 37.2, 29.6, 19.5, 13.8; IR (KBr): 3071, 2980, 2929, 1651, 1608, 1449, 1345, 1226, 1152, 1019, 980, 821, 735 cm⁻¹. HRMS (ESI) calcd for C₁₈H₁₇O₆Cl₂: 399.03967, found: 399.03959.

(4R)-Ethyl 2-hydroxy-6-methyl-4-(naphthalen-2-yl)-8-oxo-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate (3i). Brown solid; m.p. 122–124 °C; yield: 94%; [α]²⁷_D = −86.2 (c = 0.6, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 18.0 min, t_major = 25.7 min (>99% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.90–7.78 (m, 3H), 7.75 (s, 1H), 7.58–7.44 (m, 3H), 7.30 (dd, J = 1.3, 8.5 Hz, 1H), 6.20 (s, 1H), 5.13 (brs, 0.3H), 4.95 (t, J = 7.9 Hz, 0.4H), 4.50 (dd, J = 6.6, 12.5 Hz, 1H), 4.38–4.24 (m, 2H), 3.92 (dd, J = 8.9, 18.7 Hz, 0.5H), 3.64 (dd, J = 6.4, 18.7 Hz, 0.4H), 2.60 (t, J = 13.4 Hz, 0.8H), 2.45 (dd, J = 6.2, 13.9 Hz, 0.7H), 2.28 (s, 3H), 1.38–1.28 (m, 3.4H); ¹³C-NMR (125 MHz, CDCl₃): 191.3, 173.9, 173.3, 168.3, 165.5, 164.3, 160.5, 150.1, 149.0, 140.4, 139.4, 136.5, 135.9, 133.4, 132.7, 128.7, 127.7, 127.6, 127.5, 126.4, 126.3, 126.1, 125.6, 125.5, 110.4, 94.1, 63.1, 62.7, 41.7, 39.9, 38.2, 37.3, 29.6, 20.0, 19.5, 13.9; IR (KBr): 3077, 1757, 1653, 1608, 1508, 1452, 1341, 1225, 1201, 1144, 1022, 984, 820, 744, 616 cm⁻¹. HRMS (ESI) calcd for C₂₂H₂₁O₆: 381.13326, found: 381.13318.

(4R)-Ethyl 2-hydroxy-6-methyl-8-oxo-4-(thiophen-2-yl)-2,3,4,8-tetra hydropyrano[3,2-b]pyran-2-carboxylate (3j). Brown solid; m.p. 128–130 °C; yield: 96%; [α]²⁷_D = −78.1 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 17.6 min, t_major = 21.0 min (93% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.33–7.25 (m, 1.3H), 7.21 (d, J = 7.6 Hz, 0.4H), 7.09–6.99 (m, 2H), 6.95 (d, J = 3.8 Hz, 0.3H), 6.18 (d, J = 6.8 Hz, 1.3H), 5.12 (t, J = 7.6 Hz, 0.5H), 4.92 (brs, 0.5H),4.66 (dd, J = 6.0, 12.1 Hz, 0.6H), 4.33 (q, J = 7.6 Hz, 2H), 3.77 (dd, J = 8.3, 18.9 Hz, 0.5H), 3.62 (dd, J = 6.8, 18.9 Hz, 0.5H), 2.63 (t, J = 13.6 Hz, 0.5H), 2.49 (dd, J = 6.8, 13.6 Hz, 0.6H), 2.32 (s, 1.5H), 2.16 (s, 3H),1.35 (t, J = 6.8 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃): 190.7, 174.0, 173.2, 168.0, 165.5, 164.2, 160.3, 148.8, 148.0, 141.1, 140.4, 140.0, 138.5, 126.8, 126.4, 125.6, 124.9, 124.8, 113.5, 94.0, 63.1, 62.7, 42.8, 37.0, 34.7, 33.0, 20.0, 19.5, 13.9; IR (KBr): 3072, 2850, 1750, 1650, 1606, 1450, 1384, 1273, 1207, 1023, 981, 700, 617 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₇O₆S: 337.07404, found: 337.07374.

(4R)-Methyl 2-hydroxy-4-(4-methoxyphenyl)-6-methyl-8-oxo-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate (3k). Brown solid; m.p. 128–130 °C; yield: 90%; [α]²⁷_D = −78.3 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 70 : 30, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 12.3 min, t_major = 16.1 min (90% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.28 (d, J = 8.3 Hz, 1.4H), 7.15 (d, J = 8.3 Hz, 1.3H), 6.94–6.82 (m, 2.4H), 6.18 (s, 1.3H), 5.04 (brs, 0.2H), 4.73 (dd, J = 6.8, 8.3 Hz, 0.4H), 4.27 (dd, J = 6.8, 12.1 Hz, 0.5H), 3.92–3.76 (m, 6H), 3.51 (dd, J = 6.6, 18.5 Hz, 0.3H), 2.54–2.32 (m, 1H), 2.28 (s, 1.3H), 2.09 (s, 2.5H); ¹³C-NMR (75 MHz, CDCl₃): 171.4, 167.6, 162.7, 157.5, 148.9, 137.8, 129.2, 127.9, 127.4, 113.0, 112.0, 93.3, 53.9, 51.5, 36.9, 35.8, 18.2; IR (KBr): 3070, 3001, 2932, 2838, 1752, 1651, 1607, 1512, 1456, 1350, 1258, 1170, 1111, 1029, 980, 829 cm⁻¹; HRMS (ESI) calcd for C₁₉H₁₈O₄NNa: 347.11280, found: 347.11126.

(4R)-Methyl 4-(furan-2-yl)-2-hydroxy-6-methyl-8-oxo-2,3,4,8-tetra hydropyrano[3,2-b]pyran-2-carboxylate (3l). Brown solid; m.p. 130–132 °C; yield: 90%; [α]²⁷_D = −90.2 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_major = 29.4 min (>99% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.45–7.30 (m, 1.2H), 6.34–6.27 (m, 2H), 6.25–6.11 (m, 1.4H), 5.22 (brs, 0.4H), 4.92 (t, J = 6.6 Hz, 0.4H), 4.51 (dd, J = 6.1, 12.5 Hz, 0.5H), 3.92–3.84 (m, 4H), 3.66 (t, J = 6.5 Hz, 0.8H), 2.70 (t, J = 13.1 Hz, 0.7H), 2.39 (dd, J = 5.6, 13.3 Hz, 0.6H), 2.31–2.14 (m, 3H); ¹³C-NMR (125 MHz, CDCl₃ + DMSO-d₆): 190.3, 172.9, 173.7, 172.9, 168.4, 165.1, 163.8, 160.4, 150.0, 147.7, 136.7, 142.2, 141.8, 138.4, 128.6, 127.9, 113.2, 110.2, 110.1, 108.0, 94.2, 52.9, 33.4, 31.7, 19.7, 19.3; IR (KBr): 3075, 2951, 2927, 2842, 1752, 1653, 1606, 1452, 1345, 1279, 1207, 1159, 1027, 904, 879, 738 cm⁻¹; HRMS (ESI) calcd for C₁₅H₁₅O₇: 307.08123, found: 307.07984.

(4R)-Methyl 2-hydroxy-6-methyl-8-oxo-4-phenyl-2,3,4,8-tetra hydro pyrano[3,2-b]pyran-2-carboxylate (3m). Yellow solid; m.p. 150–152 °C; yield: 95%; [α]²⁷_D = −57.4 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 21.9 min, t_major = 27.2 min (99% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.40–7.29 (m, 3H), 7.22 (d, J = 7.1 Hz, 2H), 6.22 (s, 0.5H), 6.19 (s, 0.8H), 5.85 (brs, 0.5H), 4.79 (dd, J = 6.6, 8.7 Hz, 0.4H), 4.34 (dd, J = 7.2, 11.7 Hz, 1H), 3.88–3.79 (m, 4H), 3.54 (dd, J = 6.4, 18.8 Hz, 0.4H), 2.51–2.38 (m, 2H), 2.29 (s, 1.3H), 2.17 (s, 2H); ¹³C-NMR (75 MHz, CDCl₃): 171.4, 167.6, 162.7, 157.8, 148.9, 137.8, 129.2, 127.9, 127.4, 112.9, 112.0, 93.3, 53.9, 51.5, 36.9, 35.8, 18.2; IR (KBr): 3074, 2948, 2930, 2852, 1754, 1727, 1653, 1606, 1534, 1426, 1203, 1169, 1209, 1025, 948, 878, 701 cm⁻¹. HRMS (ESI) calcd for C₁₇H₁₇O₆: 317.10196, found: 317.10158.

(4R)-Isopropyl 2-hydroxy-6-methyl-8-oxo-4-phenyl-2,3,4,8-tetrahydr-opyrano[3,2-b]pyran-2-carboxylate (3n). Off-white solid; m.p. 136–138 °C; yield: 81%; [α]²⁷_D = −78.2 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 11.7 min, t_major = 16.6 min (88% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.41–7.30 (m, 4.5H), 7.29–7.21 (m, 2.4H), 6.18 (d, J = 9.6 Hz, 1.4H), 5.16–5.07 (m, 1H), 5.03 (brs, 0.1H), 4.78 (t, J = 7.3 Hz, 0.5H), 4.31 (dd, J = 6.6, 12.4 Hz, 0.6H), 3.80 (dd, J = 9.0, 18.5 Hz, 0.6H), 3.51 (dd, J = 6.3, 18.5 Hz, 0.5H), 2.47 (t, J = 1.7 Hz, 0.7H), 2.36 (d, J = 6.6, 13.7 Hz, 0.6H), 2.33–2.24 (m, 2.7H), 1.36–1.26 (m, 6H); ¹³C-NMR (125 MHz, CDCl₃ + DMSO-d₆): 191.3, 172.6, 167.4, 164.3, 163.5, 159.5, 149.6, 140.5, 138.9, 138.4, 128.3, 128.2, 127.6127.5, 127.2, 126.9, 112.9, 111.2, 110.3, 93.9, 70.4, 69.8, 41.2, 38.7, 37.6, 37.4, 21.0, 19.0; IR (KBr): 3083, 2984, 2935, 1745, 1654, 1615, 1448, 1351, 1289, 1235, 1205, 1163, 1099, 1026, 986, 851, 619 cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₁O₆: 345.13326, found: 345.13293.

(4R)-tert-Butyl 2-hydroxy-6-methyl-8-oxo-4-phenyl-2,3,4,8-tetrahydro pyrano[3,2-b]pyran-2-carboxylate (3o). Brown solid; m.p. 108–110 °C; yield: 88%; [α]²⁷_D = −56.2 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 9.3 min, t_major = 10.0 min (90% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.42–7.18 (m, 5H), 6.30 (s, 0.6H), 6.18 (d, J = 9.0 Hz, 1H),5.41 (brs, 0.5H), 4.79 (t, J = 6.6 Hz, 0.5H), 4.30 (dd, J = 7.4, 11.1 Hz, 0.9H), 3.75 (dd, J = 8.7, 18.3 Hz, 0.5H), 3.48 (dd, J = 6.4, 18.5 Hz, 0.4H), 2.47–2.34 (m, 1.6H), 2.29 (s, 3H), 1.50 (s, 9H); ¹³C-NMR (125 MHz, CDCl₃): 192.3, 174.3, 173.9, 173.3, 167.2, 166.4, 165.2, 164.0, 159.8, 150.0, 149.4, 145.2, 140.8, 139.5, 139.2, 138.8, 137.3, 128.8, 128.1, 127.6, 127.4, 111.3, 110.5, 94.1, 84.2, 41.5, 39.5, 38.1, 37.5, 29.5, 27.6, 19.9, 19.4; IR (KBr): 3081, 2923, 2852, 1756, 1652, 1609, 1493, 1447, 1363, 1252, 1205, 1149, 1111, 984, 840, 700 cm⁻¹; HRMS (ESI) calcd for C₂₀H₂₃O₆: 359.14891, found: 359.14756.

(4R)-Ethyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxy-8-oxo-4-phenyl-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate (5a). Brown solid; m.p. 140–142 °C; yield: 93%; [α]²⁷_D = −80.1 (c = 0.6, CHCl₃) .The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 0.08 mL min⁻¹, 254 nm; t_minor = 5.4 min, t_major = 6.8 min (92% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.42–7.30 (m, 3.9H), 7.28 (d, J = 8.8 Hz, 0.3H), 7.25 (dd, J = 6.6 Hz, 1.3H), 6.51–6.45 (m, 1H), 5.38 (brs, 0.4H), 4.82 (t, J = 6.6 Hz, 0.4H), 4.49 (s, 1H), 4.39–4.29 (m, 5H), 3.82 (dd, J = 8.8, 18.8 Hz, 0.4H), 3.55 (dd, J = 5.5, 17.7 Hz, 0.5H), 3.24 (t, J = 13.3 Hz, 0.5H), 2.43 (dd, J = 6.6, 13.3 Hz, 0.6H), 1.39–1.32 (m, 3H), 0.91 (m, 9H), 0.08 (m, 6.6H); ¹³C-NMR (125 MHz, CDCl₃): 191.2, 174.0, 173.2, 168.1, 167.0, 165.9, 160.4, 149.7, 149.0, 141.2, 139.7, 139.7, 139.0, 138.4, 128.8, 128.1, 127.6, 127.5, 111.2, 108.2, 94.1, 62.8, 62.5, 61.3, 61.0, 41.7, 39.6, 38.0, 37.5, 25.5, 18.0, 13.8, −5.6, −5.8; IR (KBr): 3177, 2930, 2887, 2857, 1741, 1657, 1630, 1595, 1449, 1366, 1252, 1205, 1164, 1104, 1008, 838, 775, 701 cm⁻¹; HRMS (ESI) calcd for C₂₄H₃₃O₇Si: 461.19901, found: 461.19782.

(4R)-Ethyl 4-(4-bromophenyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxy-8-oxo-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxyl-ate (5b). White solid; m.p. 148–150 °C; yield: 95%; [α]²⁷_D = −96.4 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 0.8 mL min⁻¹, 254 nm; t_minor = 9.3 min, t_major = 12.1 min (94% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.42–7.27 (m, 3.9H), 7.13 (d, J = 7.6 Hz, 0.7H), 7.01 (d, J = 8.3, Hz, 2H), 6.35 (s, 1.1H), 5.21 (brs, 0.3H), 4.35 (s, 0.8H), 4.27–4.08 (m, 4.6H), 3.67 (dd, J = 8.3, 18.6 Hz, 0.6H), 3.42 (dd, J = 6.8, 18.9 Hz, 0.3H), 2.41–2.19 (m, 1.6H), 1.28–1.16 (m, 3H), 0.78 (m, 9H), 0.05 (m, 6H); ¹³C-NMR (75 MHz, CDCl₃): 191.1, 173.9, 173.2, 168.1, 166.0, 154.1, 148.9, 139.8, 137.4, 132.2, 132.0, 129.9, 129.4, 121.6, 111.4, 108.2, 93.9, 63.8, 62.7, 61.4, 61.1, 41.5, 39.2, 37.6, 37.2, 25.6, 18.1, 13.9, −5.5, −5.6; IR (KBr): 3177, 2930, 2887, 2857, 1741, 1657, 1630, 1595, 1449, 1366, 1252, 1205, 1164, 1104, 1008, 838, 775, 701 cm⁻¹; HRMS (ESI) calcd for C₂₂H₃₂O₆BrSi: 434.1993, found: 434.2000.

(4R)-Ethyl 6-(chloromethyl)-2-hydroxy-8-oxo-4-phenyl-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate (5c). Brown solid; m.p. 102–104 °C; yield: 94%; [α]²⁷_D = −86.3 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 80 : 20, flow rate 0.8 mL min⁻¹, 254 nm; t_minorr = 16.2 min, t_major = 28.3 min (95% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.42–7.31 (m, 3.7H), 7.29–7.22 (m, 1.8H), 6.46 (s, IH), 5.03 (brs, 0.5H), 4.83 (dd, J = 6.3, 9.2 Hz, 0.4H), 4.39–4.27 (m, 4H), 4.20–4.06 (m, 1.7H), 3.85 (dd, J = 9.2, 18.8 Hz, 0.5H), 3.54 (dd, J = 6.3, 18.9 Hz, 0.4H), 2.51 (t, J = 13.4 Hz, 0.7H), 2.42 (dd, J = 6.6, 13.7 Hz, 0.7H), 1.37–1.30 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃ + DMSO-d₆): 172.0, 167.6, 160.0, 150.0, 139.4, 137.7, 128.2, 127.5, 126.9, 113.5, 94.1, 61.6, 40.2, 37.4, 37.3, 13.3 IR (KBr): 3250, 2958, 2931, 2855, 1652, 1630, 1590, 1554, 1458, 1375, 1254, 1220, 1083, 1011, 842, 782, 734, 682 cm⁻¹. HRMS (ESI) calcd for C₁₈H₁₈O₆Cl: 365.07864, found: 365.07837.

(4R)-Ethyl 6-(((4-chlorophenyl)thio)methyl)-2-hydroxy-8-oxo-4-phen yl-2,3,4,8-tetrahydropyrano[3,2-b]pyran-2-carboxylate (5d). Brown solid; m.p. 92–94 °C; yield: 95%; [α]²⁷_D = −76.7 (c = 0.5, CHCl₃). The ee was determined by HPLC using a Daicel Chiralcel AD-H column, n-hexane/i-PrOH 90 : 10, flow rate 1.00 mL min⁻¹, 254 nm; t_minor = 18.9 min, t_major = 23.7 min (95% ee); ¹H-NMR (300 MHz, CDCl₃): δ 7.41–7.25 (m, 4H), 7.24–7.14 (m, 4h), 7.11 (d, J = 8.4 Hz, 1H), 6.21 (s, 0.6H), 6.13 (s, 0.4H), 4.75 (dd, J = 6.1, 9.3 Hz, 0.4H), 4.35–4.22 (m, 2.5H), 3.83–3.75 (m, 1.5H), 3.70–3.58 (m, 1H), 3.47 (dd, J = 6.1, 18.8 Hz, 0.4H), 2.47 (t, J = 13.4 Hz, 0.5H), 2.39 (dd, J = 6.7, 13.7 Hz, 0.5H), 1.37–1.27 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃) 173.0, 163.1, 150.2, 140.3, 138.4, 132.4, 132.0, 129.2, 128.8, 127.8, 127.9, 127.5, 113.0, 62.7, 38.7, 36.7, 13.8; IR (KBr): 3412, 2985, 1746, 1647, 1475, 1446, 1293, 1227, 1199, 1096, 1008, 755 cm⁻¹; HRMS (ESI) calcd for C₂₄H₂₂O₆ClS: 473.08201, found: 473.08087.

X-ray crystallography

Crystal data for 3i: C₂₂H₂₀O₆, M = 380.38, colorless block, 0.18 × 0.15 × 0.06 mm³, orthorhombic, space group P2₁2₁2₁ (no. 19), a = 6.2121(16), b = 9.387(3), c = 32.186(9) Å, V = 1876.9(9) ų, Z = 4, D_c = 1.346 g cm⁻³, F₀₀₀ = 800, CCD Area Detector, MoKα radiation, λ = 0.71073 Å, T = 294(2) K, 2θ_max = 50.0°, 17714 reflections collected, 1956 unique (R_int = 0.0705). Final GooF = 1.339, R1 = 0.0955, wR2 = 0.2149, R indices based on 1843 reflections with I > 2σ(I) (refinement on F²), 295 parameters, 94 restraints, μ = 0.098 mm⁻¹ (ESI).†

Crystal data for 5c: C₁₈H₁₇ClO₆, M = 364.77, colorless block, 0.16 × 0.15 × 0.06 mm³, orthorhombic, space group P2₁2₁2₁ (no. 19), a = 7.9426(11), b = 8.8414(12), c = 24.229(3) Å, V = 1701.4(4) ų, Z = 4, D_c = 1.424 g cm⁻³, F₀₀₀ = 760, Bruker SMART APEX CCD area-detector, MoKα radiation, λ = 0.71073 Å, T = 294(2) K, 2θ_max = 50.0°, 16379 reflections collected, 2999 unique (R_int = 0.0503). Final GooF = 1.102, R1 = 0.0508, wR2 = 0.1232, R indices based on 2573 reflections with I > 2σ(I) (refinement on F²), 231 parameters, 0 restraints, μ = 0.256 mm⁻¹. Absolute structure parameter = −0.07(10) (Flack & Bernardinelli, 2000) (ESI).†

Acknowledgements

MS and SMR thanks CSIR, New Delhi for the award of a fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectrum of products. Additional characterization data and copies of the NMR spectra of the Michael adducts. CCDC 979348 and 1017996. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra06938b

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