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. 2020 Apr 23;5(17):10217–10224. doi: 10.1021/acsomega.0c01474

Stereoselective Synthesis of the C1–C16 Fragment of the Purported Structure of Formosalide B

Srinivas Gajula †,‡, Aedula Vishnu V Reddy †, D Prabhakar Reddy †,‡, Jhillu S Yadav †, Debendra K Mohapatra †,‡,*
PMCID: PMC7203982  PMID: 32391510

Abstract

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The first stereoselective synthesis of the C1–C16 fragment possessing stereo-enriched fully substituted tetrahydropyran (THP) along with tetrahydrofuran (THF) rings of the proposed structure of formosalide B is described in 12 longest linear steps with 22% overall yield, starting from two cheap and commercially available 1,5-pentanediol and l-glutamic acid, following a convergent approach. The key steps involve in this synthesis are Horner–Wadsworth–Emmons reaction, Sharpless asymmetric dihydroxylation, and acid-mediated ketalization to assemble the substituted THP ring, one-pot Sharpless dihydroxylation–SN2-type cyclization, and Wittig homologation to construct the THF derivative.

Introduction

Marine dinoflagellates have been proven to be important sources for isolation of a diverse range of biologically active natural products, which intrigue chemists of their complexity in structures.1 Few representative bioactive molecules from dinoflagellates are okadaic acids, brevetoxins, and amphidinolides with unique structures. An okadaic acid, a polyether isolated from the black sponge Halichondria okadai, is a potent inhibitor for protein phosphatase PP1 and PP2A;2 brevetoxins, cyclic polyethers produced by Karenia brevis, are activators for voltage-sensitive sodium channels;3 amphidinolides are complex macrolides isolated from Amphidinium sp., which have exhibited strong cytotoxic activities against tumor cell lines.4

Recently, Lu’s research group isolated formosalides A (1) and B (2) from the cultured marine dinoflagellate Prorocentrum sp., which was extracted from the wash-off epiphytes of sea woods at South bay, southern Taiwan (Figure 1).5 Formosalides A (1) and B (2) are 17-membered ring macrolides consist of a substituted tetrahydropyran (THP) ring along with a tetrahydrofuran (THF) ring and a C-14 linear side chain attached to a ring at C16 having four cis-olefins. The gross structure and relative configuration of formosalides A and B were assigned based on the 1H NMR coupling constants and extensive 2D NMR studies (Figure 1). Only the relative configurations of the tetrahydrofuran, tetrahydropyran, and C16–C18 moieties have been determined by NMR analysis. However, the relative configuration between these moieties and the total absolute configuration have not been identified yet. Formosalides A and B also have been shown to exhibit good cytotoxicity activity against CCRF-CEM human T-cell acute lymphoblastic leukemia cells and/or DLD-1 human colon adenocarcinoma cells in vitro. (LD50 values of A: 0.54 and >40 μg/mL; those of B: 0.43 and 2.73 μg/mL, respectively).

Figure 1.

Figure 1

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Proposed structures of formosalide A and B (1, 2).

In continuation of our research efforts toward the total syntheses of biologically active natural products that contain THF and THP rings,6 herein, we report a simple, efficient, and convergent synthetic strategy for the synthesis of the C1–C16 fragment of the proposed structure of formosalide B (2). It is worth mentioning here that even though the molecule was isolated in 2009, till now, no synthesis or synthetic approach is reported for formosalides A and B.

According to our retrosynthetic analysis, the THP–THF core 3 of formosalide B (C1–C16 fragment) could be synthesized by acid-catalyzed ketalization of diol, which could be derived via Sharpless asymmetric dihydroxylation of enone 4. The key intermediate 4 would be accessed from the Horner–Wadsworth–Emmons (HWE) reaction of phosphonate 5 and the aldehyde 6. The THF ring of phosphonate 5 could be derived from the well-known lactone 7 via tandem Sharpless asymmetric dihydroxylation (SAD)–SN2 cyclization on α,β-unsaturated ester in a complete stereospecific manner. The aldehyde 6 from commercially available 1,5-petanediol (8) via Wittig olefination, reduction of α,β-unsaturated ester, and Sharpless asymmetric epoxidation is shown in Scheme 1.

Scheme 1. Retrosynthetic Plan Featuring SAD/Ketalization and HWE Reaction.

Scheme 1

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Results and Discussion

The synthesis of phosphonate fragment 5 was started from the well-known TBDPS ether derivative 7(7) of (S)-5-hydroxymethyl-2,3-dihydrofuran-2(3H)-one, which was readily prepared from l-glutamic acid (Scheme 2). The lactone 7 was reduced with DIBAL-H at −78 °C, and the resulting hemiacetal was immediately allowed to undergo Wittig olefination using (ethoxycarbonyl-methylene)triphenyl phosphonate8 to provide the corresponding δ-hydroxy α,β-unsaturated ester as a mixture of geometrical isomers (95% of E-isomer confirmed by 1H NMR). The minor (Z)-isomer was then easily separated from the major (E)-isomer 9 by column chromatography.

Scheme 2. Synthesis of the Fragment 5.

Scheme 2

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The hydroxyl group of 9 was then converted into its mesylate ester 10 with MeSO2Cl, Et3N, and DMAP (catalytic) in CH2Cl2. The mesylate ester (plays dual role) can be used as a protecting group and a leaving group at the next stage of the synthesis. The mesylate derivative 10 was subjected to Sharpless asymmetric dihydroxylation9,10 (Scheme 2) with ligand hydroquinidine-1,4-phthalazinediyldiether [(DHQD)2PHAL], K3Fe(CN)6, K2CO3, MeSO2NH2, and OsO4 in t-BuOH/H2O (1:1) for 24 h to afford the trans-tetrahydrofuran 11 in 88% yield. The reaction proceeded via asymmetric dihydroxylation followed by intramolecular SN2 displacement in one pot to result in the trans-fused THF ring with excellent stereoselectivity (no traces of the other isomer was detectable by NMR), as shown in Scheme 2. The ester functionality of 11 was reduced with LiBH4 to obtain the diol 12 in 87% yield. Oxidative cleavage of diol with NaIO411 followed by Wittig olefination of the corresponding aldehyde 13 furnished α,β-unsaturated ester 14 in 80% yield over two steps. Ester 14 was then subjected to hydrogenation with the Pd/C catalyst in ethyl acetate under a hydrogen atmosphere to furnish the saturated ester 15 in quantitative yield. Nucleophilic addition of the lithiated derivative of dimethyl methyl phosphonate on ester 15 furnished the required β-keto phosphonate 5 in 90% yield (Scheme 2).

The synthesis of aldehyde 6 commenced from the known epoxy alcohol 16,12 which was prepared from commercially available 1,5-pentane diol (8) in five steps with 60% overall yield. Regioselective epoxide opening proceeded smoothly after treatment of the epoxy alcohol 16 with lithium dimethylcuprate (Me2CuLi) to afford 1,3-diol accompanied by the undesired 1,2-diol (6:1). The minor isomer 1,2-diol was readily removed by treating the mixture with sodium periodate to obtain pure 1,3-diol 17 in 75% yield possessing the anti-stereochemistry. Protection of the primary and secondary alcohols as bis-TBS ether 18 followed by selective deprotection of primary silyl ether with PPTS in methanol provided primary alcohol 19, which upon oxidation with Dess–Martin periodinane13 afforded the required aldehyde fragment 6 in 73% yield over three steps (Scheme 3).

Scheme 3. Synthesis of the Fragment 6.

Scheme 3

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After having the phosphonate 5 and aldehyde 6 in hand, we planned to conduct an experiment to couple both the fragments to achieve the THP ring. Accordingly, phosphonate 5 and aldehyde 6 were coupled under Horner–Wadsworth–Emmons conditions using LiCl and DIPEA in acetonitrile to furnish the enone 4 in 91% yield with E-geometry as the sole product. Dihydroxylation of the enone 4 using the Sharpless ligand (DHQD)2PHAL afforded the diol 20 in 80% yield with a diastereomeric ratio of 9:1. The low reactivity of the double bond in 20 required a longer reaction time at room temperature. The undesired minor isomer during the dihydroxylation reaction was separated by silica gel column chromatography. Finally, acid-mediated ketalization of diol 20 with PPTS in MeOH smoothly gave the fully functionalized THF–THP core structure 3 in 82% yield (Scheme 4). The 2,6-syn-geometry in the THF ring was expected to have the minimum dipole–dipole interaction compared to the 2,6-trans-geometry. The 2,6-syn-geometry was further assigned by the help of the NOESY experiment (Figure 2).

Scheme 4. Synthesis of the C1–C16 Fragment 3.

Scheme 4

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Figure 2.

Figure 2

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NOE interactions in the advanced intermediate 3.

The structure of C1–C16 fragment 3 was established by 1H, 13C, and 2D NMR data. The relative stereochemistry assignments of fragment 3 were made with the aid of TOCSY and NOESY experiments. The observation of NOE between H9 and H11, H10 and H12, H5 and H8, and H12 and H33 supported the relative stereochemistry of substituted THP and THF compound 3, which completes the synthesis of the C1–C16 fragment of the proposed structure of formosalide B (Figure 2).

Conclusions

In summary, we have developed an efficient and convergent stereoselective route for the synthesis of the C1–C16 fragment of the proposed formosalide B, a cytotoxic 17-membered ring macrolide, which consists of stereo-enriched substituted THP and THF rings. Our strategy is flexible and operationally simple, and we strongly believe that the synthetic strategy described in the manuscript is robust and will allow the completion of the total synthesis of formosalides A and B as well as other biologically significant similar THP and THF ring-containing natural products.

Experimental Section

General Information

Experiments that required an inert atmosphere were carried out under argon in flame-dried glassware. THF was freshly distilled over sodium/benzophenone and transferred via a syringe. Dichloromethane was freshly distilled from CaH2. Tertiary amines were freshly distilled over KOH. Commercially available reagents were used as received. Unless detailed otherwise, “workup” means pouring the reaction mixture into brine followed by extraction with the solvent indicated in parentheses. If the reaction medium was acidic (basic), additional washing with saturated aqueous NaHCO3 solution (saturated aqueous NH4Cl solutions) was performed. Washing with brine, drying over anhydrous Na2SO4, and evaporating the solvent under reduced pressure followed by chromatography on a silica gel column (60–120 mesh) with the indicated eluent furnished the corresponding products. The solutions were filtered through a Celite pad, the pad was additionally washed with the same solvent used, and the washings were incorporated to the main organic layer. 1H and 13C NMR chemical shifts (δ) are reported in ppm, and coupling constants (J) are reported in hertz (Hz). High-resolution mass spectra were run by the electron impact mode (ESIMS, 70 eV) or by the FAB mode (m-nitrobenzyl alcohol matrix) using an orbitrap mass analyzer. IR data were measured with oily films on NaCl plates (oils) or KBr pellets (solids). Specific optical rotations [α]D are given in 10–1 deg cm2 g–1 and were measured at 25 °C or otherwise mentioned. The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, and br = broad.

(S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (7)

To a stirred solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (2.0 g, 17.24 mmol) in CH2Cl2 (60 mL) under a nitrogen atmosphere was added imidazole (2.3 g, 34.48 mmol) followed by tert-butyldiphenylchlorosilane (5.6 g, 20.68 mmol) at 0 °C and allowed to stir for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (50 mL) and diluted with CH2Cl2 (100 mL), and the organic layer was separated. The organic layer was washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product that on purification by silica gel column chromatography (ethyl acetate/hexane produced = 1:19), furnished the desired lactone 7 (5.42 g, 89%). [α]D25 + 28.7 (c 0.9, CHCl3); lit.7d [α]D + 28.95 (c 2.0, CHCl3); IR (KBr): νmax 2952, 2858, 1772, 1110, 702 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.70–7.63 (m, 4 H), 7.47–7.65 (m, 6H), 4.62–4.57 (m, 1H), 3.88 (dd, J = 11.4, 3.4 Hz, 1H), 3.69 (dd, J = 11.4, 3.4 Hz, 1H), 2.71–2.63 (m, 1H), 2.55–2.47 (m, 1H), 2.33–2.18 (m, 2H), 1.06 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 177.4, 135.6, 135.5, 129.9, 127.8, 79.9, 65.5, 28.5, 26.7, 23.6, 19.2 ppm; HRMS (ESI): m/z calcd for C21H26O3Si [M + Na]+, 377.1549; found, 377.1568.

(S,E)-Ethyl-7-((tert-butyldiphenylsilyl)oxy)-6-hydroxyhept-2-enoate (9)

To a stirred solution of lactone 7 (4.5 g, 12.71 mmol) in CH2Cl2 (50 mL) at −78 °C under a nitrogen atmosphere, DIBAL-H (9.98 mL, 1.4 M in toluene, 13.98 mmol) was slowly added over a period of 15 min. After 30 min of stirring at the same temperature (TLC), the reaction was quenched by slow addition of saturated sodium potassium tartrate solution (50 mL), diluted with CH2Cl2 (50 mL), and allowed to stir at room temperature for another 2 h to get clear two separated layers. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 80 mL). The combined organic layer was washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude lactol, which was directly used for the next reaction without purification. The corresponding lactol was dissolved in toluene (100 mL) and was added with ethoxycarbonylmethylenetriphenyl phosphorane (8.84 g, 25.42 mmol) at room temperature. After stirring for 4 h at 100 °C, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to give 9 (4.43 g, 82% over two steps). [α]D25 – 6.07 (c 1.8, CHCl3); IR (KBr): νmax 3427, 2978, 1716, 1445, 1151, 1039, 922 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.67–7.63 (m, 4H), 7.45–7.36 (m, 6H), 6.94 (dt, J = 13.8, 7.0 Hz, 1H), 5.81 (dt, J = 17.2, 3.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.75–3.68 (m, 1H), 3.65 (dd, J = 10.2, 3.6 Hz, 1H), 3.49 (dd, J = 10.2, 7.2 Hz, 1H), 2.49 (d, J = 3.7 Hz, 1H), 2.40–2.19 (m, 2H), 1.66–1.46 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.07 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 166.6, 148.5, 135.5, 133.0, 130.0, 127.8, 121.6, 71.0, 67.8, 60.2, 31.1, 28.2, 26.8, 19.2, 14.2 ppm; HRMS (ESI): m/z calcd for C25H34O4Si [M + Na]+, 449.2119; found, 449.2134.

(S,E)-Ethyl-7-((tert-butyldiphenylsilyl)oxy)-6-((methylsulfonyl)oxy)hept-2-enoate (10)

To the mixture of 9 (4.1 g, 9.61 mmol) and triethylamine (2.7 mL, 19.23 mmol) in CH2Cl2 (60 mL), methanesulphonylchloride (1.1 mL, 14.42 mmol) was added dropwise at 0 °C. After stirring for 3 h at the same temperature, the reaction was quenched with saturated aqueous NaHCO3 (30 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layer was washed with brine (70 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product that was passed through a short plug silica gel to get the mesylated product 10 (4.59 g, 95%) as colorless oil. [α]D25 – 4.49 (c 1.95, CHCl3); IR (KBr): νmax 2939, 2861, 1715, 1353, 1173, 701 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.74–7.62 (m, 4H), 7.49–7.35 (m, 6H), 6.90 (dt, J = 15.7, 13.7 Hz, 1H), 5.83 (dt, J = 15.7, 13.7 Hz, 1H), 4.76–4.69 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.85–3.71 (m, 2H), 2.96 (s, 3H), 2.38–2.21 (m, 2H), 1.93–1.79 (m, 2H), 1.28 (t, J = 7.1 Hz, 2H), 1.07 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.3, 146.9, 135.5, 135.4, 134.7, 132.6, 132.5, 130.0, 130.0, 127.9, 122.2, 82.3, 65.1, 60.2, 38.6, 29.7, 27.4, 26.8, 19.2, 14.2 ppm; HRMS (ESI): m/z calcd for C26H36O6SSi [M + Na]+, 527.1894; found, 527.1902.

(S)-Ethyl-2-((2R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-2-hydroxyacetate (11)

A mixture of K2OsO2(OH)2 (16.6 mg, 0.045 mmol, 0.006 equiv), (DHQD)2PHAL (88 mg, 0.11 mmol, 0.015 equiv), K3Fe(CN)6 (7.44 g, 22.6 mmol, 3.0 equiv), K2CO3 (3.12 g, 22.6 mmol, 3.0 equiv), and MeSO2NH2 (716 mg, 7.53 mmol, 1.0 equiv) in 1:1 t-BuOH/H2O (100 mL) was stirred for 30 min at room temperature. This mixture was slowly poured into 4 °C solution of 10 (3.8 g, 7.53 mmol, 1.0 equiv) in t-BuOH/H2O (500 mL). The reaction was stirred at 4 °C for 24 h. After completion of the reaction, solid Na2S2O3 (10 g) was added and the mixture was stirred for 1.5 h while warming to room temperature (color change from orange to dark green). After phase separation, the aqueous layer was extracted with ethyl acetate (5 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product that was purified by silica gel column chromatography (ethyl acetate/hexane = 4:1) to give 11 (2.93 g, 88%). [α]D25 – 8.3 (c 1.6, CHCl3); IR (KBr): νmax 3477, 2931, 2858, 1739, 1110, 704 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.73–7.60 (m, 4H), 7.46–7.34 (m, 6H), 4.37 (dt, J = 13.9, 7.1 Hz, 1H), 4.43–4.16 (m, 3H), 4.07 (dd, J = 8.1, 2.0 Hz, 1H), 3.63 (dq, J = 10.6, 4.6 Hz, 2H), 2.94 (d, J = 8.2 Hz, 1H), 2.13–2.20 (m, 3H), 1.98–1.86 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 173.0, 135.6, 135.5, 134.8, 133.6, 133.5, 129.6, 129.5, 127.6, 127.6, 80.8, 80.0, 72.5, 66.2, 61.6, 28.1, 27.8, 26.7, 19.2, 14.1 ppm; HRMS (ESI): m/z calcd for C25H34O5Si [M + Na]+, 465.2068; found, 465.2085.

(R)-1-((2R,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)ethane-1,2-diol (12)

To a solution of ester 11 (2.5 g, 5.65 mmol) in diethyl ether (50 mL), LiBH4 (184 mg, 8.48 mmol) was added at 0 °C in a single portion. MeOH (5 mL) was added to the above reaction mixture at the same temperature. The above reaction mixture was stirred for additional 2 h at room temperature. After completion of reaction (TLC), it was quenched with aqueous NaHCO3 solution (20 mL) and extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give the crude product that was purified by silica gel column chromatography (ethyl acetate/hexane = 1:1) to furnish diol 12 (1.96 g, 87%) as a colorless viscous liquid [α]D25 – 4.0 (c 1.3, CHCl3); IR (KBr): νmax 3421, 2931, 2858, 1427, 1110, 703 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.70–7.66 (m, 4H), 7.45–7.35 (m, 6H), 4.18–4.09 (m, 1H), 4.03, 3.97 (m, 1H), 3.72–3.60 (m, 4H), 3.53 (q, J = 4.4 Hz, 1H), 2.72 (br s, 1H), 2.58 (br s, 1H), 2.03–1.76 (m, 4H), 1.05 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 135.6, 133.6, 133.5, 129.6, 127.6, 80.7, 80.2, 72.8, 66.3, 64.9, 28.1, 27.9, 26.8, 19.2 ppm; HRMS (ESI): m/z calcd for C23H32O4Si [M + Na]+, 423.1962; found, 423.1970.

(2R,5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-carbaldehyde (13)

To the solution of 12 (1.4 g, 3.5 mmol) in CH2Cl2 (80 mL), NaIO4–silica (35 g) was added at 0 °C. The reaction was stirred for 30 min at room temperature. After completion of reaction (TLC), the reaction mixture was filtered and washed with CH2Cl2 (2 × 30 mL). The resulting solution was concentrated under reduced pressure to provide the crude product that upon silica gel column chromatography purification (ethyl acetate/hexane = 1:5), afforded 13 (0.828 g, 90%) as a colorless viscous liquid. [α]D25+ 3.41 (c 3.45, CHCl3); IR (KBr): νmax 2931, 2858, 1733, 1427, 1110, 704 cm–1; 1H NMR (500 MHz, CDCl3): δ 9.66 (d, J = 1.67 Hz, 1H), 7.70–7.66 (m, 4H), 7.44–7.35 (m, 6H), 4.36–4.32 (m, 1H), 4.29–4.22 (m, 1H), 3.71 (dq, J = 10.8, 4.4 Hz, 2H), 2.24–2.16 (m, 1H), 2.01–1.90 (m, 3H), 1.06 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 202.8, 135.5, 133.3, 133.3, 129.7, 127.6, 83.3, 81.0, 65.9, 27.3, 27.2, 26.8, 19.2 ppm; HRMS (ESI): m/z calcd for C22H28O3Si [M + NH4]+, 386.2146; found, 386.2155.

(E)-Ethyl-3-((2R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)acrylate (14)

To a stirred suspension of ethyl 2-(triphenylposphoranylidene)acetate (1.5 g, 4.34 mmol) in toluene (50 mL) was added a solution of 13 (800 mg, 2.17 mmol). It was added at reflux and maintained for 5 h. The reaction mass was cooled to room temperature and poured into water carefully. The mixture was extracted with ethyl acetate (2 × 40 mL), and the organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The resulting syrup was purified by silica gel column chromatography (EtOAc/hexane = 1:9) to give compound 14 (846 mg, 89%) as a colorless liquid. [α]D25 + 6.2 (c 2.2, CHCl3); IR (KBr): νmax 2932, 2859, 1721, 1187, 1110, 704 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.73–7.57 (m, 4H), 7.45–7.32 (m, 6H), 6.91 (dd, J = 15. 7, 4.7 Hz, 1H), 6.02 (dd, J = 15.7, 1.6 Hz, 1H), 4.63–4.57 (m, 1H), 4.30–4.09 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.67 (d, J = 4.6 Hz, 2H), 2.23–1.58 (m, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.36–1.20 (m, 2H), 1.06 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.6, 148.5, 135.6, 133.5, 129.6, 127.8, 127.6, 120.1, 79.8, 78.0, 66.3, 60.3, 31.8, 27.6, 26.8, 19.2, 14.2 ppm; HRMS (ESI): m/z calcd for C26H34O4Si [M + NH4]+, 456.2564; found, 456.2564.

Ethyl-3-((2R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)propanoate (15)

To a solution of α,β-unsaturated ester 14 (800 mg, 1.82 mmol) in ethyl acetate (15 mL) was added Pd/C (0.2 g, 0.18 mmol) under a hydrogen atmosphere at room temperature and stirred continuously for 2 h. After completion of the reaction (monitored by TLC), the reaction mass was passed through a small Celite pad and washed with ethyl acetate (2 × 25 mL). The filtrate was concentrated under reduced pressure to provide the crude product that was purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to furnish 15 (794 mg, 99%) as a colorless viscous liquid. [α]D25 – 3.9 (c 2.2, CHCl3); IR (KBr): νmax 2930, 2858, 1732, 1108, 701 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.71–7.66 (m, 4H), 7.43–7.35 (m, 6H), 4.14–4.08 (m, 3H), 3.99–3.93 (m, 1H), 3.63 (dd, J = 4.6, 1.5 Hz, 2H), 2.49–2.42 (m, 1H), 2.40–2.33 (m, 1H), 2.06–1.96 (m, 2H), 1.88–1.78 (m, 3H), 1.56–1.47 (m, 1H), 1.64 (br s, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.05 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 173.6, 135.6, 133.7, 129.5, 127.6, 78.9, 78.5, 66.5, 60.3, 31.7, 31.2, 30.8, 29.7, 28, 26.8, 19.2, 14.2 ppm; HRMS (ESI): m/z calcd for C26H36O4Si [M + Na]+, 463.2281; found, 463.2267.

Dimethyl-4-((2R,5R)-5-((tert-butyldiphenylsilyloxy)methyl)tetrahydrofuran-2-yl)-2-oxobutylphosphonate (5)

To a stirred solution of dimethylmethylphosphonate (570 mg, 4.60 mmol) in THF (30 mL), n-BuLi (1.7 mL, 4.29 mmol, 2.5 M in hexane) was slowly added at −78 °C under an argon atmosphere and allowed to slowly warm to 0 °C. After 1 h, the reaction mixture was again cooled to −78 °C, and the solution of ester 15 (450 mg, 1.02 mmol) in THF (30 mL) was slowly added and stirred at the same temperature for 1 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. The organic layer was concentrated under reduced pressure to obtain the crude mass that on purification by silica gel column chromatography (ethyl acetate/hexane = 1:1), afforded the desired 5 (428 mg, 90%) as a colorless liquid. [α]D25 – 4.0 (c 1.0, CHCl3); IR (KBr): νmax 2933, 2859, 1716, 1109, 1034, 702 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.70–7.65 (m, 4H), 7.44–7.35 (m, 6H), 4.12–4.05 (m, 1H), 3.96–3.89 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.65–3.58 (m, 2H), 3.16–3.04 (m, 2H), 2.80–2.61 (m, 2H), 2.05–1.95 (m, 2H), 1.85–1.70 (m, 3H), 1.55–1.46 (m, 1H), 1.05 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 201.7, 201.7, 135.6, 133.7, 129.5, 127.6, 78.9, 78.3, 66.5, 53.0, 52.9, 41.8, 40.9, 40.7, 31.7, 29.5, 28, 26.8, 19.2 ppm; HRMS (ESI): m/z calcd for C27H39O6Psi [M + NH4]+, 536.2591; found, 536.2598.

(2R,3S)-7-((4-Methoxybenzyl)oxy)-2-methylheptane-1,3-diol (17)

To a solution of chiral epoxide 16 (1.8 g, 6.76 mmol) in dry THF (40 mL), CuI (0.128 g, 0.676 mmol) was added and the mixture was stirred at 25 °C for 30 min. It was cooled to −5 °C, and methyl magnesium bromide (20.28 mL, 1 M in THF, 20.28 mmol) was slowly added at the same temperature. It was allowed to stir for another 12 h at the same temperature. After completion of the reaction (TLC), it was quenched with saturated NH4Cl (30 mL) and diluted with ethyl acetate (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product that was then purified by column chromatography over silica gel (ethyl acetate/hexane = 1:1) to afford the product 17 (1.43 g, 75%). [α]D25 – 8.0 (c 0.51, CHCl3); IR (KBr): νmax 3385, 2936, 2863, 1512, 1247, 1032, 770 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.71 (dd, J = 10.8, 3.7 Hz, 1H), 3.59–3.49 (m, 2H), 3.49–3.42 (m, 2H), 1.73–1.36 (m, 7H), 0.85 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.1, 132.0, 129.3, 113.7, 76.8, 72.5, 70.0, 67.5, 55.2, 39.7, 34.8, 29.5, 21.8, 13.8 ppm; HRMS (ESI): m/z calcd for C16H26O4 [M + Na]+, 305.1723; found, 305.1739.

(5S,6R)-5-(4-((4-Methoxybenzyl)oxy)butyl)-2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecane (18)

To a stirred solution of 17 (1.2 g, 4.25 mmol) in CH2Cl2 (40 mL) under a nitrogen atmosphere was added DIPEA (2.67 mL, 14.88 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (2.81 g, 10.63 mmol) at 0 °C and was stirred for 6 h. After completion of the reaction (monitored by TLC), it was quenched with water (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 40 mL). The combined organic layer was washed with brine (70 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product that on purification by silica gel column chromatography (ethyl acetate/hexane = 1:19), furnished 18 (1.97 g, 91%). [α]D25 – 6.9 (c 1.6, CHCl3); IR (KBr): νmax 2934, 2857, 1515, 1250, 1094, 837, 772 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.69 (q, J = 4.6 Hz, 1H), 3.55 (dd, J = 10.0, 6.5 Hz, 1H), 3.46–3.37 (m, 3H), 1.88–1.75 (m, 1H), 1.64–1.24 (m, 6H), 0.89 (s, 9H), 0.88 (s, 9H), 0.83 (d, J = 7.0 Hz, 3H), 0.03 (s, 12H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.0, 130.8, 129.2, 113.7, 73.1, 72.5, 70.2, 65.2, 55.3, 40.9, 32.4, 30.0, 25.9, 21.8, 18.3, 18.1, 12.2, −4.4, −4.6, −5.4, −5.5 ppm; HRMS (ESI): m/z calcd for C28H54O4Si2 [M + NH4]+, 528.3898; found, 528.3902.

(2R,3S)-3-((tert-Butyldimethylsilyl)oxy)-7-((4-methoxybenzyl)oxy)-2-methylheptan-1-ol (19)

To a stirred solution of 18 (1.6 g, 3.13 mmol) in CH2Cl2 (40 mL) and MeOH (40 mL), pyridinium p-toluenesulfonate (78 mg, 0.31 mmol) was added at 0 °C. The reaction was stirred for 6 h at the same temperature. Triethylamine (3 mL) was added to the reaction mixture and concentrated under reduced pressure to get the crude product that was purified by silica gel chromatography (ethyl acetate/hexane = 1:9) to furnish 19 (1.1 g, 90%) as a colorless liquid. [α]D25 + 5.3 (c 0.51 CHCl3); IR (KBr): νmax 3447, 2932, 2857, 1513, 1249, 772 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.77 (dd, J = 10.8, 3.8 Hz, 1H), 3.69 (dd, J = 11.13, 5.18 Hz, 1H), 3.52 (dd, J = 10.8, 5.2 Hz, 1H), 3.44 (dt, J = 6.4, 1.7 Hz, 2H), 1.76 (m, 1H), 1.63–1.50 (m, 4H), 1.37 (q, J = 7.9 Hz, 2H), 0.99 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 159.1, 130.6, 129.2, 113.7, 77.2, 72.6, 69.9, 65.3, 55.2, 37.7, 34.6, 29.9, 25.8, 21.6, 18.0, 14.6, −4.3, −4.8 ppm; HRMS (ESI): m/z calcd for C22H40O4Si [M + Na]+, 419.2594; found, 419.2581.

(2S,3S)-3-(tert-Butyldimethylsilyloxy)-7-(4-methoxybenzyloxy)-2-methylheptanal (6)

To a solution of alcohol 19 (0.9 g, 2.27 mmol) in CH2Cl2 (25 mL), NaHCO3 (0.381 g, 4.54 mL) and Dess–Martin periodinane (1.92 g, 4.54 mmol) were added at 0 °C under a nitrogen atmosphere and was stirred for 2 h at room temperature. After complete conversion of the starting material (monitored by TLC), the reaction was quenched with water (20 mL) and diluted with CH2Cl2 (25 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get the crude product that was passed through silica gel (ethyl acetate/hexane = 1:5) to afford the aldehyde 6 (0.797 g, 89%) as a colorless liquid. [α]D25 + 8.0 (c 1.5, CHCl3); IR (KBr): νmax 2930, 2856, 1724, 1512, 1250, 773 cm–1; 1H NMR (500 MHz, CDCl3): δ 9.81 (d, J = 2.59 Hz, 1H), 5.90 (dd, J = 17.3, 10.8 Hz, 1H), 5.20 (dd, J = 17.2, 1.5 Hz, 1H), 5.00 (dd, J = 10.7, 1.5 Hz, 1H), 4.17 (ddd, J = 14.3, 8.2, 6.1 Hz, 1H), 2.54–2.47 (m, 1H), 1.97–1.88 (m, 2H), 1.83–1.75 (m, 2H), 1.31 (s, 3H), 1.05 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 204.6, 144.2, 111.8, 79.6, 78.6, 51.9, 37.4, 32.2, 26.4, 23.4 ppm; HRMS (ESI): m/z calcd for C22H38O4Si [M + Na]+, 417.2437; found, 417.2426.

(6R,7S,E)-7-((tert-Butyldimethylsilyl)oxy)-1-((2R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-11-((4-methoxybenzyl)oxy)-6-methylundec-4-en-3-one (4)

To a stirred solution of the keto phosphonate 5 (0.157 g, 0.303 mmol) in MeCN (15 mL) was added DIPEA (39 mg, 0.303 mmol) at 0 °C under a nitrogen atmosphere. LiCl (13 mg, 0.303 mmol) followed by aldehyde 6 (120 mg, 0.303 mmol) was slowly added to the reaction mixture and stirred at the same temperature for 1 h. The reaction was allowed to warm to room temperature, and stirring was then continued for 8 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl (15 mL) and diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get the crude product that on purification by silica gel column chromatography (ethyl acetate/hexane = 1:8), furnished the desired ketone 4 (0.216 g, 91%) as a colorless liquid. [α]D25 + 4.6 (c 1.0, CHCl3); IR (KBr): νmax 2931, 2857, 1669, 1249, 1106, 701 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.71–7.65 (m, 4H), 7.44–7.33 (m, 6H), 7.25 (d, J = 8.55 Hz, 2H), 6.87 (d, J = 8.7 2H), 6.82 (dd, J = 16.0, 7.8 Hz, 1H), 6.07 (dd, J = 16.0, 0.9 Hz, 1H), 4.41 (s, 2H), 4.15–4.08 (m, 1H), 3.99–3.91 (m, 1H), 3.79 (s, 3H), 3.68–3.57 (m, 3H), 3.45–3.37 (m, 2H), 2.78–2.68 (m, 1H), 2.64–2.54 (m, 1H), 2.49–2.40 (m, 1H), 2.06–1.96 (m, 2H), 1.88–1.70 (m, 3H), 1.60–1.48 (m, 3H), 1.48–1.24 (m, 4H), 1.05 (s, 9H), 1.04 (d, J = 0.9 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3): δ 200.3, 159.1, 149.1, 135.6, 133.7, 130.7, 130.2, 129.5, 129.2, 127.6, 113.7, 78.9, 78.7, 75.3, 72.5, 69.9, 66.5, 52.2, 41.9, 36.7, 34.1, 31.8, 29.9, 29.9, 28.1, 26.8, 25.9, 22.1, 19.2, 18.1, 15.4, −4.3, −4.5 ppm; HRMS (ESI): m/z calcd for C47H70O6Si2 [M + NH4]+, 804.5049; found, 804.5066.

(4S,5R,6R,7S)-7-((tert-Butyldimethylsilyl)oxy)-1-((2R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-11-((4-methoxybenzyl)oxy)-6-methylundecan-3-one (20)

A mixture of K2OSO2(OH)2 (0.33 mg, 0.0009 mmol, 0.006 equiv), (DHQD)2PHAL (1.78 mg, 0.002 mmol, 0.015 equiv), K3Fe(CN)6 (150 mg, 0.45 mmol, 3.0 equiv), K2CO3 (63 mg, 0.45 mmol, 3.0 equiv), and MeSO2NH2 (14.5 mg, 0.152 mmol, 1.0 equiv) in 1:1 t-BuOH/H2O (50 mL) was stirred for 30 min at room temperature. The mixture was slowly poured into a 4 °C solution of 4 (120 mg, 0.152 mmol, 1.0 equiv) in t-BuOH/H2O (30 mL). Then, the reaction was stirred at 4 °C for 36 h. After completion of reaction (TLC), solid Na2S2O3 (0.5 g) was added and the mixture was stirred for 1.5 h while warming to room temperature (color changed from orange to dark green). After phase separation, the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide the crude product that was purified by silica gel column chromatography (ethyl acetate/hexane = 3:7) to furnish 20 (100 mg, 80%). [α]D25 + 15.25 (c 0.8, CHCl3); IR (KBr): νmax 3468, 2931, 2857, 1714, 1471, 1112, 704 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.70–7.64 (m, 4H), 7.44–7.34 (m, 6H), 7.25 (d, J = 8.7 Hz, H), 6.87 (d, J = 8.7 Hz, 2H), 4.42 (s, 2H), 4.20–4.04 (m, 3H), 3.99–3.90 (m, 1H), 3.88–3.81 (m, 1H), 3.79 (s, 3H), 3.77–3.71 (m, 1H), 3.69–3.56 (m, 3H), 3.45–3.69 (m, 2H), 3.1–3.0 (m, 1H), 2.74–2.64 (m, 1H), 2.08–1.94 (m, 2H), 1.93–1.72 (m, 4H), 1.68–1.44 (m, 7H), 1.43–1.30 (m, 1H), 1.05 (s, 9H), 1.03 (d, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.08–0.06 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3): δ 11.6, 159.0, 135.6, 133.6, 130.7, 130.6, 129.6, 129.2, 127.6, 113.7, 78.9, 78.6, 76.3, 72.6, 71.5, 70.1, 69.9, 66.4, 55.2, 40.3, 39.5, 35.3, 33.8, 31.7, 29.8, 29.5, 28.0, 26.8, 25.9, 22.0, 21.6, 19.2, 18.0, 12.0, −4.4, −4.4, −4.6, −4.7 ppm; HRMS (ESI): m/z calcd for C47H72O8Si2 [M + Na]+, 843.4658; found, 843.4656.

(2R,3S,4R,5R,6S)-2-(2-((2R,5R)-5-((tert-Butyldiphenylsilyloxy)methyl)tetrahydrofuran-2-yl)ethyl)-2-methoxy-6-(3-(4-methoxybenzyloxy)propyl)-5-methyltetrahydro-2H-pyran-3,4-diol (3)

To the solution of keto diol 20 (60 mg, 0.073 mmol) in MeOH (20 mL), pyridinium p-toluenesulfonate (1.8 mg, 0.0073 mmol) was added at 0 °C. The resulting solution was stirred for 12 h at room temperature. After completion of the reaction (TLC), triethylamine (0.5 mL) was added and concentrated under reduced pressure to give the crude residue that was purified by silica gel chromatography (ethyl acetate/hexane = 3:7) to furnish the C1–C16 fragment of formosalide 3 (42 mg, 82%) as a colorless liquid. [α]D25–31.2 (c 1.0, CHCl3); IR (KBr): νmax 3424, 2933, 2859, 1513, 1428, 1112, 705 cm–1; 1H NMR (500 MHz, CDCl3): δ 7.71–7.65 (m, 4H), 7.44–7.34 (m, 6H), 7.25 (d, J = 7.5 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.43 (s, 2H), 4.19–4.09 (m, 1H), 3.95–3.88 (m, 1H), 3.79 (s, 3H), 3.64 (dd, J = 4.8, 0.9 Hz, 2H), 3.46–3.27 (m, 4H), 3.18 (s, 3H), 2.58 (d, J = 8.8 Hz, 1H), 2.40 (br s, 1H), 2.05–1.94 (m, 2H), 1.87–1.73 (m, 4H), 1.64–1.33 (m, 8H), 1.05 (s, 9H), 0.95 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.1, 135.6, 133.7, 129.5, 129.2, 127.6, 113.7, 100.5, 79.8, 79.1, 75.8, 74.8, 73.4, 72.5, 70.0, 66.5, 55.2, 47.4, 41.2, 32.1, 31.9, 29.9, 29.9, 29.7, 29.4, 28.0, 26.8, 21.9, 19.2, 12.9 ppm; HRMS (ESI): m/z calcd for C42H60O8Si [M + Na]+, 743.3955; found, 743.3945.

Acknowledgments

The authors thank the Director, CSIR-IICT, for his constant support and providing research facilities. S.G., A.V.V.R., and D.P.R. thank CSIR and UGC, New Delhi, India, for financial assistance in the form of fellowships.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c01474.

  • Copies of 1H and 13C NMR spectra for all new compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao0c01474_si_001.pdf (3.2MB, pdf)

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