Copper-Catalyzed Stereoselective Synthesis of 2-Deoxygalactosides

Abstract

An efficient glycosylation method to synthesize 2-deoxy-O-galactosides based on a Cu(II)-catalyzed reaction without additional ligand has been developed. The glycosylation was amenable to different protected glycal donors and a wide range of acceptors including alcohols, amino acids, sugars, and phenol, and proceeds with excellent yield and high α-selectivity under mild conditions. The reaction proceeds readily on a gram scale, and its versatility is exemplified in the synthesis of oligosaccharides.

Key words

copper catalyst - 2-deoxygalactosides - glycosylation - ­glycals - stereoselectivity

Deoxyglycosides are common components of a wide range of bioactive natural products (Figure [1]),[1] and they often display antibiotic, anticancer, or cardiotonic activities.[2] As a result, many methods have been developed for the synthesis of 2-deoxyglycosides.[3] However, unlike fully oxygenated glycosides, the lack of substituents at C-2 to direct the nucleophilic approach presents an additional synthetic challenge that has piqued the interest of researchers for many decades.[4] To overcome these problems, many indirect approaches have been developed for the synthesis of 2-deoxyglycosides, usually by installing a temporary directing group at the C-2 position, which makes this methodology inherently inefficient.[4b] [c] [5] Thus, several direct approaches have been formulated to achieve the stereoselective synthesis of these compounds.[6] Among them, it is still the most atom-efficient route to synthesize 2-deoxyglycosides by adding an alcohol to a glycal directly in a catalyzed process.[7–10]

Figure 1 Representative deoxyglycoside-containing natural products

Recently, many methodologies using glycal to synthesis 2-deoxyglycosides have been reported, including organocatalysis,[11] [12] [13] Lewis acid catalysis,[14–16] and Brønsted acid catalysis[8a,17] (Scheme [1]). For instance, Galan et al.[7] in 2012, reported the selective synthesis of 2-deoxy-O-galactosides using thiourea as an organocatalyst. Subsequently, in 2105, Galan et al.[12a] used pyridinium cations as novel organocatalyst to synthesize 2-deoxyglycosides efficiently. Since 2017, Galan’s group[7] [8] [9] [10] have developed several practical methods by using Lewis acids, such as Au(I) in combination with AgOTf, and Pd(II) in combination with a monodentate phosphine ligand and B(C₆F₅)₃. Meanwhile, Wang[11] reported the selective synthesis of 2-deoxy-O-glycosides catalyzed by photoacid. Despite the great efforts that have been made in this area, noble metals or expensive ligands are still required as catalysts in the reaction. Thus, there is a need to find improved and more general catalysts to access these high-value glycosides.

Scheme 1 Representative strategies for the synthesis of deoxyglycosides from glycals

In recent years, copper catalysts have been widely employed in organic chemistry because of its abundance, ready availability, and low toxicity.[18] For example, Debaraj et al. reported Cu(OTf)₂ mediated stereoselective synthesis of C-glycosides from unactivated alkynes.[18b] A recent reaction was developed by Tang et al., in which glycosyl isoquinoline-1-carboxylate was used as glycosyl donor, promoted by the Cu(OTf)₂ salt under mild reaction conditions.[18e] More recently, Messaoudi et al. reported Cu(OAc)₂∙H₂O catalyzed anomeric O-arylation of carbohydrate derivatives at room temperature.[18f] However, copper salts have not been applied to the stereoselective synthesis of 2-deoxyglycosides. Based on our continuing interest in 2-deoxyglycosides,[15] we hoped to apply copper salts to the synthesis of 2-deoxyglycosides. Fortunately, we found that when CuBr₂ was used as the catalyst, 2-deoxy-O-glycosides could be successfully obtained with α-selectivity. Herein, we described an unprecedented Cu(II) direct activation of glycals to yield 2-deoxygalactosides under mild conditions (Scheme [1]).

Table 1 Optimization of the Reaction Conditions^a

Entry	Catalyst	Cat. (equiv.)	Solvent	Time (h)	Yield (%)b	α:β
1	FeCl3·6H2O/C	0.2	DCM	4	22	–
2	FeCl3/C	0.2	DCM	3	30	–
3	Fe3O4@C@Fe(III)	0.2	DCM	2	45	–
4	PdCl2	0.2	DCM	6	48	–
5	CuCl2	0.2	DCM	12	N.R	–
6	CoCl2	0.2	DCM	12	N.R	–
7	CoBr2	0.2	DCM	12	N.R	–
8	ZnCl2	0.2	DCM	0.5	5	–
9	CuBr2	0.2	DCM	0.5	77	>30:1
10	CuNO3·3H2O	0.2	DCM	12	N.R	–
11	CuSO4	0.2	DCM	12	N.R	–
12	Cu(OTf)2	0.2	DCM	12	71	–
13	Cu(OAc)2	0.2	DCM	12	N.R	–
14	CuBr	0.2	DCM	12	5	–
15	CuI	0.2	DCM	12	N.R	–
16	CuBr2	0.2	DCE	1.5	68	–
17	CuBr2	0.2	CH3CN	0.5	72	–
18	CuBr2	0.2	THF	0.5	70	–
19	CuBr2	0.2	DMF	2	N.R	–
20	CuBr2	0.2	dioxane	2	N.R	–
21	CuBr2	0.2	DMSO	2	N.R	–
22c	CuBr2	0.2	DCM	4	71	>30:1
23d	CuBr2	0.2	DCM	0.5	75	>30:1
24	CuBr2	0.1	DCM	1	80	>30:1
25	CuBr2	0.05	DCM	1	82	>30:1
26	CuBr2	0.025	DCM	3	79	>30:1

^a Reaction conditions: glycal donor 1a (0.1 mmol), acceptor 2g (0.12 mmol), catalyst (0.02 mmol), solvent (1.0 mL), 25 °C, N₂.

^b Isolated yield.

^c The reaction was conducted at 0 °C.

^d The reaction was conducted at 40 °C.

We started our studies with galactal 1a and galactoside acceptor 2g as model substrates. Initially, we examined a series of iron(III) catalysts: FeCl₃·6H₂O/C, FeCl₃/C, Fe₃O₄@C@Fe(III), which have been widely used as efficient catalysts in glycosylation reactions.[19] [20] [21] As shown in Table [1], product 3g was gained with poor yield, with the formation of more 2,3-unsaturated Ferrier product (yield 42–60%; entries 1–3). Next, a series of commercial Lewis catalysts were screened (entries 4–9). To our delight, when CuBr₂ was used as catalyst, the addition product 3g could be obtained with 77% yield and α:β stereocontrol of >30:1 (entry 9).[9] Subsequently, other copper salts were further tested as catalysts (entries 10–15). The results indicated CuBr₂ was the best catalyst among copper salt catalysts. Solvent effect was also evaluated. Reactions in DMF, 1,4-dioxane, or DMSO did not proceed (entries 19–21), whereas reactions in DCE, CH₃CN and THF gave lower yields than in DCM (entries 16–18). When the reaction was carried out at 0 or 40 °C, product 3g was obtained in 71 and 75% yield, respectively (entry 22 and 23). Further optimization studies of catalyst loadings were conducted that revealed that 0.05 equivalent ­CuBr₂ provided the highest yield (82%; entry 25). Increasing the number of equivalents of CuBr₂ to 0.1 or decreasing it to 0.025, both led to decreased yields of 3g (entries 24 and 26). Therefore, the optimized reaction conditions were: 1.0 equiv donor, 1.2 equiv acceptor and 0.05 equiv CuBr₂ as catalyst in DCM at 25 °C.

Having established the optimum reaction conditions, our attention then turned to expanding the substrate scope of the glycosyl acceptors to other alcohols (Scheme [2]; 2a–i). Fortunately, in all cases, deoxy products 3a–i could be obtained within three hours in good to excellent yields with high stereoselectivities (α:β >30:1). When simple primary alcohols such as benzyl alcohol 2a and ethanol 2b were used as nucleophilic acceptors, products 3a and 3b were obtained in yields of 86% and 95%, respectively. Additionally, trichloroethanol 2c, an electron-deficient alcohol, reacted with glycal donor 1a smoothly in 82% yield, albeit with longer time (3 h) due to the presence of a strong electron-withdrawing group. Notably, when tert-butanol was used as nucleophile, the expected product 3d was also obtained in good yield (65%), despite its greater steric hindrance. 5-Hydroxymethylfurfural (HMF) 2e, which is an important biofuel, and its sugar derivatives, shows antitumor activity in our previous research,[22] was also applied in this catalytic system with 89% yield.

Scheme 2 Alcoholic acceptor scope of glycosylation reactions with galactal 1a. Reagents and conditions: donor (0.1 mmol), acceptor (0.12 mmol), CuBr₂ (5 mol%), stirred in DCM (1.0 mL), 25 °C, nitrogen atmosphere. All yields are isolated yields; α:β ratio of all products was >30:1 and was determined based on the ¹H NMR spectra. ^a CuBr₂ (0.1 equiv) was used.

The catalytic system was also suitable for use with amino acid acceptors. For example, Fmoc-protected serine 2f afforded the corresponding glycoside product 3f in 93% yield within 1.5 h (Scheme [2]). Moreover, sugar acceptors, for instance, galactoside 2g, glucoside 2h, and rhamnoside 2i also afforded the desired 2-deoxy products in good yields (63–82%) and with high α-selectivities. The results showed that aliphatic acceptors including simple alcohols, amino acids, and sugars could be used to obtain glycosides in excellent yields with high α-selectivities.

Scheme 3 Phenolic acceptor scope of glycosylation reactions with galactal 1a. Reagents and conditions: donor (0.1 mmol), acceptor (0.12 mmol), CuBr₂ (5 mol%), stirred in DCM (1.0 mL), 25 °C, nitrogen atmosphere. All yields are isolated yields; α:β ratio of all products was >30:1 based on the ¹H NMR spectra.

Encouraged by these results, the substrate scope of this reaction was further extended to phenol acceptors, which are scarcely studied.[15a] [24] As illustrated in Scheme [3], reactions involving phenol acceptors 2j–r were complete within 3 h in excellent yields (75−85%) and very high anomeric selectivities (α:β >30:1). The glycosylation of phenols with electron-donating substituents at the para-position such as p-tert-butyl and p-methoxy groups proceeded smoothly, giving the desired products 3k and 3l with excellent yields. In addition, phenols with electron-withdrawing substituents at the para-position such as p-fluoro, p-chloro and p-bromo were also employed to afford the desired products 3m–o in satisfactory yields. Moreover, coupling of glycal donor 1a with the relatively hindered acceptors 2p–q also proceeded successfully. In earlier reports,[23] [24] the synthesis of naphthol 2-deoxygalactoside 3r usually involves 2-thioglycosides, which is a difficult donor to obtain; furthermore, the selectivity of the product was not very high. To our delight, 2-naphthol could also be directly applied in the catalytic system with excellent yield (77%) and pure α-selectivity.

We then further investigated the donor scope of this glycosylation. A series of differentially protected galactals 1b–g were prepared and reacted with 2g as a model nucleophile under standard conditions (Scheme [4]). Pleasingly, excellent yields (76–92%) and high selectivities (α:β >30:1) for the α-linked disaccharides were obtained in all cases except when 1e was employed as glycal donor. The reason was postulated as the low activity of the disarmed peracetylated galactal.[9] Encouragingly, the reaction was also applicable to glycosylation with glycal donors 1f and 1g, which possess a readily removable protecting group at the 6-position. In addition, galactal donor 1c could react with secondary alcohol 2s with 71% yield. These results demonstrate that our reaction is tolerant of most protecting groups used in galactals, including benzyl, ethyl, allyl, and silyl ethers. The reaction was also amenable to glycosylation with perbenzylated glucal 1h, affording the glycoside products in 77% yields with similarly high α-stereocontrol. However, ¹H NMR analysis showed that the product 4h was a mixture of addition product and Ferrier rearrangement product with 8:1 ratio. The structure and stereochemistry of all glycosidation products were determined through spectroscopic analysis and by comparison with the reported data.[7]

Scheme 4 Glycals scope of glycosylation reactions with acceptor 2g. Reagents and conditions: donor (0.1 mmol), acceptor (0.12 mmol) and CuBr₂ (5 mol%), stirred DCM (1.0 mL) at 25 °C, nitrogen atmosphere. ^a CuBr₂ (0.1 equiv) was used. ^b Product 4h was obtained as a mixture of addition product and Ferrier rearrangement product with 8:1 ratio. All yields are isolated yields; α/β ratio of all products was >30:1 based on the ¹H NMR spectra. N/A = not applicable.

It should be noted that this novel reaction could be readily scaled up. A gram-scale reaction of 2 mmol of 1a (0.83 g) and 2.4 mmol of 2g (0.63 g) was carried out with 2.5 mol% CuBr₂ at room temperature (Scheme [5]). To our delight, the reaction finished within 1 h and 1.73 g of 3g was obtained with 78% isolated yield and pure stereocontrol (α:β >30:1).

Scheme 5 Gram scale-up reaction

In addition, we extended the methodology to synthesize oligosaccharides 5f (Scheme [6]). Firstly, galactal 1f was reacted with 2g under the optimized condition, in which disaccharide 4f was obtained in a yield of 89%. Considering that the silyl protecting group at the 6′-position of 4f could be selectively removed using TBAF/THF solution, disaccharide 4f could act as a new glycosyl acceptor for further glycosylation. Thus, we tried to synthesize trisaccharide 5f by using our strategy. To our delight, deoxygalactose-containing trisaccharide 5f was successfully obtained in two steps with 51% yield and high α-selectivity.

Scheme 6 Synthetic applications

In conclusion, we have demonstrated a direct and stereoselective synthesis of 2-deoxygalactosides catalyzed by ligand-free Cu(II) catalyst. Moreover, the new method is widely applicable to a range of differentially protected galactal donors and nucleophile acceptors. The reaction proceeds with excellent yields and high selectivities for the α-anomer in short time. In addition, its synthetic potential was successfully demonstrated in gram-scale reaction and by a simple synthesis of oligosaccharides. It should be pointed out that the reaction may result from various processes:[25] [26] Cu-alcohol-complexes that lower the pK _a of the alcohol components is the most likely, but ‘hidden acid catalysis’ (i.e., hydrolysis/alcoholysis of the salt), acid impurities in the salt used, or bromine formation from CuBr₂ may also be operating.

Acknowledgment

We are thankful to the analytical centre of East China Normal University for data measurements. The authors express sincere gratitude for helpful discussions with Mr Zekun Ding.

• References and Notes

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• 27 6-O-(3’,4’,6’-Tri-O-benzyl-2’-deoxy-α-d-galactopyranosyl)-1,2:3,4-di-O-isopropylidene-α-d-galactopyranoside (3g)Under a nitrogen atmosphere, glycal donor 1a (0.10 mmol, 41.6 mg) and nucleophile acceptor 2g (0.12 mmol, 31.2 mg) were dissolved in anhydrous DCM (1.0 mL). Meanwhile CuBr₂ (0.005 mmol, 1.3 mg) was added to the system quickly. The reaction mixture was stirred at 25 °C until the reaction was determined to be complete by TLC. The reaction was then quenched with sat. aq. NaHCO₃, and the mixture was extracted with DCM. The combined organic phases were washed with sat. aq. NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EtOAc = 6:1) to give a yellow syrup. Yield: 55.4 mg (82%), α:β >30:1. Trichloroethyl-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3c) Yield: 46.2 mg (82%); colorless syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.39–7.26 (m, 15 H), 5.24 (d, J = 2.3 Hz, 1 H), 4.95 (d, J = 11.6 Hz, 1 H), 4.62 (d, J = 11.4 Hz, 3 H), 4.51 (d, J = 11.8 Hz, 1 H), 4.44 (d, J = 11.8 Hz, 1 H), 4.19 (d, J = 11.5 Hz, 1 H), 4.07 (d, J = 11.5 Hz, 1 H), 4.04–3.98 (m, 2 H), 3.96 (s, 1 H), 3.59 (d, J = 6.3 Hz, 2 H), 2.29 (td, J = 12.5, 3.4 Hz, 1 H), 2.16 (dd, J = 12.7, 4.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 138.81, 138.39, 138.09, 128.52, 128.50, 128.34, 128.34, 127.82, 127.70, 127.68, 127.53, 98.87, 96.85, 79.15, 74.43, 73.55, 72.90, 71.03, 70.69, 69.46, 30.73. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₉H₃₁Cl₃NaO₅: 587.1129; found: 587.1110. Furfuraldehyde-5-methyl-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3e) Yield: 48.2 mg (89%); yellow syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 9.61 (s, 1 H), 7.36–7.26 (m, 15 H), 7.17 (d, J = 3.5 Hz, 1 H), 6.48 (d, J = 3.5 Hz, 1 H), 5.08 (d, J = 3.1 Hz, 1 H), 4.94 (d, J = 11.6 Hz, 1 H), 4.66–4.58 (m, 4 H), 4.56–4.42 (m, 3 H), 3.96–3.90 (m, 3 H), 3.61–3.54 (m, 2 H), 2.26 (td, J = 12.6, 3.6 Hz, 1 H), 2.04 (dd, J = 12.8, 4.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 177.84, 157.96, 152.84, 138.85, 138.51, 138.11, 128.49, 128.31, 127.88, 127.81, 127.63, 127.37, 111.63, 97.69, 74.60, 74.39, 73.58, 72.93, 70.58, 70.48, 69.59, 60.96, 30.93. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₃₄NaO₇: 565.2197; found: 565.2196. N-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3f)Yield: 70.4 mg (93%); yellow syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.76 (d, J = 7.6 Hz, 2 H), 7.58 (d, J = 7.4 Hz, 2 H), 7.41–7.26 (m, 19 H), 5.91 (d, J = 8.7 Hz, 1 H), 4.94 (dd, J = 14.2, 7.0 Hz, 2 H), 4.64–4.56 (m, 3 H), 4.56–4.45 (m, 2 H), 4.43–4.32 (m, 3 H), 4.21 (t, J = 7.1 Hz, 1 H), 3.99 (dd, J = 10.8, 3.7 Hz, 1 H), 3.93–3.83 (m, 4 H), 3.75 (s, 3 H), 3.62–3.57 (m, 1 H), 3.56–3.51 (m, 1 H), 2.23 (td, J = 12.4, 3.4 Hz, 1 H), 1.96 (dd, J = 12.5, 3.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 170.81, 156.09, 143.91, 141.36, 138.79, 138.40, 138.03, 128.60, 128.21, 128.05, 127.53, 127.46, 127.13, 125.19, 120.04, 99.22, 74.38, 73.49, 72.82, 70.55, 69.58, 68.77, 67.18, 54.56, 52.63, 47.19, 31.12. HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₆H₄₇NNaO₉: 780.3143; found: 780.3127. 4-t-Butyl-Phenyl-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3k) Yield: 47.0 mg (83%); yellow syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.26 (m, 15 H), 7.24 (d, J = 7.2 Hz, 2 H), 7.00 (d, J = 8.7 Hz, 2 H), 5.69 (d, J = 2.9 Hz, 1 H), 4.98 (d, J = 11.5 Hz, 1 H), 4.70–4.64 (m, 3 H), 4.43 (d, J = 11.6 Hz, 1 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.15 (dd, J = 11.1, 3.2 Hz, 1 H), 4.09 (t, J = 6.5 Hz, 1 H), 4.03 (s, 1 H), 3.70–3.64 (m, 1 H), 3.56 (dd, J = 9.3, 5.7 Hz, 1 H), 2.40 (td, J = 12.4, 3.6 Hz, 1 H), 2.21 (dd, J = 12.7, 4.4 Hz, 1 H), 1.30 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 154.83, 144.65, 138.92, 138.57, 138.15, 128.52, 128.39, 128.3, 127.85, 127.69, 127.66, 127.62, 127.43, 126.26, 116.15, 96.82, 74.73, 74.51, 73.42, 72.98, 70.65, 69.32, 34.21, 31.59, 31.43. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₇H₄₂NaO₅: 589.2924; found: 589.2916. 4-Fluoro-Phenyl-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3m) Yield: 41.7 mg (79%); colorless syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.19 (m, 15 H), 7.01 (dd, J = 8.7, 4.4 Hz, 2 H), 6.93 (t, J = 8.5 Hz, 2 H), 5.62 (s, 1 H), 4.97 (d, J = 11.5 Hz, 1 H), 4.71–4.61 (m, 3 H), 4.43 (d, J = 11.6 Hz, 1 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.12 (d, J = 11.6 Hz, 1 H), 4.04 (dd, J = 15.5, 9.2 Hz, 2 H), 3.67–3.60 (m, 1 H), 3.55 (dd, J = 9.2, 6.1 Hz, 1 H), 2.39 (dd, J = 12.4, 3.1 Hz, 1 H), 2.20 (dd, J = 12.7, 4.1 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 159.05, 157.14, 153.08, 138.83, 138.48, 138.06, 128.55, 128.43, 128.36, 128.32, 127.79, 127.77, 127.72, 127.68, 127.44, 118.14, 118.08, 115.94, 115.76, 97.36, 74.56, 74.51, 73.45, 72.93, 70.80, 70.66, 69.40, 31.31. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₃₃FNaO₅: 551.2204; found: 551.2194. 4-Chloro-Phenyl-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3n) Yield: 45.8 mg (75%); colorless syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.19 (m, 17 H), 6.99 (t, J = 6.1 Hz, 2 H), 5.66 (d, J = 3.0 Hz, 1 H), 4.97 (d, J = 11.5 Hz, 1 H), 4.70–4.62 (m, 3 H), 4.41 (d, J = 11.6 Hz, 1 H), 4.36 (d, J = 11.6 Hz, 1 H), 4.10 (ddd, J = 11.9, 4.3, 2.3 Hz, 1 H), 4.03–3.97 (m, 2 H), 3.63 (dd, J = 9.3, 7.2 Hz, 1 H), 3.52 (dd, J = 9.4, 5.8 Hz, 1 H), 2.40 (td, J = 12.5, 3.6 Hz, 1 H), 2.20 (dd, J = 12.8, 4.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 155.51, 138.81, 138.45, 138.01, 129.40, 128.56, 128.44, 128.36, 128.31, 127.81, 127.78, 127.74, 127.69, 127.44, 126.94, 118.05, 96.86, 74.53, 74.50, 73.44, 72.86, 70.87, 70.67, 69.29, 31.20, 29.79. HRMS (ESI): m/z[M + Na]⁺ calcd for C₃₃H₃₃ClNaO₅: 567.1909; found: 567.1895. 2-Methyl-Phenyl-3,4,6-tri-O-benzyl-2-deoxy-α-d-galactopyranoside (3p) Yield: 39.8 mg (76%); colorless syrup; α:β >30:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.20 (m, 15 H), 7.15–7.08 (m, 3 H), 6.94–6.86 (m, 1 H), 5.71 (d, J = 1.9 Hz, 1 H), 4.99 (d, J = 11.5 Hz, 1 H), 4.73–4.62 (m, 3 H), 4.42 (d, J = 11.6 Hz, 1 H), 4.36 (d, J = 11.6 Hz, 1 H), 4.18–4.11 (m, 1 H), 4.03 (d, J = 7.6 Hz, 2 H), 3.67 (t, J = 8.4 Hz, 1 H), 3.53 (dd, J = 9.2, 5.5 Hz, 1 H), 2.42 (td, J = 12.5, 3.4 Hz, 1 H), 2.22–2.18 (m, 1 H), 2.17 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 154.98, 138.92, 138.37, 138.05, 130.69, 128.53, 128.41, 128.33, 128.30, 127.89, 127.74, 127.73, 127.62, 127.15, 126.95, 121.58, 114.24, 96.28, 74.51, 74.28, 73.47, 72.96, 70.78, 70.53, 69.18, 31.50, 16.3. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₃₆NaO₅: 547.2455; found: 547.2441.