Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor

Abstract

Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity.

INTRODUCTION

Heat shock protein 90 (Hsp90) is ubiquitously expressed and essential for the folding of many nascent polypeptides.^1–4 As a molecular chaperone, Hsp90 regulates the conformational maturation of more than 200 client proteins, including steroid hormone receptors, Akt, Raf-1 and the Src-family kinases.⁵ Many of these Hsp90-dependent client proteins regulate signaling pathways associated with cell survival, cell proliferation, as well as cellular transformation and oncogenesis.^{6, 7} Prior studies have shown that Hsp90 is upregulated in malignant cells and that Hsp90 inhibitors accumulate more efficiently in tumor cells than in the surrounding normal tissue.⁸ Consequently, Hsp90 inhibition represents a multi-faceted approach toward the treatment of cancer. ^{9, 10}

Natural products represent a class of diverse structures that contribute to clinically relevant therapeutics.^{11, 12} They serve as lead compounds and/or scaffolds upon which molecules with improved efficacy and drugability can be pursued.¹³ Structure-activity relationships studies on natural products have led to the identification of structurally less complex molecules that are clinically used today. (−)-Epigallocatechin-3-gallate (EGCG (1)) is a polyphenolic natural product that can be isolated from green tea leaves and has been shown to inhibit Hsp90’s function and induce the degradation of client proteins; including telomerase, multiple kinases and the aryl hydrocarbon receptor (AhR).^14–16 Palermo and coworkers demonstrated through affinity chromatography that (−)-EGCG binds to amino acids 538-728 within the Hsp90 C-terminus and inhibits AhR-mediated transcription through interactions with Hsp90¹⁷. Unfortunately, the exact mechanism by which EGCG inhibits the Hsp90 protein folding machinery remains undetermined. Similar to EGCG, novobiocin (2) also binds Hsp90 within amino acids 538-728 and represents another naturally occurring C-terminal inhibitor (Figure 1).^{4, 18} The bioavailability and lipophilicity exhibited by EGCG along with its metabolically susceptible functionalities and modest efficacy against various cancer cell lines make EGCG a poor lead compound for development.¹⁹ However, only two natural products are known to inhibit the Hsp90 C-terminus, and therefore EGCG was pursued as a probe to further investigate the mechanism by which C-terminal inhibitors modulate the Hsp90 protein folding machinery.

Figure 1.

Hsp 90 C-terminal inhibitors

EGCG is well known for its antioxidant activity both in vitro and in vivo, which also leads to epimerization and/or dimerization (Scheme 1) and contributes to its low efficacy and metabolic instability.^{20, 21} Epimerization of the methine hydrogen leads to formation of the thermodynamically more stable anti product, GCG (Figure 2), whose activity against Hsp90 has not been investigated. Studies by Suzuki and co-workers have shown that incorporation of hydroxyl groups onto the B-ring can lead to epimerization at C-2, whereas O-methylated derivatives at the 4–position prevent epimerization.²² Therefore, the design of new EGCG analogues must take into account these prior studies in an effort to produce stable derivatives that are not prone to oxidation/epimerization.^23–28 To probe EGCG’s structure-activity relationships with Hsp90, three series of analogues (Scheme 2) were pursued; (I) 3′,4′,5′-trimethoxy groups were incorporated into the B-ring, (II) compounds omitting substituents on the B-ring were prepared, and (III) compounds lacking the B-ring were also constructed. Furthermore, the phenols on the A-ring were converted to methyl ethers for biological evaluation and finally, the gallic acid moiety (D-ring) of EGCG was replaced with various aryl acids for elucidation of additional SAR trends. These aryl acids were chosen to probe the effect of substitution at the 3- and 4-position of the D-ring and to incorporate optimized novobiocin appendages to evaluate their potential for overlapping binding modes.^29–31

Scheme 1.

(a) Epimerization of EGCG to GCC, (b) Auto-oxidation products of EGCG.

Figure 2.

Western blot analyses of MCF-7 cell lysates for Hsp90 client protein degradation after 24h of incubation. (a) Compounds 27b, 27e, 10e and 11e at two different concentrations. “H” (high) represents a concentration 5 × IC₅₀ value, whereas and “L” (low) represents a concentration at one half the IC₅₀ value as determined by anti-proliferative studies; (b) Compound 11e at increasing concentrations.

Scheme 2.

(a) Scaffolds derived from EGCG for Hsp90 inhibition, (b) Aryl acids used to replace the gallic acid moiety.

RESULTS AND DISCUSSION

Synthesis of the A-, B- and D-ring modified compounds (10a–j & 11a–j) are described in Scheme 3. Prior work by Li and coworkers provided rapid access towards preparation of the flavon-3-ol core, enlisting the use of a silica/sulfuric acid catalyst to couple electron rich phenols (4a–b) with substituted cinnamyl alcohols (5a–b), which worked surprisingly well and led to various substituted A- and B-ring analogues (6a–d).³² Dihydroxylation of the resulting alkenes (6a–d) with catalytic osmium tetroxide and excess N-methylmorpholine-N-oxide gave the corresponding diol’s, 7a–d.³³ Various methods have been reported for cyclization and construction of the benzopyran core, however, stereochemical control at the 2,3-ring junction is dependent upon substituents on the B-ring. Therefore, cylization of diol’s 7a–d to furnish the 2,3-dihydrobenzopyran core in a stereoselective manner was pursued via two steps. Treatment of 7a–d with trimethylorthoacetate in the presence of catalytic pyridinium p-toluenesulfonate, led to formation of the corresponding orthoesters, which upon the addition of 10% boron trifluoride diethyl etherate produced the desired cyclic products. Without purification, the cyclized products were subjected to solvolysis conditions to furnish alcohols 8a–d in high yields and with the anti configuration. ³⁴ The 2,3-syn products, 9a–d, were established by Dess-Martin oxidation of the secondary alcohols (8a–d) to the corresponding ketones, which underwent subsequent reduction with L–selectride to give syn products, 9a–d, respectively.³⁵ These flavon-3-ol moieties (9a–d) served as late stage intermediates to incorporate additional substitutions onto the D-ring. Aryl acids 12–16 (Scheme 2) were chosen as replacements for the metabolically susceptible gallic ester moiety of EGCG and also represent optimized side chains identified from prior studies with the other Hsp90 C-terminal inhibitor, novobiocin.^{36, 37} Coupling of the alcohols (9a–d) with aromatic acids 12–16 enlisting 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) and 4-dimethylaminopyrine (DMAP) gave the corresponding esters, 10a–t.³⁸ Hydrogenolysis of 10k–t with palladium/carbon and hydrogen gas gave 11a–j in high yield.

Scheme 3.

Synthesis of EGCG analogues containing modifications to the A-, B- and D-rings

Upon preparation of the A-, B- and the D-ring modified EGCG analogues (10a–j and 11a–j), these compounds were evaluated against MCF-7 and SKBr3 breast cancer cell lines for determination of their anti-proliferative activities (Table 1). The SKBr3 (estrogen receptor negative, Her2 overexpressing) and the MCF-7 (estrogen receptor positive) cell lines were chosen due to the fact that both Her2 and the estrogen receptor are Hsp90-dependent client proteins. Four of the D-ring analogues that contain two methoxy groups on the A-ring and no substituents on the B-ring (10a–d) were inactive against both MCF-7 and SKBr3 cell lines and only compound 10e manifested significant anti-proliferative activity with an IC₅₀ value of 25.35 ± 5.25 μM against MCF-7 and 36.1 ± 2.51 μM against SKBr3 cell lines. Similar trends were observed for compounds (10f–j) containing the 3,4,5-trimethoxy substituents on the B-ring, as only 10j was found to be potent and exhibits an IC₅₀ value of 19.48 ± 2.5 μM and 24.87 ± 3.29 μM against MCF-7 and SKBr-3 cell lines, respectively.

Table 1.

Anti-proliferative activities produced by A-, B- and the D-ring modified EGCG analogues

Entry	R1, R2	R3, R4, R5	R	MCF-7 (IC50, μM)	SKBr3 (IC50, μM)
(−)-EGCG	7-	-	-	74.4 ± 2.19	100.16 ± 0.03
Geldanamycin	-	-	-	0.05 ± 0.03	0.008 ± 0.02
10a	Me	H	a	>100	>100
10b	Me	H	b	>100	>100
10c	Me	H	c	>100	>100
10d	Me	H	d	>100	>100
10e	Me	H	e	25.35 ± 5.25	36.1 ± 2.51
10f	Me	OMe	a	>100	>100
10g	Me	OMe	b	91.18 ± 0.76	>100
10h	Me	OMe	c	>100	>100
10i	Me	OMe	d	88.7 ± 11.3	>100
10j	Me	OMe	e	19.48 ± 2.5	24.87 ± 3.29
11a	OH	H	a	15.26 ± 0.57	18.67 ± 0.82
11b	OH	H	b	13.10 ± 0.86	15.42 ± 1.04
11c	OH	H	c	13.12 ± 0.54	17.26 ± 2.27
11d	OH	H	d	14.14 ± 0.7	19.88 ± 3.22
11e	OH	H	e	3.99 ± 1.4	21.45 ± 4.75
11f	OH	OMe	a	65.88 ± 2.1	>100
11g	OH	OMe	b	45.72 ± 0.4	37.92 ± 4.08
11h	OH	OMe	c	42.80 ± 7.30	62.90 ± 0.70
11i	OH	OMe	d	47.31 ± 3.39	71.9 ± 2.76
11j	OH	OMe	e	42.08 ± 1.85	50.4 ± 1.39

Analogues 11a–e that contain phenols on the A-ring were also evaluated and found to be more potent when compared to EGCG and analogues 10a–j. Incorporation of a methoxy group at the meta- and the para- positions of the D-ring (11b and 11c) did not alter activity as compared to unsubstituted analogue, 11a. Compound 11e was found to be the most potent of this series and displayed an IC₅₀ value of 3.99 ± 1.4 μM against the MCF-7 cell line. In contrast, compounds with 3-,4-,5-trimethoxy groups on the B-ring (11f–j) were less active when compared to analogues without substitution on the B-ring (11a–e). This data suggests that substitutions on the B-ring are detrimental to activity, whereas replacement of the gallate ester moiety with prenyl benzoate enhances potency. In addition, the MCF-7 cell line was found to be more sensitive than the SKBr3 cell line upon administration of these analogues. Furthermore, the anti isomer of 11e was synthesized and evaluated and found to be less active (IC₅₀ = 33.7 ± 1.8 against MCF-7 cell line), confirming that syn-stereochemistry is important for inhibitory activity.

Simultaneous with the above studies, synthesis of analogues that lack the B-ring were commenced by the treatment of 3,5-dibenzyloxyphenol (Scheme 4) with allyl bromide in the presence of potassium carbonate to give allyl ether 18a.³⁹ 3,3-Rearrangement of the O-allylated product (18a) gave 19a in high yield.⁴⁰ Dihydroxylation of the resulting olefin afforded diol 20a. Unfortunately, attempts to cyclize via the orthoester were unsuccessful as only the 5-membered product was formed. Therefore, an alternative strategy for the cyclization of 20a was pursued. Treatment of the primary alcohol present in 20a with p-toluenesulfonyl chloride resulted in formation of the corresponding p-toluenesulfonic ester, which underwent intramolecular cyclization upon exposure to potassium carbonate to give a 1:1 mixure of 5- and 6-membered rings that were separated by silica gel chromatography. Subsequent coupling of 22a with various substituted benzoic acids produced the requisite esters, which underwent hydrogenolysis to afford 23a–i, respectively.

Scheme 4.

Synthesis of esters of 3,5-dihydroxychroman-3-ol.

Upon construction of analogues that lack the B-ring, each phenol on the A-ring was systematically investigated. Therefore, derivatives 23i–s that contain only one hydroxyl at either the 5- or the 7-position were pursued similar to that described above. Allylation of the phenol (17) gave ally ether, 18b. 3,3-Rearrangement of the allyl ether (18b) gave a mixture of two regioisomers, 19b and 19c, which upon dihydroxylation and subsequent ring closure gave 22b and 22c, respectively.

Results from the anti-proliferative studies with compounds 23a–s are summarized in Table 2. In addition to previously investigated substituents, the effect of hydroxyl substitution on the D-ring was also explored. Many of the compounds were found to be more efficacious than EGCG itself. This data suggests that methoxy substitution on the D-ring is more beneficial than the naturally occurring phenols, which corresponds to an overall pattern represented by O-alkyl substitutions at the 3′-position are more active than those at the 4′-position. Data also suggests that aryl and prenyl substitution on the D-ring produce enhanced efficacy, as 23i manifested an IC₅₀ value of 10.66 ± 1.09 μM against MCF-7 cells and 23.15 ± 0.25μM against SKBr3 cells. The IC₅₀ values of compounds containing only one phenolic group at the 7-position on the A-ring resulted in decreased activity, except for 23n. Similarly, compounds with 5-hydroxyl substitution on the A-ring also resulted in decreased activity with the exception of 23r, which manifested enhanced activity and an IC₅₀ value of 21.6 ± 2.55 against the MCF-7 cell line. Similar to the most active analogue produced from the B-ring series, 11e, the most active analogue identified in this series was 23i (IC₅₀ = 10 μM in MCF-7 cell line), which also incorporates the prenylated benzoate side chain.

Table 2.

Anti-proliferative activities produced by 3,5-dihydroxychroman-3-ol esters.

Entry	R1	R2	R3	R4	R5	MCF-7 (IC50, μM)	SKBr3 (IC50, μM)
23a	OH	OH	H	H	H	98.24 ± 1.76	>100
23b	OH	OH	OMe	H	H	57.75 ± 3.12	50
23c	OH	OH	H	OMe	H	>100	>100
23d	OH	OH	OMe	OMe	H	>100	>100
23e	OH	OH	OMe	H	OMe	96.50 ± 3.51	>50
23f	OH	OH	OH	H	H	61.94 ± 6.85	85.30 ± 5.36
23g	OH	OH	H	OH	H	>100	>100
23h	OH	OH	m OMePh	OMe	H	21.93 ± 2.27	34.84 ± 16.29
23i	OH	OH	Prenyl	OAc	H	10.66 ± 1.09	23.15 ± 0.25
23j	OH	H	H	H	H	>100	>100
23k	OH	H	OMe	H	H	>100	>100
22l	OH	H	H	OMe	H	>100	>100
23m	OH	H	m-OMePh	OMe	H	55.09 ± 5.53	57.73 ± 4.28
23n	OH	H	Prenyl	OAc	H	15.94 ± 1.86	25.25 ± 4.05
23o	H	OH	H	H	H	>100	>100
23p	H	OH	OMe	H	H	>100	>100
22q	H	OH	H	OMe	H	>100	>100
23r	H	OH	m-OMePh	OMe	H	21.6 ± 2.55	41.72 ± 0.34
23s	H	OH	Prenyl	OAc	H	60 ± 7.38	>100

In an effort to further investigate the A-ring, the free phenols were replaced with methyl ethers. 5,7-Dimethoxychroman-3-ol (26) was synthesized in two steps using a gold(III)-mediated procedure as described by Zhangjie and coworkers (Scheme 5).⁴¹ Commencing with commercially available 3,5-dimethoxyphenol and enlistment of epichlorohydrin and sodium hydride, produced oxirane 25, which underwent 6-endo cyclization to yield 26 upon treatment with a gold(III) chloride/silver trifluormethanesulfonate catalyst. Upon construction of the chroman-3-ol core (26), subsequent coupling with various substituted aryl acids to furnish the corresponding esters, 27a–m. The final products 28a–e were prepared via hydrogenolysis of 27i–m.

Scheme 5.

Synthesis of 3,5-dimethoxychroman-3-ol esters.

In addition, investigation of the linker connecting the B- and D-rings was pursued. The ester linker was replaced with an amide functionality. These amide-based analogues were prepared from previously synthesized alcohol 26, which was transformed into azide 29 via Mitsunobu conditions with diisopropyl azodicarboxylate, triphenylphosphine and diphenylphosphoryl azide, followed by Staudinger reduction with triphenylphosphine to afford amine 30 (Scheme 6).⁴² Subsequent coupling of amine 30 with the optimal aryl acids gave the corresponding amides, 31a–d. ³⁷

Scheme 6.

Synthesis of 3,5-dimethoxychroman-3-ol amides.

Results from anti-proliferative studies for compounds lacking the B-ring are summarized in Table 3. The 3-methoxy substituted compound 28b was found to be the most active compound against the MCF-7 and the SKBr3 cell lines, and manifested IC₅₀ values 0.775 ± .02 μM and 0.88 ± 0.06 μM, respectively. Increasing the length of side chain resulted in decreased activity for compound 27h. The hydroxyl group was found to be more beneficial at the 4′-position in lieu of the 3′-position. Unfortunately, the combination of 3-methoxy and 4-hydroxyl substitutions on the D-ring (28e) did not improve anti-proliferative activity. Once again, MCF-7 cells exhibited greater sensitivity to these compounds. The IC₅₀ values for 27d and 27e (Table 4) correlate directly with prior studies using novobiocin, suggesting a beneficial effect for inclusion of aryl or prenyl group on the D-ring. The linker between the B- and D-ring was also evaluated and replacement of the ester with an amide (31a–d) was found detrimental.

Table 3.

Anti-proliferative activity produced by 3,5-dimethoxychroman-3-ol esters.

Entry	R1	R2	R3	MCF-7 (IC50, μM)	SKBr3 (IC50, μM)
27a	H	H	H	14.02 ± 0.91	44.605 ± 5.40
27b	OMe	H	H	0.77 ± .02	0.88 ± 0.06
27c	H	OMe	H	32.89 ± 2.05	50.40 ± 1.39
27d	m-OMePh	OMe	H	31.20 ± 18.17	80.13 ± 9.67
27e	Prenyl	OAc	H	38.66 ± 7.71	47.90 ± 0.71
27f	OMe	OMe	H	10.89 ± 0.27	36.98 ± 5.24
27g	OMe	H	OMe	21.8 ± 3.08	29.5 ± 1.5
27h	OEt	H	H	8.19 ± 0.16	33.35 ± 4.81
28a	OH	H	H	37.72 ± 6.75	64.11 ± 13.95
28b	H	OH	H	17.51 ± 0.86	17.73 ± 5.97
28c	OH	H	OH	>100	>100
28d	OH	OH	H	22.12 ± 1.01	30.63 ± 11.89
28e	OMe	OH	H	51.29 ± 1.13	76.50 ± 1.10

Table 4.

Anti-proliferative activity produced by analogues containing amide linkers.

Entry	R1	R2	MCF-7 (IC50, μM)	SKBr3 (IC50, μM)
31a	H	H	>100	>100
31b	OMe	H	>100	>100
31c	m-OMePh	OMe	>100	>100
31d	Prenyl	OAc	54.5 ± 0.6	55.2 ± 1.2

After determination of anti-proliferative activity for EGCG analogues, four representative examples were chosen for subsequent western blot analyses to confirm Hsp90 inhibition, based on each class of scaffold investigated. Since Hsp90 inhibition results in the induction of client protein degradation via the ubiquitin-proteasome pathway, immunoblots are used to confirm Hsp90 inhibitory activity. As shown in Figure 2, 11e, 27e and 10e induced the degradation of Hsp90 client proteins Her2, Raf and pAkt at concentrations that mirror the concentration needed to exhibit anti-proliferative activity, thereby linking Hsp90 inhibition to cell viability. Analog 27b failed to induce client protein degradation, demonstrating that this compound manifests anti-proliferative activity through a mechanism independent of Hsp90 inhibition. However a related compound containing the prenylated benzoate side chain, 27e, was shown to exhibit Hsp90 inhibitory activity. Further investigation of 11e at increasing concentrations demonstrated client protein degradation in a dose-dependent manner, while actin levels remained the same. Actin is not an Hsp90-dependent protein and is therefore unaffected by Hsp90 inhibition. Similar to other Hsp90 C-terminal inhibitors, the level of Hsp90 was unaffected.

CONCLUSIONS

In summary, we have synthesized and evaluated the first structure-activity relationships between EGCG and Hsp90 (Figure 3). The results obtained suggest that phenolic groups on the A-ring are beneficial for Hsp90 inhibition, while phenolic substituents on the D-ring are detrimental. The inclusion of a novobiocin-derived prenyl benzoate was found to be a suitable replacement for the gallic acid moiety present on EGCG, and suggests that both novobiocin and the EGCG may bind similarly to the Hsp90 C-terminus. Results from these studies have led to the development of analogue 11e, which exhibits a 18-fold improvement over EGCG and can serve as a probe for further biological investigations.

Figure 3.

Summary of EGCG structure-activity relationships.

EXPERIMENTAL SECTION

All reactions were performed in oven-dried glassware under argon atmosphere unless otherwise stated. Dichloromethane (DCM), tetrahydrofuran (THF), and toluene were passed through a column of activated alumina prior to use. Anhydrous methanol, acetonitrile, dimethylformamide (DMF), and dimethoxyethane (DME) were purchased and used without further purification. (−)-EGCG (≥95%) was purchased from Sigma-Aldrich and used as obtained. Flash column chromatography was performed using silica gel (40 – 63 μm particle size). The ¹H (500 MHz and 400 MHz) and ¹³C-NMR (proton 125 MHz and 100 MHz) spectra were recorded on 500 MHz and 400 MHz spectrometer. Data are reported as p = pentet, q = quartet, t = triplet, d = doublet, s = singlet, bs = broad singlet, m = multiplet; coupling constant (s) in Hz. Infrared spectra were obtained using FT/IR spectrometer. High resolution mass spectral data were obtained on a Electrospray Ionization spectra were acquired on a LCT Premier, time of flight mass spectrometer. The purity of all compounds was determined to be >95% by ¹H and ¹³C NMR spectra, unless otherwise noted.

3,5-Bis(benzyloxy)phenol (4b) and (E)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-ol (5b) and 3-(benzyloxy)phenol (17) were prepared following literature procedures.^{32, 43–44} Reactions of phenols (4a–b) with cinnamyl alcohols (5a–b) to yield compounds 6a–d were accomplished via the protocol described by Li et. al. ³²

2-Cinnamyl-3,5-dimethoxyphenol (6a)

A solution of 3,5-dimethoxy phenol (2.3 g, 14.91 mmol) and cinnamyl alcohol (2.0 g, 14.91 mmol) in a solvent mixture of dichloromethane (30 mL) and carbon disulfide (30 mL) was treated with 25% H₂SO₄/SiO₂ catalyst (2.4 g, 5.96 mmol) at rt. The resulting mixture was stirred for 4 h and then filtered through a plug of SiO₂ (40 – 63 μm particle size). Solvent was removed and the residue purified by flash chromatography (SiO₂, 1:9 EtOAc/Hexanes) to give 6a (1.735 g, 43.15 %) as an amorphous light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.37 – 7.26 (m, 2H), 7.30 (dd, J = 7.2, 1.7 Hz, 2H), 7.23 – 7.17 (m, 1H), 6.48 (dt, J = 16.0, 1.7 Hz, 1H), 6.34 (dt, J = 15.9, 6.3 Hz, 1H), 6.15 (d, J = 2.3 Hz, 1H), 6.11 (d, J = 2.3 Hz, 1H), 5.06 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.56 (d, J = 1.6 Hz, 1H), 3.55 (d, J = 1.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.9, 159.0, 155.9, 137.4, 130.6, 128.6 (2), 128.6, 128.5, 127.3, 126.3, 106.1, 93.9, 91.8, 56.0, 55.5, 26.4; IR (KBr)ν_max 3367, 1614, 1596, 1454, 1423, 1201, 1147, 1097, 1053, 811, 736, 692 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₇H₁₉O₃, 271.1334, found 271.1336.

3,5-Bis(benzyloxy)-2-cinnamylphenol (6b)

A solution of 3,5-bis(benzyloxy)phenol (3.3 g, 9.98 mmol) and cinnamyl alcohol (1.34 g, 9.98 mmol) in a solvent mixture of dichloromethane (20 mL) and carbon disulfide (20 mL) was treated with 25% H₂SO₄/SiO₂ catalyst (1.59g, 3.99 mmol) at rt. The resulting mixture was stirred for 4 h and then filtered through a plug of SiO₂ (40 – 63 μm particle size). Solvent was removed and the residue purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give 6b (1.425 g, 33.7 %) as amorphous light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.48 – 7.29 (m, 15H), 6.53 – 6.44 (m, 1H), 6.39 – 6.30 (m, 1H), 6.29 (d, J = 2.2 Hz, 1H), 6.18 (d, J = 2.3 Hz, 1H), 5.03 (m, 5H), 3.60 (dd, J = 6.5, 1.6 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 159.0, 158.1, 155.9, 137.5, 137.2, 137.0 (2), 128.8 (2), 128.7 (2), 128.6 (3), 128.5, 128.2, 128.0, 127.8, 127.5 (2), 127.3, 126.3 (2), 107.0, 95.3, 93.9, 70.5, 70.3, 26.7; IR (KBr)ν_max 3419, 3028, 2925, 1618, 1596, 1452, 1436,1375, 1147, 1091, 734, 696 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₉H₂₇O₃, 423.1960, found 423.1966.

(E)-3,5-Dimethoxy-2-(3-(3,4,5-trimethoxyphenyl)allyl)phenol (6c)

A solution of 3,5-dimethoxy phenol (2.06 g, 13.4 mmol) and (E)-3,4,5-trimethoxycinnamyl (3.0 g, 13.4 mmol) in a solvent mixture of dichloromethane (26 mL) and carbon disulfide (26 mL) was treated with 25% H₂SO₄/SiO₂ catalyst (2.2g, 5.36 mmol) at rt. The resulting mixture was stirred for 4 h and then filtered through a plug of SiO₂ (40 – 63 μm particle size). Solvent was removed and the residue purified by flash chromatography (SiO₂, 1:2 EtOAc/Hexanes) to give 6c as an amorphous light yellow solid: (1.660 g, 39.4 %): ¹H NMR (500 MHz, CDCl₃) δ 6.56 (s, 2H), 6.38 (dt, J = 15.8, 1.7 Hz, 1H), 6.23 (dt, J = 15.8, 6.2 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 6.10 (d, J = 2.3 Hz, 1H), 5.09 (s, 1H), 3.85 (s, 6H), 3.83 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.54 (dd, J = 6.2, 1.7 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 159.9, 159.0, 155.9, 153.4 (2), 137.6, 133.2, 130.4, 128.1, 106.1, 103.3 (2), 93.9, 91.7, 61.1, 56.2 (2), 56.0, 55.5, 26.2; IR (KBr)ν_max 3379, 3379, 2937, 1620, 1593, 1506, 1421, 1361, 1330, 1201, 1147, 1053, 817, 707 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₀H₂₅O₆, 361.1651, found 361.1657.

(E)-3,5-Bis(benzyloxy)-2-(3-(3,4,5-trimethoxyphenyl)allyl)phenol (6d)

A solution 3,5-bis(benzyloxy)phenol (5.2 g, 6.97 mmol) and (E)-3,4,5 trimethoxycinnamyl alcohol (3.81 g, 16.97 mmol) in a solvent mixture of dichloromethane (33 mL) and carbon disulfide (33 mL) was treated with 25% H₂SO₄/SiO₂ catalyst (1.11 g, 2.8 mmol) at rt. The resulting mixture was stirred for 4 h and then filtered through a plug of SiO₂ (40 – 63 μm particle size). Solvent was removed and the residue purified by flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give 6d (1.970 g, 22.6 %) as an amorphous light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.47 – 7.28 (m, 10H), 6.54 (s, 2H), 6.39 (dt, J = 15.8, 1.7 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 6.24 (dt, J = 15.8, 6.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.05 (s, 2H), 5.03 (s, 1H), 5.02 (s, 2H), 3.90 – 3.80 (m, 9H), 3.65 – 3.56 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 159.1, 158.2, 155.9, 153.5 (2), 137.6, 137.3, 137.1, 133.3, 130.7, 128.9 (2), 128.8 (2), 128.7, 128.3 (2), 128.1 (2), 127.8 (2), 127.5, 107.0, 103.4, 95.3, 93.9, 70.6, 70.4, 61.2, 56.3 (2), 26.6. IR (KBr)ν_max 3400, 2937, 1614, 1585, 1454, 1328, 1238, 1126, 1001, 736, 696 cm⁻¹. HRMS (ESI+) m/z [M+Na⁺] calcd for C₃₂H₃₂NaO₆, 535.2097, found 535.2100.

3-(2-Hydroxy-4,6-dimethoxyphenyl)-1-phenylpropane-1,2-diol (7a)

N-methylmorpholine-N-oxide (1.26g, 10.76 mmol) was added to a solution of 6a (1.7g, 6.33 mmol) in a solvent mixture of tetrahydrofuran (18 mL) and H₂O (12 mL). The resulting solution was stirred for 15 min at rt before the addition osmium tetraoxide (0.1 mmol, 4% solution in water). The mixture was stirred for 14 h at rt before quenching with 20% of sodium metabisulphite (15 mL). The aqueous layer was extracted with ethyl acetate (3 × 25 mL) and the combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:2 EtOAc/Hexanes) to afford 7a (1.55 g, 81 %) as a colorless oil: ¹H NMR: (500 MHz, CDCl₃) δ 7.98 (brs, 1H), 7.43 – 7.37 (m, 2H), 7.37 – 7.32 (m, 3H), 6.17 (d, J = 2.4 Hz, 1H), 6.03 (d, J = 2.4 Hz, 1H), 4.55 (d, J = 6.6 Hz, 1H), 4.04 (ddd, J = 7.4, 6.5, 3.8 Hz, 1H), 3.77 (s, 3H), 3.59 (s, 3H), 3.23 (brs, 1H), 2.84 (dd, J = 14.8, 3.8 Hz, 1H), 2.74 (dd, J = 14.8, 7.4 Hz, 1H), 2.46 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 160.2, 158.9, 157.5, 140.6, 128.7 (2), 128.5 (2), 127.2, 105.5, 76.9, 76.5, 94.6, 91.5, 55.5 (2), 26.2; IR (KBr)ν_max 3348, 2837, 1622, 1593, 1496, 1456, 1338, 1199, 1147, 1105, cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₇H₁₉O₅, 303.1233, found 303.1227.

3-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)-1-phenylpropane-1,2-diol (7b)

N-methylmorpholine-N-oxide (393 mg, 3.36 mmol) was added to a solution of 6a (0.9g, 2.1 mmol) in a solvent mixture of tetrahydrofuran (9 mL) and H₂O (6 mL). The resulting solution was stirred for 15 min at rt before the addition osmium tetraoxide (0.02 mmol, 4% solution in water). The mixture was stirred for 14 h at rt before quenching with 20% of sodium metabisulphite (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the combined organic layers were washed with saturated sodium chloride solution (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to afford 7b (0.78g, 80.1 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.03 (s, 1H), 7.46 – 7.36 (m, 5H), 7.36 – 7.29 (m, 6H), 7.27 – 7.25 (m, 2H), 7.19 – 7.06 (m, 2H), 6.29 (d, J = 2.3 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 5.01 (s, 2H), 4.90 – 4.82 (m, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.04 (ddd, J = 8.5, 6.7, 3.5 Hz, 1H), 3.32 (s, 1H), 2.93 (dd, J = 14.7, 3.5 Hz, 1H), 2.75 (dd, J = 14.6, 8.4 Hz, 1H), 2.46 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.3, 158.0, 157.7, 140.4, 137.1, 137.0, 128.8 (5), 128.7 (2), 128.6, 128.2, 127.8 (4), 127.2 (2), 127.0 (2), 106.3, 96.1, 93.6, 70.3 (2), 26.6; IR (KBr)ν_max 3363, 3330 3087, 3031, 1701, 1620, 1598, 1452, 1375, 1147, 1099, 815, 698 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₉H₂₉O₅, 457.2015, found 457.2028.

3-(2-Hydroxy-4,6-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)propane-1,2-diol (7c)

N-methylmorpholine-N-oxide (702 mg, 6 mmol) was added to a solution of 6c (1.350 g, 3.75 mmol) in a solvent mixture of tetrahydrofuran (12 mL) and H₂O (8 mL). The resulting solution was stirred for 15 min at rt before the addition osmium tetraoxide (0.04 mmol, 4% solution in water). The mixture was stirred for 14 h at rt before quenching with 20% of sodium metabisulphite (12 mL). The aqueous layer was extracted with EtOAc (3 × 25 mL) and the combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:10 Acetone/Dichloromethane) to afford 7c (1.33 g, 90.4 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.08 (s, 1H), 6.54 (s, 2H), 6.14 (d, J = 2.4 Hz, 1H), 6.03 (d, J = 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 1H), 3.98 (ddd, J = 8.0, 6.1, 3.8 Hz, 1H), 3.84 (s, 6H), 3.82 (s, 3H), 3.75 (s, 3H), 3.62 (s, 3H), 3.44 (brs, 1H), 3.10 – 2.92 (m, 1H), 2.85 (dd, J = 14.7, 3.8 Hz, 1H), 2.73 (dd, J = 14.7, 7.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 160.1, 159.0, 157.3, 153.4 (2), 137.6, 136.5, 105.6, 103.9 (2), 94.6, 91.4, 76.9, 76.7, 61.0, 56.3 (2), 55.7, 55.5, 26.5; IR (KBr)ν_max 3405, 2932, 1620, 1591, 1498, 1439, 1379, 1218, 1146, 1029, 817 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₀H₂₇O₈, 395.1706, found 395.1719.

3-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)propane-1,2-diol (7d)

N-methylmorpholine-N-oxide (444 mg, 3.79 mmol) was added to a solution of 6c (1.0 g, 2.36 mmol) in a solvent mixture of tetrahydrofuran (7.5 mL) and H₂O (5 mL). The resulting solution was stirred for 15 min at rt before the addition osmium tetraoxide (0.02 mmol, 4% solution in water). The mixture was stirred for 14 h at rt before quenching with 20% of sodium metabisulphite (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the combined organic layers were washed with saturated sodium chloride solution (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:10 Acetone/Dichloromethane) to afford 7d (595 g, 56.7 %) as an amorphous light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (brs, 1H), 7.47 – 7.28 (m, 10H), 6.54 (s, 2H), 6.28 (d, J = 2.3 Hz, 1H), 6.22 (d, J = 2.3 Hz, 1H), 5.06 – 4.95 (m, 4H), 4.91 (d, J = 3.0 Hz, 1H), 4.52 (d, J = 6.0 Hz, 1H), 3.77 (d, J = 10.2 Hz, 9H), 3.25 (brs, 1H), 3.01 – 2.95 (m, 1H), 2.83 (dd, J = 14.6, 8.3 Hz, 1H), 2.74 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.4, 158.1, 157.6, 153.5 (2), 137.1, 137.0, 136.4, 129.0, 128.8, 128.7, 128.5, 128.4, 128.3 (2), 128.1, 127.8, 127.5, 127.4, 127.3, 126.9, 106.3, 103.8 (2), 96.2, 93.7, 70.3 (2), 61.0, 56.3, 56.3, 27.0; IR (KBr)ν_max 3446, 2935, 2837, 1591, 1498, 1456, 1328, 1232, 1126, 1004, 736 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₃₂H₃₃O₈, 547.2332, found 547.2347.

5,7-Dimethoxy-2-phenylchroman-3-ol (8a)

Trimethyl orthoacetate (2.50 mmol, 300 μl) and pyridinium p-toluenesulfonate (9 mg, 0.036 mmol) were added to a solution of 7a (600 mg, 1.92 mmol) in dichloromethane (36 mL) at rt. The resulting mixture was stirred for 30 min at rt and then cooled to 0 °C before the dropwise addition of borontrifluoride diethyletherate (25 μl, 0.192 mmol). The reaction mixture was warmed to rt and stirred for another 15 min before quenching with aqueous acetone (4 mL). Solvent was removed and the residue was dissolved methanol (32 mL). Potassium carbonate (225 mg, 1.84 mmol) was added and mixture stirred for 6 h at rt. Methanol was removed, water (25 mL) was added and the products extracted with ethyl acetate (2 × 30 mL). Organic layers were combined and washed with saturated sodium chloride solution (60 mL). The organic phase was dried over anhydrous Na₂SO₄ and filtered. Solvent was removed and residue was purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to yield compound 8a (422 mg, 77.7 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.47 – 7.34 (m, 5H), 6.16 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 4.79 (d, J = 7.8 Hz, 1H), 4.11 (td, J = 8.1, 5.5 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.00 (dd, J = 16.4, 5.5 Hz, 1H), 2.63 (dd, J = 16.4, 8.4 Hz, 1H), 1.71 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.7, 158.8, 155.1, 138.1, 128.8, 128.6, 127.1, 101.4, 93.0, 91.9, 81.7, 68.2, 55.5, 55.4, 27.2; IR (KBr)ν_max 3446, 2937, 2839, 1618, 1593, 1496, 1213, 1143, 1120, 1051, 1022, 813, 761, 689 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₇H₁₉O₄, 287.1283, found 287.1270.

5,7-Bis(benzyloxy)-2-phenylchroman-3-ol (8b)

Trimethyl orthoacetate (1.48 mmol, 188 μl) and pyridinium p-toluenesulfonate (6 mg, .012 mmol) were added to a solution of 7b (560 mg, 1.22 mmol) in dichloromethane (24 mL) at rt. The resulting mixture was stirred for 30 min and cooled to 0 °C before the addition of borontrifluoride diethyletherate (18 μl, 0.24 mmol) dropwise. The reaction mixture was warmed to rt and stirred for another 15 min before quenching with aqueous acetone (4 mL). Solvent was removed and the residue was dissolved methanol (18 mL). Potassium carbonate (185 mg, 1.34 mmol) was added and mixture stirred for 6 h at rt. Methanol was removed, water (20 mL) was added and the products extracted with ethyl acetate (2 × 25 mL). The combined organic layers and washed with saturated sodium chloride solution (60 mL). The organic phase was dried over anhydrous Na₂SO₄ and filtered. Solvent was removed and the residue was purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to yield compound 8b (420 mg, 78.2 %) as a pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.61 – 7.23 (m, 15H), 6.28 – 6.09 (m, 2H), 5.09 – 4.76 (m, 4H), 4.73 (d, J = 7.9 Hz, 1H), 4.07 (td, J = 8.4, 5.6 Hz, 1H), 3.05 (dd, J = 16.5, 5.5 Hz, 1H), 2.65 (dd, J = 16.4, 8.6 Hz, 1H); IR (KBr)ν_max 3460, 2912, 1617, 1592, 1375, 1145, 1126, 1076, 973, 813, 696 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₉H₂₇O₄, 439.1909, found 439.1897.

5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-ol (8c)

Trimethyl orthoacetate (1.92 mmol, 250 μl) and pyridinium p-toluenesulfonate (10 mg, 0.032 mmol) were added to a solution of 7c (620 mg, 1.6 mmol) in dichloromethane (32 mL) at rt. The resulting mixture was stirred for 30 min at rt and then cooled to 0 °C before the dropwise addition of borontrifluoride diethyletherate (20 μl, 0.16 mmol). The reaction mixture was warmed to rt and stirred for another 15 min before quenching with aqueous acetone (4 mL). Solvent was removed and the residue dissolved in methanol (32 mL). Potassium carbonate (240 mg, 1.76 mmol) was added and mixture stirred for 6 h at rt. Methanol was removed, water (25 mL) was added and the products extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous Na₂SO₄ and filtered. Solvent was removed and the residue was purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to yield compound 8c (460 mg, 77.8) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 6.68 (s, 2H), 6.15 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 4.63 (d, J = 8.5 Hz, 1H), 4.07 (ddd, J = 9.3, 8.5, 5.8 Hz, 1H), 3.87 (s, 6H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.11 (dd, J = 16.3, 5.8 Hz, 1H), 2.60 (dd, J = 16.3, 9.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.9, 158.9, 155.4, 153.7 (2), 138.2, 133.6, 104.3 (2), 101.9, 93.2, 92.2, 82.4, 68.5, 61.0, 56.3 (2), 55.7, 55.6, 28.0; IR (KBr)ν_max 3438, 3001, 2916, 2848, 1622, 1593, 1496, 1622, 2593, 1456, 1361, 1215, 1145, 1120, 810, 667 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₀H₂₄NaO₇, 399.1420, found 399.1414.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-ol (8d)

Trimethyl orthoacetate (0.94 mmol, 120 μl) and pyridinium p-toluene sulfonate (4 mg, 0.016 mmol) were added to a solution of 7d (425 mg, 0.78 mmol) in dichloromethane (16 mL) at rt. The resulting mixture was stirred for 30 min at rt and then cooled to 0 °C before the dropwise addition of borontrifluoride diethyletherate (11 μl, 0.08 mmol) dropwise. The reaction mixture was warmed to rt and stirred for another 15 min before quenching with aqueous acetone (3 mL). Solvent was removed and the residue dissolved in methanol (16 mL). Potassium carbonate (118 mg, 0.85 mmol) was added and mixture stirred for 6 h at rt. Methanol was removed, water (20 mL) was added and the products extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous Na₂SO₄ and filtered. Solvent was removed and the residue was purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford 8d (265 mg, 63.3 %) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.49 – 7.37 (m, 8H), 7.37 – 7.30 (m, 2H), 6.69 (s, 2H), 6.30 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.3 Hz, 1H), 5.11 – 4.96 (m, 4H), 4.65 (d, J = 8.5 Hz, 1H), 4.10 (td, J = 8.9, 5.8 Hz, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.22 (dd, J = 16.3, 5.8 Hz, 1H), 2.69 (dd, J = 16.4, 9.3 Hz, 1H), 1.82 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.0, 157.9, 155.4, 153.7 (2), 137.1, 137.0 (2), 133.5, 128.8 (2), 128.7 (2), 128.2, 128.1, 127.7, 127.3 (3), 104.3 (2), 102.6, 94.5, 94.1, 82.4, 70.3, 70.1, 68.5, 61.0, 56.3 (2), 28.2; IR (KBr)ν_max 3481, 2935, 1618, 1593, 1498, 1460, 1421, 1346, 1145, 1128, 1022, 829, 752, 734 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₂H₃₃O₇, 529.2226, found 529.2234.

Transformations of anti-alcohols to syn-alcohols was accomplished via following the procedure described by Tuckmantel et. al.²⁶

5,7-Dimethoxy-2-phenylchroman-3-ol (9a)

Obtained as a colorless oil (232 mg, 55%): ¹H NMR (400 MHz, CDCl₃) δ 7.58 – 7.52 (m, 2H), 7.45 (dd, J = 8.4, 6.7 Hz, 2H), 7.43 – 7.33 (m, 1H), 6.23 (d, J = 2.3 Hz, 1H), 6.15 (d, J = 2.3 Hz, 1H), 5.05 (s, 1H), 4.34 (s, 1H), 3.82 (s, 3H), 3.80 (d, J = 0.7 Hz, 3H), 3.04 – 2.82 (m, 2H), 1.73 (brs, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 159.9, 159.5, 155.4, 138.4, 129.0, 128.8, 128.3, 126.5, 126.4, 100.4, 93.5, 92.4, 78.8, 66.6, 55.7, 55.6, 28.3. IR (KBr)ν_max 3451, 1952, 2923, 2854, 1618, 1593, 1203, 1145, 1118, 1058, 968, 811, 746, 700 cm⁻¹. HRMS (ESI+) m/z [M+H⁺] C₁₇H₁₉O₄, 287.1283, found 287.1277.

5,7-Bis(benzyloxy)-2-phenylchroman-3-ol (9b)

Obtained as a pale yellow oil (198 mg, 47%). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.65 – 7.31 (m, 15H), 6.23 (d, J = 2.3 Hz, 1H), 6.16 (d, J = 2.3 Hz, 1H), 5.62 (dt, J = 7.6, 4.9 Hz, 1H), 5.13 (d, J = 5.3 Hz, 1H), 4.99 (d, J = 1.9 Hz, 4H), 3.25 (dd, J = 14.6, 4.9 Hz, 1H), 2.89 (dd, J = 14.6, 8.0 Hz, 1H); IR (KBr)ν_max 3449, 2954, 2842, 1618, 1593, 1498, 1458, 1198, 1145, 1120, 1080, 729 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₉H₂₆NaO₄, 461.1729, found 461.1724.

5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-ol (9c)

Obtained as a colorless oil (175 mg, 43%). ¹H NMR (500 MHz, CDCl₃) δ 6.75 (s, 2H), 6.21 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 4.93 (s, 1H), 4.44 – 4.23 (m, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.00 – 2.93 (m, 1H), 2.89 (dd, J = 17.3, 4.4 Hz, 1H), 1.88 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.8, 159.4, 155.2, 153.6 (2), 137.5, 134.2, 103.4 (2), 100.4, 93.5, 92.4, 78.8, 66.6, 61.0, 56.3 (2), 55.6, 55.5, 28.2; IR (KBr)ν_max 3460, 2997, 2939, 2839, 1620, 1593, 1498, 1456, 1419, 1357, 1330, 1317, 1236, 1197, 1145, 1120, 1081, 939, 815, 729 cm⁻; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₀H₂₅O₇, 377.1600, found 377.1593.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-ol (9d)

Obtained as an amorphous pale yellow solid (72 mg, 68 %): ¹H NMR (500 MHz, CDCl₃) δ 7.44 – 7.34 (m, 10H), 6.75 (s, 2H), 6.32 (d, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.06 – 5.00 (m, 4H), 4.97 (s, 1H), 4.30 (d, J = 4.3 Hz, 1H), 3.91 (s, 6H), 3.87 (s, 3H), 3.07 (dd, J = 17.4, 2.5 Hz, 1H), 2.98 (dd, J = 17.3, 4.5 Hz, 1H), 1.78 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.0, 158.5, 155.3, 153.7 (2), 137.2 (2), 137.1, 134.1, 128.8 (2), 128.7 (2), 128.2, 128.1, 127.8 (2), 127.4 (2), 103.4 (2), 101.1, 94.9, 94.4, 78.9, 70.4, 70.2, 66.8, 61.1, 56.4 (2), 28.5; IR (KBr)ν_max 3461, 2925, 2834, 1593, 1458, 1375, 1236, 1145, 1126, 1078, 1010, 813, 738, 696 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₂H₃₃O₇, 529.2226, found 529.2234.

5,7-Dimethoxy-2-phenylchroman-3-yl benzoate (10a)

Benzoyl chloride (8 μl, 0.07 mmol) in dichloromethane (0.5 mL) was added to a solution of 9a (10 mg, 0.035 mmol) and 4-dimethylaminopyridine (11 mg, 0.08 mmol) in dichloromethane (1mL) at 0 °C. The resulting mixture was stirred for 6 h at rt. Solvent was removed and the residue purified via flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give the desired ester, 10a, as an amorphous white solid: (11 mg, 88.8%): ¹H NMR (500 MHz, CDCl₃) δ 7.95 – 7.87 (m, 2H), 7.56 – 7.47 (m, 3H), 7.41 – 7.28 (m, 5H), 6.27 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 5.69 (ddd, J = 4.1, 3.2, 1.4 Hz, 1H), 5.21 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.15 – 3.02 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.9, 159.9, 159.1, 155.7, 138.0, 133.1, 130.2, 129.9 (2), 128.5 (3), 128.3 (2), 126.7, 100.4, 93.5, 92.1, 78.0, 68.8, 55.6 (2), 26.1; IR (KBr)ν_max 2956, 1935, 2839, 1714, 1593, 1458, 1419, 1361, 1257, 1147, 1124, 1101, 1029, 1006, 846, 813, 769 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₄H₂₃O₅, 391.1545, found 391.1538.

5,7-Dimethoxy-2-phenylchroman-3-yl 3-methoxybenzoate (10b)

A solution of 9a (8 mg, 0.027 mmol) in dichloromethane (0.5 mL) was added to a solution of 3-methoxybenzoic acid (8 mg, 0.05 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (9.5 mg, 0.05 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt and then diluted with dichloromethane (5 mL). The organic phase was washed with saturated sodium bicarbonate solution (2 × 4 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent removed. The residue was purified via flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give the desired ester, 10a (9 mg, 76.9%), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.56 – 7.46 (m, 3H), 7.42 (dd, J = 2.7, 1.5 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.29 (t, J = 2.6 Hz, 1H), 7.27-7.21 (m, 1H), 7.04 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.26 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 5.67 (ddd, J = 4.1, 3.2, 1.4 Hz, 1H), 5.21 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.10 – 3.04 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 165.8, 159.9, 159.6, 159.1, 155.7, 138.0, 131.5, 129.5 (2), 128.5 (2), 128.3, 126.7, 122.3, 119.6, 114.4, 100.3, 93.5, 92.1, 77.9, 69.0, 55.6 (3), 26.0. IR (KBr)ν_max 2925, 2837, 1718, 1618, 1593, 1319, 1274, 1220, 1147, 1105, 1041, 958, 910, 811, 752, 696 cm⁻¹. HRMS (ESI+) m/z [M+H⁺] calcd for C₂₅H₂₅O₆, 421.1651, found 421.1642

5,7-Dimethoxy-2-phenylchroman-3-yl 4-methoxybenzoate (10c)

A solution of 9a (10 mg, 0.035 mmol) in dichloromethane (0.5 mL) was added to a solution 4-methoxybenzoic acid (18 mg, 0.07 mmol), N-(3-Dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (13.5 mg, 0.07 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt and then diluted with dichloromethane (5 mL). The organic phase was washed saturated sodium bicarbonate solution (2 × 4 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed. The residue was purified via flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give the desired ester, 10c, as a colorless oil (9.5 mg, 81.1%): ¹H NMR (500 MHz, CDCl₃) δ 7.93 – 7.83 (m, 2H), 7.57 – 7.49 (m, 2H), 7.36 – 7.30 (m, 2H), 7.28 (d, J = 7.0 Hz, 1H), 6.87 – 6.82 (m, 2H), 6.26 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 5.66 (td, J = 3.7, 1.5 Hz, 1H), 5.20 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.08 – 3.04 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 163.5, 159.8, 159.1, 155.7, 138.1, 131.9 (2), 128.5 (2), 128.2 (2), 126.7, 122.6, 113.7 (2), 100.5, 93.5, 92.1, 78.0, 68.4, 55.6 (3), 26.1; IR (KBr)ν_max 2958, 2935, 2839, 1716, 1618, 1255, 1203, 1147, 1101, 1029, 906, 846, 700 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₅H₂₅O₆, 421.1651, found 421.1644.

(5,7-Dimethoxy-2-phenylchroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (10d)

A solution of 9a (10 mg, 0.035 mmol) in dichloromethane (0.5 mL) was added to a solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (18 mg, 0.07 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (13.5 mg, 0.07 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt and then diluted with dichloromethane (5 mL). The organic phase was washed with saturated sodium bicarbonate solution (2 × 4mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to give desired ester, 10d (14 mg, 76%), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.94 – 7.84 (m, 2H), 7.58 – 7.48 (m, 2H), 7.38 – 7.31 (m, 3H), 7.31 – 7.28 (m, 1H), 7.05 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 7.01 (dd, J = 2.6, 1.6 Hz, 1H), 6.96 – 6.87 (m, 2H), 6.24 (d, J = 2.3 Hz, 1H), 6.11 (d, J = 2.3 Hz, 1H), 5.65 (td, J = 3.7, 1.5 Hz, 1H), 5.21 (s, 1H), 3.84 (d, J = 0.7 Hz, 6H), 3.80 (s, 3H), 3.78 (s, 3H), 3.11 – 3.04 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.5, 160.2, 159.6, 159.3, 158.9, 155.5, 138.8, 137.9, 132.5, 131.0, 130.2, 129.0 (2), 128.3, 128.1 (2), 126.5, 122.5, 122.0, 115.2, 112.9, 110.5, 100.2, 93.3, 91.9, 77.8, 68.5, 55.8, 55.4 (2), 55.3, 25.8; IR (KBr)ν_max 2933, 1716, 1616, 1595, 1298, 1245, 1205, 1147, 1108, 1027, 918, 813, 696, 649 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₃₂H₃₀NaO₇, 549.1889, found 549.1863.

5,7-Dimethoxy-2-phenylchroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (10e)

A solution of 9a (20 mg, 0.07 mmol) in dichloromethane (0.5 mL) was added to a solution of 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (35 mg, 0.14 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol) and 4-dimethylaminopyridine (25 mg, 0.21 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, diluted with dichloromethane (5 mL) and washed saturated sodium bicarbonate solution (2 × 4 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed. The residue was purified via flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to give desired ester, 10e (20 mg, 55.5 %), as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.4, 2.1 Hz, 1H), 7.50 (dd, J = 7.9, 1.4 Hz, 2H), 7.34 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.11 (d, J = 2.3 Hz, 1H), 5.68 – 5.57 (m, 1H), 5.22 – 5.15 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.21 (d, J = 7.3 Hz, 2H), 3.05 (d, J = 3.5 Hz, 2H), 2.31 (s, 3H), 1.75 (d, J = 1.5 Hz, 3H), 1.71 – 1.62 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.10, 155.48, 154.11, 151.35, (2), 136.7 (2), 128.39 (5), 128.30(5), 126.14, 111.17 (2), 104.62, 102.86, 78.23, 66.5, 60.7, 60.4 (2), 31.0, 29.7, 26.8, 20.7; IR (KBr)ν_max 2925, 1760, 1716, 1593, 1369, 1201, 1147, 1108, 813 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₁H₃₃O₇, 517.2226, found 517.2215.

(2R,3R)-5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl benzoate (10f)

Benzoyl chloride (14 μl, 0.12 mmol) in dichloromethane (0.5 mL) was added to a solution of 9c (15 mg, 0.04 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) in dichloromethane 1 (mL) at 0 °C and stirred for 6 h at rt. The solvent was removed and the residue purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to give desired ester, 10f (17 mg, 89.4%), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.02 – 7.89 (m, 2H), 7.59 – 7.47 (m, 1H), 7.42 – 7.33 (m, 2H), 6.72 (s, 2H), 6.27 (d, J = 2.3 Hz, 1H), 6.14 (d, J = 2.3 Hz, 1H), 5.69 (td, J = 3.5, 1.3 Hz, 1H), 5.09 (t, J = 1.0 Hz, 1H), 3.82 (s, 3H), 3.80 (d, J = 1.7 Hz, 6H), 3.71 (s, 6H), 3.10 – 3.05 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.5, 159.6, 158.9, 155.5, 153.1 (2), 137.7, 133.3, 133.1, 130.0, 129.7 (3), 128.3 (2), 103.8 (2), 100.2, 93.4, 92.0, 78.0, 68.5, 60.8, 55.9, 55.4 (2), 26.1; IR (KBr)ν_max 2910, 2848, 1718, 1595, 1461, 1271, 1118 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₇H₂₉O₈, 481.1862 found 481.1863.

5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 3-methoxybenzoate (10g)

A solution of 9c (12 mg, 0.03mmol) in dichloromethane (0.5 mL) was added to a solution of 3-methoxybenzoic acid (10 mg, 0.06 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (13 mg, 0.06 mmol) and 4-dimethylaminopyridine (8 mg, .06 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, diluted with dichloromethane (5 mL) and washed with saturated NaHCO₃ (2 × 4 mL) solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give desired ester product 10g as a colorless oil (13 mg, 80.4%): ¹H NMR (500 MHz, CDCl₃) δ 7.56 (dt, J = 7.7, 1.2 Hz, 1H), 7.48 (dd, J = 2.7, 1.5 Hz, 1H), 7.30 – 7.26 (m, 1H) 7.05 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.72 (s, 2H), 6.26 (d, J = 2.3 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.67 (td, J = 3.6, 1.3 Hz, 1H), 5.08 (s, 1H), 3.81 (s, 3H), 3.81 – 3.78 (m, 9H), 3.73 (s, 6H), 3.07 (d, J = 3.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.4, 159.6, 158.9, 155.5, 153.1 (2), 137.7, 133.3, 131.3, 129.3 (2), 122.0, 119.1, 114.7, 103.8 (2), 100.1, 93.4, 92.0, 78.0, 68.6, 60.8, 55.9 (2), 55.4 (3), 26.0; IR (KBr)ν_max 2937, 1718, 1622, 1593, 1498, 1456, 1274, 1218, 1124, 1047, 754 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₈H₃₁O₉, 511.1968, found 511.1977.

5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-methoxybenzoate (10h)

4-methoxybenzoyl chloride (10 μl, 0.07 mmol) in dichloromethane (0.5 mL) was added to a solution of 9c (13 mg, 0.035 mmol) and 4-dimethylaminopyridine (13 mg, 0.1 mmol) in dichloromethane 0.7 (mL)-pyridine (0.3 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, solvent was removed and the residue purified via flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give desired ester, 10h, (15 mg, 87.4 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.77 – 7.55 (m, 2H), 6.66 – 6.53 (m, 2H), 6.46 (s, 2H), 6.01 (d, J = 2.3 Hz, 1H), 5.88 (d, J = 2.3 Hz, 1H), 5.41 (td, J = 3.5, 1.3 Hz, 1H), 4.82 (s, 1H), 3.58 (s, 3H), 3.57 (s, 3H), 3.55 (s, 3H), 3.54 (s, 3H), 3.48 (s, 6H), 2.80 (d, J = 3.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.2, 163.4, 159.6, 158.9, 155.5, 153.1 (2), 133.4, 131.8 (2), 122.4, 113.5 (2), 103.9 (2), 100.3, 93.4, 91.9, 78.1, 68.0, 60.8, 55.9 (2), 55.4 (4), 26.1; IR (KBr)ν_max 2927, 1731, 1604, 1591, 1508, 1458, 1458, 1419, 1373, 1326, 1255, 1234, 1126, 1099, 846, 763 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₈H₃₁O₉, 511.1968, found 511.1961.

5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (10i)

A solution of 9c (15 mg, 0.04 mmol) in dichloromethane (0.5 mL) was added to a solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (21 mg, 0.08 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol) and 4-dimethylaminopyridine (9.6 mg, .08 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, diluted with dichloromethane (5 mL) and washed saturated sodium bicarbonate (2 × 4 mL) solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give desired ester, 10i (15 mg, 62.5 %), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.95 (dd, J = 8.6, 2.3 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.02 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.99 (dd, J = 2.6, 1.6 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.90 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.75 (s, 2H), 6.25 (d, J = 2.3 Hz, 1H), 6.13 (d, J = 2.3 Hz, 1H), 5.65 (ddd, J = 4.2, 2.9, 1.3 Hz, 1H), 5.16 – 5.02 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.69 (s, 6H), 3.07 (t, J = 3.3 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.3, 160.3, 159.6, 159.3, 158.9, 155.5, 153.1 (2), 138.7, 133.4, 132.4, 131.0, 130.4 (2), 129.1, 122.5, 121.9, 115.1, 113.0, 110.5, 103.8 (2), 100.3, 93.4, 92.0, 78.0, 68.4, 60.8, 55.9 (2), 55.8, 55.4 (2), 55.3, 26.1; IR (KBr)ν^max 2927,2848, 1716, 1593, 1496, 1456, 1361, 1238, 1126, 771 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₅H₃₇O₁₀, 617.2387, found 617.2382.

5,7-Dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (10j)

A solution of 9c (24 mg, 0.064 mmol) in dichloromethane (0.5 mL) was added to a solution of 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (32 mg, 0.13 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol) and 4-dimethylaminopyridine (15 mg, 0.13 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, diluted with dichloromethane (5 mL) and washed saturated sodium bicarbonate solution (2 × 4 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to give desired ester, 10j (28 mg, 72.5%), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 8.3, 2.2 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.69 (s, 2H), 6.26 (d, J = 2.3 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.67 (td, J = 3.4, 1.2 Hz, 1H), 5.14 (dddd, J = 7.3, 5.8, 2.9, 1.4 Hz, 1H), 5.08 (brs, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.71 (s, 6H), 3.21 (d, J = 7.2 Hz, 2H), 3.05 (d, J = 3.3 Hz, 2H), 2.30 (s, 3H), 1.72 (s, 3H), 1.66 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.8, 164.9, 159.6, 158.9, 155.4, 153.1 (2), 152.7, 137.8, 134.0, 133.9, 133.3, 131.8, 128.6, 127.8, 122.4, 120.7, 103.8 (2), 100.0, 93.3, 92.0, 77.9, 68.4, 60.8, 56.0, 55.4 (3), 28.6, 25.7 (2), 20.9, 17.8; IR (KBr)ν_max 2921, 2850, 1716, 1593, 1458, 1282, 1201, 1142, 1010, 948, 813 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₄H₃₉O₁₀, 607.2543, found 607.2541.

5,7-Bis(benzyloxy)-2-phenylchroman-3-yl benzoate (10k)

A solution of 9b (20 mg, 0.046 mmol) in dichloromethane (0.5 mL) was added to a solution of 3-methoxybenzoic acid (14 mg, 0.09 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and 4-dimethylaminopyridine (12 mg, 0.09 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate (2 × 4 mL) solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to give the desired ester, 10k (23 mg, 93 %), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.97 – 7.91 (m, 2H), 7.55 – 7.51 (m, 3H), 7.50 – 7.44 (m, 2H), 7.42 – 7.30 (m, 13H), 6.38 (d, J = 2.3 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 5.72 (ddd, J = 4.4, 2.9, 1.4 Hz, 1H), 5.22 (s, 1H), 5.06 (d, J = 4.9 Hz, 2H), 5.02 (d, J = 2.6 Hz, 2H), 3.21 – 3.08 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.7, 158.8, 158.0, 155.6, 137.7, 136.9, 136.8, 133.0, 129.9 (2), 129.7 (2), 128.6 (2), 128.5 (2), 128.3 (4), 128.1, 128.0, 127.9, 127.6 (2), 127.2 (2), 126.5, 100.9, 94.7, 93.9, 77.8, 70.2, 70.0, 68.6, 26.1; IR (KBr)ν_max 2952, 2923, 2852, 1716, 1616, 1269, 1147, 1107, 1027, 1002, 906, 811, 739 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₃₆H₃₀NaO₅, 565.1991, found 565.1998.

5,7-Bis(benzyloxy)-2-phenylchroman-3-yl 3-methoxybenzoate (10l)

A solution of 9b (20 mg, 0.046 mmol) in dichloromethane (0.5 mL) was added to a solution of 3-methoxybenzoic acid (14 mg, 0.09 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and 4-dimethylaminopyridine (12 mg, 0.09 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate (2 × 4 mL) solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to give the desired ester, 10l (23.5 mg, 90 %), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.55 – 7.50 (m, 3H), 7.48 – 7.44 (m, 2H), 7.44 – 7.28 (m, 13H), 7.06 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.69 (ddd, J = 4.4, 2.8, 1.5 Hz, 1H), 5.22 (s, 1H), 5.05 (d, J = 4.2 Hz, 2H), 5.02 (d, J = 2.4 Hz, 2H), 3.80 (s, 3H), 3.20 – 3.09 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 159.4, 158.8, 158.0, 155.6, 137.8, 136.9, 136.8, 131.3, 129.3, 128.6 (2), 128.5 (2), 128.4 (2), 128.3, 128.1 (2), 128.0, 127.9, 127.6, 127.2 (2), 126.5, 122.2, 119.4, 114.2, 100.9, 94.7, 93.9, 77.7, 70.2, 70.0, 68.8, 55.4, 26.0; IR (KBr)ν_max 2960, 2927, 2854, 1716, 1652, 1496, 1436, 1205, 1153, 1095, 1068, 1024, 798, 754, 684 cm⁻¹. HRMS (ESI+) m/z [M+H⁺] calcd for C₃₇H₃₃O₆, 573.2277, found 573.2263.

5,7-Bis(benzyloxy)-2-phenylchroman-3-yl 4-methoxybenzoate (10m)

A solution of 9b (20 mg, 0.046 mmol) in dichloromethane (0.5 mL) was added to a solution of 4-methoxybenzoic acid (14 mg, 0.09 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and 4-dimethylaminopyridine (12 mg, 0.09 mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt and then diluted with dichloromethane (5 mL). The organic phase was washed with saturated sodium bicarbonate solution (2 × 4 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to give desired ester, 10m (22 mg, 85%), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J = 2.0 Hz, 1H), 7.89 – 7.85 (m, 1H), 7.53 – 7.49 (m, 2H), 7.49 – 7.44 (m, 2H), 7.44 – 7.30 (m, 11H), 6.86 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.69 (ddd, J = 4.5, 2.9, 1.5 Hz, 1H), 5.21 (brs, 1H), 5.06 (d, J = 4.8 Hz, 2H), 5.04 – 5.00 (m, 2H), 3.83 (s, 3H), 3.19 – 3.05 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.4, 163.4, 158.8, 158.0, 155.6, 137.8, 136.9, 136.8, 131.8, 128.6, 128.5 (3), 128.3 (3), 128.1 (2), 128.0, 127.9 (2), 127.6 (2), 127.2, 126.5, 122.4, 113.5 (2), 101.0, 94.7, 93.8, 77.9, 70.2, 69.9, 68.2, 55.4, 26.1; IR (KBr)ν_max 2925, 2852, 1716, 1147, 1095, 1026, 798, cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₃₇H₃₂NaO₆, 595.2097, found 595.2109.

5,7-Bis(benzyloxy)-2-phenylchroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (10n)

A solution of 9b (20 mg, 0.045 mmol) in dichloromethane (0.5 mL) was added to a solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (25 mg, 0.09 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.00 mmol) and 4-dimethylaminopyridine (11 mg, 0.09mmol) in dichloromethane (1 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt and the diluted with dichloromethane (5 mL). The organic phase was washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to give desired ester, 10n (27 mg, 90 %), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.94 – 7.89 (m, 2H), 7.55 – 7.52 (m, 2H), 7.48 – 7.44 (m, 2H), 7.42 – 7.29 (m, 12H), 7.09 – 7.04 (m, 1H), 7.03 (dd, J = 2.6, 1.5 Hz, 1H), 6.96 – 6.89 (m, 2H), 6.36 (d, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.68 (ddd, J = 4.3, 3.1, 1.5 Hz, 1H), 5.22 (brs, 1H), 5.04 (d, J = 3.5 Hz, 2H), 5.02 (d, J = 2.2 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.20 – 3.11 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.5, 160.2, 159.2, 158.7, 157.9, 155.6, 138.8, 137.9, 136.9, 136.8, 132.5, 131.0, 130.2, 129.0, 128.6 (3), 128.5 (2), 128.3, 128.1, 128.0, 127.9 (2), 127.6 (2), 127.2, 126.5, 122.4, 122.0, 115.2 (2), 112.9, 110.5, 101.0, 94.7, 93.8, 77.8, 70.2, 69.9, 68.5, 55.8, 55.3, 26.0; IR (KBr)ν_max 2952, 2923, 2852, 1716, 1558, 1456, 1245, 1145, 1101, 1026, 798 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₄₄H₃₉O₇, 679.2696, found 679.2682.

5,7-Bis(benzyloxy)-2-phenylchroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (10o)

A solution of 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (34 mg, 0.138 mmol) in THF (5 mL) was treated with thionyl chloride (20 μl, 0.276 mmol). The resulting solution was heated at 70 0 °C for 3 h, cooled to rt and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and added to a solution of 9b (20 mg, 0.046 mmol) and 4-dimethylaminopyridine (22 mg, 0.184 mmol) in dichloromethane 1 (mL) at 0 °C. The resulting mixture was stirred for 6 h at rt. The solvent was removed and the residue was purified via flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to give the ester 10o (22.5 mg, 83.5 %), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.73 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.4, 2.2 Hz, 1H), 7.46 – 7.35 (m, 5H), 7.34 – 7.22 (m, 11H), 6.94 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 6.21 (d, J = 2.3 Hz, 1H), 5.58 (ddd, J = 4.3, 3.1, 1.5 Hz, 1H), 5.17 – 5.06 (m, 2H), 5.00 – 4.89 (m, 4H), 3.13 (d, J = 7.5 Hz, 2H), 3.04 (t, J = 2.6 Hz, 2H), 2.23 (s, 3H), 1.67 (q, J = 1.3 Hz, 3H), 1.60 (d, J = 1.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.9, 165.1, 158.8, 158.0, 155.5, 152.5, 137.8, 136.9, 136.8, 134.0, 133.7, 131.9, 128.7, 128.6 (2), 128.5 (2), 128.4 (2), 128.1, 128.0, 127.9 (2), 127.8 (2), 127.6 (2), 127.2, 126.4, 122.3, 120.8, 100.8, 94.6, 93.8, 77.7, 70.2, 70.0, 68.7, 29.7, 28.5, 26.1, 20.9, 17.84; IR (KBr)ν_max 2921, 2852, 1760, 1716, 1616, 1373, 1257, 1201, 1149, 1114, 1027, 736 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₄₃H₄₀NaO₇, 691.2672, found 691.2682.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-yl benzoate (10p)

Benzoyl chloride (8 μl, 0.064 mmol) in dichloromethane (0.5 mL) was added to a solution of 9d (17 mg, 0.032 mmol) and 4-dimethylaminopyridine (12 mg, 0.092 mmol) in dichloromethane 0.7 (mL) with pyridine (0.3 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt. The resulting mixture was stirred for 6 h at rt. The solvent was removed and the residue purified via flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give desired ester, 10p (16 mg, 83.5%), as an amorphous white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.01 – 7.96 (m, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.53 – 7.34 (m, 12H), 6.72 (s, 2H), 6.38 (d, J = 2.3 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 5.71 (ddd, J = 4.1, 3.0, 1.3 Hz, 1H), 5.10 (d, J = 3.8 Hz, 1H), 5.08 – 5.01 (m, 4H), 3.80 (s, 3H), 3.71 (s, 6H), 3.18 – 3.10 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 172.0, 165.5, 158.8, 158.0, 155.6, 153.1, 137.7, 136.9, 136.8, 133.8, 133.3, 133.2, 130.2, 130.0, 129.8 (2), 129.3, 128.6 (2), 128.6, 128.5, 128.3 (2), 128.0, 127.9 (2), 127.6, 127.2, 100.9, 94.8, 94.0, 78.1, 70.2, 70.0, 68.5, 60.8, 55.9 (2), 26.3; IR (KBr)ν_max 2929, 2839, 1716, 1616, 1591, 1506, 1456, 1361, 1226, 1149, 1126, 1041, 811, 754 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₃₉H₃₆ NaO₈, 655.2308, found 655.2307.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 3-methoxybenzoate (10q)

3-methoxybenzoyl chloride (9 μl, 0.064 mmol) in dichloromethane (0.5 mL) was added to a solution of 9d (17 mg, 0.032 mmol) and 4-dimethylaminopyridine (12 mg, 0.092 mmol) in dichloromethane 0.7 (mL) with pyridine (0.3 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt. The resulting mixture was stirred for 6 h at rt. The solvent was removed and the residue purified via flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give desired ester, 10q (16 mg, 85.1%), as an amorphous white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.58 (dt, J = 7.7, 1.2 Hz, 1H), 7.50 – 7.30 (m, 12H), 7.07 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 6.72 (s, 2H), 6.37 (d, J = 2.3 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 5.68 (ddd, J = 4.2, 3.0, 1.3 Hz, 1H), 5.17 – 5.03 (m, 4H), 5.03 (s, 1H), 3.80 (s, 6H), 3.73 (s, 6H), 3.17 – 3.11 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.4, 159.5, 158.8, 158.0, 155.6, 153.1 (2), 137.7, 136.9, 136.8, 133.3, 131.3, 129.3, 128.6 (3), 128.5, 128.0, 127.9 (3), 127.6, 127.2 (2), 122.1, 119.1, 114.7, 103.8 (2), 100.8, 94.8, 94.0, 78.0, 70.2, 70.0, 68.6, 60.8, 55.9, 55.4, 26.2; IR (KBr)ν_max 2931, 2664, 1716, 1593, 1506, 1456, 1361, 1269, 1217, 1126, 1070. 1008 cm⁻¹; HRMS (ESI+) m/z [M+Na+] calcd for C₄₀H₃₈NaO₉, 685.2414, found 685.2401.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-methoxybenzoate (10r)

4-methoxybenzoyl chloride (9 μl, 0.064 mmol) in dichloromethane (0.7 mL) was added to a solution of 9d (17 mg, 0.032 mmol) and 4-dimethylaminopyridine (12 mg, 0.092 mmol) in dichloromethane 0.7 (mL) with pyridine (0.3 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt. The solvent was removed and the residue purified via flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give desired ester product 10r (17 mg, 87.4%) as an amorphous white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.98 – 7.89 (m, 2H), 7.49 – 7.44 (m, 2H), 7.44 – 7.31 (m, 8H), 6.88 – 6.84 (m, 2H), 6.71 (s, 2H), 6.37 (d, J = 2.3 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 5.68 (tt, J = 3.1, 1.2 Hz, 1H), 5.08 (s, 1H), 5.08 – 5.01 (m, 4H), 3.84 (s, 3H), 3.80 (s, 3H), 3.72 (s, 6H), 3.12 (t, J = 3.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.2, 163.5, 158.7, 158.0, 155.6, 153.1, 137.7, 136.9, 136.8, 133.3 (2), 131.8, 128.6 (2), 128.5 (2), 128.0 (2), 127.9 (2), 127.6 (2), 127.2, 122.4, 113.5 (2), 103.9 (2), 101.0, 94.8, 93.9, 78.1, 70.2, 70.0, 68.0, 60.8, 60.0, 55.9, 55.5, 26.4; IR (KBr)ν_max 3348, 2952, 2927, 1716, 1506, 1417, 1257, 1168, 1126, 1035, 821 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₄₀H₃₉O₉, 663.2594, found 663. 2608.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (10s)

A solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (35 mg, 0.135 mmol) in THF (5 mL) was treated with thionyl chloride (20 μl, 0.27 mmol). The resulting solution was heated at reflux for 3 h, cooled to rt before the solvent was removed. The crude was dissolved in dichloromethane (0.5 mL) and added to a solution of 9d (18 mg, 0.045 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol) in dichloromethane (0.7 mL) with pyridine (0.3 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt, the solvent was removed and the residue purified via flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give desired ester, 10s (28 mg, 83%), as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.97 (dd, J = 8.6, 2.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 1.3 Hz, 1H), 7.43 – 7.29 (m, 10H), 7.03 (dt, J = 7.7, 1.2 Hz, 1H), 7.00 (dd, J = 2.6, 1.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.91 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.71 (s, 2H), 6.37 (d, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.67 (td, J = 3.6, 1.4 Hz, 1H), 5.10 (s, 1H), 5.07 – 5.01 (m, 4H), 3.86 – 3.79 (m, 9H), 3.69 (s, 6H), 3.15 (d, J = 3.6 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 160.6, 159.5, 159.0, 158.2, 155.8, 153.3 (2), 138.9, 137.1, 137.1, 133.6, 132.6, 131.3, 130.7, 129.3, 128.9, 128.8 (2), 128.3 (2), 128.2 (2), 127.8 (2), 127.4 (2), 122.7, 122.1, 115.4, 113.2, 110.7, 104.0 (2), 101.3, 95.0, 94.2, 78.3, 70.4, 70.2, 68.6, 61.1, 56.2, 56.1 (2), 55.5, 26.5; IR (KBr)ν_max 3434, 2929, 1712, 1616, 1593, 1500, 1456, 2440, 2303, 1238, 1149, 1126, 1027, 821, 736,698 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₄₇H₄₄NaO₁₀, 791.2832, found 791.2766.

5,7-Bis(benzyloxy)-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (10t)

A solution of 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (33.5 mg, 0.135 mmol) in THF (5 mL) was treated with thionyl chloride (20 μl, 0.27 mmol). The resulting solution was heated at 70 0 °C for 3 h and cooled to rt and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and added to a solution of 9d (18 mg, 0.045 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol) in dichloromethane (0.7 mL) with pyridine (0.3 mL) at 0 °C. The resulting mixture was stirred for 6 h at rt. The solvent was removed and the residue purified via flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give desired ester, 10t (26.6 mg, 78%), as colorless a oil: ¹H NMR (500 MHz, CDCl₃) δ 7.78 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.4, 2.2 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.44 – 7.36 (m, 2H), 7.39 – 7.28 (m, 6H), 7.01 (d, J = 8.4 Hz, 1H), 6.79 (s, 2H), 6.29 – 6.37 (m, 2H), 5.76 (ddd, J = 4.3, 2.9, 1.4 Hz, 1H), 5.22 (m, 1H), 5.15 (m, 3H), 5.00 (s, 2H), 3.81 (s, 3H), 3.77 (s, 6H), 3.20 (d, J = 7.4 Hz, 2H), 3.19 – 3.06 (m, 2H), 2.31 (s, 3H), 1.71 (d, 1.6 Hz, 3H), 1.66 (d, J = 1.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.0, 165.1, 156.7, 155.1, 153.3, 152.9 (2), 152.1, 137.7, 136.9, 136.6, 134.3, 134.1, 133.0, 132.0, 128.9, 128.8 (2), 128.3 (2), 128.2 (2), 127.8 (2), 127.4 (2), 127.3 (2), 122.6, 120.8, 103.5 (2), 102.6, 93.0, 92.9, 78.2, 71.5, 70.5, 68.0, 61.0, 56.2 (2), 28.8, 26.5, 25.9, 21.0, 18.0; IR (KBr)ν_max 2960, 2925, 1714, 1604, 1456, 1353, 1261, 1236, 1174, 1126, 1012, 819 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₄₆H₄₇O₁₀, 759.3169, found 759.3195.

5,7-Dihydroxy-2-phenylchroman-3-yl benzoate (11a)

10k (20 mg, 0.036 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:12) to give 11a (12 mg, 90 %) as a colorless oil: ¹H NMR (500 MHz, CD₃OD) δ 7.87 – 7.79 (m, 2H), 7.56 – 7.47 (m, 3H), 7.43 – 7.34 (m, 2H), 7.31 – 7.19 (m, 3H), 6.01 (d, J = 2.3 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 5.66 (ddd, J = 4.6, 2.4, 1.3 Hz, 1H), 5.23 (s, 1H), 3.08 (dd, J = 17.5, 4.6 Hz, 1H), 2.93 (ddd, J = 17.6, 2.5, 0.9 Hz, 1H); ¹³C NMR (125 MHz, CD₃OD) δ 167.1, 158.0, 157.9, 157.1, 139.9, 134.2, 131.2, 130.5, 129.5 (2), 129.1 (2), 128.8 (2), 127.5 (2), 99.1, 96.7, 95.8, 78.6, 70.6, 26.7; IR (KBr)ν_max 3427, 2921, 2848, 1701, 1560, 1473, 1271, 1097 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₂H₁₉O₅, 363.1232, found 363.1241.

5,7-Dihydroxy-2-phenylchroman-3-yl 3-methoxybenzoate (11b)

10l (20 mg, 0.034 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:10) to give 11b (20 mg, 89%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.50 (dt, J = 7.7, 1.2 Hz, 3H), 7.41 (dd, J = 2.7, 1.5 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.31 – 7.27 (m, 2H), 7.05 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 5.67 (ddd, J = 4.4, 2.9, 1.5 Hz, 1H), 5.21 (brs, 1H), 5.18 (brs, 1H), 5.05 (brs, 1H), 3.79 (s, 3H), 3.22 – 3.00 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 159.6, 156.2, 155.5, 155.3, 137.8, 131.3, 129.6, 128.5, 128.4 (2), 126.6 (2), 122.3, 119.7, 114.4, 99.1, 96.5, 96.2, 77.8, 68.9, 55.6, 25.7; IR (KBr)ν_max 3359, 2923, 2852, 1714, 1631, 1461, 1274, 1103, 754, cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₂₃H₁₉O₆, 391.1182, found 391.1181.

5,7-Dihydroxy-2-phenylchroman-3-yl 4-methoxybenzoate (11c)

10m (16 mg, 0.027 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:10) to afford 11c (10 mg, 91%) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.20 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.72 – 7.67 (m, 2H), 7.51 – 7.41 (m, 2H), 7.25 – 7.16 (m, 2H), 7.16 – 7.08 (m, 1H), 6.84 – 6.79 (m, 2H), 5.95 (s, 2H), 5.53 (ddd, J = 4.7, 2.4, 1.4 Hz, 1H), 5.21 (s, 1H), 3.71 (s, 3H), 2.99 (dd, J = 17.7, 4.4 Hz, 1H), 2.87 (ddd, J = 17.4, 2.4, 0.9 Hz, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 165.7, 164.6, 158.0, 157.6, 156.9, 139.9, 132.3 (2), 129.0 (2), 128.6 (2), 127.5, 123.4, 114.7 (2), 98.9, 96.7, 95.9, 78.2, 69.6, 56.0, 26.6; IR (KBr)ν_max 3369, 2925, 2852, 1714, 1604, 1512, 1456, 1257, 1168, 1101, 1029, 667 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₂₃H₁₉O₆, 391.1182, found 391.1175.

5,7-Dihydroxy-2-phenylchroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (11d)

10n (20 mg, 0.029 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:9) to give 11d (13 mg, 89%) as a colorless oil: (500 MHz, CDCl₃) ¹H NMR δ 7.83 – 7.78 (m, 2H), 7.45 – 7.39 (m, 2H), 7.31 – 7.22 (m, 3H), 7.23 – 7.20 (m, 1H), 6.98 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.93 (dd, J = 2.6, 1.6 Hz, 1H), 6.88 – 6.80 (m, 2H), 6.08 (d, J = 2.2 Hz, 1H), 5.91 (d, J = 2.4 Hz, 1H), 5.57 (tt, J = 3.3, 1.5 Hz, 1H), 5.13 (s, 1H), 5.01 (s, 1H), 4.91 (s, 1H), 3.76 (d, J = 1.4 Hz, 6H), 3.08 – 2.95 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.8, 160.5, 159.4, 156.2, 155.5, 155.3, 138.9, 137.9, 132.7, 131.2, 130.5, 129.2, 128.5 (2), 128.3 (2), 126.7, 122.5, 122.2, 115.5, 113.1, 110.7, 99.2, 96.6, 96.2, 77.9, 68.6, 56.0, 55.5, 25.7; IR (KBr)ν_max 3374, 2952, 2852, 1714, 1558, 1456, 1271, 1101, 1026 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₀H₂₇O₇, 499.1757, found 499.1744.

5,7-Dihydroxy-2-phenylchroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (11e)

A solution of palladium acetate (2 mg, 0.008 mmol), triethylamine (13μL, 0.09 mmol), triethylsilane (64μL, 0.405) in dichloromethane (0.8 mL) was stirred for 15 min before the addition of 10j (30 mg, 0.045 mmol) in dichloromethane (0.4 mL). The resulting mixture was stirred for 15 h, quenched with saturated ammonium chloride (2 mL), and extracted with diethyl ether (3 × 4 mL). The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous Na₂SO₄. The solvent was removed and residue purified via flash chromatography (SiO₂, 5:95 MeOH/DCM) to give 11e (4 mg, 18.9 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.71 – 7.63 (m, 2H), 7.51 – 7.45 (m, 2H), 7.33 – 7.25(m, 3H), 6.69 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H), 6.22 (d, J = 2.2 Hz, 1H), 5.68 – 5.56 (m, 2H), 5.26 (m, 2H), 5.13 (d, J = 1.2 Hz, 1H), 3.32 (d, J = 7.2 Hz, 2H), 3.06 (t, J = 3.2 Hz, 2H), 2.30 (s, 3H), 1.81 – 1.72 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0, 165.8, 158.9, 156.0, 154.9, 150.0, 137.7, 135.9, 132.2, 130.0 (2), 128.5 (2), 128.3 (2), 126.9, 126.6, 122.2, 121.1, 115.7, 104.7, 103.0, 101.9, 78.0, 67.9, 29.6, 26.1 (2), 21.4, 18.1; IR (KBr)ν_max 3432, 2922, 1701, 1562, 1471, 1101, 1271, 1093 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₂₉H₂₇O₇, 487.1757, found 487.1755.

5,7-Dihydroxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl benzoate (11f)

10p (15 mg, 0.023 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:8) to give the desired product 11f (9.5 mg, 88.5 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.99 – 7.86 (m, 2H), 7.53 (ddt, J = 8.7, 7.2, 1.3 Hz, 1H), 7.45 – 7.33 (m, 2H), 6.70 (s, 2H), 6.19 (d, J = 2.3 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 5.70 (ddd, J = 4.3, 2.8, 1.3 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 6H), 3.15 – 3.00 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 156.1, 155.3 (2), 155.1 (2), 153.1, 137.7, 133.3, 129.8(2), 129.7 (3), 128.4, 103.8 (2), 98.9, 96.5, 96.1, 77.9, 68.3, 60.9, 55.9 (2), 25.8 cm⁻¹; IR (KBr)ν_max 3421, 2931, 2850, 1717, 1596, 1465, 1276, 1126, 756 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₂₅H₂₃O₈, 451.1393, found 451.1412.

5,7-Dihydroxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 3-methoxybenzoate (11g)

10q (14 mg, 0.021 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:8) to afford 11g (9 mg, 89%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.55 (dt, J = 7.7, 1.2 Hz, 1H), 7.45 (dd, J = 2.7, 1.5 Hz, 1H), 7.06 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.18 (d, J = 2.3 Hz, 1H), 5.94 (d, J = 2.3 Hz, 1H), 5.68 (ddd, J = 4.2, 2.8, 1.3 Hz, 1H), 5.43 (s, 1H), 5.29 (s, 1H), 5.15 – 5.05 (m, 1H), 3.15 – 3.03 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 159.5, 156.0, 155.4, 155.2, 153.1 (2), 137.6, 133.4, 131.1, 129.4, 122.0, 119.4, 114.6, 103.8 (2), 98.8, 96.3, 96.1, 77.9, 68.6, 60.8, 55.9, 55.4 (2), 25.7; IR (KBr)ν_max 3419, 3404, 3010, 2927, 2852, 1716, 1596, 1463, 1274, 1128,1105, 754 cm⁻¹; HRMS (ESI+) m/z [M-H⁻] calcd for C₂₆H₂₅O₉, 481.1499, found 481.1509.

5,7-Dihydroxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-methoxybenzoate (11h)

10r (14 mg, 0.021 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:8) to give 11h (9 mg, 89 %) as a colorless oil: ¹H NMR (500 MHz, CD₃OD) δ 7.93 – 7.76 (m, 2H), 6.98 – 6.90 (m, 2H), 6.79 (s, 2H), 6.00 (q, J = 2.3 Hz, 2H), 5.63 (ddd, J = 4.7, 2.3, 1.2 Hz, 1H), 5.14 (s, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.67 (s, 6H), 3.07 (dd, J = 17.4, 4.6 Hz, 1H), 2.95 – 2.86 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 165.2, 163.8, 156.2, 155.5, 155.3, 153.3, 137.3, 133.5, 132.0 (3),122.4, 113.8 (2), 104.0 (2), 99.2, 96.6, 96.2, 78.2, 68.1, 63.0, 56.1, 55.7 (2), 26.0; IR (KBr)ν_max 3419, 2931, 2842, 1701, 1604, 1506, 1458, 1361, 1257, 1166, 1126, 1101, 1018 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₂₆H₂₅O₉, 481.1499, found 481.1518.

5,7-dihydroxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (11i)

10r (25 mg, 0.032 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, Acetone/Dichloromethane 1:8) to give the 11g (17.4 mg, 91 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.83 – 7.78 (m, 2H), 7.45 – 7.39 (m, 2H), 7.31 – 7.22 (m, 3H), 7.23 – 7.20 (m, 1H), 6.98 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.93 (dd, J = 2.6, 1.6 Hz, 1H), 6.88 – 6.80 (m, 2H), 6.08 (d, J = 2.2 Hz, 1H), 5.91 (d, J = 2.4 Hz, 1H), 5.57 (tt, J = 3.3, 1.5 Hz, 1H), 5.13 (s, 1H), 5.01 (s, 1H), 4.91 (s, 1H), 3.76 (d, J = 1.4 Hz, 6H), 3.08 – 2.95 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 165.7, 160.6, 159.4, 156.2, 155.6, 155.4, 153.3 (2), 138.8, 133.6, 132.6, 131.2, 130.6, 129.3 (2), 122.5, 122.1, 115.3, 113.2, 110.7, 103.9 (2), 99.2, 96.6, 96.3, 78.1, 68.5, 61.0, 56.1, 56.0, 55.5, 53.6, 29; IR (KBr)ν_max 3429, 2931, 2851, 1699, 1604, 1508, 1476, 1248, 1166, 1145, 1098, cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₃H₃₃O₁₀, 589.2074 found 589.2057.

5,7-Dihydroxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (11j)

A solution of palladium acetate (1 mg, 0.004 mmol), triethylamine (7 μL, 0.047 mmol), triethylsilane (34 μL, 0.208 in dichloromethane (0.5 mL) was stirred for 15 minutes before the addition of 10t (20 mg, 0.026 mmol) in dichloromethane (0.4 mL). The resulting mixture was stirred for 15 h, quenched with saturated ammonium chloride (2 mL) and extracted with diethyl ether (3 × 4 mL). The combined organic layers were washed with saturated sodium chloride solution and dried over anhydrous Na₂SO₄. Solvent was removed and residue was purified via flash chromatography (SiO₂, 5:95 MeOH/DCM) to give 11j (4 mg, 18.9 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.71 (dd, J = 6.4, 2.4 Hz, 2H), 6.67 (s, 3H), 6.43 (d, J = 2.2 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 5.74 (s, 1H), 5.66 – 5.59 (m, 1H), 5.36 (brs, 1H), 5.22 (dddt, J = 7.3, 5.8, 2.9, 1.5 Hz, 1H), 4.97 (s, 1H), 3.32 (d, J = 7.4 Hz, 2H), 3.07 – 2.99 (m, 2H), 2.30 (d, J = 5.3 Hz, 3H), 1.80 – 1.64 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 170.1, 165.6, 159.2, 156.0, 155.0, 153.3 (2), 150.0, 137.9, 136.0, 133.2, 132.2, 130.0, 127.1 (2), 122.2, 121.0, 115.7, 104.8, 103.9 (2), 103.1, 102.1, 78.2, 67.7, 61.0, 56.2, 29.7, 26.0 (2), 21.4, 18.1; IR (KBr)ν_max 3412, 2937, 2843, 1715, 1693, 1562, 1473, 1126 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₃₂H₃₃O₁₀, 577.2074, found 577.2079.

(((5-(Allyloxy)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene (18a)

A solution of 4b (1.2 g, 3.9 mmol), potassium carbonate (2.17g, 15.7 mmol) and ally bromide (0.44 mL, 5.1 mmol) in dimethyl formamide (40 mL) was heated at 90 °C for 12 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (200 mL), washed with water (3 × 100 mL) and then saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂ 1:9 EtOAc/Hexanes) to give 18a (1.62 g, 89%) as a light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.51 – 7.29 (m, 10H), 6.27 (t, J = 2.2 Hz, 1H), 6.21 (d, J = 2.1 Hz, 2H), 6.04 (ddt, J = 17.2, 10.6, 5.4 Hz, 1H), 5.40 (dq, J = 17.3, 1.6 Hz, 1H), 5.29 (dq, J = 10.5, 1.4 Hz, 1H), 5.01 (s, 4H), 4.49 (dt, J = 5.4, 1.5 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃) δ 160.8 (2), 160.6, 137.0 (2), 133.3, 128.8 (4), 128.2 (2), 127.8 (4), 118.0, 95.0, 94.9 (2), 70.3 (2), 69.1; IR (KBr)ν_max 3390, 2975, 2908, 2864, 1622, 1591, 1506, 1434, 1213, 1159, 1110, 1066, 1043, 933, 810, 703 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₃H₂₃O₃, 347.1647, found 347.1647.

1-(Allyloxy)-3-(benzyloxy)benzene (18b)

A solution of 17 (2.45g, 12.3 mmol), potassium carbonate (6.62g, 49.2 mmol) and ally bromide (1.34 mL, 16 mmol)) dimethylformamide (60 mL) was stirred for 12 h at 90 °C. The reaction mixture was cooled to rt, diluted with EtOAc (200 mL), washed with water (3 × 100 mL times) and saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:9 EtOAc/Hexanes) to give 18b (2.8g, 95.2 %) as light yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.47 – 7.43 (m, 2H), 7.42 – 7.38 (m, 2H), 7.37 – 7.32 (m, 1H), 7.19 (t, J = 8.1 Hz, 1H), 6.06 (ddt, J = 17.2, 10.6, 5.3 Hz, 1H), 5.42 (dq, J = 17.2, 1.6 Hz, 1H), 5.29 (dq, J = 10.5, 1.4 Hz, 1H), 5.06 (s, 2H), 4.53 (dt, J = 5.3, 1.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 160.2, 160.0, 137.3, 133.4, 130.1, 128.8 (2), 128.2 (2), 127.7, 117.9, 107.5, 107.4, 102.3, 70.2, 69.0; IR (KBr)ν_max 3031, 2866, 1591, 1490, 1454, 1379, 1288, 1261, 1178, 1149, 1039, 1027, 927, 835, 734, 696 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₁₆H₁₆NaO₂, 263.1048, found 263.1053.

2-Allyl-3,5-bis(benzyloxy)phenol (19a)

18a (1.62 g, 4.66 mmol) was dissolved in N,N-diethylaniline (23 mL) and heated at 210 °C for 12 h. Reaction mixture was cooled to rt, diluted with ethyl acetate (200 mL), washed with 1N HCl (3 × 100mL), and then saturated sodium chloride solution. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to afford 19a (1.215g, 75%) as a pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.47 – 7.32 (m, 11H), 6.27 (d, J = 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.98 (ddt, J = 16.3, 10.0, 6.1 Hz, 1H), 5.18 (q, J = 1.8 Hz, 1H), 5.13 (dq, J = 5.0, 1.7 Hz, 1H), 5.07 (s, 1H), 5.02 (s, 2H), 5.01 (s, 2H), 3.46 (dt, J = 6.2, 1.7 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 161.9, 160.5, 158.3, 137.0 (2), 136.9, 128.8 (4), 128.2 (2), 127.8 (4), 116.0, 106.3, 95.0, 92.9, 70.3, 69.1, 26.3; IR (KBr)ν_max 2925, 2867, 1596, 1456, 1375, 1213, 1153, 1058, 927, 817, 736 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₂₃H₂₁O₃, 345.1491, found 345.1503.

3-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)propane-1,2-diol (20a)

A mixture of 19a (1.062g, 3.1 mmol) in tetrahydrofuran-water (13mL-9mL), 4% aqueous solution of osmium tetraoxide in water (0.03 mmol) and N-methyl morphline-N-oxide (575 mg, 4.9 mmol) was stirred for 12 h before quenching with 10 % aqueous sodium metabisulfite. The aqueous layer was extracted with ethyl acetate (3 × 50 mL) and the combined organic layers washed with saturated sodium chloride solution (100 mL). The solvent was removed and the residue purified by flash chromatography (SiO₂, 2:5 EtOAc/Hexanes) to afford 20a (744 mg, 64 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.77 (s, 1H), 7.50 (dd, J = 8.1, 1.4 Hz, 2H), 7.48 – 7.44 (m, 2H), 7.39 (td, J = 7.9, 7.5, 1.5 Hz, 4H), 7.36 – 7.30 (m, 2H), 6.32 (d, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.10 (s, 2H), 5.05 (s, 2H), 4.65 (d, J = 5.2 Hz, 1H), 3.91 (brs, 1H), 3.81 (d, J = 6.1 Hz, 1H), 3.53 (brs, 1H), 3.41 (dd, J = 11.3, 6.4 Hz, 1H), 2.96 (dd, J = 14.1, 5.0 Hz, 1H), 2.79 (dd, J = 14.1, 6.8 Hz, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 159.9, 159.1 (2), 138.7 (2), 129.4 (2), 129.3 (2), 128.9, 128.7, 128.6, 128.5, 128.2, 107.6, 96.8, 96.8, 93.6, 74.1, 70.9, 70.5, 66.6, 27.8; IR (KBr)ν_max 3298, 1616, 1598, 1452, 1436, 1375, 1217, 1147, 1105, 1045, 1027, 908, 813, 736, 696, 649 cm⁻¹; HRMS (ESI−) m/z [M+H⁺] calcd for C₂₃H₂₅O₅, 381.1702, found 381.1709.

3-(4-(Benzyloxy)-2-hydroxyphenyl)propane-1,2-diol (20b)

18b (2.7g, 11.23 mmol) was dissolved in N,N-diethylaniline (70 mL) and heated at 210 °C for 12 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (200 mL), washed with 1N HCl (3 × 100mL), and then with saturated sodium chloride solution. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give a mixture of 19b and 19c. The mixture of 19b & 19c (2.02g, 8.41 mmol) in tetrahydrofuran-water (18mL-12mL), 4% aqueous solution osmium tetraoxide in water (0.168mmol) and N-methyl morphline-N-oxide (1.67g, 14.29 mmol) was stirred 12 h before quenching with 10 % aqueous sodium metabisulfite. The aqueous phase was extracted with ethyl acetate (3 × 200 mL), the combined organic layers were washed with saturated sodium chloride solution and solvent was removed. The residue was purified by flash chromatography (1:5 Acetone-DCM) to afford 20b (1.24g) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 7.49 – 7.43 (m, 2H), 7.427.35 (m, 2H), 7.34 – 7.27 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 6.45 (dd, J = 8.2, 2.5 Hz, 1H), 3.90 (tt, J = 6.9, 4.4 Hz, 1H), 3.54 – 3.49 (m, 1H), 3.47 – 3.40 (m, 1H), 2.83 – 2.75 (m, 1H), 2.74 – 2.66 (m, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 159.6, 157.7, 138.6, 132.6, 129.2, 129.1, 128.4 (2), 128.2, 118.8, 106.7, 103.8, 74.2, 70.2, 66.2, 35.3; IR (KBr)ν_max 3311, 2931, 1618, 1585, 1506, 1454, 1279, 1286, 1166, 1108, 1024, 842, 736, 696 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₆H₁₇O₄, 273.1127, found 273.1129.

3-(2-(Benzyloxy)-6-hydroxyphenyl)propane-1,2-diol (20c)

The mixture of 19b & 19c (2.02g, 8.41 mmol) in tetrahydrofuran-water (18mL-12mL), 4% aqueous solution osmium tetraoxide in water (0.168mmol) and N-methyl morphline-N-oxide ( (1.67g, 14.29 mmol) was stirred 12 h before quenching with 10 % aqueous sodium metabisulfite. The aqueous phase was extracted with ethyl acetate (3 × 200 mL, and the combined organic layers washed with saturated sodium chloride solution. The solvent was removed and the residue purified by flash chromatography (1:5 Acetone-DCM) to afford 20c (0.8 g) as a colorless oil was used as is in the next step: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.70 (s, 1H), 7.53 – 7.48 (m, 2H), 7.42 – 7.35 (m, 2H), 7.35 – 7.29 (m, 1H), 7.02 (t, J = 8.2 Hz, 1H), 6.59 (dd, J = 8.3, 1.0 Hz, 1H), 6.52 (dd, J = 8.1, 1.0 Hz, 1H), 5.10 (s, 2H), 4.86 – 4.48 (m, 1H), 3.97 (tdd, J = 6.7, 5.3, 4.0 Hz, 1H), 3.83 (brs, 1H), 3.55 (dd, J = 11.2, 4.0 Hz, 1H), 3.43 (dd, J = 11.2, 6.6 Hz, 1H), 3.04 (dd, J = 13.8, 5.3 Hz, 1H), 2.89 (dd, J = 13.8, 6.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 157.47, 156.58, 136.82, 128.69 (2), 128.10 (2), 127.40 (2), 112.99, 110.56, 104.13, 72.83, 70.54, 65.24, 26.59; IR (KBr)ν_max 3334, 2929, 1618, 1583, 1506, 1454, 1279, 1286, 1217, 1166, 1045, 1025, 849 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₆H₁₇O₄, 273.1127, found 273.1127.

3-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (21a)

Pyridine (0.46mL, 5.8 mmol) was added to a solution of 19a (500 mg, 1.37 mmol) and p-toluenesulfonyl chloride (282 mg, 1.5 mmol) in dichloromethane (14 mL) at 0 °C. The resulting mixture was stirred for 12 h at rt before quenching with 2N HCl (20mL). The aqueous layer was extracted with dichloromethane (2 × 30mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 2:5 EtOAc/Hexanes) to give 21a (427 mg, 58%) as a pale yellow oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.51 (s, 1H), 7.72 – 7.67 (m, 2H), 7.50 – 7.44 (m, 4H), 7.43 – 7.37 (m, 6H), 7.37 – 7.30 (m, 2H), 6.31 (d, J = 2.4 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.07 (s, 2H), 5.04 (s, 2H), 4.84 (d, J = 4.5 Hz, 1H), 4.11 – 3.94 (m, 2H), 3.95 – 3.70 (m, 1H), 2.42 (s, 3H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 160.0, 159.1, 158.0, 145.7, 138.4 (2), 130.8 (2), 129.4 (2), 129.3 (2), 128.6 (5), 128.5 (2), 128.1 (2), 106.1, 96.2, 93.3, 75.2, 70.6, 70.4, 70.2, 28.0, 21.5; IR (KBr)ν_max 3334, 2925, 1625, 1506, 1361, 1174, 1108, 1095, 975 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₀H₃₁O₇S, 535.1790, found 535.1773.

3-(4-(Benzyloxy)-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (21b)

Pyridine (0.46mL, 5.8 mmol) was added to a solution of 19b (500 mg, 1.37 mmol) and p-toluenesulfonyl chloride (282 mg, 1.5 mmol) in dichloromethane (14 mL) at 0 °C. The resulting mixture was stirred for 12 h at rt before quenching with 2N HCl (20mL). The aqueous layer was extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with saturated sodium chloride solution (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 2:5 EtOAc/Hexanes) to give 21b (.97g, 58.6 %) as a pale yellow oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 7.82 – 7.74 (m, 3H), 7.50 – 7.43 (m, 5H), 7.43 – 7.28 (m, 4H), 6.92 (d, J = 8.2 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.42 (dd, J = 8.3, 2.5 Hz, 1H), 4.17 – 3.97 (m, 3H), 3.89 (dd, J = 9.9, 6.7 Hz, 1H), 2.76 – 2.67 (m, 2H), 2.45 (s, 3H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 159.8 (2), 145.8, 138.6, 134.1, 132.8, 130.9, 130.8, 129.3 (2), 128.8, 128.7, 128.6 (2), 128.4, 106.8, 103.5, 74.3, 70.4, 70.3, 34.9, 21.5; IR (KBr)ν_max 3348, 2928, 1627, 1361, 1174, 1108, 1096 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₃H₂₅O₆S, 429.1372, found 429.1383.

3-(2-(Benzyloxy)-6-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (21c)

Pyridine (0.47 mL, 15.4 mmol) was added to a solution of 20c (410 mg, 1.5 mmol) and p-toluenesulfonyl chloride (310 mg, 1.7 mmol) in dichloromethane (14 mL) at 0 °C. The resulting mixture was stirred for 12 h at rt before quenching with 2N HCl (20mL). The aqueous layer was extracted with dichloromethane (2 × 30mL). The combined organic layers were washed with saturated sodium chloride solution (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 2:5 EtOAc/Hexanes) to give 21c (367 mg, 57 %) as a pale yellow oil and was used as is in the next step.

5,7-Bis(benzyloxy)chroman-3-ol (22a)

Potassium carbonate (115 mg, 0.83 mmol) was added to a solution of 21a (277 mg, 0.58 mmol) in methanol (2.6 mL) and the resulting mixture was stirred for 6 h at rt. Methanol was removed, the residue was partitioned between water (5 mL) and dichloromethane (5 mL) The aqueous layer was extracted with dichloromethane (2 × 5 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to give 22a (86 mg, 46%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.45 – 7.37 (m, 8H), 7.34 (ddt, J = 7.4, 4.0, 1.7 Hz, 2H), 6.26 (d, J = 2.3 Hz, 1H), 6.18 (d, J = 2.3 Hz, 1H), 5.02 (s, 2H), 5.01 (s, 2H), 4.33 – 4.15 (m, 1H), 4.15 – 3.97 (m, 2H), 2.93 (dd, J = 17.0, 5.0 Hz, 1H), 2.75 (dd, J = 17.0, 4.5 Hz, 1H), 1.89 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 158.9, 158.4, 155.2, 137.1, 137.1, 128.8 (2), 128.7, 128.7, 128.2, 128.1, 127.8, 127.7, 127.4 (2), 101.6, 94.8, 94.0, 70.3, 70.1, 69.8, 63.2, 28.4; IR (KBr)ν_max 3392, 2925, 2871, 1616, 1591, 1496, 1456, 1145, 1122, 1062, 1027, 811, 696 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₃H₂₃O₄, 363.1596, found 363.1596.

7-(Benzyloxy)chroman-3-ol (22b)

Potassium carbonate (440 mg, 3.18 mmol) was added to a solution of 21a (830 mg, 1.98 mmol) in methanol (5 mL) and the resulting solution was stirred for 6 h at rt. Methanol was removed, the residue was partitioned between water 105 mL) and dichloromethane (10 mL) The aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to give desire product 22b (200 mg, 40 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.51 – 7.30 (m, 5H), 7.04 (d, J = 8.0 Hz, 1H), 6.52 – 6.45 (m, 2H), 5.03 (s, 2H), 4.98 – 4.80 (m, 1H), 3.84 (dd, J = 12.0, 3.3 Hz, 1H), 3.74 (dd, J = 12.0, 6.4 Hz, 1H), 3.19 (dd, J = 15.1, 9.4 Hz, 1H), 2.94 (ddd, J = 15.1, 7.2, 1.2 Hz, 1H), 2.07 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.7, 137.2, 128.8 (2), 128.1 (2), 127.6, 125.2, 118.9, 107.3, 97.5, 84.3, 70.5, 65.2, 30.8; IR (KBr)ν_max 3382, 2927, 1614, 1494, 1145, 1029 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₁₆H₁₆NaO₃, 279.0097, found 279.1002.

5-(Benzyloxy)chroman-3-ol (22c)

Potassium carbonate 21c (262 mg, 0.61 mmol), potassium carbonate (135 mg, 0.98 mmol) in methanol (2 mL) and the resulting solution was stirred for 6 h at rt. Methanol was removed, the residue was partitioned between water (5 mL) and dichloromethane (5 mL) The aqueous layer was extracted with dichloromethane (2 × 5 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to give desire product 22c (70 mg, 45 %) as a colorless oil: ¹H NMR (500 MHz, CD₃OD) δ 7.49 – 7.43 (m, 2H), 7.37 (ddd, J = 7.7, 6.4, 1.2 Hz, 2H), 7.30 (td, J = 7.1, 1.4 Hz, 1H), 7.01 (t, J = 8.2 Hz, 1H), 6.55 (dd, J = 8.3, 1.1 Hz, 1H), 6.43 (dd, J = 8.1, 1.1 Hz, 1H), 5.07 (s, 2H), 3.88 (ddd, J = 10.7, 6.4, 1.5 Hz, 1H), 2.99 (ddd, J = 17.3, 5.3, 1.6 Hz, 1H), 2.66 (dd, J = 17.1, 5.9 Hz, 1H); ¹³C NMR (125 MHz, CD₃OD) δ 158.8, 156.3, 139.0, 129.5, 128.8, 128.3, 128.1 (2), 110.5, 110.3, 104.8 (2), 71.0, 70.3, 63.7, 29.3; IR (KBr)ν_max 3388, 2928, 1616, 1591, 1496, 1146, 1061, 1027 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₁₆H₁₆NaO₃, 279.0997, found 279.0993.

5,7-Dihydroxychroman-3-yl benzoate (23a)⁴⁵

A solution of alcohol (14 mg, 0.04 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of benzoic acid (10 mg, 0.08 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered concentrate. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford give 5,7-bis(benzyloxy)chroman-3-yl benzoate (16.2 mg, 90%) as a colorless oil, which was used as for hydrogenolysis. 5,7-Bis(benzyloxy)chroman-3-yl benzoate (16.2 mg, 0.034 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23a (8 mg, 81.6 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.32 (s, 1H), 8.05 (s, 1H), 8.02 – 7.91 (m, 2H), 7.71 – 7.59 (m, 1H), 7.57 – 7.44 (m, 2H), 6.05 (d, J = 2.3 Hz, 1H), 5.91 (d, J = 2.3 Hz, 1H), 5.60 – 5.41 (m, 1H), 3.02 (ddd, J = 17.1, 5.3, 1.2 Hz, 1H), 2.90 – 2.83 (m, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.4, 157.9, 157.5, 156.5, 134.1, 131.3 (2), 130.3 (2), 129.5, 99.2, 96.5, 95.8, 67.4, 67.3, 25.6; IR (KBr)ν_max 3385, 2933, 2840, 1716, 1622, 1593, 1496, 1452, 1272, 1201, 1145, 1056, 813, 711 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₆H₁₄O₅, 287.0919, found 287.0912.

5,7-Dihydroxychroman-3-yl 3-methoxybenzoate (23b)

A solution of alcohol (14 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3-methoxybenzoic acid (12 mg, 0.08 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford give 5,7-bis(benzyloxy)chroman-3-yl 3-methoxybenzoate (18 mg, 89%) as a colorless oil, which was used as for hydrogenolysis. 5,7-bis(benzyloxy)chroman-3-yl 3-methoxybenzoate (18 mg) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23b (11 mg, 96 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (ddd, J = 7.7, 1.5, 1.0 Hz, 1H), 7.53 (dd, J = 2.7, 1.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.09 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.03 (d, J = 2.3 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 5.54 – 5.45 (m, 1H), 5.43 – 5.33 (m, 1H), 5.24 (s, 1H), 4.29 (ddd, J = 11.4, 5.0, 1.8 Hz, 1H), 4.20 (ddd, J = 11.4, 2.3, 1.0 Hz, 1H), 3.04 (ddd, J = 16.9, 5.4, 1.2 Hz, 1H), 2.88 (ddd, J = 16.9, 4.5, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3, 159.7, 155.7, 155.4, 155.3, 131.3, 129.7, 122.4, 119.8, 114.6, 99.5, 96.3, 96.1, 66.9, 66.2, 55.7, 24.9; IR (KBr)ν_max 3404, 2960, 1716, 1596, 1469, 1278, 1224, 1099, 933, 752 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₇H₁₅O₆, 315.0869, found 315.0830.

5,7-Dihydroxychroman-3-yl 4-methoxybenzoate (23c)

A solution of 22a (13 mg, 0.036 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 4-methoxybenzoic acid (11 mg, 0.072 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford 5,7-bis(benzyloxy)chroman-3-yl 4-methoxybenzoate (16.7 mg, 93.8%) as a colorless oil, which was used as for hydrogenolysis. 5,7-bis(benzyloxy)chroman-3-yl 4-methoxybenzoate (16.2 mg, 0.033 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23c (10 mg, 98 %) as colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.30 (s, 1H), 8.04 (s, 1H), 7.99 – 7.88 (m, 2H), 7.03 – 6.94 (m, 2H), 6.05 (d, J = 2.3 Hz, 1H), 5.90 (d, J = 2.3 Hz, 1H), 5.42 (dtd, J = 5.4, 4.5, 2.2 Hz, 1H), 4.24 (ddd, J = 11.4, 4.7, 1.9 Hz, 1H), 4.19 (ddt, J = 11.5, 1.9, 0.9 Hz, 1H), 3.86 (s, 3H), 3.00 (ddd, J = 17.2, 5.3, 1.2 Hz, 1H), 2.83 (ddd, J = 17.2, 4.4, 1.9 Hz, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.1 (2), 164.6, 157.8, 157.5, 156.5, 132.4 (2), 123.5, 114.7, 99.2, 96.5, 95.7, 67.3, 66.9, 56.0, 25.6; IR (KBr)ν_max 3404, 2958, 1716, 1596, 14266, 1284 1224, 1098 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₇H₁₇O₆, 317.1025, found 317.1029.

5,7-Dihydroxychroman-3-yl 3,4-dimethoxybenzoate (23d)

A solution of 22a (12 mg, 0.033 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 4-methoxybenzoic acid 3,4-methoxybenzoic acid (14 mg, 0.066 mmol), N,N′-dicyclohexylcarbodiimide (14 mg, 0.066 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and the solvent removed. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford 5,7-bis(benzyloxy)chroman-3-yl 3,4-methoxybenzoate (17 mg, 95%) as colorless oil which was used as for hydrogenolysis. 5,7-bis(benzyloxy)chroman-3-yl 3,4-methoxybenzoate (17 mg, 0.032 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23d (9.5 mg, 86 %) as colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.30 (s, 1H), 8.04 (s, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H), 5.90 (d, J = 2.3 Hz, 1H), 5.41 (qd, J = 4.7, 2.5 Hz, 1H), 4.21 (td, J = 4.2, 3.5, 1.4 Hz, 2H), 3.87 (s, 4H), 3.83 (s, 3H), 3.01 (ddd, J = 17.1, 5.3, 1.1 Hz, 1H), 2.88 – 2.73 (m, 1H); ¹³C NMR (125 MHz (CD₃)₂CO) δ 166.2, 157.9, 157.5, 156.6, 154.7, 150.0, 124.4, 123.5, 113.2, 111.8, 99.3, 96.5, 95.7, 78.1, 67.1, 56.3, 56.2, 25.7; IR (KBr)ν_max 3404, 2921, 1699, 1515, 1271, 1145, 1022, 761, 667 cm⁻¹; HRMS (ESI+) m/z [M+H+] calcd for C₁₈H₁₉O₇, 347.1131, found 347.1128.

5,7-Dihydroxychroman-3-yl 3,5-dimethoxybenzoate (23e)

A solution of 22a (13 mg, 0.036 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 4-methoxybenzoic acid 3,5-dimethoxybenzoic acid (13 mg, 0.072 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol)and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford 5,7-bis(benzyloxy)chroman-3-yl 3,5-dimethoxybenzoate (17.8 mg, 94.6%) as a colorless oil, which was used as for hydrogenolysis. 5,7-bis(benzyloxy)chroman-3-yl 3,5-methoxybenzoate (17 mg, 0.032 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23e (9.5 mg, 86 %) as colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.31 (s, 1H), 8.04 (s, 1H), 7.10 (d, J = 2.4 Hz, 2H), 6.72 (t, J = 2.4 Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H), 5.90 (d, J = 2.3 Hz, 1H), 5.53 – 5.35 (m, 1H), 4.32 – 4.16 (m, 2H), 3.15 – 2.95 (m, 1H), 2.86 – 2.82 (m, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.1, 161.8 (2), 157.8, 157.4, 156.4, 133.2, 108.1 (2), 105.6, 99.1, 96.4, 95.6, 77.1, 67.5, 67.2, 55.9, 25.5; IR (KBr)ν_max 1916, 2848, 1702, 1683, 1558, 1244, 1145, 1103, cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₁₈H₁₈NaO₇, 369.0950, found 369.0962.

5,7-Dihydroxychroman-3-yl 3-hydroxybenzoate (23f)⁴⁵

A solution of 22a (14 mg, 0.039 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 4-(benzyloxy)benzoic acid (13 mg, 0.072 mmol), N,N′-dicyclohexylcarbodiimide (16 mg, 0.077 mmol)and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford 5,7-bis(benzyloxy)chroman-3-yl 3-(benzyloxy)benzoate (19 mg, 86.3 %), which was used further as obtained. 5,7-bis(benzyloxy)chroman-3-yl 3-(benzyloxy)benzoate (18 mg, 0.031 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:9 Acetone/Dichloromethane) to give 23f (8.6 mg, 92.6 %) as a colorless oil: ¹H NMR (500 MHz, MeOD) δ 7.83 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.94 (d, J = 2.3 Hz, 1H), 5.84 (d, J = 2.3 Hz, 1H), 5.37 (ddd, J = 5.3, 4.5, 2.7 Hz, 1H), 4.19 (ddd, J = 11.4, 4.9, 1.8 Hz, 1H), 4.14 (dd, J = 11.4, 2.1 Hz, 1H), 2.95 (ddd, J = 17.1, 5.4, 1.1 Hz, 1H), 2.77 (ddd, J = 17.1, 4.5, 1.7 Hz, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.2, 158.3, 157.7, 157.4, 156.4, 132.6, 130.5, 121.5, 121.0, 116.7, 99.1, 96.3, 95.6, 67.6, 67.2, 25.5; IR (KBr)ν_max 3384, 2910, 1848, 1699, 1436, 1290, 1145 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₆H₁₃O₆, 301.0712, found 301.0717.

5,7-Bis(benzyloxy)chroman-3-yl 4-(benzyloxy)benzoate (23g)³⁶

A solution of 22a (14 mg, 0.039 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 4-(benzyloxy)benzoic acid (13 mg, 0.072 mmol), N,N′-dicyclohexylcarbodiimide (16 mg, 0.077 mmol)and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. The resulting solution was stirred for 6 h at rt and filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to afford 5,7-bis(benzyloxy)chroman-3-yl 4-(benzyloxy)benzoate (20 mg, 90.4 %) as a colorless oil, which was used as for hydrogenolysis. 5,7-bis(benzyloxy)chroman-3-yl 3-(benzyloxy)benzoate (18 mg, 0.031 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23g (9.8 mg, 97%) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 9.15 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 6.97 – 6.83 (m, 2H), 6.05 (d, J = 2.3 Hz, 1H), 5.90 (d, J = 2.3 Hz, 1H), 5.57 – 5.28 (m, 1H), 4.23 (ddd, J = 11.4, 4.7, 1.8 Hz, 1H), 4.18 (ddt, J = 11.4, 2.1, 0.9 Hz, 1H), 2.99 (ddd, J = 17.0, 5.4, 1.1 Hz, 1H), 2.82 (ddd, J = 17.0, 4.4, 1.7 Hz, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.2, 160.7, 159.8, 159.4, 156.1, 133.1, 108.7, 108.1, 101.1, 94.2, 92.2, 67.3, 66.8, 55.8, 55.5, 25.3; IR (KBr)ν_max 3363, 2962, 2927, 1683, 1608, 1355, 1272, 1166, 1143, 1099, 1014, 769 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₆H₁₅O₆, 303.0869, found 303.0878.

5,7-Dihydroxychroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (23h)

A solution of 22a (11 mg, 0.03 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (16 mg, 0.06 mmol), N,N′-dicyclohexylcarbodiimide (13 mg, 0.06 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in dichloromethane (1 mL) 0 °C. The resulting solution was stirred for 6 h at rt and filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, EtOAc/Hexanes) to afford 5,7-bis(benzyloxy)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (17.5 mg, 96.1%) as a colorless oil, which was used as for hydrogenolysis. 5,7-bis(benzyloxy)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (17 mg, 0.028 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23h (11.1 mg, 93.2 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 7.97 (dd, J = 8.7, 2.2 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.37 – 7.29 (m, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.10 – 7.00 (m, 2H), 6.91 (ddd, J = 8.3, 2.6, 1.1 Hz, 1H), 6.04 (d, J = 2.3 Hz, 1H), 5.89 (d, J = 2.3 Hz, 1H), 5.50 – 5.35 (m, 1H), 4.33 – 4.23 (m, 1H), 4.22 – 4.18 (m, 1H), 3.89 (s, 4H), 3.81 (s, 3H), 3.01 (ddd, J = 17.1, 5.3, 1.2 Hz, 1H), 2.92 – 2.80 (m, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.0, 161.4, 160.4, 157.8, 157.4, 156.5, 139.9, 132.7, 131.7, 131.3, 129.9, 123.5, 122.5, 116.0, 113.6, 112.1, 99.2, 96.4, 95.7, 67.3, 67.0, 55.5 (2), 25.6; IR (KBr)ν_max 3355, 2923, 1701, 1606,1458, 1251, 1145, 1031, 752, 667 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₄H₂₃O₇, 423.1444, found 423.1454.

5,7-Dihydroxychroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (23i)

4-Acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (34 mg, 0.137 mmol) and thionyl chloride (33 μL, 0.27 mmol) in tetrahydrofuran (5 mL) was heated at reflux for 3 h, cooled to rt and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and added to a stirred solution of 22a (25 mg, 0.069 mmol) in dichloromethane (0.7 mL) with triethylamine (0.3 mL) under at 0°C. The resulting mixture was stirred for 6 h, concentrated and the residue was purified by flash chromatography (SiO₂, 1:4 EtOAc/Hexanes) to give 5,7-bis(benzyloxy)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (34 mg, 85 %) as colorless a oil, which was used as for hydrogenolysis. A solution of palladium acetate (5 mg, 0.023 mg), triethylamine (15μL, 0.108 mmol), triethylsilane (82μL, 0.108) in dichloromethane (0.8 mL) was stirred for 15 minutes before the slow addition of a solution of bis(benzyloxy)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (34 mg, 0.057 mmol) in dichloromethane (0.4 mL). The resulting mixture was stirred for 15 h, quenched with saturated ammonium chloride (2 mL) and extracted with ether (3 × 4 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (silica, 5:95 MeOH/DCM) to afford 23i as a colorless oil: ¹H NMR (500 MHz, CDCl₃): δ 7.92 (dd, J = 13.7, 2.2 Hz, 1H), 7.86 (dd, J = 8.4, 2.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.03 – 5.99 (m, 1H), 5.96 (d, J = 2.4 Hz, 1H), 5.50 (ddt, J = 7.2, 4.8, 2.4 Hz, 1H), 5.18 (dddd, J = 7.3, 5.8, 2.9, 1.5 Hz, 1H), 4.29 (ddd, J = 11.5, 4.9, 1.9 Hz, 1H), 4.24 – 4.14 (m, 1H), 3.25 (d, J = 7.2 Hz, 2H), 3.07 – 2.98 (m, 1H), 2.87 (ddd, J = 16.9, 4.4, 1.8 Hz, 1H), 2.32 (s, 3H), 1.72 (q, J = 1.3 Hz, 2H), 1.68 (d, J = 1.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.1, 165.7, 155.4, 155.3 (2), 152.9, 134.2, 134.1, 132.2, 129.0, 127.9, 122.6, 121.0, 99.4, 96.3, 96.0, 66.9, 65.9, 28.9, 25.9, 24.9, 21.1, 18.1; IR (KBr)ν_max 3363, 2921, 1703, 1606, 1252, 1146 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₃H₂₅O₇, 413.1600, found 413.1617.

7-Hydroxychroman-3-yl 4-methoxybenzoate (23j)

A solution of 22b (15 mg, 0.06 mmol) in dichloromethane (0.5 mL) was added to a stirred solution benzoic acid (14 mg, 0.12 mmol), N,N′-dicyclohexylcarbodiimide (24 mg, 0.12 mmol) and 4-dimethylaminopyridine (7.2 mg, 0.06 mmol) at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to afford 7-(benzyloxy)chroman-3-yl benzoate as a colorless oil (21 mg, 90%), which was used as for hydrogenolysis. 7-(benzyloxy)chroman-3-yl benzoate (14 mg, 0.04 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23j (11.1 mg, 90.4 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.04 – 7.93 (m, 2H), 7.54 (ddt, J = 8.7, 7.7, 1.3 Hz, 1H), 7.40 (ddt, J = 7.3, 6.3, 1.0 Hz, 2H), 6.92 (dt, J = 8.1, 0.9 Hz, 1H), 6.42 (dd, J = 8.2, 2.6 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 5.49 (qd, J = 4.8, 2.2 Hz, 1H), 4.71 (s, 1H), 4.32 (ddd, J = 11.5, 4.8, 1.9 Hz, 1H), 4.23 (dtd, J = 11.5, 1.5, 0.8 Hz, 1H), 3.18 (ddt, J = 16.6, 5.1, 1.1 Hz, 1H), 3.02 – 2.89 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3, 155.3, 154.8, 133.4, 130.8 (2), 130.1, 130.0, 128.6 (2), 111.4, 108.9, 103.5, 67.1, 66.4, 29.8; IR (KBr)ν_max 3392, 2925, 1716, 1699, 1519, 1456, 1272, 1145, 1027, 1016, 821, 711cm⁻¹; HRMS (ESI−) m/z [M+H⁺] calcd for C₁₆H₁₅O₄, 271.0970, found 271.0966.

7-Hydroxychroman-3-yl 3-methoxybenzoate (23k)

A solution of 22b (11 mg, 0.04 mmol) in dichloromethane (0.5 mL) was added to a stirred solution 3-methoxybenzoic acid (12 mg, 0.08 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol)and 4-dimethylaminopyridine (5 mg, 0.04 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to afford 7-(benzyloxy)chroman-3-yl 3-methoxybenzoate (15 mg, 89.5) as a colorless oil, which was used as for hydrogenolysis. 7-(benzyloxy)chroman-3-yl 3-methoxybenzoate (11 mg, 0.028 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23k (7.5 mg, 89.4 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.58 (dt, J = 7.7, 1.2 Hz, 1H), 7.52 (dd, J = 2.7, 1.5 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.09 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 6.92 (dt, J = 8.2, 1.0 Hz, 1H), 6.43 (dd, J = 8.2, 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.49 (qd, J = 4.9, 2.3 Hz, 1H), 4.81 (brs, 1H), 4.32 (ddd, J = 11.5, 4.9, 1.9 Hz, 1H), 4.24 (ddt, J = 11.4, 1.8, 1.0 Hz, 1H), 3.19 (ddt, J = 16.7, 5.2, 1.2 Hz, 1H), 3.03 – 2.84 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.2, 159.7, 155.3, 154.8, 131.4, 130.9, 129.6, 122.4, 119.8, 114.5, 111.3, 108.9, 103.5, 67.1, 66.5, 55.7, 29.9; IR (KBr)ν_max 3384, 2910, 2848, 1701, 1635, 1508, 1259, 1164, 1116, 667 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₇H₁₇O₅, 301.1076, found 301.1076.

7-Hydroxychroman-3-yl 4-methoxybenzoate (23l)

A solution of 22b (11 mg, 0.04 mmol) in dichloromethane (0.5 mL) was added to a stirred solution 4-methoxybenzoic acid (12 mg, 0.08 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to afford 7-(benzyloxy)chroman-3-yl 4-methoxybenzoate (15.5 mg, 79.2 %) as a colorless oil, which was used as for hydrogenolysis. 7-(Benzyloxy)chroman-3-yl 4-methoxybenzoate (11 mg, 0.028 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23l (8 mg, 94.3 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.00 – 7.88 (m, 2H), 6.93 (dt, J = 8.3, 0.9 Hz, 1H), 6.91 – 6.87 (m, 2H), 6.43 (dd, J = 8.2, 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.48 (qd, J = 4.8, 2.2 Hz, 1H), 4.78 (brs, 1H), 4.32 (ddd, J = 11.5, 4.9, 1.9 Hz, 1H), 4.23 (dtd, J = 11.5, 1.5, 0.8 Hz, 1H), 3.85 (s, 3H), 3.18 (ddt, J = 16.5, 5.0, 1.2 Hz, 1H), 2.95 (dtd, J = 16.7, 2.4, 1.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 163.7, 155.3, 154.8, 132.0, 130.9 (2), 122.5 (2), 113.8, 111.5, 108.8, 103.5, 67.2, 66.0, 55.7, 29.9; IR (KBr)ν_max 3392, 2918, 2848, 1701, 1606, 1510, 1458, 1259, 1164, 1108, 1022 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₇H₁₇O₅, 301.1076, found 301.1071.

7-Hydroxychroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (23m)

A solution of 22b (10 mg, 0.039 mmol)in dichloromethane (0.5 mL) was added to a stirred solution 4-methoxybenzoic acid (12 mg, 0.08 mmol), N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol)a nd 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL) dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to afford 7-(benzyloxy)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (17 mg, 87.4 %) as a colorless oil, which was used further as for hydrogenolysis. 7-(benzyloxy)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (12 mg, 0.024 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23m (9 mg, 91.4 %) as colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.01 – 7.94 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.10 – 7.05 (m, 1H), 7.03 (dd, J = 2.6, 1.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.95 – 6.88 (m, 2H), 6.42 (dd, J = 8.2, 2.6 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.73 (brs, 1H), 4.31 (ddd, J = 11.4, 5.1, 1.8 Hz, 1H), 4.24 (ddd, J = 11.5, 2.4, 1.1 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.19 (ddt, J = 16.6, 5.0, 1.2 Hz, 1H), 3.03 – 2.90 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 160.6, 159.5, 155.3, 154.8, 138.9, 132.7, 131.3, 130.9, 130.6, 129.3, 122.5, 122.2, 115.5, 113.1, 111.5, 110.8, 108.9, 103.5, 67.2, 66.2, 56.0, 55.5, 30.0; IR (KBr)ν_max 3411, 2921, 1701, 1598, 1510, 1278, 1224, 1155, 1116, 1043, 754 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₄H₂₃O₆, 407.1495, found 407.1475.

7-Hydroxychroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (23n)

4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (39 mg, 0.156 mmol) and thionyl chloride (38 μL, 0.312 mmol) in THF (5 mL) were heated at reflux for 3 h under argon, cooled to rt and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and added drop wise to a stirred solution of 22b (20 mg, 0.078) in dichloromethane (0.7 mL) with triethylamine (0.3 mL) under argon at 0 °C. The resulting mixture was stirred for and stirred for 6 h at rt before solvent was removed. The residue was purified by flash chromatography (SiO₂ 1:4 EtOAc/Hexanes) to give 7-benzyloxychroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (26 mg, 84 %) as q colorless oil, which was used as for hydrogenolysis. A solution of palladium acetate (1.3 mg, 0.006 mg), triethylamine (4μL, 0.03 mmol), triethylsilane (24 μL, 0.15) in dichloromethane (0.8 mL) was stirred for 15 minutes under argon before the addition of a solution of 7-benzyloxychroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (15 mg, 0.03 mmol) in dichloromethane (0.4 mL). The resulting mixture was stirred for 15 h, quenched with saturated ammonium chloride (2 mL) and extracted with ether (3 × 4 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered and concentrated solvent. The residue was purified by flash chromatography (SiO₂, 1:2 EtOAc/Hexanes) to give 23n as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.4, 2.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.92 (dt, J = 8.3, 0.9 Hz, 1H), 6.46 – 6.40 (m, 1H), 6.38 (d, J = 2.5 Hz, 1H), 5.49 (qd, J = 4.7, 2.2 Hz, 1H), 5.17 (dddt, J = 7.3, 5.9, 2.9, 1.4 Hz, 1H), 4.63 (s, 1H), 4.32 (ddd, J = 11.5, 4.8, 1.9 Hz, 1H), 4.22 (dt, J = 11.4, 1.6 Hz, 1H), 3.24 (d, J = 7.2 Hz, 2H), 3.18 (ddt, J = 16.7, 5.1, 1.2 Hz, 1H), 2.94 (ddd, J = 16.5, 4.7, 1.8 Hz, 1H), 2.32 (s, 3H), 1.72 (q, J = 1.3 Hz, 3H), 1.67 (d, J = 1.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.8, 164.4, 154.0, 153.6, 151.7, 132.9, 130.9, 129.6 (2), 127.7, 126.7 (2), 121.4, 119.7, 110.1, 107.6, 102.2, 65.8, 65.1, 28.7, 27.7, 24.6, 19.8, 16.8; IR (KBr)ν_max 3419, 2823, 2854, 1716, 1596, 1456, 1286, 1201, 1163, 1054, 796 cm⁻¹; HRMS (ESI−) m/z [M+H⁺] calcd for C₂₃H₂₅O₆, 397.1651, found 397.1642.

5-Hydroxychroman-3-yl benzoate (23o)

A solution of 22c (9 mg, 0.035 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of benzoic acid (8.6 mg, 0.07 mmol), N,N′-dicyclohexylcarbodiimide (23 mg, 0.11 mmol) and 4-dimethylaminopyridine (4.2 mg, 0.035 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:9 EtOAc/Hexanes) to afford give 5-(benzyloxy)chroman-3-yl benzoate (21 mg, 90%) as a colorless oil, which was used as for hydrogenolysis. obtained. 5-(benzyloxy)chroman-3-yl benzoate (5 mg, 0.014 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23o (3 mg, 93 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.10 – 7.92 (m, 2H), 7.62 – 7.47 (m, 1H), 7.47 – 7.35 (m, 2H), 7.01 (t, J = 8.1 Hz, 1H), 6.52 (dd, J = 8.2, 1.0 Hz, 1H), 6.38 (dd, J = 8.0, 1.0 Hz, 1H), 5.55 (tdd, J = 5.2, 4.4, 2.2 Hz, 1H), 4.84 (brs, 1H), 4.33 (ddd, J = 11.4, 4.9, 1.9 Hz, 1H), 4.22 (dt, J = 11.6, 1.5 Hz, 1H), 3.12 (dd, J = 17.4, 5.5 Hz, 1H), 2.97 (ddd, J = 17.5, 4.3, 1.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3, 155.3, 154.5, 133.4, 130.1, 130.0, 128.6 (2), 127.7 (2), 109.4, 107.4, 107.2, 66.8, 65.9, 25.3. IR (KBr)ν_max 3374, 2921, 1703, 1681,1476, 1098, 770 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₆H₁₃O₄, 269.0814, found 269.0804.

5-Hydroxychroman-3-yl 3-methoxybenzoate (23p)

A solution of 22c (14 mg, 0.055 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 3-methoxybenzoic acid (17 mg, 0.11 mmol), N,N′-dicyclohexylcarbodiimide (23 mg, 0.11 mmol) and 4-dimethylaminopyridine (8 mg, 0.11mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The eluent was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and the solvent removed. The residue was purified by flash chromatography (SiO₂, 1:9 EtOAc/Hexanes) to afford give give 5-(benzyloxy)chroman-3-yl 3-methoxybenzoate (19 mg, 90%) as a colorless oil, which was used as for hydrogenolysis. 5-(benzyloxy)chroman-3-yl 3-methoxybenzoate (18 mg, 0.044 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23p (12.9 mg, 92.4 %) as colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.53 (dt, J = 7.7, 1.3 Hz, 1H), 7.46 (dd, J = 2.7, 1.5 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.02 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 6.93 (t, J = 8.1 Hz, 1H), 6.44 (dd, J = 8.3, 1.0 Hz, 1H), 6.31 (dd, J = 8.0, 1.0 Hz, 1H), 5.54 – 5.43 (m, 1H), 4.87 (s, 1H), 4.27 – 4.21 (m, 1H), 4.15 (dt, J = 11.4, 1.6 Hz, 1H), 3.75 (s, 3H), 3.06 (dd, J = 17.4, 5.5 Hz, 1H), 2.90 (ddd, J = 17.4, 4.6, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.2, 159.7, 155.3, 154.5, 131.4, 129.6, 127.7, 122.4, 119.8, 114.5, 109.4, 107.4, 107.2, 66.8, 66.1, 55.7, 25.3. IR (KBr)ν_max cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₇H₁₅O₅, 299.0920, found 299.0934.

5-Hydroxychroman-3-yl 4-methoxybenzoate (23q)

A solution of 22c (11 mg, 0.042 mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 4-methoxybenzoic acid (13 mg, 0.09 mmol), N,N′-dicyclohexylcarbodiimide (18 mg, 0.085 mmol) and 4-dimethylaminopyridine (5 mg, 0.05mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:9 EtOAc/Hexanes) to give 5-(benzyloxy)chroman-4-yl 3-methoxybenzoate (15 mg, 91.5%) as a colorless oil, which was used as for hydrogenolysis. 5-(Benzyloxy)chroman-3-yl 4-methoxybenzoate (5 mg, 0.014 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23q (3.5 mg, 93 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.10 – 7.92 (m, 2H), 7.64 – 7.49 (m, 1H), 7.49 – 7.38 (m, 2H), 7.02 (t, J = 8.1 Hz, 1H), 6.53 (dd, J = 8.2, 1.0 Hz, 1H), 6.40 (dd, J = 8.0, 1.0 Hz, 1H), 5.56 (tdd, J = 5.2, 4.4, 2.2 Hz, 1H), 4.86 (s, 1H), 4.35 (ddd, J = 11.4, 4.9, 1.9 Hz, 1H), 4.23 (dt, J = 11.6, 1.6 Hz, 1H), 3.14 (dd, J = 17.4, 5.5 Hz, 1H), 2.99 (ddd, J = 17.5, 4.3, 1.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3, 155.3, 154.5 (2), 133.4 (2), 130.1, 130.0, 128.6, 127.7, 109.4 (2), 107.4, 107.2, 66.8, 65.9, 25.3; IR (KBr)ν_max 3384, 2921, 1701, 1683, 1606, 1471, 1259, 1168, 1099, 771 cm⁻¹; HRMS (ESI−) m/z [M−H⁻] calcd for C₁₇H₁₅O₅, 299.0920, found 299.0928.

5-hydroxychroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (23r)

A solution of 22c (11 mg, 0.042 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (22 mg, 0.085 mmol),, N,N′-dicyclohexylcarbodiimide (18 mg, 0.085 mmol) and 4-dimethylaminopyridine (5 mg, 0.0042mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to afford 7-(benzyloxy)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (18 mg, 85 %) as a colorless oil, which was used further as obtained. 7-(benzyloxy)chroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (18 mg, 0.036 mmol) and palladium/carbon (10%) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 23r (13 mg, 88.2 %) as colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.96 – 7.88 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.00 (dt, J = 7.6, 1.2 Hz, 1H), 6.96 (dd, J = 2.6, 1.5 Hz, 1H), 6.94 – 6.87 (m, 2H), 6.83 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.44 (dd, J = 8.3, 1.0 Hz, 1H), 6.31 (dd, J = 8.0, 1.1 Hz, 1H), 5.55 – 5.34 (m, 1H), 4.86 (brs, 1H), 4.22 (ddd, J = 11.3, 5.2, 1.7 Hz, 1H), 4.16 (ddd, J = 11.4, 2.4, 1.2 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.06 (dd, J = 17.3, 5.6 Hz, 1H), 2.92 – 2.83 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 160.6, 159.4, 155.3, 154.5, 138.9, 132.7, 131.3, 130.7, 129.3, 127.6, 122.5, 122.2, 115.4, 113.2, 110.7, 109.4, 107.4, 107.3, 66.9, 65.7, 56.0, 55.5, 25.4; IR (KBr)ν_max 3396, 2933, 2837, 1712, 1598, 1469, 1440, 1249, 1031, 771, 711 cm⁻¹; HRMS (ESI−) m/z [M+H⁺] calcd for C₂₄H₂₃O₆, 407.1495, found 407.1482.

5-Hydroxychroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (23s)

A solution of 22c (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (20 mg, 0.08 mmol), N,N′-dicyclohexylcarbodiimide (16 mg, 0.08 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and solvent was removed. The residue was purified by flash chromatography (SiO₂, 1:8 EtOAc/Hexanes) to give 5-(benzyloxy)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (13 mg, 72.2 %) as a colorless oil, which was used as in the next step. For benzyl group removal, a solution of palladium acetate (1 mg, 0.004 mmol), triethylamine (4μL, .025 mmol), triethylsilane (19μL, 0.0112) in DCM (0.8 mL) was stirred for 15 minutes under argon before the addition of a solution of 5-(benzyloxy)chroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (12 mg, 0.025mmol) in dichloromethane (0.2 mL) was added and reaction was stirred for 15 hours. Then reaction was quenched with saturated ammonium chloride (2 mL) and extracted with ether (3 × 4 mL). The combined organic layers were washed with saturated sodium chloride solution, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:2 EtOAc/Hexanes) to afford 23s as colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.02 – 7.67 (m, 2H), 7.05 (d, J = 8.3 Hz, 1H), 7.03 – 6.98 (m, 1H), 6.53 (dd, J = 8.3, 1.1 Hz, 1H), 6.43 (dd, J = 8.1, 1.0 Hz, 1H), 5.52 (tdd, J = 5.1, 4.2, 2.1 Hz, 1H), 5.17 (dddt, J = 7.3, 5.8, 2.9, 1.4 Hz, 1H), 4.31 (ddd, J = 11.5, 4.8, 2.0 Hz, 1H), 4.24 – 4.12 (m, 1H), 3.24 (d, J = 7.2 Hz, 2H), 3.05 (dd, J = 17.6, 5.3 Hz, 1H), 2.94 (ddd, J = 17.5, 4.4, 1.8 Hz, 1H), 2.32 (s, 3H), 1.71 (q, J = 1.3 Hz, 3H), 1.69 – 1.65 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.8, 165.4, 155.0, 154.6, 152.7, 133.9, 131.9, 128.8, 127.8 (2), 127.1, 122.4, 120.8, 110.8, 110.5, 109.5, 66.4, 66.0, 28.7, 25.8, 25.7, 20.9, 17.8; IR (KBr)ν_max 3429, 2854, 1716, 1595, 1458, 1286, 1161, 1054 cm⁻¹; HRMS (ESI−) m/z [M+H⁺] calcd for C₂₃H₂₅O₆, 397.1651, found 397.1662.

5,7-Dimethoxychroman-3-yl benzoate (27a)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of benzoic acid (12 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to afford 27a (13 mg, 90 %) as a colorless oil ¹H NMR (500 MHz, CDCl₃) δ 8.14 – 7.91 (m, 2H), 7.55 (ddt, J = 7.6, 6.8, 1.1 Hz, 1H), 7.47 – 7.37 (m, 2H), 6.11 (s, 2H), 5.52 (tdt, J = 5.5, 4.5, 1.9 Hz, 1H), 4.32 (dddd, J = 11.4, 4.9, 1.9, 0.9 Hz, 1H), 4.21 (ddd, J = 11.5, 2.2, 1.2 Hz, 1H), 3.79 (dd, J = 2.9, 0.9 Hz, 6H), 3.09 – 2.94 (m, 1H), 2.88 (ddd, J = 17.4, 4.3, 1.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3, 159.8, 159.1, 155.3, 133.4, 130.3, 130.1 (2), 128.6 (2), 100.8, 93.4, 92.0, 67.1, 66.2, 55.7, 55.6, 25.1; IR (KBr)ν_max 2931, 1716, 1620, 1591, 1499, 1456, 1145, 1045, 754 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₈H₁₉O₅, 315.1232, found 315.1239.

5,7-Dimethoxychroman-3-yl 3-methoxybenzoate (27b)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3-methoxybenzoic acid (15 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:6 EtOAc/Hexanes) to afford 27b (13 mg, 80 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.61 (dt, J = 7.7, 1.2 Hz, 1H), 7.54 (dd, J = 2.7, 1.5 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.09 (ddd, J = 8.3, 2.7, 1.1 Hz, 1H), 6.10 (d, J = 1.2 Hz, 2H), 5.69 – 5.42 (m, 1H), 4.30 (ddd, J = 11.4, 5.1, 1.8 Hz, 1H), 4.24 – 4.16 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.02 (ddd, J = 17.5, 5.6, 1.3 Hz, 1H), 2.86 (ddd, J = 17.4, 4.5, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.2, 159.8, 159.7, 159.0, 155.3, 131.5, 129.6, 122.4, 119.6, 114.5, 100.7, 93.4, 92.0, 67.0, 66.3, 55.7, 55.6, 55.6, 25.1; IR (KBr)ν_max 2935, 2839, 1716, 1622, 1593, 1498, 1456, 1276, 1145, 1045, 754 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₉H₂₁O₆, 345.1338, found 345.1347.

5,7-Dimethoxychroman-3-yl 4-methoxybenzoate (27c)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 4-methoxybenzoic acid (15 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:6 EtOAc/Hexanes) to afford 27c (14 mg, 86 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.98 (ddd, J = 10.7, 5.1, 2.6 Hz, 2H), 7.27 (td, J = 4.5, 1.5 Hz, 1H), 6.89 (ddd, J = 8.5, 5.7, 2.6 Hz, 2H), 6.10 (m, 2H), 5.56 – 5.37 (m, 1H), 4.29 (m, 1H), 4.26 – 4.12 (m, 1H), 3.88 – 3.81 (s, 3H), 3.78 (s, 6H), 3.10 – 2.93 (m, 1H), 2.85 (dddd, J = 17.5, 5.7, 4.3, 2.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 163.7, 159.8, 159.0, 155.3, 132.1 (2), 122.7, 113.8 (2), 100.9, 93.3, 91.9, 67.1, 65.8, 55.6, 55.6 (2), 25.1; IR (KBr)ν_max 2935, 1716, 1620, 1593, 1499, 1456, 1145, 1043 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₉H₂₁O₆, 345.1338, found 345.1347.

5,7-Dimethoxychroman-3-yl 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylate (27d)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (15 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:6 EtOAc/Hexanes) to afford 27d (18.4 mg, 82 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.06 – 7.97 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.08 (dt, J = 7.7, 1.2 Hz, 1H), 7.04 (dd, J = 2.6, 1.5 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.91 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.10 (s, 2H), 5.54 – 5.42 (m, 1H), 4.28 (ddd, J = 11.3, 5.2, 1.7 Hz, 1H), 4.21 (ddd, J = 11.2, 2.3, 1.1 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.02 (ddd, J = 17.4, 5.6, 1.2 Hz, 1H), 2.85 (ddd, J = 17.2, 4.6, 1.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 160.5, 159.7, 159.4, 159.0, 155.3, 139.0, 132.6, 131.3, 130.6, 129.2, 122.7, 122.2, 115.4, 113.1, 110.7, 100.9, 93.3, 91.9, 67.1, 66.0, 56.0, 55.62, 55.6, 55.5, 25.2. IR (KBr)ν_max 2954, 2931, 1712, 1595, 1498, 1456, 1436, 1247, 1215, 1052, 813, 756 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₆H₂₆NaO₇, 473.1576, found 473.1566.

5,7-Dimethoxychroman-3-yl 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoate (27e)

A solution of 26 (20 mg, 0.08 mmol), in dichloromethane (1 mL) was added to a stirred solution of 4-acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (48 mg, 0.19 mmol), N,N′-dicyclohexylcarbodiimide (40 mg, 0.19 mmol) and 4-dimethylaminopyridine (12 mg, 0.084 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (10 mL), washed with 0.5N HCl (2 × 8 mL) and then with saturated sodium bicarbonate (2 × 8 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (8 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:7 EtOAc/Hexanes) to afford 27e (17 mg, 53%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 8.4, 2.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.18 (s, 2H), 5.57 – 5.44 (m, 1H), 5.18 (dddd, J = 7.2, 5.8, 2.8, 1.4 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.25 (d, J = 7.2 Hz, 2H), 2.99 (ddd, J = 17.3, 5.4, 1.2 Hz, 1H), 2.86 (ddd, J = 17.4, 4.4, 1.8 Hz, 1H), 2.32 (s, 3H), 1.72 (q, J = 1.2 Hz, 3H), 1.69 – 1.63 (m, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 169.1, 165.7, 159.8, 159.0, 155.2, 152.9, 134.1 (2), 132.1, 129.0, 128.1, 122.6, 121.1, 100.7, 93.3, 91.9, 66.9, 66.2, 55.6, 55.6, 28.9, 25.9, 25.1, 21.1, 18.1; IR (KBr)ν_max 2937, 2844, 1737, 1622, 2595, 1242, 1218, 1201, 1145, 1128, 1058, 811 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₅H₂₉O₇, 441.1913, found 441.1894.

5,7-Dimethoxychroman-3-yl 3,4-dimethoxybenzoate (27f)

A solution of 26 (5 mg, 0.025mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 3,4-dimethoxybenzoic acid (9mg, 0.05 mmol), N,N′-dicyclohexylcarbodiimide (10mg, 0.05 mmol) and 4-dimethylaminopyridine (3mg, 0.025 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:6 EtOAc/Hexanes) to afford 27f (10 mg, 71.4 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.65 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.10 (s, 2H), 5.57 – 5.41 (m, 1H), 4.28 (ddd, J = 11.3, 5.1, 1.8 Hz, 1H), 4.21 (ddd, J = 11.3, 2.2, 1.1 Hz, 1H), 3.92 (d, J = 8.3 Hz, 6H), 3.79 (d, J = 4.1 Hz, 6H), 3.02 (ddd, J = 17.2, 5.5, 1.2 Hz, 1H), 2.86 (ddd, J = 17.3, 4.5, 1.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.9 (2), 159.5 (2), 155.4 (2), 138.5, 128.8, 128.3, 126.5, 100.5, 93.5, 92.4, 78.9, 66.6, 55.7 (2), 55.6 (2), 28.4; IR (KBr)ν_max 2931, 1701, 1558, 1458, 1419, 1271, 732 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₀H₂₂NaO₇, 397.1263, found 397.1269.

5,7-Dimethoxychroman-3-yl 3,5-dimethoxybenzoate (27g)

A solution of 26 (5 mg, 0.025mmol) in dichloromethane (0.5 mL) was added to a stirred solution of 3,4-dimethoxybenzoic acid (9mg, 0.05 mmol), N,N′-dicyclohexylcarbodiimide (10mg, 0.05 mmol) and 4-dimethylaminopyridine (3mg, 0.025 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 ×4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:6 EtOAc/Hexanes) to afford 27g (11.9mg, 85 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.16 (d, J = 2.4 Hz, 2H), 6.64 (t, J = 2.4 Hz, 1H), 6.10 (s, 2H), 5.57 – 5.43 (m, 1H), 4.28 (ddd, J = 11.3, 5.2, 1.7 Hz, 1H), 4.21 (ddd, J = 11.3, 2.4, 1.1 Hz, 1H), 3.85 – 3.73 (m, 13H), 3.02 (ddd, J = 17.3, 5.5, 1.2 Hz, 1H), 2.85 (ddd, J = 17.4, 4.7, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 159.9 (2), 159.5 (2), 155.4 (2), 138.5, 128.8, 128.3, 126.5, 100.5 (2), 93.5, 92.4, 78.9, 66.6, 55.7, 55.6 (2), 28.4. IR (KBr)ν_max 2931, 1701, 1558, 1458, 1419, 1271, 732 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₀H₂₂NaO₇, 397.1263, found 397.1269.

5,7-Dimethoxychroman-3-yl 3-ethoxybenzoate (27h)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3-ethoxybenzoic acid (17 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h and filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:6 EtOAc/Hexanes) to afford 27h (14 mg, 82.3 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 7.52 (ddd, J = 7.7, 1.5, 1.0 Hz, 1H), 7.46 (dd, J = 2.6, 1.5 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.16 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 6.06 (d, J = 2.4 Hz, 1H), 5.50 – 5.41 (m, 1H), 4.32 (ddd, J = 11.5, 4.5, 2.0 Hz, 1H), 4.22 (ddt, J = 11.5, 1.9, 0.9 Hz, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 2.99 (ddd, J = 17.3, 5.2, 1.1 Hz, 1H), 2.89 – 2.78 (m, 1H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.2, 160.7, 160.0, 159.8, 156.1, 132.5, 130.5, 122.3, 120.1, 115.9, 101.1, 94.2, 92.2, 67.3, 67.1, 64.3, 55.8, 55.5, 25.4, 15.0; IR (KBr)ν_max 2910, 1718, 1622, 1593, 1498, 1423, 1274, 1217, 1145, 1051, 754 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₀H₂₃O₆, 359.1495, found 359.1483.

5,7-Dimethoxychroman-3-yl 3-(benzyloxy)benzoate (27i)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3-(benzyloxy)benzoic acid (23 mg, 0.1 mmol) (17 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt then filterd. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to afford 27i (18 mg, 90 %) as a pale yellow amorphous solid: ¹H NMR (500 MHz, CDCl₃) δ 7.62 (dd, J = 7.2, 1.5 Hz, 2H), 7.48 – 7.36 (m, 4H), 7.37 – 7.27 (m, 3H), 7.19 – 7.12 (m, 1H), 6.11 (s, 2H), 5.50 (ddt, J = 5.3, 4.2, 2.5 Hz, 1H), 5.09 (s, 2H), 4.31 (ddd, J = 11.3, 4.9, 1.9 Hz, 1H), 4.20 (ddd, J = 11.4, 2.2, 1.2 Hz, 1H), 3.02 (ddd, J = 17.4, 5.5, 1.2 Hz, 1H), 2.87 (ddd, J = 17.4, 4.3, 1.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.1, 159.8, 159.0, 158.8, 155.3, 136.7, 131.6, 129.6 (2), 128.9 (2), 128.3 (2), 127.8, 122.7, 120.4, 115.6, 100.7, 93.4, 92.0, 70.4, 67.0, 66.3, 55.6, 55.6, 25.1; IR (KBr)ν_max 2918, 1701, 1683, 1558, 15036, 1458, 1203, 1145, cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₅H₂₅O₆, 421.1651, found 421.1637.

5,7-Dimethoxychroman-3-yl 4-(benzyloxy)benzoate (27j)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 4-(benzyloxy)benzoic acid (23 mg, 0.1 mmol) (23 mg, 0.1 mmol) (17 mg, 0.1 mmol), N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to afford 27j (17 mg, 85%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.62 (dd, J = 7.2, 1.5 Hz, 2H), 7.46 – 7.37 (m, 4H), 7.36 – 7.29 (m, 2H), 7.21 – 7.04 (m, 1H), 6.11 (s, 2H), 5.50 (ddt, J = 5.3, 4.2, 2.5 Hz, 1H), 5.09 (s, 2H), 4.31 (ddd, J = 11.3, 4.9, 1.9 Hz, 1H), 4.20 (ddd, J = 11.4, 2.2, 1.2 Hz, 1H), 3.81 – 3.78 (m, 6H), 3.02 (ddd, J = 17.4, 5.5, 1.2 Hz, 1H), 2.87 (ddd, J = 17.4, 4.3, 1.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 165.9, 162.8, 159.7, 159.0, 155.3, 136.4, 132.1 (2), 128.9 (2), 128.4, 127.7, 122.9, 114.6 (2), 100.8, 93.3, 91.9, 70.3, 67.1, 65.8, 55.6, 55.6, 25.1. IR (KBr)ν_max, 2918, 2817, 1701, 1683, 1558, 1503, 1458, 1203, 1145, 729 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₂₅H₂₅O₆, 421.1651, found 421.1666.

5,7-Dimethoxychroman-3-yl 3,5-bis(benzyloxy)benzoate (27k)

A solution of 26 (10 mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3,5-bis(benzyloxy)benzoic acid (33.4 mg, 0.1 mmol) N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to afford 27k (22 mg, 88%) as an amorphous pale yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.51 – 7.27 (m, 12H), 6.79 (t, J = 2.3 Hz, 1H), 6.11 (s, 2H), 5.47 (qd, J = 5.0, 2.2 Hz, 1H), 5.04 (s, 4H), 4.29 (ddd, J = 11.4, 5.0, 1.8 Hz, 1H), 4.25 – 4.12 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.01 (ddd, J = 17.4, 5.5, 1.1 Hz, 1H), 2.85 (ddd, J = 17.4, 4.5, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 159.9 (2), 159.8, 159.0, 155.3, 136.6 (2), 132.1, 128.9 (4), 128.4 (4), 127.9 (2), 108.8 (2), 107.3, 100.7, 93.4, 92.0, 70.5 (2), 66.9, 66.5, 55.6, 55.6, 25.1; IR (KBr)ν_max 2955, 2852, 1697, 1596, 1456, 1145, 1251, 1009, 769, cm⁻¹. HRMS (ESI+) m/z [M+H⁺] calcd for C₃₂H₃₁O₇, 527.2070, found 527.2087.

5,7-Dimethoxychroman-3-yl 3,4-bis(benzyloxy)benzoate (27l)

A solution of 26 (9mg, 0.04 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 3,4-bis(benzyloxy)benzoic acid (33.4 mg, 0.1 mmol) N,N′-dicyclohexylcarbodiimide (20.6 mg, 0.1 mmol) and 4-dimethylaminopyridine (5 mg, 0.042 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to afford 27l (20.8 mg, 92%) as an amorphous pale yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.61 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 – 7.40 (m, 4H), 7.40 – 7.29 (m, 6H), 6.88 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 5.56 – 5.39 (m, 1H), 5.22 (s, 2H), 5.17 (s, 2H), 4.27 (ddd, J = 11.3, 4.9, 1.8 Hz, 1H), 4.22 – 4.14 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.98 (ddd, J = 17.3, 5.5, 1.2 Hz, 1H), 2.83 (ddd, J = 17.4, 4.3, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 165.9, 159.8, 159.0, 155.3, 153.1, 148.4, 137.0, 136.7, 128.8 (3), 128.7, 128.2, 128.1, 127.7 (2), 127.3 (2), 124.4, 123.1, 115.8, 113.3, 100.8, 93.3, 91.9, 71.3, 71.0, 67.0, 65.9, 55.6, 55.6, 25.1. IR (KBr)ν_max 2921, 2848, 1699, 1618, 1510, 1454, 1290, 1203, 1058 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₃₂H₃₁O₇, 527.2070, found 527.2081.

5,7-Dimethoxychroman-3-yl 4-(benzyloxy)-3-methoxybenzoate (27m)

A solution of 26 (20 mg, 0.1 mmol), in dichloromethane (0.5 mL) was added to a stirred solution of 4-(benzyloxy)-3-methoxybenzoic acid (49 mg, 0.19 mmol) N,N′-dicyclohexylcarbodiimide (39 mg, 0.19 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) under argon at 0 °C. The resulting solution was stirred for 6 h at rt and then filtered. The filtrate was diluted with dichloromethane (5 mL), washed with 0.5N HCl (2 × 4 mL) and then with saturated sodium bicarbonate (2 × 4 mL) solution. The combined organic layers were washed with saturated sodium chloride solution (4 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/Hexanes) to afford 27m (34 mg, 81%) as an amorphous pale yellow solid. IR (KBr)ν_max 2921, 2848, 1699, 1618, 1510, 1454, 1290, 1203, 1058 cm−1. HRMS (ESI+) m/z [M+H⁺] calcd for C₂₆H₂₇O₇, 451.1757, found 451.1668.

5,7-Dimethoxychroman-3-yl 3-hydroxybenzoate (28a)

Palladium/carbon (10%) and 27i (18 mg, 0.03 mmol) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give 28a (8.8 mg, 92.6%) as a colorless oil: ¹H NMR (500 MHz, CD₃CN) δ 7.41 (ddd, J = 7.7, 1.6, 1.0 Hz, 1H), 7.33 (dd, J = 2.6, 1.6 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.24 – 7.16 (m, 1H), 7.03 (ddd, J = 8.1, 2.6, 1.1 Hz, 1H), 6.14 (d, J = 2.3 Hz, 1H), 6.07 (d, J = 2.3 Hz, 1H), 5.52 – 5.36 (m, 1H), 4.30 (ddd, J = 11.7, 4.2, 2.1 Hz, 1H), 4.15 (ddt, J = 11.6, 1.9, 1.0 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.92 (ddd, J = 17.4, 5.2, 1.1 Hz, 1H), 2.86 – 2.71 (m, 1H). ¹³C NMR (125 MHz, CD₃CN) δ 166.5, 160.7, 159.9, 157.9, 156.1, 132.6, 130.8, 122.5, 121.9, 118.3, 117.0, 94.2, 92.4, 67.4, 67.0, 56.2, 55.9, 25.1. IR (KBr)ν_max 3335, 2918, 1701, 1683, 1558, 15036, 1458, 1203, 1145, cm⁻¹. HRMS (ESI+) m/z [M+H⁺] calcd for C₁₈H₁₉O_6, 331.1182, found 331.1188.

5,7-Dimethoxychroman-3-yl 4-hydroxybenzoate (27b)

Palladium/carbon (10%) and 27j (12 mg, 0.028 mmol) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give the 28b (9 mg, 90 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 9.16 (s, 1H), 7.88 – 7.80 (m, 2H), 6.94 – 6.86 (m, 2H), 6.14 (d, J = 2.3 Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H), 5.49 – 5.36 (m, 1H), 4.29 (ddd, J = 11.5, 4.6, 2.0 Hz, 1H), 4.24 – 4.14 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.97 (ddd, J = 17.3, 5.3, 1.1 Hz, 1H), 2.80 (ddd, J = 17.3, 4.0, 1.9 Hz, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.1, 162.7, 160.7, 159.8, 156.1, 132.5 (2), 122.4, 116.0 (2), 101.2, 94.2, 92.2, 67.4, 66.4, 55.8, 55.5, 25.5. IR (KBr)ν_max 3365, 2956, 2852, 1701, 1596, 1456, 1214, 1145, 1051, 767cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₁₈H₁₈ NaO₆, 353.1001, found 353.0991.

5,7-Dimethoxychroman-3-yl 3,5-dihydroxybenzoate (28c)

Palladium/carbon (10%) and 27k (12 mg, 0.028 mmol) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:1 EtOAc/Hexanes) to give 28c (12 mg, 91 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂CO) δ 8.58 (s, 2H), 6.96 (d, J = 2.3 Hz, 2H), 6.56 (t, J = 2.3 Hz, 1H), 6.15 (d, J = 2.3 Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H), 5.43 (dtd, J = 5.5, 4.1, 1.9 Hz, 1H), 4.31 (ddd, J = 11.6, 4.3, 2.1 Hz, 1H), 4.19 (ddt, J = 11.7, 1.9, 1.0 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.97 (ddd, J = 17.6, 5.4, 1.2 Hz, 1H), 2.82 – 2.74 (m, 1H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 166.2, 160.7, 159.8 (2), 159.4, 156.1, 133.1, 108.7, 108.1, 101.1, 94.2, 92.2, 67.3, 66.8, 55.8, 55.5 (2), 25.3. IR (KBr)ν_max 3365, 3330, 2956, 2850, 1697, 1596, 1456, 1361, 1145, 1054, 1004, 769, cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₈H₁₉O₇, 347.1131, found 347.1134.

5,7-Dimethoxychroman-3-yl 3,4-dihydroxybenzoate (28d)

Palladium/carbon (10%) and 27l (18 mg, 0.034 mmol) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give the desired product 28d (11 mg, 92 %) as a colorless oil: ¹H NMR (500 MHz, (CD₃)₂ CO) δ 7.45 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.15 (d, J = 2.3 Hz, 1H), 6.10 – 6.04 (m, 1H), 5.49 – 5.38 (m, 1H), 4.29 (ddd, J = 11.5, 4.4, 2.0 Hz, 1H), 4.22 – 4.14 (m, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 2.97 (ddd, J = 17.4, 5.5, 1.2 Hz, 1H). ¹³C NMR (125 MHz, (CD₃)₂ CO)) δ 159.9, 160.2 (2), 158.1 (2), 123.6 (2), 122.85, 117.21, 115.9, 101.3, 94.3, 92.3, 67.47, 66.4, 55.9, 55.6, 25.5; IR (KBr)ν_max 3381, 3321, 2924, 2839, 1698, 16120, 1510, 1456, 1203, 1056, 728 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₈H₁₉O₇, 347.1131, found 347.1125:

5,7-Dimethoxychroman-3-yl 4-hydroxy-3-methoxybenzoate (28e)

Palladium/carbon (10%) and 27l (24 mg, 0.053 mmol) were suspended in tetrahydrofuran (2 mL) and stirred for 18 h under a hydrogen atmosphere. The suspension was filtered through a small plug of SiO₂ (40 – 63 μm particle size). The eluent was concentrated and the residue purified by flash chromatography (SiO₂, 1:3 EtOAc/Hexanes) to give the desired product 28e (17 mg, 91 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (dd, J = 8.4, 1.9 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.10 (s, 2H), 6.07 (s, 1H), 5.47 (dq, J = 7.5, 2.6 Hz, 1H), 4.28 (ddd, J = 11.3, 5.1, 1.8 Hz, 1H), 4.24 – 4.16 (m, 1H), 3.92 (s, 3H), 3.78 (d, J = 3.5 Hz, 6H), 3.01 (ddd, J = 17.5, 5.6, 1.2 Hz, 1H), 2.85 (ddd, J = 17.3, 4.6, 1.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 165.8, 159.6, 158.2, 155.2, 150.2, 146.1, 124.5, 122.1, 114, 111.8, 100.6, 93.1, 91.7, 66.9, 65.8, 56.1, 55.4, 55.3, 24.9; IR (KBr)ν_max 3385, 2939, 2841, 1699, 1612, 1508, 1214, 1145, 729 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₉H₂₁O₇, 361.1287, found 361.1278.

3-Azido-5,7-dimethoxychroman (29)

A solution of 26 (75, 0.36 mmol) and triphenylphosphine (161 mg, 0.61) in tetrahydrofuran (2.5 ml) at 0 °C was treated with diisopropyl azodicarboxylate (120 μl, 0.61 mmol) and diphenylphosphoryl azide (130 μl, 0.61 mmol). The resulting mixture was stirred for 15 h at 25°C before the solvent was removed. The residue was purified by flash chromatography (SiO₂, 1:20 EtOAc/Hexanes) to give 29 (75 mg, 83.9 %) as a light yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 6.09 (d, J = 2.4 Hz, 1H), 6.06 (d, J = 2.4 Hz, 1H), 4.15 (ddd, J = 10.8, 2.6, 1.3 Hz, 1H), 4.02 (ddd, J = 10.9, 6.4, 1.5 Hz, 1H), 3.96 (qd, J = 6.0, 2.6 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 2.95 (ddd, J = 16.7, 5.5, 1.4 Hz, 1H), 2.71 (ddd, J = 16.7, 6.0, 1.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 159.0, 157.9, 154.1, 99.3, 92.3, 91.2, 66.3, 54.7, 54.6, 52.4, 23.8; IR (KBr)ν_max 2931, 2847, 2113, 1558, 1456, 1276,811 cm⁻¹;HRMS (ESI+) m/z [M+H⁺] calcd for C₁₁H₁₄N₃O₃, 236.1035, found 236.1028.

5,7-Dimethoxychroman-3-amine (30)

To a solution of 29 and triphenylphosphine in water in THF (3 mL), water (22 μl, 0.93 mmol) was added and stirred for 30 h at rt. The solvent was removed and the residue purified via flash chromatography (silica gel 3:97 MeOH/CHCl₃) to give 30 (55 mg, 83%) as yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 6.23 – 5.87 (m, 2H), 4.09 (ddd, J = 10.5, 2.8, 1.5 Hz, 1H), 3.84 – 3.79 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.34 (tdd, J = 6.8, 5.5, 2.9 Hz, 1H), 2.88 (ddd, J = 16.5, 5.5, 1.5 Hz, 1H), 2.36 (ddd, J = 16.4, 6.6, 1.2 Hz, 1H), 2.04 (d, J = 5.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 159.7, 159.1, 155.3, 101.7, 93.2, 91.8, 71.3, 55.6, 55.5, 44.0, 28.9; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₁H₁₆NO₃, 210.1130, found 210.1133.

N-(5,7-Dimethoxychroman-3-yl)benzamide (31a)

Benzoic acid (15 mg, 0.12 mmol) and N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.14 mmol) were added to a solution of alcohol 30 (12 mg, 0.057 mmol) in dichloromethane (0.7 mL) with pyridine (0.3 mL). The resulting mixture was stirred for 16 h and then the reaction mixture was diluted with dichloromethane (2 mL). The organic phase was washed with saturated NaHCO₃ (2 × 2 mL) and saturated sodium chloride solution (3 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:2 Hexanes/EtOAc) to give 31a (12 mg, 81%) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.78 – 7.66 (m, 2H), 7.54 – 7.46 (m, 1H), 7.41 (tt, J = 6.6, 1.4 Hz, 2H), 6.39 (d, J = 8.0 Hz, 1H), 6.17 – 5.90 (m, 2H), 4.70 (ddtd, J = 7.5, 5.5, 3.5, 1.8 Hz, 1H), 4.26 (ddd, J = 10.9, 3.8, 2.1 Hz, 1H), 4.15 (dd, J = 10.9, 1.8 Hz, 1H), 3.78 (d, J = 1.1 Hz, 6H), 2.91 (dd, J = 17.2, 5.7 Hz, 1H), 2.78 (ddd, J = 17.1, 3.2, 2.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 167.4, 159.9, 159.4, 155.3, 134.5, 131.8, 128.7 (2), 127.2 (2), 101.0, 93.5, 92.2, 68.3, 55.6, 55.6, 42.6, 25.6; IR (KBr)ν_max 3307, 2925, 2850, 1645, 1635, 1622, 1539, 1521, 1145, 1122, 813, 756cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₈H₂₀NO₄, 314.1392, found 314.1391.

N-(5,7-Dimethoxychroman-3-yl)-3-methoxybenzamide (31b)

3-Methoxybenzoic acid (15 mg, 0.12 mmol) and N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.14 mmol) were added to a solution of alcohol 30 (12 mg, 0.057 mmol) in dichloromethane (0.7 mL) with pyridine (0.3 mL). The resulting mixture was stirred for 16 h and then the reaction mixture was diluted with dichloromethane (2 mL). The organic phase was washed with saturated sodium bicarbonate (2 × 2 mL) and saturated sodium chloride solution (3 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:2 Hexanes/EtOAc) to give 31b (12 mg, 70%) as pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.26 (dd, J = 2.6, 1.6 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.14 (dt, J = 7.7, 1.3 Hz, 1H), 6.94 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 6.01 (d, J = 2.4 Hz, 1H), 4.60 (dtt, J = 7.7, 3.8, 1.8 Hz, 1H), 4.17 (ddd, J = 10.9, 3.9, 2.1 Hz, 1H), 4.11 – 4.01 (m, 1H), 3.77 (s, 3H), 3.70 (s, 6H), 2.83 (dd, J = 17.1, 5.7 Hz, 1H), 2.69 (ddd, J = 17.2, 3.4, 2.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 167.3, 160.0, 159.9, 159.4, 155.3, 136.0, 129.7, 119.0, 117.9, 112.7, 100.9, 93.5, 92.2, 68.2, 55.7, 55.6 (2), 42.6, 25.5; IR (KBr)ν_max 3363, 2921, 2850, 1712, 1681, 1498, 1454, 1272, 1145, 771 cm⁻¹; HRMS (ESI+) m/z [M+H⁺] calcd for C₁₉H₂₂NO₅, 344.1498, found 344.1498.

N-(5,7-dimethoxychroman-3-yl)-3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxamide (31c)

3-3′,6-Dimethoxy-[1,1′-biphenyl]-3-carboxylic acid (25 mg, 0.1 mmol) and N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.12 mmol) were added to a solution of alcohol 30 (10 mg, 0.048 mmol) in dichlormethane (0.7 mL) with pyridine (0.3 mL). The resulting mixture was stirred for 16 h and then the reaction mixture was diluted with dichloromethane (2 mL) and organic phase was washed with saturated NaHCO₃ (2 × 2 mL) and saturated sodium chloride solution (2 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:2 Hexanes/EtOAc) to give 31c (19.3 mg, 90%) as an amorphous light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.76 (dd, J = 8.6, 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.39 – 7.30 (m, 1H), 7.08 (dt, J = 7.7, 1.1 Hz, 1H), 7.04 (dd, J = 2.6, 1.6 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.91 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.32 (d, J = 7.9 Hz, 1H), 6.09 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 4.68 (ddt, J = 7.8, 3.9, 1.9 Hz, 1H), 4.24 (ddd, J = 10.8, 4.0, 2.0 Hz, 1H), 4.15 (dd, J = 10.7, 1.9 Hz, 1H), 3.84 (s, 6H), 3.77 (s, 6H), 2.92 (dd, J = 17.1, 5.7 Hz, 1H), 2.76 (ddd, J = 17.2, 3.5, 1.9 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 166.9, 159.8, 159.5, 159.3 (2), 155.3, 139.1, 130.7, 129.8, 129.3, 128.4, 126.9, 122.2, 115.4, 113.1, 110.9, 101.1, 93.5, 92.2, 68.3, 56.0, 55.6, 55.6, 55.5, 42.6, 25.6; IR (KBr)ν_max 3315, 2931 1620, 1596, 1531, 1498, 1249, 1201, 1249, 1215, 1145, 1051, 752 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₆H₂₇NaNO₆, 472.1736, found 472.1738.

4-((5,7-dimethoxychroman-3-yl)carbamoyl)-2-(3-methylbut-2-en-1-yl)phenyl acetate (31d)

4-Acetoxy-3-(3-methylbut-2-en-1-yl)benzoic acid (47mg, 0.19 mmol) and N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (37 mg, 0.24 mmol) were added to a solution of alcohol 30 (20 mg, 0.096 mmol), in dichlormethane (1.4 mL) with pyridine (0.6 mL). The resulting mixture was stirred for 16 h and then the reaction mixture was diluted with dichloromethane (4 mL). The organic phase was washed with saturated NaHCO₃ (2 × 4 mL) and saturated sodium chloride solution (4 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 1:2 Hexanes/EtOAc) to give 31c (33 mg, 77%) as an amorphous light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.66 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.3, 2.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 6.10 (d, J = 2.3 Hz, 1H), 5.20 (dddd, J = 7.2, 5.8, 2.9, 1.4 Hz, 1H), 4.68 (dtt, J = 7.6, 3.6, 1.7 Hz, 1H), 4.26 (ddd, J = 10.9, 3.8, 2.1 Hz, 1H), 4.15 (dd, J = 10.8, 1.8 Hz, 1H), 3.80 (s, 6H), 3.27 (d, J = 7.2 Hz, 2H), 2.91 (dd, J = 17.1, 5.6 Hz, 1H), 2.86 – 2.71 (m, 1H), 2.33 (s, 3H), 1.74 (s, 3H), 1.72 – 1.66 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.2, 166.9, 159.9, 159.4, 155.3, 151.5, 134.4, 134.0, 132.5, 129.6, 125.7, 122.6, 121.1, 100.9, 93.5, 92.2, 68.2, 55.6, 55.6, 42.6, 29.0, 25.9, 25.5, 21.1, 18.1; IR (KBr)ν_max 3325, 2932 1623, 1602, 1596, 1531, 1496, 1249, 1201, 1251, 1215, 1145, 749 cm⁻¹; HRMS (ESI+) m/z [M+Na⁺] calcd for C₂₅H₂₉NaNO₆, 462.1893, found 462.1872

4. Anti-proliferation Assay

MCF-7 and SKBr3 cells were maintained in a 1:1 mixture of advanced DMEM/F12 (Gibco) containing non-essential amino acids, L-glutamine (2 mM), streptomycin (500 μg/mL), penicillin (100 units/mL), and 10% FBS as supplements. Cells were grown to confluence in a humidified atmosphere (37 °C, 5% CO2) and seeded (2000/well, 100 μL) in 96-well plates, and allowed to attach for 24 hr. Compounds or geldanamycin at 6 increasing concentrations in DMSO (1% DMSO final concentration) were added, and cells were returned to the incubator for 72 h. At 72 h, the number of viable cells was determined using an MTS/PMS cell proliferation kit (Promega) per the manufacturer’s instructions. Cells incubated in 1% DMSO were used as 100% proliferation, and values were adjusted accordingly. IC₅₀ values were calculated from minimum two separate experiments performed in triplicate using GraphPad Prism program.

5. Western Blot Analysis

MCF-7 cells were cultured as described previously and treated with various concentrations of the compound to be tested, Geldanamycin in DMSO (1% DMSO final concentration), or vehicle (DMSO) for 24 h. Cells were harvested in cold PBS and lysed in RIPA lysis buffer containing 1 mM PMSF, 2 mM sodium orthovanadate, and protease inhibitors on ice for 1 h. Lysates were clarified at 1400 g for 10 min at 4 °C. Protein concentrations were determined by using the Pierce BCA assay kit per the manufacturer’s instructions. Equal amounts of proteins (4 μg) were electrophoresed under reducing conditions, transferred to a nitrocellulose membrane, and immunoblotted with the corresponding specific antibodies. Membranes were incubated with an appropriate horseradish peroxidase-labeled secondary anti-body, developed with chemiluminescent substrate, and visualized.