Chemical and Pharmaceutical Bulletin
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Total Synthesis of Marine Polyketide Plakortone Q
Shinnosuke OkazakiKaho SendaAyaka TokutaMisa InagakiKazuo KamaikeKoichiro Ota Hiroaki Miyaoka
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Supplementary material

2024 Volume 72 Issue 2 Pages 179-185

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Abstract

The total synthesis of the natural bicyclo[3.3.0]furanolactone polyketide, plakortone Q, was achieved in 24 steps from (R)-Roche ester. The main feature of this synthetic strategy is the stereoselective construction of a central tetrahydrofuran moiety with four consecutive stereoisomeric centers using the Upjohn dihydroxylation of oxiranyl-substituted alkenes and acid-mediated 5-endo-tet cyclization.

Introduction

In 2016, Taglialatela-Scafati et al. discovered plakortone Q (1), a novel polyketide with a bicyclo[3.3.0]furanolactone core,18) during their search for and structural elucidation of biologically active components from the marine sponge Plakortis simplex9) (Fig. 1). They assigned the overall planar structure and relative configuration of the bicyclic moiety in 1 based on a combination of 3JH–H values and J-based configuration analysis and nuclear Overhauser effect spectroscopy (NOESY) correlation-based conformational analysis. In addition, the absolute configurations of the rigid bicyclic core were identified as 3S, 4S, 5S, and 6S via the modified Mosher method using α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) esters derived from 1.

Fig. 1. Structure of Plakortone Q (1)

However, the absolute configuration of C-8 could not be determined because the conformational relationship had been truncated by sp3-hybridized C-7 methylene carbon. In 2017, Zhang and colleagues reported the deduced absolute configuration of the C-8 position as the S configuration based on quantum mechanical and time-dependent density functional theory electron circular dichroism (TDDFT ECD) calculations of the 8S and 8R stereoisomers and comparison with the spectral data of 1.10) In our 2022 study of the biomimetic total synthesis of plakortone Q (1), we synthesized both 8S and 8R stereoisomers and determined their absolute configurations as 3S, 4S, 5S, 6S, and 8S.11)

In our previous study,11) we found structural homology between plakdiepoxide (2), an unprecedented acyclic polyketide containing a vicinal syn-diepoxide moiety on the acyclic chain isolated from P. simplex, and plakortone Q (1). Therefore, we hypothesized that these two natural products would be biosynthesized via the same precursor. Based on this hypothesis, we set out to biomimetically synthesize 1 via 2 (Chart 1). Synthesis of 1 was achieved using two asymmetric epoxidation reactions of C-5/C-6 and C-3/C-4 double bonds to give a vicinal syn-diepoxide with four stereocenters. This was followed by C1-homologation and esterification to 2 and sequential 5-endo-tet/5-endo-tet cyclization under acidic conditions. This was the first reported total synthesis of plakortone Q (1) and plakdiepoxide (2). Furthermore, by applying this synthetic route to the enantiomer of allylic alcohol 3, we were able to identify various spectral differences between the synthesized 8R isomers and natural 1 and 2. Thus, we determined the absolute configuration of the C-8 position as the S configuration.

Chart 1. Previously Reported Biomimetic Synthesis of Plakortone Q (1) via Plakdiepoxide (2)

However, there were two problems with this synthetic method. First, the poor stereoselectivity (diastereomeric ratio [dr] 6 : 1) of the first asymmetric epoxidation, which formed the C5–C6 epoxide, made it impossible to separate the resulting stereoisomers by column chromatography or to derivatize them to crystalline compounds under various conditions. Although the dr of vicinal-syn-diepoxide 6 was improved to 20 : 1 during the second asymmetric epoxidation, the synthesized plakdiepoxide and plakortone Q contained trace amounts of stereoisomers. Second, the synthesis of plakdiepoxide from vicinal-syn-diepoxide 6 using the C1-homologation process resulted in a low three-step yield (24%).

Therefore, in the current study, we developed a new synthetic route for the efficient synthesis of plakortone Q (1) by overcoming these two problems. Alkene A is stereoselectively dihydroxylated with a C-5/C-6 epoxide to form epoxydiol B by introducing the corresponding four stereocenters on the tetrahydrofuran ring (Chart 2). Epoxydiol B is then cyclized with epoxide cleavage under acidic conditions to form tetrahydrofuran, followed by oxidative lactonization of tetrahydrofuran C to stepwise construct the bicyclo[3.3.0]furanolactone motif.

Chart 2. New Synthetic Strategy for Plakortone Q (1)

Results and Discussion

The synthesis of plakortone Q (1) began with the stereoselective construction of tetrahydrofuran 14 (Chart 3). Epoxyketone 8 (dr 6 : 1) was prepared via Sharpless asymmetric epoxidation in a manner similar to that used for the synthesis of 1 in our previous report.11) It was then converted to a C3-homologated silylether using the Wittig reaction by treatment with phosphonium ylide generated from (3-((tert-butyldimethylsilyl)oxy)propyl)triphenylphosphonium bromide.12) Subsequent desilylation afforded (E)-homoallylic alcohol 9 (dr 6 : 1) in 77% yield and (Z)-homoallylic alcohol 10 (dr 6 : 1) in 14% yield. The configurations of the double bonds formed in homoallylic alcohols 9 and 10 were determined using NOESY. For compound 9, the nOe correlations observed at H2-2/H2-13, H-3/H-5, and H-5/H-7α indicated that the geometry of the trisubstituted olefin is E. Similarly, for compound 10, the nOe correlations observed at H-2α/H-5 and H-3/H3-14 indicated that the configuration of the trisubstituted olefin is Z. These assignments were sufficient to determine the geometry of the trisubstituted olefins; however, because compounds 9 and 10 are mixtures of stereoisomers related to epoxides, steric compression effects were determined using chemical shifts.13,14) The chemical shift at C-5 as determined by 13C-NMR for the major stereoisomer 9a of compound 9 was 65.9 ppm, and for the major stereoisomer 10a of compound 10, it was 64.7 ppm. This indicated that the signal of compound 10a had shifted upfield. The C-13 chemical shift was 22.2 ppm for compound 9a and 27.4 ppm for compound 10a. This indicated that the signal of compound 9a had shifted upfield. Similar trends were observed for minor isomers 9b and 10b (see Supplementary Materials for details). These results suggest a shielding effect based on steric compression at the C-13 position (the E configuration) for compound 9 and at the C-5 position (the Z configuration) for compound 10, which supports the NOESY stereochemical assignment. The hydroxy group of (E)-homoallylic alcohol 9 was acetylated to give acetate 11 in 90% yield. This was followed by Upjohn dihydroxylation15) to obtain epoxydiols 12 with 3S, 4R, 5R, and 6R and 3R, 4S, 5S, and 6S configurations (dr 6 : 1). However, their stereoisomeric counterparts, epoxydiols 13 with 3R, 4S, 5R, and 6R and 3S, 4R, 5S, and 6S, were not formed. The stereochemistry of each product was then determined.

Chart 3. Synthesis of Tetrahydrofuran 15

Reagents and conditions: (a) (3-((tert-Butyldimethylsilyl)oxy)propyl)triphenylphosphonium bromide, KHMDS, THF, room temperature (r.t.); (b) TBAF, THF, r.t., 77% (for 9, 2 steps), 14% (for 10, 2 steps); (c) acetic anhydride, pyridine, r.t., 90%; (d) OsO4, NMO, H2O, acetone/tBuOH, r.t.; (e) 10-camphorsulfonic acid, CH2Cl2, r.t., 95% (2 steps); (f) 2,2-dimethoxypropane, pTsOH·H2O, CH2Cl2, r.t.; (g) K2CO3, MeOH, r.t., 80% (for 15, 2 steps), 13% (for 16, 2 steps).

A plausible mechanism for the Upjohn dihydroxylation stereoselectivity of the major stereoisomer 11a is shown in Chart 4. In general, isopropenyl-substituted epoxides preferentially adopt a conformation in which the C=C double bond of the isopropenyl group and the C–O bond of the oxirane are in gauche configuration in the ground state.16) Considering the two conformers TS-a and TS-b, in which the C3=C4 double bond and the C5–O single bond are in gauche configuration, conformer TS-b is considered to be energetically unfavorable compared to conformer TS-a because conformer TS-b is expected to have side-chain repulsion. In addition, the C5–C6 single bond must be in an eclipsed conformation with the C3=C4 double bond. Conversely, conformer TS-a can adopt a staggered conformation and has no energetically unfavorable factors. Therefore, it is expected that the main conformation of alkene 11a is almost always the gauche-form TS-a. Furthermore, for (3 + 2) cycloaddition to the C3=C4 double bond in conformer TS-a, considering both repulsive electrostatic interaction by the oxirane oxygen atom and steric repulsion from the side chain, the stereoselectivity can be easily explained by considering that it is caused by the approach of OsO4 from the opposite side of the C5–O bond in the gauche-form TS-a.17)

Chart 4. Plausible Mechanism for Osmium-Mediated Stereoselective Dihydroxylation

When the inseparable diastereomeric mixture epoxydiol 12 was subjected to a catalytic amount of 10-camphorsulfonic acid (CSA) in dichloromethane, 5-endo-tet cyclization proceeded to give tetrahydrofuran 14 in 95% yield in two steps as an inseparable diastereomeric mixture in a ratio of 6 : 1. After further protection of the 1,2-diol with 2,2-dimethoxypropane and pTsOH·H2O and deacetylation of the resulting acetonide by basic solvolysis, primary alcohol 15 was afforded as a single stereoisomer in 80% yield in two steps, and primary alcohol 16, a diastereomer derived from the stereoisomeric byproduct of the C-5/C-6 epoxide construction, was successfully separated from the main product in 13% yield in two steps. The absolute configurations of alcohols 15 and 16 were determined using NOESY (Fig. 2). For tetrahydrofuran 15, nOe correlations between H-3/H-7α, H-3/H3-14, H-3/H3-17, H-5/H-7β, H-5/H3-14, and H-5/H3-16 were observed. Similarly, nOe correlations between H-3/H-7α, H-3/H3-14, H-5/H-7α, H-5/H-7β, H-5/H3-14, and H-7α/H3-14 were observed for tetrahydrofuran 16. These results indicate that the H-3, H-5, H2-7, and H2-13 protons are located on the same side of the tetrahydrofuran ring in alcohols 15 and 16. Furthermore, because the absolute configuration at the C-5 chiral center is enantioselectively introduced by a known asymmetric epoxidation and there is no possibility of inversion, it was determined that the absolute configuration around the tetrahydrofuran ring in alcohol 15 is 3S, 4R, 5S, and 6S; similarly, the absolute configuration of alcohol 16 is 3R, 4S, 5R, and 6R.

Fig. 2. Selective nOe Correlations of Tetrahydrofurans 15 and 16

After the construction of tetrahydrofuran, to separate the stereoisomer derived from the byproducts of the asymmetric epoxidation, we were able to obtain alcohol 15 as a single stereoisomer by the conversion of the protecting group. We then proceeded with the total synthesis of plakortone Q (1). After deprotection of the isopropylidene group of alcohol 15 to form triol 17 in 83% yield, the primary and secondary alcohols were protected as bis-silyl ether 18 in 97% yield. Oxidation with pyridinium chlorochromate (PCC) led to oxidative lactonization with deprotection of the primary alcohol tert-butyldimethylsilyl (TBS) group. Finally, tetrabutylammonium fluoride (TBAF) was used to deprotect the secondary alcohol to synthesize 1 in 80% yield in two steps (Chart 5).

Chart 5. Completion of the Total Synthesis of Plakortone Q (1)

Reagents and conditions: (a) Conc. HCl aq., MeOH, 45 °C, 83%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 97%; (c) PCC, celite, CH2Cl2, r.t.; (d) TBAF, THF, r.t., 80% (2 steps).

We were very pleased to find that the spectroscopic data of 1, including 1H- and 13C-NMR spectra and the high-resolution mass spectrum, were identical to those of naturally occurring plakortone Q.9) In addition, signals derived from trace amounts of stereoisomer observed in the NMR spectra of our previously reported synthesis of plakortone Q via plakdiepoxide were not observed in the current synthesis. Furthermore, the optical rotation of synthetic 1 was [α]D25 −19.9 (c 0.32, CHCl3). This is consistent with [α]D −2.4 (c 0.4, CHCl3) for natural plakortone Q and is purer than the value of [α]D25 −19.8 (c 0.81, CHCl3) reported in our previous synthesis.11) Therefore, we believe this to be indicative of the true optical rotation value of plakortone Q.

Conclusion

We achieved efficient total synthesis of bicyclo[3.3.0]furanolactone polyketide, plakortone Q (1), in 11 steps and 34% overall yield, starting from a diastereomeric mixture of epoxyketone 8 derived from (R)-Roche ester. The synthetic route included osmium-mediated stereoselective dihydroxylation of oxiranyl-substituted alkene 11, acid-mediated 5-endo-tet cyclization, and oxidative lactonization as key steps to provide the unique fused bicyclic skeleton of the natural product.

Experimental

General Experimental Procedures

Optical rotations were measured with a JASCO P-1030 polarimeter. IR spectra were recorded with a JASCO FT-IR/620 spectrometer. 1H- and 13C-NMR spectra were recorded on a Bruker Biospin AVANCE III HD 400 (400 MHz for 1H, 100 MHz for 13C) and a Bruker Biospin AVANCE III HD 500 (500 MHz for 1H, 125 MHz for 13C). The reported chemical shifts (δ) in parts per million (ppm) were relative to the internal CHCl3 (7.26 ppm for 1H and 77.0 ppm for 13C); the coupling constant (J) values were measured in hertz. The coupling patterns are denoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). High resolution-electrospray ionization (HR-ESI)-MS spectra were obtained using a Micromass LCT spectrometer with a time-of-flight (TOF) analyzer. Precoated silica gel plates with a fluorescent indicator (Merck 60 F254) were used for analytical and preparative TLC. Flash column chromatography was performed using Kanto Chemical silica gel 60N (spherical, natural) 40–50 µm. All reagents and solvents were of commercial quality and were used as received.

(E)-4-((2R,3R)-3-Ethyl-3-((S)-2-methylhexyl)oxiran-2-yl)hex-3-en-1-ol and (E)-4-((2S,3S)-3-Ethyl-3-((S)-2-methylhexyl)oxiran-2-yl)hex-3-en-1-ol (9) and (Z)-4-((2R,3R)-3-ethyl-3-((S)-2-methylhexyl)oxiran-2-yl)hex-3-en-1-ol and (Z)-4-((2S,3S)-3-Ethyl-3-((S)-2-methylhexyl)oxiran-2-yl)hex-3-en-1-ol (10)

To a stirring suspension of (3-((tert-butyldimethylsilyl)oxy)propyl)triphenylphosphonium bromide (1.84 g, 3.57 mmol) in tetrahydrofuran (THF) (18.0 mL) was added potassium hexamethyldisilazide (KHMDS) (5.95 mL, 2.98 mmol, 0.5 M in toluene) dropwise at 0 °C and the mixture was stirred for 20 min at same temperature. A solution of acetate 8 (269 mg, 1.19 mmol) in THF (7.80 mL) was then added to the mixture at −78 °C and then warmed to ambient temperature. After stirring for 2.5 h, the reaction mixture was quenched with sat.NH4Cl aq., diluted with Et2O, washed with H2O and brine, dried over anhydrous MgSO4 and Na2SO4, and then concentrated in vacuo. The residue was passed through a pad of silica gel (hexane/EtOAc, 60 : 1) and then concentrated in vacuo to give a crude silyl ether.

To a stirring solution of above crude silyl ether in THF (23.8 mL) was added TBAF (3.57 mL, 3.57 mmol, 1.00 M in THF) at ambient temperature. After stirring for 1 h at same temperature, the reaction mixture was diluted with Et2O, washed with H2O and brine, dried over anhydrous MgSO4 and Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc, 4 : 1) to give (E)-homoallylic alcohol 9 (245 mg, 77% overall yield for two steps, dr 6 : 1) as a colorless oil and (Z)-homoallylic alcohol 10 (45.0 mg, 14% overall yield for two steps, dr 6 : 1) as a colorless oil.

(E)-Homoallylic alcohol 9: Rf 0.40 (hexane/EtOAc, 2 : 1); IR (neat) νmax = 3399, 2964, 2928, 2872, 1462, 1376, 1049 cm−1; 1H-NMR (CDCl3, 500 MHz) δ: 5.29 (1H, t, J = 7.6 Hz), 3.65 (2H, t, J = 6.6 Hz), 3.21 (0.86H, s), 3.17 (0.14H, s), 2.48–2.27 (2H, m), 2.22–2.08 (2H, m), 1.98 (1H, dd, J = 4.9, 13.9 Hz), 1.53–1.38 (2H, m), 1.36–1.16 (8H, m), 1.03 (0.43H, t, J = 7.7 Hz), 1.02 (2.57H, t, J = 7.6 Hz), 0.96–0.88 (9H, m); 13C-NMR (CDCl3, 125 MHz, major isomer) δ: 138.2 (C), 121.3 (CH), 66.0 (C), 65.9 (CH), 62.5 (CH2), 41.9 (CH2), 37.5 (CH2), 30.7 (CH2), 29.73 (CH), 29.3 (CH2), 22.92 (CH2), 22.2 (CH2), 21.0 (CH2), 20.0 (CH3), 14.1 (CH3), 13.4 (CH3), 9.2 (CH3); 13C-NMR (CDCl3, 125 MHz, minor isomer) δ = 138.0 (C), 121.2 (CH), 66.1 (C), 65.1 (CH), 62.5 (CH2), 42.0 (CH2), 36.8 (CH2), 29.8 (CH), 29.69 (CH2), 29.2 (CH2), 22.97 (CH2), 22.4 (CH2), 21.3 (CH2), 20.4 (CH3), 14.1 (CH3), 13.5 (CH3), 9.4 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H32O2Na 291.2300, Found 291.2294.

(Z)-Homoallylic alcohol 10: Rf 0.50 (hexane/EtOAc, 2 : 1); IR (neat) νmax = 3399, 2962, 2928, 2873, 1462, 1378, 1051 cm−1; 1H-NMR (CDCl3, 500 MHz) δ: 5.38 (1H, ddd, J = 1.5, 7.0, 8.6 Hz), 3.70 (1H, dt, J = 5.6, 11.1 Hz), 3.59 (1H, ddd, J = 5.1, 8.5, 10.2 Hz), 3.38 (0.86H, s), 3.34 (0.14H, s), 2.60–2.50 (1H, m), 2.36–2.28 (1H, m), 2.06–1.99 (2H, m), 1.95 (1H, dd, J = 5.0, 14.1 Hz), 1.75–1.43 (4H, m), 1.36–1.11 (6H, m), 1.05 (3H, t, J = 7.5 Hz), 0.97 (3H, t, J = 7.5 Hz), 0.94 (3H, d, J = 6.7 Hz), 0.90 (3H, t, J = 6.8 Hz); 13C-NMR (CDCl3, 125 MHz, major isomer) δ: 138.7 (C), 123.5 (CH), 64.7 (CH), 63.75 (C), 62.1 (CH2), 41.4 (CH2), 37.5 (CH2), 31.45 (CH2), 29.6 (CH), 29.25 (CH2), 27.4 (CH2), 22.87 (CH2), 22.8 (CH2), 20.2 (CH3), 14.1 (CH3), 12.8 (CH3), 9.0 (CH3); 13C-NMR (CDCl3, 125 MHz, minor isomer) δ: 138.8 (C), 123.2 (CH), 63.9 (C), 63.74 (CH), 62.2 (CH2), 41.6 (CH2), 37.1 (CH2), 31.51 (CH2), 29.7 (CH), 29.23 (CH2), 27.6 (CH2), 23.1 (CH2), 22.93 (CH2), 20.5 (CH3), 14.1 (CH3), 12.9 (CH3), 9.3 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H32O2Na 291.2300, Found 291.2294.

(E)-4-((2R,3R)-3-Ethyl-3-((S)-2-methylhexyl)oxiran-2-yl)hex-3-en-1-yl Acetate and (E)-4-((2S,3S)-3-Ethyl-3-((S)-2-methylhexyl)oxiran-2-yl)hex-3-en-1-yl Acetate (11)

To a solution of (E)-homoallylic alcohol 9 (161 mg, 0.600 mmol) in pyridine (1.46 mL, 18.0 mmol) was added Ac2O (1.14 mL, 12.0 mmol) at ambient temperature, and the mixture was stirred at the same temperature for 30 min. The mixture was concentrated in vacuo, and then the residue was purified with flash column chromatography on silica gel (hexane/EtOAc, 15 : 1) to give acetate 11 (168 mg, 90% yield, dr 6 : 1) as a colorless oil.

Acetate 11: Rf 0.50 (hexane/EtOAc, 5 : 1); IR (neat) νmax = 2964, 2929, 2873, 1744, 1466, 1380, 1364, 1239, 1035 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 5.28 (1H, t, J = 7.3 Hz), 4.06 (2H, t, J = 6.9 Hz), 3.20 (0.86H, s), 3.16 (0.14H, s), 2.48–2.34 (2H, m), 2.20–2.05 (2H, m), 2.03 (3H, s), 1.97 (1H, dd, J = 4.9, 13.9 Hz), 1.53–1.10 (10H, m), 1.07–1.00 (3H, m), 0.96–0.88 (9H, m); 13C-NMR (CDCl3, 100 MHz) δ: 171.0 (C), 137.7 (C), 137.6 (C), 120.7 (CH), 120.6 (CH), 66.0 (C), 65.8 (C), 65.7 (CH), 64.9 (CH), 63.9 (CH2), 42.0 (CH2), 41.8 (CH2), 37.4 (CH2), 36.8 (CH2), 29.8 (CH), 29.7 (CH), 29.21 (CH2), 29.18 (CH2), 26.6 (CH2), 22.93 (CH2), 22.87 (CH2), 22.2 (CH2), 22.1 (CH2), 21.1 (CH2), 20.9 (CH3), 20.8 (CH2), 20.4 (CH3), 20.0 (CH3), 14.1 (CH3), 13.34 (CH3), 13.30 (CH3), 9.4 (CH3), 9.1 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H34O3Na 333.2406, Found 333.2397.

2-((2S,3S,4R,5S)-3,5-Diethyl-3,4-dihydroxy-5-((S)-2-methylhexyl)tetrahydrofuran-2-yl)ethyl Acetate and 2-((2R,3R,4S,5R)-3,5-Diethyl-3,4-dihydroxy-5-((S)-2-methylhexyl)tetrahydrofuran-2-yl)ethyl Acetate (14)

To a stirring solution of acetate 11 (110 mg, 0.354 mmol) in tBuOH/acetone/H2O (1 : 1 : 1, 7.00 mL) were added OsO4 (45.0 mg, 0.0177 mmol, 10% in microcapsule) and NMO (62.2 mg, 0.531 mmol) at ambient temperature. After stirring for 80 h, Na2SO3 was added to the reaction mixture, and the mixture was diluted with Et2O. The organic layer was washed with H2O and brine. The organic layer was dried over Na2SO4, and then concentrated in vacuo, the residue was passed through a pad of silica gel (hexane/EtOAc, 4 : 1) and then concentrated in vacuo to give a mixture of crude epoxydiol 12.

To the above crude epoxydiol 12 was added a solution of 10-camphorsulfonic acid (69.9 mg, 0.301 mmol) in CH2Cl2 (7.00 mL) at ambient temperature. After stirring for 30 min, the reaction mixture was concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc, 3 : 1) to give tetrahydrofuran 14 (115 mg, 95% overall yield for two steps, dr 6 : 1) as a colorless oil.

Tetrahydrofuran 14: Rf 0.40 (hexane/EtOAc, 2 : 1); IR (neat) νmax = 3473, 2960, 2928, 1741, 1722, 1462, 1365, 1246, 1044 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 4.26 (1H, ddd, J = 5.5, 6.4, 10.9 Hz), 4.14 (1H, ddd, J = 6.9, 7.9, 10.9 Hz), 3.79 (0.14H, d, J = 9.2 Hz), 3.71 (0.86H, d, J = 8.9 Hz), 3.65 (1H, dd, J = 4.6, 8.2 Hz), 2.53 (0.86H, d, J = 8.9 Hz), 2.51 (0.14H, d, J = 9.2 Hz), 2.05 (0.43H, s), 2.04 (2.57H, s), 1.99 (0.86H, s), 1.96 (0.14H, s), 1.88–1.82 (2H, m), 1.70–1.12 (13H, m), 0.98 (3H, t, J = 7.5 Hz), 0.96–0.88 (9H, m); 13C-NMR (CDCl3, 100 MHz) δ: 171.0 (C), 85.0 (C), 84.6 (C), 82.2 (CH), 81.7 (CH), 80.5 (C), 80.4 (C), 76.4 (CH), 76.2 (CH), 62.03 (CH2), 62.00 (CH2), 43.2 (CH2), 42.5 (CH2), 38.5 (CH2), 38.2 (CH2), 29.3 (CH2), 29.2 (CH2), 29.0 (CH), 28.80 (CH2), 22.75 (CH), 28.4 (CH2), 28.2 (CH2), 26.7 (CH2), 22.9 (CH2), 21.00 (CH3), 20.97 (CH3), 14.1 (CH3), 8.4 (CH3), 8.04 (CH3), 8.02 (CH3), 7.97 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H36O5Na 367.2460, Found 367.2454.

2-((3aR,4S,6S,6aS)-3a,6-Diethyl-2,2-dimethyl-6-((S)-2-methylhexyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol (15) and 2-((3aS,4R,6R,6aR)-3a,6-Diethyl-2,2-dimethyl-6-((S)-2-methylhexyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol (16)

To a stirring solution of tetrahydrofuran 14 (115 mg, 0.334 mmol) in CH2Cl2 (6.60 mL) were added 2,2-dimethoxypropane (0.368 mL, 3.01 mmol) and pTsOH·H2O (6.4 mg, 0.0334 mmol) at ambient temperature. After stirring for 60 min, the mixture was diluted with Et2O. The organic layer was washed with sat.NaHCO3 aq., H2O, and brine. The organic layer was dried over Na2SO4, and then concentrated in vacuo, the residue was passed through a pad of silica gel (hexane/EtOAc, 12 : 1) and then concentrated in vacuo to give a mixture of crude acetonide.

To a stirring solution of the above crude acetonide in MeOH (6.20 mL) was added K2CO3 (171 mg, 1.24 mmol) at ambient temperature. After stirring for 60 min, the mixture was diluted with Et2O and then filtrated through a pad of silica gel (Et2O) and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc, 5 : 1) to give primary alcohol 15 (90.0 mg, 80% overall yield for two steps) as a colorless oil and primary alcohol 16 (15.0 mg, 13% overall yield for two steps) as a colorless oil.

Primary alcohol 15: Rf 0.30 (hexane/EtOAc, 4 : 1); [α]25D −39.5 (c 1.00, CHCl3); IR (neat) νmax = 3434, 2961, 2928, 2875, 1462, 1378, 1366, 1240, 1135, 1059 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 3.94 (1H, s), 3.80–3.76 (2H, m), 3.76 (1H, dd, J = 2.8, 9.8 Hz), 2.57 (1H, dd, J = 4.0, 7.2 Hz), 2.00 (1H, m), 1.88–1.64 (6H, m), 1.56 (3H, s), 1.51 (3H, s), 1.34 (1H, dd, J = 3.1, 14.8 Hz), 1.29–1.18 (7H, m), 1.02 (3H, t, J = 7.3 Hz), 0.98 (3H, d, J = 6.6 Hz), 0.90 (3H, t, J = 6.8 Hz), 0.87 (3H, t, J = 7.5 Hz); 13C-NMR (CDCl3, 100 MHz) δ: 112.5 (C), 93.7 (C), 90.4 (CH), 88.1 (C), 82.2 (CH), 61.7 (CH2), 38.9 (CH2), 36.1 (CH2), 32.2 (CH2), 30.5 (CH2), 29.2 (CH2), 28.5 (CH), 28.0 (CH3), 27.9 (CH3), 24.6 (CH2), 22.9 (CH2), 20.2 (CH3), 14.1 (CH3), 9.1 (CH3), 9.0 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H38O4Na 365.2668, Found 365.2661.

Primary alcohol 16: Rf 0.40 (hexane/EtOAc, 4 : 1); [α]25D +30.9 (c 0.53, CHCl3); IR (neat) νmax = 3434, 2962, 2928, 2872, 1462, 1378, 1367, 1240, 1136, 1059 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 3.95 (1H, s), 3.79–3.75 (2H, m), 3.71 (1H, dd, J = 2.7, 10.1 Hz), 2.59 (1H, br s), 2.00 (1H, dddd, J = 5.4, 7.4, 10.0, 14.8 Hz), 1.86–1.53 (7H, m), 1.51 (3H, s), 1.41 (3H, s), 1.40 (1H, dd, J = 6.4, 14.9 Hz), 1.33–1.21 (4H, m), 1.20 (1H, dd, J = 5.3, 14.9 Hz), 1.07 (1H, m), 1.02 (3H, t, J = 7.4 Hz), 0.93 (3H, d, J = 6.7 Hz), 0.89 (3H, t, J = 7.0 Hz), 0.88 (3H, t, J = 7.5 Hz); 13C-NMR (CDCl3, 100 MHz) δ: 112.5 (C), 93.8 (C), 90.1 (CH), 87.8 (C), 82.3 (CH), 61.9 (CH2), 37.2 (CH2), 36.9 (CH2), 32.1 (CH2), 30.6 (CH2), 29.4 (CH2), 28.3 (CH), 28.1 (CH3), 27.9 (CH3), 24.8 (CH2), 23.0 (CH2), 21.6 (CH3), 14.2 (CH3), 9.1 (CH3), 9.0 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H38O4Na 365.2668, Found 365.2661.

(2S,3R,4S,5S)-2,4-Diethyl-5-(2-hydroxyethyl)-2-((S)-2-methylhexyl)tetrahydrofuran-3,4-diol (17)

To a stirring solution of primary alcohol 15 (44.0 mg, 0.128 mmol) in MeOH (10.2 mL) were added 12 M HCl aq. (2.56 mL) at ambient temperature and then warmed to 45 °C. After stirring for 50 h, the mixture was cooled to ambient temperature and diluted with Et2O. The organic layer was washed with H2O and brine. The organic layer was dried over Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc, 3 : 2) to give triol 17 (32.1 mg, 83% yield) as a colorless oil.

Triol 17: Rf 0.20 (hexane/EtOAc, 2 : 1); [α]25D −17.5 (c 0.83, CHCl3); IR (neat) νmax = 3390, 2960, 2926, 2873, 1462, 1378, 1054 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 3.86–3.79 (2H, m), 3.76 (1H, dd, J = 3.8, 9.0 Hz), 3.72 (1H, d, J = 8.9 Hz), 2.77 (1H, d, J = 8.9 Hz), 2.77 (2H, br s), 1.90 (1H, dddd, J = 4.0, 9.0, 14.7, 17.8 Hz), 1.76 (1H, ddq, J = 3.6, 5.6, 9.2 Hz), 1.74–1.39 (6H, m), 1.34–1.12 (7H, m), 0.98 (3H, t, J = 7.6 Hz), 0.95 (3H, d, J = 6.5 Hz), 0.92 (3H, t, J = 7.4 Hz), 0.89 (3H, t, J = 6.7 Hz); 13C-NMR (CDCl3, 100 MHz) δ: 85.6 (C), 81.8 (CH), 80.2 (C), 79.8 (CH), 60.9 (CH2), 42.8 (CH2), 38.4 (CH2), 30.7 (CH2), 29.2 (CH2), 29.1 (CH2), 28.7 (CH), 26.6 (CH2), 22.9 (CH2), 21.2 (CH3), 14.1 (CH3), 8.3 (CH3), 8.1 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H34O4Na 325.2355, Found 325.2352.

(2S,3R,4R,5S)-4-((tert-Butyldimethylsilyl)oxy)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,5-diethyl-5-((S)-2-methylhexyl)tetrahydrofuran-3-ol (18)

To a stirring solution of triol 17 (15.5 mg, 0.0512 mmol) in CH2Cl2 (1.00 mL) were added 2.6-lutidine (0.0588 mL, 0.256 mmol) and TBSOTf (0.0596 mL, 0.512 mmol) at 0 °C. After stirring for 60 min, the mixture was diluted with Et2O. The organic layer was washed with sat.NaHCO3 aq., H2O, and brine. The organic layer was dried over Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc, 50 : 1) to give bis-silyl ether 18 (26.3 mg, 97% yield) as a colorless oil.

Bis-silyl ether 18: Rf 0.80 (hexane/EtOAc, 5 : 1); [α]25D −19.8 (c 1.32, CHCl3); IR (neat) νmax = 3545, 2956, 2929, 2858, 1472, 1361, 1256, 1088 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 3.87 (1H, s), 3.82 (1H, dd, J = 4.7, 7.4 Hz), 3.77 (1H, dq, J = 0.9, 9.9 Hz), 3.71 (1H, ddd, J = 6.6, 7.6, 9.9 Hz), 2.70 (1H, br s), 1.80–1.75 (2H, m), 1.66–1.42 (5H, m), 1.38–1.09 (8H, m), 0.95–0.88 (12H, m), 0.93 (9H, s), 0.88 (9H, s), 0.13 (3H, s), 0.12 (3H, s), 0.041 (3H, s), 0.039 (3H, s); 13C-NMR (CDCl3, 100 MHz) δ: 84.2 (C), 82.4 (CH), 79.3 (C), 75.9 (CH), 60.4 (CH2), 43.9 (CH2), 38.7 (CH2), 33.4 (CH2), 30.3 (CH2), 29.4 (CH2), 28.9 (CH), 27.5 (CH2), 25.93 (CH3) × 3, 25.88 (CH3) × 3, 23.0 (CH2), 21.6 (CH3), 18.2 (C), 18.1 (C), 14.2 (CH3), 8.5 (CH3), 8.3 (CH3), −3.8 (CH3), −4.4 (CH3), −5.3 (CH3), −5.4 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C29H62O4NaSi2 553.4084, Found 553.4083.

(3aS,5S,6S,6aS)-5,6a-Diethyl-6-hydroxy-5-((S)-2-methylhexyl)tetrahydrofuro[3,2-b]furan-2(3H)-one (1), Plakortone Q

To a stirring solution of bis-silyl ether 18 (14.3 mg, 0.0269 mmol) in CH2Cl2 (1.10 mL) were added PCC (23.2 mg, 0.108 mmol) and celite (36.0 mg) at ambient temperature. After stirring for 17 h, the mixture was diluted with Et2O and then the residue was passed through a pad of silica gel (hexane/EtOAc, 10 : 1) and then concentrated in vacuo to give a crude lactone.

To a stirring solution of above crude lactone in THF (1.10 mL) was added TBAF (0.0538 mL, 0.0538 mmol, 1.00 M in THF) at ambient temperature. After stirring for 1 h at same temperature, the reaction mixture was diluted with Et2O, washed with sat.NH4Cl aq., H2O, and brine, dried over anhydrous MgSO4 and Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/acetone, 7 : 1) to give plakortone Q (1) (6.4 mg, 80% overall yield for two steps) as a colorless oil.

Plakortone Q (1): Rf 0.40 (hexane/acetone, 3 : 1); [α]25D −19.9 (c 0.32, CHCl3); IR (neat) νmax = 3468, 2928, 1783, 1462, 1219, 1127 cm−1; 1H-NMR (CDCl3, 500 MHz) δ: 4.33 (1H, dd, J = 0.6, 5.5 Hz), 3.87 (1H, d, J = 10.3 Hz), 2.77 (1H, dd, J = 5.5, 18.5 Hz), 2.67 (1H, dd, J = 0.6, 18.5 Hz), 2.25 (1H, d, J = 10.3 Hz), 1.92 (1H, dq, J = 14.5, 7.5 Hz), 1.79 (1H, dq, J = 14.5, 7.4 Hz), 1.62 (1H, dq, J = 14.2, 7.4 Hz), 1.57–1.45 (3H, m), 1.36 (1H, dd, J = 7.0, 14.5 Hz), 1.36–1.20 (5H, m), 1.16 (1H, m), 1.04 (3H, t, J = 7.4 Hz), 0.95 (3H, d, J = 6.7 Hz), 0.91 (3H, t, J = 7.4 Hz), 0.89 (3H, t, J = 7.0 Hz); 13C-NMR (CDCl3, 125 MHz) δ: 174.7 (C), 94.9 (C), 88.3 (C), 81.6 (CH), 77.3 (CH), 42.4 (CH2), 38.3 (CH2), 38.0 (CH2), 29.2 (CH2), 29.1 (CH2), 28.5 (CH), 26.0 (CH2), 22.9 (CH2), 21.1 (CH3), 14.1 (CH3), 8.1 (CH3), 7.9 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H30O4Na 321.2042, Found 321.2041.

Conflict of Interest

The authors declare no conflict of interest.

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References
 
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