Unusual Epimerization in Styryllactones: Synthesis of (−)-5-Hydroxygoniothalamin, (−)-5-Acetylgoniothalamin, and O-TBS-Goniopypyrone

Abstract

(−)-5-Hydroxygoniothalamin, (−)-5-acetylgoniothalamin, and (+)-5-hydroxygoniothalamin, isolated from the Goniothalamus genus, are synthesized from triacetyl-O-d-glucal by employing the Ferrier reaction, Mitsunobu reaction, and Jones oxidation as key steps. The synthetic procedure also yields the epimers of (−)-5-hydroxygoniothalamin and (+)-5-hydroxygoniothalamin employing acid-mediated transition-metal-free epimerization at C-5 of styryllactones. Further studies reveal that the epimerization is facilitated by the phenyl group present on the styryllactones. Also, depending on the dihydroxylation reaction conditions, various analogues of saturated styryllactones are synthesized utilizing oxa-Michael reaction conditions.

Introduction

Most of the bioactive styryllactones have been isolated from the Goniothalamus genus. The first styryllactone goniothalamin 1 was isolated from the bark of Cryptocarya caloneura(1) (Annonaceae family) and later on has been isolated from several species belonging to the Goniothalamus genus.²⁻⁵ Pompimon and co-workers⁶ isolated (−)-5-hydroxygonio-thalamin 4, (−)-5-acetylgoniothalamin 5, and (−)-goniopypyrone 7 from Goniothalamus marcanii belonging to the Annonaceae family that is mostly found in Thailand and are being used in the Thai traditional system of medicine.⁷ Styryllactones isolated from the Goniothalamus genus have shown strong cytotoxicity.^4,8 (+)-5-Hydroxygoniothalamin 6, an enantiomer of (−)-5-hydroxygoniothalamin 4, has also been isolated from Goniothalamus dolichocarpus(9) (Figure 1).

Figure 1.

Naturally occurring diverse styryllactones (1–7).

Results and Discussion

Their anticancer activity prompted us to take up the total synthesis of (−)-5-hydroxygoniothalamin 4 and (−)-5-acetylgoniothalamin 5 from a common starting material, tri-O-acetyl-d-glucal 9. The synthesis of compound 6 was earlier reported by various groups,¹⁰ and the synthesis of (+)-5-acetoxygoniothalamin is reported by Pan et al.¹¹ The retrosynthetic approach for the synthesis of compounds 4 and 5 is delineated in Scheme 1. Natural product (−)-5-acetylgoniothalamin 5 can be synthesized from (−)-5-hydroxygoniothalamin 4 by a simple acetylation reaction. We envisaged that (−)-5-hydroxygoniothalamin 4 can be obtained from compound 8 by utilizing the Mitsunobu and Jones oxidation reactions, respectively. Compound 8 could potentially be synthesized from triacetyl-O-d-glucal 9 by using the Ferrier rearrangement¹² and Wittig reaction as key steps.^10a

Scheme 1. Retrosynthetic Analysis of the Synthesis of Styryllactones 4 and 5.

Compound 10 was synthesized from 9 in five steps by following known literature procedures.¹³ The primary hydroxyl group of compound 10 was oxidized to the aldehyde by using PCC to furnish 11 as a yellow oil and was used for the next step immediately as such, as it was found to be unstable at room temperature (Scheme 2). Compound 11 was immediately treated with sulfone in THF at −78 °C (Method A, see Experimental Section) to obtain (E)-olefin; however, we obtained the desired (E)-olefin 8 in poor yield (38%). To increase the yield of the desired (E)-olefin 8, we employed the traditional Wittig olefination reaction conditions, with benzyltriphenylphosphonium bromide in THF at room temperature (Method B, see Experimental Section) to furnish 8 in 70% yield. It is pertinent to mention that the earlier reported^10a Wittig olefination of 5,6-dihydropyran-2-ones with benzyltriphenylphosphonium bromide had resulted in (Z)-olefin formation. The formation of (E)-olefin 8 from compound 11 under the same reaction conditions may be due to the presence of an ethoxy group in compound 11 instead of the keto group as well as different stereochemistry at the aldehydic centre.

Scheme 2. Synthesis of O-TBS-(−)-5-Hydroxygoniothalamin 14.

Compound 8 upon deprotection with TBAF furnished compound 12 {[α]_D²⁴ +30.14 (c 1.7, CHCl₃)}. Now for the synthesis of 4, inversion of the stereochemistry at the C-4 group of compound 12 was achieved by utilizing the Mitsunobu protocol followed by ester deprotection to yield epimerized alcohol 13 {[α]_D²⁴ −90.87 (c 0.9, CHCl₃)}. The C-4 epimerized alcohol, 13, was treated with tert-butyldimethylsilyl chloride and imidazole in DMF at room temperature to afford a TBS-protected compound, which upon Jones oxidation afforded lactone 14 as a colorless oil. Surprisingly, the deprotection of the TBS group of compound 16 with BF₃·OEt₂ furnished a mixture of two compounds, which were identified as compound 4 (30%, oil) and its C-5 epimer compound 15 (60%, colorless solid). The formation of the C-5 epimerized compound, 15, was confirmed by NMR and its single-crystal X-ray analysis¹⁴ (Scheme 3). To study this epimerization reaction further, we synthesized another styryllactone 16 (colorless oil, 57% yield) from compound 8 by Jones oxidation (Scheme 3). Interestingly, when we treated this TBS-protected styryllactone 16 under BF₃·OEt₂ reaction conditions, we obtained two products, one was the TBS-deprotected compound 17 (30%, pale yellow solid) and the other product was found to be the C-5 epimerized product, i.e., (+)-5-hydroxygoniothalamin 6 (62%, yellow oil). The spectral data of the synthesized compound, 6, were found to be consistent with those of the reported natural product.¹⁰

Scheme 3. Synthesis of (−)-5-Hydroxygoniothalamin 4 and (+)-5-Hydroxygoniothalamin 6 along with Their C-5 Epimers 15 and 17.

The formation of the unexpected C-5 epimerized products 15 and 17 encouraged us to investigate this epimerization reaction in other 5,6-dihydropyran-2-one systems (α,β-unsaturated δ-lactones). To investigate this unexpected epimerization reaction, we prepared various substituted 5,6-dihydropyran-2-ones by following literature procedures.¹⁵ We reacted various 5,6-dihydropyran-2-one systems under the same reaction conditions mentioned above (Scheme S1, see the Supporting Information). However, we did not observe any epimerized product, and only the TBS-deprotected products were obtained. To study this epimerization reaction further, we synthesized another styryllactone 16 (colorless oil, 57% yield) from compound 8 by Jones oxidation (Scheme 3). Interestingly, when we treated this TBS-protected styryllactone 16 under BF₃·OEt₂ reaction conditions, we obtained two products, one was the TBS-deprotected compound, 17 (30%, pale yellow solid), and the other product was found to be the C-5 epimerized product, i.e., (+)-5-hydroxygoniothalamin 6 (62%, yellow oil). The spectral data of the synthesized compound, 6, were found to be consistent with those of the reported natural product.¹⁰ It is evident from the results obtained from Scheme 3 that epimerization occurs only in the styryllactones and not in other 5,6-dihydropyran-2-ones. Palladium-catalyzed epimerization of 5-vinyldihydrofuran-2(3H)-ones derived from d-glucono-δ-lactones has been reported¹⁶ in the literature. It is pertinent to mention here that we have observed acid-catalyzed epimerization in styryllactones.

Based on these results, we proposed a plausible mechanism for the formation of epimerized products, as delineated in Scheme 4. When TBS-protected styryllactone 14 was treated with BF₃·OEt₂, first it undergoes TBS deprotection to furnish compound 4. The BF₃·OEt₂ present in the reaction medium coordinates with the carbonyl group of compound 4. This facilitates the ring opening leading to the formation of intermediate A. This intermediate A undergoes ring closure leading to the formation of a thermodynamically stable compound, 15.

Scheme 4. Plausible Mechanism of Epimerization at C-5.

It is interesting to mention here that by utilizing this unexpected C-5 epimerization reaction, we synthesized all possible isomers of (−)-5-hydroxygoniothalamin 4, i.e., 15, 6, and 17 starting from triacetyl-O-d-glucal 9 as the starting material. Compound (−)-5-acetylgoniothalamin 5 was obtained from (−)-5-hydroxygoniothalamin 4 by acetylation as a pale yellow solid (85%). The absolute configuration and structure were further confirmed by its single-crystal X-ray analysis (Scheme 5).¹⁴

Scheme 5. Synthesis of (−)-5-Acetylgoniothalamin 5.

We further envisaged that (−)-goniopypyrone 7 could be synthesized from (−)-5-hydroxygoniothalamin 4 by dihydroxylation followed by intramolecular oxa-Michael addition reactions. To synthesize 7, the TBS-protected lactone, 16, was subjected to Upjohn dihydroxylation conditions.¹⁷ The reaction mixture upon completion of the reaction showed a single spot on TLC and upon usual basic workup furnished the expected dihydroxylated product, 18, and to our surprise, we also obtained the oxa-Michael addition product, 19, due to the basic workup conditions (Scheme 6). The formation of oxa-Michael addition^15,18 product 19 along with dihydroxylated product 18 could be due to quenching of the reaction mixture with sat. NaHCO₃. The base might abstract a proton from the benzylic OH group, which in turn facilitates the formation of the oxa-Michael addition product, 19. Finally, the formation of product 18 was further confirmed using single-crystal X-ray analysis.¹⁴ Our attempts on the deprotection of the TBS group of compound 19 resulted in the formation of a complex mixture, and hence, it was not pursued further. When TBS-protected lactone 16 was subjected to Sharpless dihydroxylation conditions¹⁹⁻²² [AD-mix-α in t-BuOH/H₂O (1:1) in the presence of methanesulfonamide], which led to the formation of an intramolecular oxa-Michael addition product 20 (75% yield) as a single product instead of the usual dihydroxylation product, B (Scheme 6). The formation of product 20 might be due to the close proximity of the C-6 hydroxyl group than the benzylic hydroxyl group. Further, the structure of the intramolecular oxa-Michael addition product, 20, was confirmed by its single-crystal X-ray analysis.¹⁴

Scheme 6. Dihydroxylation Studies of Styryllactones.

Conclusions

In conclusion, we have successfully achieved the synthesis of all possible isomers of (−)-5-hydroxygoniothalamin 4 from triacetyl-O-d-glucal 9 by utilizing the unexpected epimerization reaction of styryllactones. We have also synthesized (−)-5-acetylgoniothalamin 5 from (−)-5-hydroxygoniothalamin 4. It is pertinent to mention here that the dihydroxylation reactions performed using either Upjohn or Sharpless conditions resulted in the formation of oxa-Michael addition products, which allowed the synthesis of various saturated styryllactones.

Experimental Section

General Information

All melting points were recorded using a Büchi melting point apparatus in open capillaries and are uncorrected. Flash chromatography was performed with a CombiFlash Rf 200i apparatus equipped with a UV/vis detector and an ELSD (Isco Teledyne Inc.) using a RediSep prepacked column (SiO₂). ¹H NMR spectra were recorded using a Bruker 200, 400, or 500 MHz spectrometer and ¹³C NMR spectra were recorded at 50, 100, or 125 MHz. Chemical shifts are reported as δ values (ppm) relative to the residual solvent peak of CDCl₃. HRMS (ESI) data were recorded using an Orbitrap (quadrupole plus ion trap). Petroleum ether and ethyl acetate were distilled by the usual methods. Dried solvents were purchased and used without further drying. Molecular sieves were activated prior to use and kept under vacuum while not in use.

(2S,3S,6S)-3-((tert-Butyldimethylsilyl)oxy)-6-ethoxy-3,6-dihydro-2H-pyran-2-carb-aldehyde (11)

To a solution of PCC (755 mg, 2 equiv) in DCM, molecular sieves (4 Å, 875 mg) were added at rt under an argon atmosphere. The resulting solution was stirred at rt for 2 h. Afterward, alcohol 10 (505 mg, 1.75 mmol, 1 equiv) in DCM (15 mL) was added slowly over 20 min. The resulting black color solution was further stirred at rt for 24 h. After completion of the reaction (TLC), the reaction mixture was filtered and washed with DCM (2 × 20 mL). The combined DCM layers were dried over anhydrous Na₂SO₄. After solvent evaporation under reduced pressure, the crude aldehyde, 11, was obtained, which was used as such for the next step without further purification.

tert-Butyl (((2R,3S,6S)-6-Ethoxy-2-((E)-styryl)-3,6-dihydro-2H-pyran-3-yl)oxy)-dimethylsilane (8)

Method A: To a solution of sulfone tetrazole (1.2 g, 4.18 mmol, 2.0 equiv) in THF (15 mL), KHMDS (1 M in THF, 4.2 mL, 2.2 equiv) was added over a period of 10 min at −78 °C under an argon atmosphere. The reaction was stirred for 5 min at the mentioned temperature. Then the solution of crude aldehyde 11 (600 mg, 2.09 mmol) in THF (15 mL) was added dropwise over a period of 10 min and stirred for 3 h at −78 °C. Finally, the reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched by addition of an aqueous solution of NaHCO₃ (10 mL). The organic layer was extracted with Et₂O (3 × 15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluted with 5% EtOAc–petroleum ether) to afford the corresponding alkene, 8 (286 mg, 38%), as a colorless oil in overall two steps.

Method B: To a suspension of methyltriphenylphosphonium bromide (1.81 g, 4.18 mmol, 2 equiv) in THF (15 mL), n-BuLi (2.8 mL, 2.2 equiv) was added over a period of 10 min at 0 °C under an argon atmosphere. The reaction was stirred for 1 h at rt. Then the solution of crude aldehyde 11 (600 mg, 2.09 mmol) in THF (15 mL) was added at 0 °C dropwise over a period of 10 min. Finally, the reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched by addition of an aqueous solution of NH₄Cl (10 mL). The organic layer was extracted with Et₂O (3 × 15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluted with 5% EtOAc–petroleum ether) to afford the corresponding alkene, 8 (528 mg, 70%), as a colorless oil in overall two steps.

R_f 0.75 (10% EtOAc–petroleum ether); [α]_D²⁴ −29.59 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ_H 7.44–7.41 (m, 2H), 7.37–7.34 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.31 (dd, J = 6.5, 16.0 Hz, 1H), 5.93 (d, J = 9.9 Hz, 1H), 5.78–5.76 (m, 1H), 5.09–5.08 (m, 1H), 4.36 - 4.34 (m, 1H), 4.11 (dd, J = 1.5, 8.8 Hz, 1H), 3.92–3.86 (m, 1H), 3.62–3.59 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ_C 136.8, 134.5, 132.0, 128.6, 127.6, 127.3, 126.4, 125.7, 94.4, 72.1, 68.7, 64.0, 25.7, 18.0, 15.4, −4.4, −4.6; HRMS (ESI) m/z: calcd for C₂₁H₃₂O₃NaSi [M + Na]⁺: 383.2013, found 383.2010.

(2R,3S,6S)-6-Ethoxy-2-((E)-styryl)-3,6-dihydro-2H-pyran-3-ol (12)

Compound 8 (578 mg, 1.6 mmol) was dissolved in THF (15 mL), and TBAF (1 M in THF, 0.9 mL, 3.2 mmol, 2 equiv) was added to the solution at rt. The reaction was stirred overnight at rt. After completion of the reaction (TLC), the reaction was quenched with water (3 mL), extracted with EtOAc (3 × 10 mL), and dried over anhydrous Na₂SO₄. The crude residue was purified by silica gel flash chromatography (eluted with 10% EtOAc–petroleum ether) to yield compound 12 (334 mg, 85%) as a colorless oil.

R_f 0.18 (10% EtOAc–petroleum ether); [α]_D²⁴ +30.14 (c 1.7, CHCl₃); ¹H NMR (200 MHz, CDCl₃) δ_H 7.45–7.28 (m, 5H), 6.8–6.72 (m, 1H), 6.31 (dd, J = 6.4, 16.0 Hz, 1H), 6.00 (td, J = 1.4, 10.1 Hz, 1H), 5.83–5.76 (m, 1H), 5.07–5.04 (m, 1H), 4.31–4.22 (m, 1H), 4.10–4.07 (m, 1H), 3.86 (dd, J = 7.2, 9.7 Hz, 1H), 3.62–3.54 (m, 1H), 1.92–1.88 (m, 1H), 1.30–1.19 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ_C 136.5, 132.4, 129.8, 128.5, 128.4, 127.8, 126.6, 125.7, 94.3, 64.0, 63.8, 21.9, 15.3; HRMS (ESI) m/z: calcd for C₁₅H₁₈O₃Na [M + Na]⁺: 269.1148, found 269.1145.

(2R,3R,6S)-6-Ethoxy-2-((E)-styryl)-3,6-dihydro-2H-pyran-3-ol (13)

To a solution of alcohol 12 (739 mg, 3.0 mmol) in THF (10 mL) at 0 °C, triphenylphosphine (1.18 g, 4.50 mmol, 1.5 equiv) and p-nitro benzoic acid (752 mg, 4.50 mmol, 1.5 equiv) were added under an argon atmosphere. After stirring for 10–15 min, DIAD (884 μL, 4.50 mmol, 1.5 equiv) was added to the reaction mixture over a period of 10 min at the same temperature. Then the reaction mixture was allowed to stir at rt for 10 h. After completion of the reaction (TLC), volatiles were removed under reduced pressure, and the crude product was purified using silica gel flash chromatography (eluted with 18% EtOAc–petroleum ether) to furnish O-PNBA-protected compound 12 as a yellow solid (1.0 g, 85%).

Mp: 93–95 °C; R_f 0.54 (30% EtOAc–petroleum ether); [α]_D²⁴ +27.34 (c 0.2, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 8.24–8.16 (m, 4H), 7.32–7.18 (m, 5H), 6.79 (d, J = 15.9 Hz, 1H), 6.29–6.24 (m, 2H), 6.16 (dd, J = 3.0, 10.1 Hz, 1H), 5.33 (dd, J = 2.1, 5.8 Hz, 1H), 5.26–5.22 (d, J = 3.0 Hz, 1H), 4.96–4.94 (m, 1H), 3.96–3.88 (m, 1H), 3.65 (dd, J = 7.3, 9.8 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ_C 164.3, 150.6, 136.3, 135.3, 132.4, 131.5, 130.8, 128.6, 127.9, 126.4, 125.1, 124.5, 123.5, 94.1, 69.3, 66.4, 64.2, 15.3 ppm; ESI-MS: m/z: 418.23 (M + Na)⁺.

O-PNBA-protected 12 (817 mg, 2.06 mmol) was dissolved in MeOH (20 mL) under an argon atmosphere, and K₂CO₃ (427 mg, 1.5 equiv) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. After the solvent was removed in vacuo, the crude alcohol obtained was subjected to silica gel column chromatography (eluted with 20% EtOAc–petroleum ether) to furnish 13 as a colorless oil (523 mg, 60%).

R_f 0.30 (30% EtOAc–petroleum ether); [α]_D²⁴ −90.87 (c 0.9, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 7.45–7.43 (m, 2H), 7.34–7.29 (m, 2H), 7.26–7.25 (m, 1H), 6.77 (d, J = 16.5 Hz, 1H), 6.40 (dd, J = 6.1, 15.9 Hz, 1H), 6.22 (dd, J = 5.5, 9.8 Hz, 1H), 5.95 (dd, J = 3.1, 9.8 Hz, 1H), 5.13–5.12 (m, 1H), 4.70 (dd, J = 1.2, 5.4 Hz, 1H), 3.88–3.83 (m, 2H), 3.64–3.58 (m, 1H), 1.77 (brs, 1H), 1.27–1.24 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ_C 136.6, 132.4, 129.8, 128.6, 128.4, 127.8, 126.6, 125.7, 94.4, 71.1, 64.0, 63.8, 21.9, 15.3; HRMS (ESI) m/z: calcd for C₁₅H₁₈O₃Na [M + Na]⁺: 269.1148, found 269.1147.

(5R,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-((E)-styryl)-5,6-dihydro-2H-pyran-2-on (14)

To a stirred solution of 13 (682 mg, 2.76 mmol) in DMF (10 mL) at rt under an argon atmosphere, imidazole (414 mg, 6.06 mmol, 2.2 equiv) was added, and the resulting mixture was cooled to 0 °C. ^tBuMe₂SiCl (624 mg, 4.14 mmol, 1.5 equiv) was then added in small portions, and the reaction mixture was allowed to warm to rt. After stirring at rt for 24 h, the reaction mixture was diluted with DCM (10 mL) and quenched by addition of sat. NaHCO₃ solution. The organic layer was separated, and the aqueous layer was further extracted with CH₂Cl₂ (2 × 10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to obtain a colorless oil (890 mg). The crude compound was used for the next step without further purification. The Jones reagent (900 μL) was added to a suspension of O-TBS-protected 13 (300 mg, 1.10 mmol) in acetone (10 mL) and anhydrous magnesium sulfate (500 mg) was added to it under stirring at 0 °C. After addition of the Jones reagent, the mixture was stirred for 10–15 min at the same temperature. After completion of the reaction (TLC), cold sat. NaHCO₃ solution was added to the reaction mixture. The mixture was concentrated in vacuo to remove acetone, and the solution was extracted with EtOAc (3 × 10 mL). The combined extracts were washed with water and brine solution, dried over anhydrous Na₂SO₄, and concentrated. The residue was eluted using silica gel column chromatography (eluted with 7% EtOAc–petroleum ether) to furnish 14 (159 mg, 58%) as a colorless liquid.

R_f 0.33 (10% EtOAc–petroleum ether); [α]_D²⁴ −22.59 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 7.41–7.28 (m, 5H), 6.84 (dd, J = 4.3, 9.8 Hz, 1H), 6.75 (d, J = 15.9 Hz, 1H), 6.38 (dd, J = 7.0, 16.2 Hz, 1H), 6.10 (d, J = 9.8 Hz, 1H), 5.02–4.96 (m, 1H), 4.41–4.35 (m, 1H), 0.89 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ_C 163.1, 145.4, 135.9, 134.4, 128.7, 128.3, 126.7, 122.9, 122.0, 81.5, 64.2, 25.6, 18.0, −4.4, −4.8; HRMS (ESI) m/z: calcd for C₁₉H₂₇O₃Si [M + H]⁺: 331.1724, found 331.1718; calcd for C₁₉H₂₆O₃NaSi [M + Na]⁺: 353.1543, found 353.1537.

(5R,6R)-5-Hydroxy-6-((E)-styryl)-5,6-dihydro-2H-pyran-2-one (4) and (5R,6S)-5-Hydroxy-6-((E)-styryl)-5,6-dihydro-2H-pyran-2-one (15)

Compound 14 (106 mg, 0.32 mmol) was dissolved in CH₃CN (5 mL), and BF₃·OEt₂ (40 μL, 0.32 mmol) was added to the solution at 0 °C. The reaction was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO₃, extracted with Et₂O (3 × 10 mL), and dried over anhydrous Na₂SO₄. The crude product was purified by silica gel flash chromatography (eluted with 10–15% EtOAc–petroleum ether) to yield (20.7 mg, 30%) 4 and (41.4 mg, 60%) 15.

Compound (4): R_f 0.22 (40% EtOAc–petroleum ether); [α]_D²⁴ −180.59 (c 1.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ_H 7.42–7.40 (m, 2H), 7.33–7.25 (m, 3H), 7.01 (dd, J = 5.3, 9.9 Hz, 1H), 6.84 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 6.5, 16.0 Hz, 1H), 6.14 (d, J = 9.9 Hz, 1H), 5.03 (ddd, J = 1.1, 3.1, 6.9 Hz, 1H), 4.29–4.28 (m, 1H), 2.62 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ_C 163.3, 144.7, 135.6, 135.2, 128.7, 128.5, 126.8, 122.8, 121.6, 81.2, 63.1; HRMS (ESI) m/z: calcd for C₁₃H₁₂O₃Na [M + Na]⁺: 239.0679, found 239.0677.

Compound (15): mp: 105–107 °C; R_f 0.34 (40% EtOAc–petroleum ether); [α]_D²⁴ +11.51 (c 0.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 7.42–7.40 (m, 2H), 7.36–7.25 (m, 3H), 6.88 (dd, J = 2.4, 9.7 Hz, 1H), 6.80 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 6.7, 15.9 Hz, 1H), 6.00 (dd, J = 1.8, 9.7 Hz, 1H), 4.87–4.83 (m, 1H), 4.42 (d, J = 9.16 Hz, 1H), 2.57 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ_C 162.8, 148.1, 135.8, 135.4, 128.7, 128.6, 126.8, 123.0, 120.7, 83.3, 66.2; HRMS (ESI) m/z: calcd for C₁₃H₁₂O₃Na [M + Na]⁺: 239.0679, found 239.0674.

(2R,3R)-6-Oxo-2-((E)-styryl)-3,6-dihydro-2H-pyran-3-yl Acetate (5)

Compound 4 (10 mg) dissolved in DCM (5 mL) was added to Ac₂O and DMAP at rt under an argon atmosphere. After completion of the reaction (TLC), a few drops of water were added and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was subjected to flash chromatography (eluted with 9% EtOAc–petroleum ether) to yield compound 5 (10.1 mg, 85%) as a light yellow solid.

Mp: 121–122 °C R_f 0.54 (30% EtOAc–petroleum ether); [α]_D²⁴ −223.44 (c 0.8, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ_H 7.41–7.39 (m, 2H), 7.37–7.33 (m, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.00 (dd, J = 5.5, 9.7 Hz, 1H), 6.83 (d, J = 16.0 Hz, 1H), 6.27 (d, J = 9.5 Hz, 1H), 6.22 (dd, J = 6.5, 16.0 Hz, 1H), 5.38 (dd, J = 3.1, 5.3 Hz, 1H), 5.20 (ddd, J = 1.1, 3.1, 6.5 Hz, 1H), 2.07 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ_C 170.0, 162.4, 140.7, 135.7, 134.9, 128.7, 128.6, 126.8, 124.9, 121.1, 79.1, 63.9, 20.6; HRMS (ESI) m/z: calcd for C₁₅H₁₄O₄Na [M + Na]⁺: 281.0784, found 281.0779.

(5S,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-((E)-styryl)-5,6-dihydro-2H-pyran-2-one (16)

The previously described Jones oxidation procedure was applied on compound 8 (250 mg) (as used for the conversion of 13 to 14) to synthesize compound 16 as an oil (131 mg, 57%) eluting with 5% EtOAc–petroleum ether.

R_f 0.41 (10% EtOAc–petroleum ether); [α]_D²⁴ +63.88 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ_H 7.41–7.40 (m, 2H), 7.36–7.33 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 6.80–6.79 (m, 1H), 6.77 (s, 1H), 6.23 (dd, J = 6.9, 16.0 Hz, 1H), 6.02 (dd, J = 1.9, 10.0 Hz, 1H), 4.85–4.82 (m, 1H), 4.42 (d, J = 8.8 Hz, 1H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ_C 162.8, 150.0, 135.8, 134.7, 128.7, 128.3, 126.7, 123.8, 119.9, 83.1, 67.4, 25.7, 25.6, 18.0, −4.6, −4.7; HRMS (ESI) m/z: calcd for C₁₉H₂₇O₃Si [M + H]⁺: 331.1724, found 331.1720; calcd for C₁₉H₂₆O₃NaSi [M + Na]⁺: 353.1543, found 353.1538.

(5S,6S)-5-Hydroxy-6-((E)-styryl)-5,6-dihydro-2H-pyran-2-one (6) and (5S,6R)-5-Hydroxy-6-((E)-styryl)-5,6-dihydro-2H-pyran-2-one (17)

The previously described BF₃·OEt₂ deprotection procedure for the conversion of 4 and 15 from 14 was employed for compound 16 (100 mg) furnishing TBS-deprotected lactone 17 (19.6 mg, 30%) and C-5-epimerized lactone 6 (40.5 mg, 62%) as yellow oils, respectively.

Compound (6): R_f 0.60 (40% EtOAc–petroleum ether); [α]_D²⁴ +61.28; ¹H NMR (400 MHz, CDCl₃) δ_H 7.40–7.28 (m, 5H), 6.87 (dd, J = 2.4, 9.8 Hz, 1H), 6.77 (d, J = 15.9 Hz, 1H), 6.22 (dd, J = 7.3, 15.9 Hz 1H), 5.97 (dd, J = 1.2, 9.8, Hz 1H), 4.86–4.81 (m, 1H), 4.43–4.38 (m, 1H), 3.13 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ_C 163.2, 148.7, 135.6, 135.5, 128.7, 128.6, 126.9, 123.2, 120.5, 83.3, 66.1 ppm; HRMS (ESI) m/z calcd for C₁₃H₁₂O₃Na [M + Na]⁺: 239.0679, found 239.0679.

Compound (17): R_f 0.48 (40% EtOAc–petroleum ether); [α]_D²⁴ +185.34 (c 2.6, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 7.41–7.36 (m, 2H), 7.32–7.24 (m, 3H), 7.00 (dd, J = 5.5, 9.8 Hz, 1H), 6.82 (d, J = 15.9 Hz, 1H), 6.39 (dd, J = 16.5, 6.7 Hz, 1H), 6.12 (d, J = 9.8 Hz, 1H), 5.01 (dd, J = 3.1, 6.7 Hz, 1H), 4.27–4.25 (m, 1H), 2.93 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ_C 163.6, 144.9, 135.7, 135.2, 128.7, 128.5, 126.9, 122.7, 121.8, 81.4, 63.1 ppm; HRMS (ESI) m/z: calcd for C₁₃H₁₂O₃Na [M + Na]⁺: 239.0679, found 239.0681.

(5S,6R)-5-((tert-Butyldimethylsilyl)oxy)-6-((1S,2R)-1,2-dihydroxy-2-phenylethyl)-5,6-dihydro-2H-pyran-2-one (18) and Oxa-Michael Addition Product (19)

TBS-protected ene-lactone 16 (135 mg) was dissolved in acetone/H₂O (2:1) at rt, and K₂OsO₄·2H₂O and the NMO were added to the resulting solution. The reaction mixture turns black. The reaction mixture was stirred at rt for 24 h. After completion of the reaction (TLC), the reaction mixture was poured into aq. Na₂S₂O₃ (5%, 20 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (3 × 20 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO₃, and then brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluted with 8% EtOAc–petroleum ether) to furnish diol 18 (89.4 mg, 60%) and oxa-Michael addition product 19 (15 mg, 10%) as colorless solids, respectively.

Compound (18): mp: 160–163 °C; R_f 0.25 (30% EtOAc–petroleum ether); [α]_D²⁴ −212.59 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 7.41–7.32 (m, 5H), 6.74 (dd, J = 3.7, 9.8 Hz, 1H), 5.95 (d, J = 9.8 Hz, 1H), 5.07–5.05 (m, 1H), 4.69 (dd, J = 3.7, 6.7 Hz, 1H), 4.42 (t, J = 6.1 Hz, 1H), 3.86 (d, J = 5.5 Hz, 1H), 3.14–3.09 (m, 1H), 3.00 (brs, 1H), 0.96 (s, 9H), 0.19 (s, 3H), 0.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ_C 162.3, 148.0, 140.5, 128.8, 128.6, 128.2, 126.7, 126.5, 120.1, 82.4, 75.6, 71.8, 63.2, 25.7, 25.5, 18.0, −4.4, −4.4; HRMS (ESI) m/z: calcd for C₁₉H₂₉O₅Si [M + H]⁺: 365.1779, found 365.1777.

Compound (19): mp: 132–134 °C; R_f 0.54 (30% EtOAc–petroleum ether); [α]_D²⁴ −82.59 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ_H 7.43–7.30 (m, 5H), 4.89 (brs, 1H), 4.72 (dd, J = 2.2, 4.58 Hz, 1H), 4.41 (dd, J = 2.2, 4.5 Hz, 1H), 4.31 (brs, 1H), 4.15–4.14 (m, 1H), 3.12 (dd, J = 5.5, 19.3 Hz, 1H), 2.80 (d, J = 19.5 Hz, 1H), 1.60 (brs, 1H), 0.92 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ_C 169.0, 135.8, 128.9, 128.4, 126.3, 79.1, 71.2, 70.4, 69.8, 61.1, 32.0, 25.6, 17.9, −4.7, −4.8; HRMS (ESI) m/z: calcd for C₁₉H₂₈O₅NaSi [M + Na]⁺: 387.1598, found 387.1595.

(1R,5R,7R,8S)-8-((tert-Butyldimethylsilyl)oxy)-7-((S)-hydroxy(phenyl)methyl)-2,6-dioxabicyclo[3.2.1]octan-3-one (20)

A round-bottom flask equipped with a magnetic stirrer was charged with tert-butyl alcohol (5 mL), water (5 mL), and 1.4 g of AD-mix-α. Stirring at rt produced two clear phases; the lower aqueous phase appears bright yellow. The mixture was cooled to 0 °C. The olefin compound, 16, was added at once and the heterogeneous slurry was stirred vigorously at 0 °C for 24 h (progress was monitored by TLC). While the mixture was stirred at 0 °C, anhydrous sodium sulfite (1.5 g) was added, and the mixture was allowed to warm to rt and further stirred for 30 min. EtOAc (10 mL) was added to the reaction mixture, and after separation of the layers, the aqueous phase was further extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude reaction mixture, thus, obtained was further purified by silica gel flash column chromatography eluting with EtOAc/petroleum ether (1:1) to afford exclusively the oxa-Michael addition product, 20 (82 mg, 65%), as a colorless solid.

Mp: 135–136 °C; R_f 0.44 (30% EtOAc–petroleum ether); [α]_D²⁴ +21.59 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ_H 7.40–7.28 (m, 5H), 4.69 (brs, 1H), 4.44 (d, J = 5.5 Hz, 1H), 4.40 (d, J = 3.7 Hz, 1H), 4.23 (brs, 1H), 4.11–4.09 (m, 1H), 2.86–2.78 (m, 2H), 2.70–2.65 (m, 1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ_C 169.3, 139.4, 128.7, 128.6, 126.5, 87.3, 79.6, 73.8, 73.5, 68.6, 36.0, 25.5, 17.9, −5.0, −5.1; HRMS (ESI) m/z: calcd for C₁₉H₂₈O₅NaSi [M + Na]⁺: 387.1598, found 387.1588.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03263.

• Copies of ¹H, ¹³C NMR spectra and HRMS data of all compounds (Scheme S1) (PDF)

Author Contributions

^§ T.K.K. and S.P. contributed equally to this work.

The authors declare no competing financial interest.