Concise Synthesis of (S)-δ-CEHC, a Metabolite of Vitamin E.

Carboxyethyl hydroxychromans (CEHCs) are natural metabolites of vitamin E (VE). Their urinary levels can serve as useful biomarkers for the nutritional assessment of VE. Moreover, specific biological activities of CEHCs deserve further investigation. Here, we report a concise method to build up a chiral 6-hydroxychroman scaffold of VE and CEHCs. The first total synthesis of (S)-δ-CEHC was accomplished in 40% overall yield and 97% ee using a chiral synthon derived from naturally occurring (-)-linalool.

Introduction

Vitamin E (VE) is a group of lipid-soluble antioxidants that include four tocopherols (α, β, γ, and δ) and four tocotrienols (α, β, γ, and δ). All of these homologs share a chiral 6-hydroxychroman scaffold, and tocopherols have a saturated phytyl tail, while tocotrienols possess an unsaturated farnesyl side chain (Figure ). The metabolism pathway of VE initiates with ω-oxidation of the side chain followed by five cycles of β-oxidation. A substantial portion of VE can undergo this pathway and be excreted in the urine as the corresponding carboxyethyl hydroxychromans (CEHCs) in free or conjugated forms.[1] Therefore, urinary levels of CEHCs may serve as useful biomarkers for the nutritional assessment of VE.

Figure 1

Structures of vitamin E and representative metabolites.

CEHCs display multiple biological effects other than their antioxidant activities, which are associated with nuclear receptors, transcription factors, membrane channels, and enzymes.[2−6] It is worth mentioning that despite the structural similarity across tocopherols, tocotrienols, and CEHCs, their biological roles could be dramatically different. For example, γ-CEHC, but not α-CEHC, is an endogenous natriuretic agent.[4]

Isolation of VE and CEHCs in pure forms from natural sources is highly challenging and costly. A number of total syntheses of these chroman derivatives, including chiral resolution approaches[7−9] and enantioselective approaches,[10−16] have been reported. However, none of these reported synthetic routes can economically generate a substantial amount of products with high optical purity in high yields. Thus, there is an emergent need to develop an efficient strategy for preparing the chiral 6-hydroxychroman scaffold.

We are particularly interested in δ-tocotrienol (DT3) and its metabolic pathway.[17,18] DT3 and γ-tocotrienol have been studied for their radioprotective effects.[19] In addition, DT3 is the most potent VE homolog in the prevention and treatment of pancreatic cancer,[20] which supports the further preclinical investigations of DT3 and its metabolites in tumorigenesis. δ-CEHC was the first VE metabolite to be identified in the urine that did not correlate with oxidative destruction of the chroman core.[21] Herein, we report an efficient synthesis route for the chiral 6-hydroxychroman scaffold and (S)-δ-CEHC involving the Heck reaction between bromohydroquinone and a chiral synthon derived from (−)-linalool, followed by pyran ring formation.

Results and Discussion

The retrosynthetic analysis of (S)-δ-CEHC (1) is depicted in Scheme . The chromanol ring could be assembled via the Heck reaction between allylic alcohol 2 and 2-bromo-6-methylbenzene-1,4-diol (3) followed by cyclization. Compound 3 is commercially available or could be readily prepared from o-cresol through a chromatography-free procedure in three steps.[22] Chiral synthon 2 can be produced smoothly using a reported method in two steps with 98% ee starting from (−)-linalool,[23] an inexpensive and commercially available natural product.

Scheme 1

Retrosynthetic Analysis of (S)-δ-CEHC

The synthesis is initiated by Heck coupling between 2 and 3 in the presence of Pd(OAc)2, tetrabutylammonium bromide (TBAB), and Na2CO3 to afford the desired product 4 in the reaction mixture (Scheme ). However, bespoke hydroquinone 4 was highly water-soluble and could be easily oxidized when exposed to air. We also noticed that the workup procedure under mild acidic conditions led to the rapid formation of furan derivative 5 as the byproduct, which was likely mediated by the formation of allylic carbocation and subsequent SN1 reaction with the terminal hydroxyl group. The optical rotation test confirmed the racemization of the chiral center. We envisioned that protection of the phenolic hydroxyl groups of 3 would prevent the formation of 5 since an acidic titration procedure will not be necessary and water solubility of the product will also be lower. Nevertheless, the Heck reaction between protected hydroquinone (-OAc, -OBn, -OTBS, structures not shown) and vinyl 2 gave low yields under similar conditions. Alternatively, we also attempted to replace Na2CO3 with weaker bases such as NaHCO3 or triethylamine to get rid of the acidic workup procedure. However, the Heck reaction was incomplete and the product was difficult to handle. Thus, we developed a new strategy to trap 4 with excess acetic anhydride in the presence of triethylamine to afford ester 6 in 64% yield and with complete retention of configuration (98% ee). Compound 6 was not air-sensitive and could be directly extracted from the reaction mixture, which was ideal for the scale-up synthesis. Palladium-catalyzed hydrogenation of 6 gave compound 7 in 99% yield. Surprisingly, treatment of 7 with a mixture of EtOH and conc. hydrochloric acid under reflux condition afforded racemic chromanol 8 and furan derivative 9.

Scheme 2

Reagents and Conditions: (a) 3, Pd(OAc)2, Na2CO3, TBAB, DMF, 80 °C; (b) Ac2O, Et3N, DCM, DMF, rt; (c) Pd/C, H2, Ethyl Acetate, rt; and (d) Conc. HCl (aq), EtOH, Reflux

The syntheses of optically active chromans using cyclodehydration reaction have been reported previously.[12,14,15,24] Cohen[24] and Maloney[12] had proposed a mechanism involving a catalytic redox cycle. In our case, the designed chiral chroman (S)-8 formation initiates with the hydrolysis of ester 7 (Scheme ). Subsequently, hydroquinone 10b is oxidized to a trace amount of quinone 11 by O2. The nucleophilic addition to quinone carbonyl-C and subsequent E1-type elimination forms hemiacetal 12, which is reduced by the starting hydroquinone 10b to generate (S)-8 and additional 11. Racemic chroman 8 was not from (S)-8 since the treatment of the latter under acidic conditions did not result in racemization. The formation of furan 9 suggested the existence of carbocation intermediates 13 and 14, which were responsible for the racemization of the chiral center.

Scheme 3

Proposed Mechanism of Chroman Formation

The mechanistic insight into this intriguing reaction suggested that acid is required to form intermediate 12 but also facilities carbocation-mediated racemization. Optimization of chroman formation holds the potential to improve the optical purity (Table ). We first reduced the reaction temperature, which resulted in an increased amount of furan 9, indicating a lower deacetylation rate and accumulation of carbocation during the reaction (entry 2). Replacement of HCl with H2SO4 reduced the formation of 9 (entry 3). The optical purity of chroman (S)-8 was improved (40% ee) when the acid concentration decreased to 1.0 M (entry 4) and was further ameliorated (89% ee) when using 0.2 M H2SO4 in the reaction (entry 5). However, further dilution of H2SO4 (entry 6) resulted in low yield and slightly decreased chiral purity, probably because of the slow hydrolysis of the acetyl groups. A similar trend was observed when the reaction temperature was reduced to 60 °C in the presence of 0.2 M H2SO4 (entry 7). Comparable yields and ee values can be achieved using TFA or AcOH as an acid. Eventually, H2SO4 was selected for further investigation because of its lower cost.

Table 1

Optimization of Chroman Formation

entry	reagents and conditions	temp (°C) time (h)	yielda (%) 8/9	ee% (S)-8
1	7, 3.0 Mb HCl in EtOH/H2O (3/1)c	80/1	74/15	0
2	7, 3.0 M HCl in EtOH/H2O (3/1)	25/16	50/42	0
3	7, 2.0 M H2SO4 in EtOH/H2O (4/1)	80/4	78/5	0
4	7, 1.0 M H2SO4 in EtOH/H2O (4/1)	80/4	76/–d	40
5	7, 0.2 M H2SO4 in EtOH/H2O (4/1)	80/4	78/–	89
6	7, 0.05 M H2SO4 in EtOH/H2O (4/1)	80/16	25/–	84
7	7, 0.2 M H2SO4 in EtOH/H2O (4/1)	60/16	60/–	85
8	10a, 0.2 M H2SO4 in EtOH/H2O (1/1)	60/24	71/–	92
9	10a, 0.1 M H2SO4 in EtOH/H2O (1/1)	60/48	74/–	98

Isolated yield.

Final concentrations of acid in the solvents.

v/v.

Almost no detectable trace of 9.

Considering that the hydrolysis of phenolic ester requires high temperature and low pH, we tried to selectively remove them to generate 10a, which might be converted to (S)-8 under milder conditions. However, the reaction was either nonselective or incomplete. Alternatively, we converted chiral synthon 2 to acetyl ester 15, which was coupled with 3 to afford hydroquinone 16 and quinone 17 after workup (Scheme ). Subsequent hydrogenation of the mixture of 16 and 17 gave 10a in 70% yield. Starting with hydroquinone 10a, the chiral purity was improved to 92% ee in the presence of 0.2 M H2SO4 at 60 °C (Table , entry 8). Further dilution of H2SO4 produced (S)-8 in 74% yield and 98% ee (Table , entry 9). The solvent ratio (EtOH/H2O) was adjusted to 50:50 (v/v) based on the solubility of the starting material 10a.

Scheme 4

Reagents and Conditions: (a) Ac2O, Et3N, DCM, 0 °C; (b) 3, Pd(OAc)2, NaHCO3, TBAB, KCl, DMF, 110 °C; (c) Pd/C, H2, Ethyl Acetate, rt; (d) 0.1 M H2SO4 in EtOH/H2O, 1:1, v/v, 60 °C; (e) i. TBSCl, Imidazole, DMF, rt; ii. CeCl3 Heptahydrate, ACN, Reflux; (f) i. Dess–Martin Periodinane, DCM, rt; ii. NaClO2, NaH2PO4, 2-Methyl-2-butanol, BuOH/H2O, 5 °C; and (g) TBAF, THF, 0 °C

With the key intermediate (S)-8 in hand, we next sought to protect the phenolic hydroxyl group. However, attempts to regioselective protection were unsuccessful. Eventually, both hydroxyl groups in (S)-8 were protected with TBS groups, and the one on the aliphatic hydroxyl group was removed selectively in the presence of CeCl3 to afford intermediate 18 in 91% yield over two steps. The terminal hydroxyl group was converted to carboxylic acid by the treatment of the Dess–Martin reagent followed by Pinnick oxidation. Finally, the TBS protection on 19 was removed in the presence of TBAF to afford (S)-δ-CEHC with quantitative yield and 97% ee.

Conclusions

In conclusion, we have developed a concise method for the synthesis of the chiral 6-hydroxychroman core for VE and CEHCs. The first total synthesis of (S)-δ-CEHC was accomplished in seven steps with 40% overall yield and 97% ee. This synthesis enables the biological and pharmacological investigations on (S)-δ-CEHC.

Materials and Methods

General Methods

THF, DCM, DMF, and acetonitrile were obtained via a solvent purification system by filtering through two columns packed with activated alumina and 4 Å molecular sieve, respectively. All other chemicals obtained from commercial sources were used without further purification. Flash chromatography was performed using silica gel (230–400 mesh) as the stationary phase. Reaction progress was monitored by thin-layer chromatography (silica-coated glass plates) and visualized by UV light, and/or by GC-MS, LC-MS. NMR spectra were recorded in CDCl3 at 400 or 600 MHz for 1H NMR and 101 or 151 MHz for 13C NMR. Chemical shifts δ are given in using tetramethylsilane as an internal standard. Multiplicities of NMR signals are designated as singlet (s), broad singlet (br s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), and multiplet (m). MS were recorded on an Agilent 5975 series GC-MS (EI) or an Advion Express (APCI or ESI) instrument. HPLC analysis for chiral compounds was performed on an Advion AVANT LC system using different columns. High-resolution mass spectra (HRMS) were recorded on an Agilent 6230 time-of-flight (TOF) mass spectrometer.

(E)-2-Methyl-6-(2-(2-methyltetrahydrofuran-2-yl)vinyl)benzene-1,4-diol (5)

A mixture of olefin 2 (45 mg, 0.35 mmol), hydroquinone 3 (40 mg, 0.20 mmol), Pd(OAc)2 (3.0 mg, 0.01 mmol), Na2CO3 (83 mg, 0.78 mmol), and TBAB (85 mg, 0.26 mmol) in DMF (2.5 mL) was stirred at 80 °C under a N2 atmosphere for 5 h. Then, it was cooled to room temperature and diluted with water. The pH was adjusted to 6–7 with aqueous HCl solution (1N). The resulting mixture was extracted with ethyl acetate × 2, and the combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (19 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ 6.73 (d, J = 16.0 Hz, 1H), 6.68 (d, J = 3.0 Hz, 1H), 6.57–6.53 (m, 1H), 6.21–6.13 (m, 1H), 5.06 (br s, 1H), 4.81 (br s, 1H), 3.96 (t, J = 6.6 Hz, 2H), 2.20 (s, 3H), 2.05–1.93 (m, 3H), 1.87–1.76 (m, 1H), 1.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.20, 145.39, 137.72, 125.80, 124.93, 121.59, 117.09, 111.13, 83.03, 67.93, 38.07, 26.94, 25.87, 16.38. HRMS (ESI) m/z calcd for C14H19O3 [M + H]+: 235.1329, found: 235.1323.

(R,E)-2-(6-Acetoxy-3-hydroxy-3-methylhex-1-en-1-yl)-6-methyl-1,4-phenylene diacetate (6)

A mixture of olefin 2 (390 mg, 3.00 mmol), hydroquinone 3 (303 mg, 1.50 mmol), Pd(OAc)2 (10 mg, 0.04 mmol), Na2CO3 (636 mg, 6.00 mmol), and TBAB (628 mg, 1.95 mmol) in DMF (15 mL) was stirred at 80 °C under a N2 atmosphere for 16 h. Then, it was cooled to room temperature and diluted with DCM (30 mL). Ac2O (710 μL, 7.50 mmol) and Et3N (2.1 mL, 15.0 mmol) were added to the solution, and the mixture was stirred at room temperature for another 10 h. The resulting mixture was extracted with DCM × 2, and the combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the desired product (361 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 2.7 Hz, 1H), 6.88–6.81 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.17 (d, J = 16.0 Hz, 1H), 4.08–4.00 (m, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H), 1.76–1.57 (m, 4H), 1.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 171.31, 169.59, 168.88, 148.23, 144.51, 139.97, 132.27, 131.13, 122.84, 120.77, 117.15, 72.81, 64.80, 38.78, 28.55, 23.46, 21.20, 21.07, 20.57, 16.59. HRMS (ESI) m/z calcd for C20H26NaO7 [M + Na]+: 401.1571, found: 401.1576. The enantiomeric excess of (R)-6 was determined by HPLC as 98% [column, CHIRALPAK OD-H (4.6 mm × 250 mm), room temperature; eluent, heptane–IPA (85:15); flow rate, 0.5 mL/min; detect, 254 nm, tR of (R)-6, 19.96 min; tR of (S)-6, 23.27 min].

(S)-2-(6-Acetoxy-3-hydroxy-3-methylhexyl)-6-methyl-1,4-phenylene diacetate (7)

A mixture of compound 6 (300 mg, 0.79 mmol) and 10% Pd/C (10% w/w, 30 mg) in ethyl acetate (10 mL) was stirred at room temperature under an atmosphere of hydrogen for 2 h. After the solid was removed by filtration, the filtrate was evaporated to dryness to afford the title compound (300 mg, 99% yield). 1H NMR (400 MHz, CDCl3) δ 6.82 (s, 2H), 4.08 (t, J = 6.5 Hz, 2H), 2.57–2.49 (m, 2H), 2.34 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H), 2.05 (s, 3H), 1.76–1.64 (m, 4H), 1.55–1.49 (m, 2H), 1.22 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 171.36, 169.68, 169.25, 148.23, 145.36, 135.76, 132.03, 121.74, 120.51, 72.20, 64.93, 42.23, 38.28, 26.74, 25.00, 23.48, 21.29, 21.15, 20.68, 16.74. HRMS (ESI) m/z calcd for C20H28NaO7 [M + Na]+: 403.1727, found: 403.1711.

2-Methyl-6-(2-(2-methyltetrahydrofuran-2-yl)ethyl)benzene-1,4-diol (9)

Compound 7 (80 mg, 0.21 mmol) in a mixture of EtOH (0.9 mL) and aqueous HCl solution (12N, 0.3 mL) was refluxed for 1 h. Then, it was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate × 2, and the combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (7.5 mg, 15% yield). 1H NMR (600 MHz, CDCl3) δ 6.91 (br s, 1H), 6.49 (d, J = 3.0 Hz, 1H), 6.41 (d, J = 3.0 Hz, 1H), 5.28 (br s, 1H), 3.98–3.85 (m, 2H), 2.68–2.49 (m, 2H), 2.19 (s, 3H), 2.04–1.91 (m, 2H), 1.87–1.68 (m, 4H), 1.22 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 148.54, 146.37, 129.62, 126.35, 115.65, 114.09, 83.73, 67.76, 41.13, 37.06, 26.16, 25.91, 25.40, 16.61. HRMS (ESI) m/z calcd for C14H24NO3 [M + NH4]+: 254.1751, found: 254.1755.

(R)-4-Hydroxy-4-methylhex-5-en-1-yl acetate (15)

To a mixture of compound 2 (4.90 g, 37.7 mmol) and Et3N (10.5 mL, 75.4 mmol) in DCM (100 mL) at 0 °C was added Ac2O (4.63 mL, 49.0 mmol). The mixture was stirred at 0 °C for 3 h and warmed to room temperature. The resulting mixture was poured into water and extracted with DCM. The organic phase was washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (6.40 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ 5.90 (dd, J = 17.3, 10.7 Hz, 1H), 5.22 (dd, J = 17.3, 1.1 Hz, 1H), 5.08 (dd, J = 10.8, 1.2 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 2.04 (s, 3H), 1.73–1.62 (m, 2H), 1.61–1.56 (m, 2H), 1.30 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 171.37, 144.86, 112.26, 73.07, 64.92, 38.48, 28.19, 23.54, 21.18. GC-MS (EI) m/z 172.1 (M+).

(R,E)-6-(2,5-Dihydroxy-3-methylphenyl)-4-hydroxy-4-methylhex-5-en-1-yl acetate (16)

A mixture of olefin 15 (508 mg, 2.95 mmol), hydroquinone 3 (400 mg, 1.97 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), NaHCO3 (680 mg, 8.10 mmol), KCl (152 mg, 2.04 mmol), and TBAB (640 mg, 1.99 mmol) in DMF (10 mL) was stirred at 110 °C under a N2 atmosphere for 16 h. Then, the mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate × 2, and the combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford a mixture of compounds 16 and 17, which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 16.1 Hz, 1H), 6.65 (d, J = 3.0 Hz, 1H), 6.54 (d, J = 2.9 Hz, 1H), 6.08 (d, J = 16.1 Hz, 1H), 4.02 (t, J = 6.3 Hz, 2H), 2.16 (s, 3H), 2.02 (s, 3H), 1.72–1.56 (m, 4H), 1.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 172.03, 149.42, 145.29, 137.69, 126.47, 125.22, 122.38, 117.43, 110.86, 73.62, 65.13, 38.70, 28.19, 23.62, 21.19, 16.47. GC-MS (EI) m/z 276.1 (M+ – H2O).

(R,E)-4-Hydroxy-4-methyl-6-(5-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)hex-5-en-1-yl acetate (17)

1H NMR (400 MHz, CDCl3) δ 6.67–6.65 (m, 1H), 6.65–6.61 (m, 2H), 6.60–6.56 (m, 1H), 4.09–4.04 (m, 2H), 2.06 (d, J = 1.6 Hz, 3H), 2.04 (s, 3H), 1.77–1.66 (m, 4H), 1.38 (s, 3H). GC-MS (EI) m/z 274.1 (M+ – H2O).

(S)-6-(2,5-Dihydroxy-3-methylphenyl)-4-hydroxy-4-methylhexyl acetate (10a)

A mixture of compounds 16 and 17 as well as 10% Pd/C (10% w/w, 40 mg) in ethyl acetate (10 mL) was stirred at room temperature under an atmosphere of hydrogen for 16 h. After the solid was removed by filtration, the filtrate was evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (406 mg, 70% yield, two steps). 1H NMR (400 MHz, CDCl3) δ 6.49 (d, J = 3.0 Hz, 1H), 6.43 (d, J = 3.0 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 2.69–2.55 (m, 2H), 2.18 (s, 3H), 2.05 (s, 3H), 1.77–1.65 (m, 4H), 1.58–1.51 (m, 2H), 1.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 171.69, 148.89, 145.99, 129.74, 126.00, 115.60, 114.22, 73.41, 65.03, 41.46, 38.32, 26.82, 24.78, 23.63, 21.20, 16.53. GC-MS (EI) m/z 296.1 (M+).

(S)-2-(3-Hydroxypropyl)-2,8-dimethylchroman-6-ol ((S)-8)

Compound 10a (240 mg, 0.81 mmol) in a mixture of EtOH (5 mL) and aqueous H2SO4 solution (0.2N, 5 mL) was stirred at 60 °C for 48 h. Then, it was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate × 2, and the combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (141 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ 6.47 (d, J = 3.0 Hz, 1H), 6.38 (d, J = 3.1 Hz, 1H), 3.72–3.62 (m, 2H), 2.81–2.61 (m, 2H), 2.11 (s, 3H), 1.86–1.60 (m, 6H), 1.25 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 148.08, 145.93, 127.53, 121.41, 115.90, 112.81, 75.48, 63.47, 36.31, 31.63, 27.10, 23.98, 22.62, 16.30. HRMS (ESI) m/z calcd for C14H24NO3 [M + NH4]+: 254.1751, found: 254.1755. The enantiomeric excess of (S)-8 was determined by HPLC as 98% [column, Lux 5 μm Cellulose-1 (4.6 mm × 250 mm), room temperature; eluent, heptane–IPA (80:20); flow rate, 0.6 mL/min; TUVC, tR of (R)-8, 11.24 min, tR of (S)-8, 11.99 min].

(S)-3-(6-((tert-Butyldimethylsilyl)oxy)-2,8-dimethylchroman-2-yl)propan-1-ol (18)

A mixture of (S)-8 (120 mg, 0.51 mmol), TBSCl (227 mg, 1.51 mmol), and imidazole (136 mg, 2.00 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with ethyl acetate × 2. The combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was dissolved in acetonitrile (10 mL) and mixed with CeCl3 heptahydrate (300 mg, 0.81 mmol). The resulting mixture was stirred at 80 °C for 16 h and cooled to room temperature. Then, it was poured into water and extracted with ethyl acetate × 2. The combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (163 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ 6.45 (s, 1H), 6.37 (s, 1H), 3.73–3.60 (m, 2H), 2.80–2.62 (m, 2H), 2.10 (s, 3H), 1.87–1.59 (m, 6H), 1.25 (s, 3H), 0.97 (s, 9H), 0.16 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 147.88, 146.27, 127.00, 121.02, 120.36, 117.44, 75.41, 63.48, 36.37, 31.72, 27.14, 25.92, 23.98, 22.63, 18.31, 16.32, −4.26. HRMS (ESI) m/z calcd for C20H35O3Si [M + H]+: 351.2350, found: 351.2350.

(S)-3-(6-((tert-Butyldimethylsilyl)oxy)-2,8-dimethylchroman-2-yl)propanoic acid (19)

A mixture of compound 18 (140 mg, 0.40 mmol) and Dess–Martin periodinane (220 mg, 0.52 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. The reaction was quenched with aqueous Na2S2O3 solution (10 wt %), and the mixture was extracted with DCM. The organic layer was washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. To a solution of this aldehyde intermediate in a 80:20 mixture of BuOH and water (2.5 mL) at 5 °C, 2-methyl-2-butene (0.7 mL, 6.61 mmol), NaH2PO4 (43 mg, 0.36 mmol), and NaClO2 (99 mg, 1.09 mmol) were successively added. The mixture was stirred at 10 °C for 10 min and quenched with aqueous Na2S2O3 solution (10 wt %). Then, it was extracted with ethyl acetate × 2, and the combined organic layer was washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (124 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 6.46 (d, J = 2.7 Hz, 1H), 6.37 (d, J = 2.9 Hz, 1H), 2.80–2.63 (m, 2H), 2.60–2.51 (m, 2H), 2.09 (s, 3H), 2.07–1.95 (m, 1H), 1.94–1.69 (m, 3H), 1.24 (s, 3H), 0.97 (s, 9H), 0.16 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 179.57, 147.79, 145.80, 126.89, 120.53, 120.21, 117.20, 74.24, 34.59, 31.48, 28.42, 25.70, 23.45, 22.27, 18.09, 16.01, −4.48. HRMS (ESI) m/z calcd for C20H33O4Si [M + H]+: 365.2143, found: 365.2128.

(S)-3-(6-Hydroxy-2,8-dimethylchroman-2-yl)propanoic acid (1)

A mixture of compound 19 (70 mg, 0.19 mmol) and TBAF (1.0 M in THF, 0.23 mL, 0.23 mmol) in THF (3 mL) was stirred at 0 °C for 15 min. Then, saturated aqueous NH4Cl solution was added to the reaction mixture and it was extracted with ethyl acetate × 3. The combined organic phases were washed with brine × 1, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified via flash column chromatography using hexanes and ethyl acetate as eluents to afford the title compound (48 mg, 100% yield). 1H NMR (600 MHz, CDCl3) δ 6.46 (d, J = 3.0 Hz, 1H), 6.38 (d, J = 3.0 Hz, 1H), 2.78–2.64 (m, 2H), 2.58–2.52 (m, 2H), 2.08 (s, 3H), 2.06–1.99 (m, 1H), 1.94–1.85 (m, 1H), 1.83–1.71 (m, 2H), 1.24 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 180.01, 148.08, 145.65, 127.57, 121.13, 116.04, 112.86, 74.51, 34.63, 31.59, 28.70, 23.65, 22.43, 16.14. HRMS (ESI) m/z calcd for C14H22NO4 [M + NH4]+: 268.1543, found: 268.1534. The enantiomeric excess of (S)-δ-CEHC was determined by HPLC as 97% [column, Lux 5 μm Cellulose-1 (4.6 mm × 250 mm), room temperature; eluent, heptane–IPA–TFA (95:5:0.1); flow rate, 1.0 mL/min; TUVC, tR of (S)-δ-CEHC, 31.67 min; tR of (R)-δ-CEHC, 29.21 min].