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. 2018 Nov 16;3(11):15628–15634. doi: 10.1021/acsomega.8b02328

Synthetic Studies toward (±)-Furanocembranoid 1: Construction of the Acyclic Carbon Framework

Chada Raji Reddy †,‡,*, Siddique Z Mohammed †,‡
PMCID: PMC6644170  PMID: 31458219

Abstract

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Herein, we report the synthesis of the entire acyclic carbon framework toward (±)-furanocembranoid 1 via the longest linear sequence of 12 steps from commercially available linalool and diethyl 2-isopropylmalonate. Key to the success of this synthetic approach is a silver-catalyzed enyne-annulation reaction for the formation of 2,4-disubstituted furan motif of unique furanocembranoid 1, isolated from Croton oblongifolius. Construction of macrocycle has also been explored using the ring-closing metathesis reaction.

Introduction

Furanocembranoids are an interesting class of 14-membered macrocycles embedded with a furan and a 5-membered lactone moiety possessing diverse biological activities.1 In all of these natural products, the macrocyclic framework is linked to C2 and C5 positions of the furan ring with C3 substitution. In 2007, a unique class of novel furanocembranoids 1–3 (Figure 1) was isolated from the stem bark of Croton oblongifolius, which contains the macrocyclic skeleton connected to C2 and C4 positions of furan without five-membered lactone.2 Their structures were determined on the basis of the NMR spectroscopy and mass spectrometry (MS) analyses. Furanocembranoid 1 (1a) and 3 (1c) displayed good cytotoxicity against human tumor cell lines such as BT474 (human breast ductol carcinoma), CHAGO (human undifferentiated lung carcinoma), Hep-G2 (human liver hepatoblastoma), KATO-3 (human gastric carcinoma), and SW-620 (human colon adrenocarcinoma). The distinctive feature of 1a, having C2–C4 linked bicyclic furan, provoked us to explore the synthesis of this molecule. To the best of our knowledge, the synthesis of furanocembranoid 1 remains unexplored to date.

Figure 1.

Figure 1

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Structures of furanocembranoids 1–3.

Alkyne-assisted annulation reactions to deliver furan skeletons have been regarded as a powerful tool for the synthesis of natural products.3−5 Recently, we have also successfully explored the cycloisomerization of enynols for the synthesis of substituted furans.6 On this basis, we considered that cyclodehydration of enyne-diol7,8 could be a key step in the late-stage construction of the 2,4-disubstituted furan core of furanocembranoid 1. Scheme 1 outlines our retrosynthetic analysis of 1a. (±)-Furanocembranoid 1 might be derived by the ring-closing metathesis (RCM) reaction of furanyl diene 2. This was believed to result from the addition of alkyne fragment 3 onto protected hydroxy ketone subunit 4. This alkyne 3 might, in turn, be accessed from one of the most widely occurring natural products, (±)-linalool, and ketone 4 was planned to be obtained from the commercially available diethyl 2-isopropylmalonate.

Scheme 1. Retrosynthetic Analysis of Furanocembranoid 1.

Scheme 1

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Results and Discussion

Our synthesis commenced with the protection of hydroxyl group of the natural linalool (5) to prepare tert-butyldimethylsilyl (TBDMS) ether 7 (Scheme 2). In the presence of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine, TBS-ether 7 was obtained in 95% yield. The thus formed 7 was subjected to allylic oxidation using SeO2 and tert-butylhydrogen peroxide in CH2Cl2 at room temperature (rt), which provided a mixture of aldehyde and alcohol. The mixture was reduced using LiAlH4 in tetrahydrofuran (THF) at 0 °C to afford the allylic alcohol 8 in 67% yield in two steps. The alcohol 8 was then converted to iodide by treatment with I2 in the presence of triphenylphosphine and imidazole. Subsequent coupling of iodide with trimethylsilylacetylene in the presence of n-BuLi led to dienyne 9 in 87% yield. Liberation of the terminal acetylene using K2CO3 in MeOH then led to the key intermediate 3 in 85% yield.

Scheme 2. Synthesis of Alkyne Fragment 3.

Scheme 2

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The synthesis of ketone subunit 4 starting from the commercially available diethyl 2-isopropylmalonate (6) is described in Scheme 3. Compound 6 underwent sequential LiAlH4-mediated reduction, followed by selective silylation to generate monosilylated alcohol 10 in 82% in two steps.9 Oxidation of this material using Dess–Martin periodinane (DMP) followed by one-carbon Wittig olefination (CH3Ph3P+Br–/tBuOK) afforded terminal alkene 11 in 76% overall yield. Tetrabutylammonium fluoride (TBAF)-mediated desilylation of 11 provided the homoallylic alcohol (volatile in nature), which was subsequently oxidized to aldehyde (volatile aldehyde was not isolated) using DMP in CH2Cl2, followed by treatment with β-ketophosphonate 13(10) in the presence of Ba(OH)2·8H2O in THF/H2O to give enone 12 in 65% yield in three steps. Selective reduction of conjugated olefin using Stryker’s reagent in toluene offered the desired ketone fragment 4 in 95% yield.11

Scheme 3. Synthesis of Ketone Subunit 4.

Scheme 3

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After acquiring both the fragments 3 and 4 in gram scale, we proceeded further toward the total synthesis of furanocembranoid 1. Thus, the alkynyl lithium anion, generated from alkyne 3 in the presence of n-BuLi, was added to ketone 4 to afford the propargylic alcohol 14 in 96% yield. Selective deprotection of primary tert-butyldimethylsilyl (TBDMS) group of 14 using TBAF in THF furnished the diol 15 in 90% yield. Much to our delight, AgNO3-mediated enyne-assisted cyclization of the enyne diol 15 in CH2Cl2 at room temperature provided the desired dienyl-furan E-16a in 90% yield. With substantial amounts of E-16a in hand, we were in a position to test the crucial ring-closing metathesis (RCM) reaction.12 Disappointingly, all of the RCM reactions tried on E-16a using different catalysts, Grubb’s first-generation (G-I) and second-generation (G-II) catalysts and the Hoveyda–Grubbs catalysts, failed to give the product (starting material recovered). Herein, we reasoned that the failure of the RCM reaction might be due to steric hindrance posed by the TBDMS group of allylic tert-hydroxyl functionality and predicted that the free tert-hydroxyl group might allow the RCM reaction. Therefore, furan 16a was transformed to 2 using TBAF in THF at 60 °C. Unfortunately, 2 is also futile to provide the desired product (formation of a nonpolar unidentified mixture of products observed) under all of the tested ring-closing metathesis reaction conditions with various catalysts (see Table S1). Disappointingly, the acetate precursor E-16b, prepared by acetylation of 2 by the action of Ac2O in pyridine, did not provide the corresponding macrocyclic derivative under the same conditions used for 2 (Scheme 4).

Scheme 4. Synthesis of Furan Segment of 1a.

Scheme 4

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Conclusions

In summary, we have achieved the chemical synthesis of the complete acyclic carbon framework toward structurally intriguing (±)-furanocembranoid 1 in the longest linear sequence of 12 steps. The synthesis featured silver-catalyzed enyne-annulation reaction, which enabled rapid construction of 2,4-disubstituted furan skeleton. An extensive synthetic exploration directed toward the completion of the total synthesis based on ring-closing metathesis was ineffective to access the macrocyle, which represents synthetic challenges for future work. Notably, multigram quantities of 3, 4, and 16 are readily prepared through this approach, which is envisioned to serve as the foundation for the synthesis of furanocembranoid 1.

General Information

Reactions were monitored by thin-layer chromatography (TLC) on silica plates using UV light, anisaldehyde, and β-napthol for visualization. Column chromatography was performed on silica gel (60–120 mesh) using petroleum ether and ethyl acetate as eluents. 1H and 13C NMR spectra were recorded in CDCl3 solvent on 400 and 500 MHz spectrometers. Chemical shifts δ and coupling constants J are given in parts per million (ppm) and hertz (Hz), respectively. Chemical shifts are reported relative to residual solvent as an internal standard for 1H and 13C (CDCl3: δ 7.26 ppm for 1H, and 77.0 ppm). IR spectra were recorded as neat compound. Mass spectra were recorded on a micromass VG 70–70H or a liquid chromatography/mass selective detector trap SL spectrometer operating at 70 eV using direct inlet system. High-resolution mass spectrometry (HRMS) data were recorded by electrospray ionization (ESI) with a quad time-of-flight mass analyzer.

Experimental Section

tert-Butyl(3,7-dimethylocta-1,6-dien-3-yloxy)dimethylsilane (7)

To a solution of linalool 5 (10 g, 64.9 mmol) in anhydrous dichloromethane (DCM, 100 mL), 2,6-lutidine (11.3 mL, 97.4 mmol) and TBSOTf (15.7 mL, 78 mmol) were added at 0 °C. The reaction mixture was stirred at the same temperature for 15 min and quenched by the addition of water (50 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product, which was purified by column chromatography using 0.5% ethyl acetate/hexane (v/v) to give pure silyl ether 7 (16.5 g) in 95% yield as a colorless oil. Rf = 0.9 (hexane/ethyl acetate = 9.5:0.5); 1H NMR (400 MHz, CDCl3): δ 5.77 (dd, J = 17.3, 10.7 Hz, 1H), 5.10–4.98 (m, 2H), 4.93–4.88 (m, 1H) 2.03–1.80 (m, 2H), 1.60 (d, J = 1.1 Hz, 3H), 1.52 (s, 3H), 1.43–1.36 (m, 2H), 1.22 (s, 3H), 0.83–0.80 (m, 9H), 0.01 to −0.03 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 147.7, 133.1, 126.8, 113.6, 77.6, 45.9, 29.5, 28.0, 27.8, 24.9, 20.4, 19.6, 0.0; IR (KBr): νmax = 2930, 2858, 1463, 1372, 1043, 774 cm–1.

(E)-6-(tert-Butyldimethylsilyloxy)-2,6-dimethylocta-2,7-dien-1-ol (8)

To a solution of TBDMS-silyl ether 7 (11 g, 41.00 mmol) in CH2Cl2 (100 mL) at room temperature, t-BuOOH (9.02 mL, 5 M in decane, 45.1 mmol) was added and stirred vigorously. Then, SeO2 (1.82 g, 16.42 mmol) was added to the mixture. The resulting mixture was stirred for 2 h, diluted with CH2Cl2, and washed with NaOH (10%); then, the organic layer was dried with Na2SO4 and concentrated. To this crude mixture of aldehyde and alcohol in dry THF, LiAlH4 (568 mg, 7.46 mmol) was added portion-wise at 0 °C. After 30 min, 1 N aqueous (aq) NaOH solution (20 mL) was added. After 1 h, the reaction mixture was filtered off with EtOAc (75 mL) and the separated organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (EtOAc/hexane = 4:1) to give allylic alcohol 8 as a colorless liquid. Rf = 0.2 (hexane/ethyl acetate = 9:1) (7.8 g, 67%, in two steps); 1H NMR (400 MHz, CDCl3): δ 5.75 (dt, J = 10.7, 8.7 Hz, 1H), 5.31 (ddd, J = 8.6, 6.0, 1.3 Hz, 1H), 5.08 (dd, J = 17.3, 1.6 Hz, 1H), 4.91 (dt, J = 7.0, 3.5 Hz, 1H), 3.92 (d, J = 9.3 Hz, 2H), 2.11–1.88 (m, 2H), 1.55 (d, J = 17.4 Hz, 3H), 1.48–1.37 (m, 2H), 1.28–1.20 (m, 3H), 0.86–0.76 (m, 9H), 0.05 to −0.05 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 147.5, 136.5, 128.7, 113.8, 77.5, 71.1, 45.5, 29.6, 28.0, 24.5, 20.4, 15.6, 0.0; IR (KBr): νmax = 2925, 2857, 1732, 1462, 1253, 1043, 837, 774 cm–1.

(E)-tert-Butyl(3,7-dimethyl-10-(trimethylsilyl)deca-1,6-dien-9-yn-3-yloxy)dimethylsilane (9)

To a solution of alcohol 8 (4.5 g, 15.84 mmol, 1 equiv) in anhydrous acetonitrile (40 mL) and ether (60 mL) at 0 °C, triphenylphosphine (8.3 g, 31.68 mmol, 2 equiv) and imidazole (2.36 g, 34.85 mmol, 2.2 equiv) were added and the mixture was stirred at 0 °C until all of the solids dissolved to give a clear colorless solution (∼5 min). Then, iodine (9.65 g, 38.02 mmol, 2 equiv) was added in four equal portions over 20 min. The resulting dark orange mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with pentane (30 mL), and the organic layer was washed with three portions of saturated aq sodium thiosulfate (3 × 15 mL) and then with two 15 mL portions of saturated aq copper(II) sulfate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude iodide as yellow oil. To the solution of trimethylsilylacetylene (3.1 g, 31.68 mmol) in THF (5 mL) at −40 °C, n-BuLi (2.5 M in n-hexane, 12.67 mL, 31.68 mmol) was added and the reaction mixture was stirred at the same temperature for 15 min and then for 20 min at −10 °C. Then, the reaction mixture was again brought to −40 °C and the above-prepared iodide was added to the reaction mixture, gradually warmed to rt, and stirred for 12 h. After completion of the reaction (monitored by TLC), saturated aq NH4Cl was added and the mixture was extracted with pentane. The organic extract was evaporated under reduced pressure to give crude product, which was purified by SiO2 column chromatography (pentane/Et2O = 10:1) to give tetramethylsilane-alkyne 9 (4.00 g, 70%) as a colorless oil. Rf = 0.9 (hexane/ethyl acetate = 9.5:0.5); 1H NMR (400 MHz, CDCl3): δ 5.84 (ddd, J = 16.1, 10.7, 5.4 Hz, 1H), 5.41–5.32 (m, 1H), 5.15 (dd, J = 17.3, 1.6 Hz, 1H), 5.04–4.93 (m, 1H), 2.90 (s, 2H), 2.15–1.93 (m, 2H), 1.66 (d, J = 6.9 Hz, 3H), 1.53–1.46 (m, 2H), 1.30 (d, J = 3.3 Hz, 3H), 0.94–0.84 (m, 9H), 0.17–0.15 (m, 9H), 0.07 (d, J = 5.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 145.5, 129.2, 126.1, 111.5, 104.6, 86.5, 75.3, 43.3, 29.8, 27.4, 25.8, 22.6, 18.2, 15.8, 0.0, −2.2; IR (KBr): νmax = 2928, 2857, 1463, 1372, 1042, 872, 682 cm–1.

(E)-tert-Butyl(3,7-dimethyldeca-1,6-dien-9-yn-3-yloxy)dimethylsilane (3)

To a stirred solution of trimethylsilylacetylene 9 (5.70 g, 15.6 mmol) in methanol (40 mL), potassium carbonate (5.4 g, 39.15 mmol) was added and the resulting mixture was stirred for 5 h at room temperature. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the solvent was removed by evaporation under reduced pressure. The residue was extracted with pentane (40 mL), washed with water (20 mL), and the organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, Et2O/hexane = 1:10) to afford compound 3 as a colorless oil (3.87 g, 85% yield). Rf = 0.9 (hexane/ethyl acetate = 9.5:0.5); 1H NMR (400 MHz, CDCl3): δ 5.77 (dd, J = 17.3, 10.7 Hz, 1H), 5.31 (tt, J = 8.7, 4.4 Hz, 1H), 5.07 (dd, J = 17.3, 1.4 Hz, 1H), 4.91 (dd, J = 10.7, 1.5 Hz, 1H), 2.80 (d, J = 15.0 Hz, 2H), 2.07–1.87 (m, 3H), 1.58 (d, J = 7.6 Hz, 3H), 1.47–1.37 (m, 2H), 1.21 (d, J = 14.5 Hz, 3H), 0.82 (s, 9H), −0.01 (d, J = 5.2 Hz, 6H); 13C NMR (125 MHz, CDCl3): δ 145.5, 129.1, 126.4, 111.7, 82.1, 75.4, 70.1, 43.4, 28.5, 27.4, 25.9, 22.7, 18.3, 15.8, −2.1; IR (KBr): νmax = 3311, 2956, 2859, 1722, 1466, 1255, 1046, 840, 641 cm–1.

2-((tert-Butyldimethylsilyloxy)methyl)-3-methylbutan-1-ol (10)9

To an argon-flushed two-neck round-bottom flask equipped with an additional funnel, a reflux condenser, and a drying tube, LiAlH4 (3.76 g, 99 mmol) and dry THF (60 mL, dropwise) were added. To this mixture, diethyl isopropylmalonate 6 (10 g, 49.5 mmol) in dry THF (50 mL) was added over 1 h at room temperature and stirred for 3 days at reflux temperature. The mixture was cooled to 0 °C, quenched with saturated aq sodium sulfate (30 mL), filtered, and concentrated under reduced pressure. The obtained crude diol was directly used for the next step without purification. Diol in THF (60 mL) was added to the stirred solution of NaH (1.06 g, 44.55 mmol) in THF (30 mL) and stirred at room temperature for 1 h. tert-Butyldimethylsilyl chloride (6.68 g, 44.55 mmol) in THF (30 mL) was added dropwise to the reaction mixture, and stirring was continued for 5 h at room temperature. The mixture was diluted with ether (20 mL) and washed successively with aq saturated K2CO3 (2 × 20 mL) and brine (20 mL). The organic extract was concentrated, and the residue was purified by column chromatography (EtOAc/hexane = 1:3) to give the alcohol 10 as a colorless liquid (9.41 g, 82%). Rf = 0.3 (hexane/ethyl acetate = 8:2); 1H NMR (500 MHz, CDCl3): δ 3.80–3.61 (m, 4H), 1.70–1.60 (m, 1H), 1.46–1.36 (m, 1H), 0.87–0.77 (m, 15H), 0.03 to −0.04 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 66.0, 65.2, 47.8, 26.2, 25.8, 20.4, 20.2, 18.1, −5.5; MS (ESI): m/z 233 (M + H)+; HRMS (ESI): m/z calcd for C12H29O2Si (M + H)+: 233.1937, found: 233.1939.

tert-Butyl(2-isopropylbut-3-enyloxy)dimethylsilane (11)

To the solution of alcohol 10 (8.3 g, 35.77 mmol) and NaHCO3 (9.4 g, 107.3 mmol) in CH2Cl2 (120 mL), Dess–Martin periodinane (22.75 g, 53.65 mmol) was added and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated aq Na2S2O3 (40 mL), and the aqueous phase was extracted with DCM (3 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was used directly for the next step without purification. To the mixture of methyltriphenylphosphonium bromide (51.08 g, 143.0 mmol) and potassium tert-butoxide (1.6 g, 143.0 mmol), THF was added at 0 °C and stirred for 40 min. To this orange solution, the above aldehyde in THF was added at 0 °C and the stirring was continued for 30 min; then, the mixture was quenched with saturated aq NH4Cl (50 mL). The mixture was diluted with water (5 mL) and extracted with pentane (3 × 40 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude was purified by silica gel column chromatography using 1% Et2O/hexane (v/v) to afford 11 as liquid (6.2 g) in 76% yield in two steps. Rf = 0.9 (hexane/ethyl acetate = 9.5:0.5); 1H NMR (500 MHz, CDCl3): δ 5.62 (ddd, J = 17.1, 10.3, 9.1 Hz, 1H), 5.07–4.91 (m, 2H), 3.64–3.48 (m, 2H), 1.95 (dq, J = 9.1, 6.1 Hz, 1H), 1.86–1.72 (m, 1H), 0.89–0.83 (m, 12H), 0.80 (t, J = 6.1 Hz, 3H), 0.02 to −0.02 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 138.3, 116.3, 64.7, 52.8, 27.5, 25.9, 20.9, 18.6, 18.3, −5.3, −5.3; IR (KBr): νmax = 2930, 2861, 1724, 1468, 1251, 930, 842, 771 cm–1; MS (ESI): m/z 229 (M + H)+; HRMS (ESI): m/z calcd for C13H29OSi (M + H)+: 229.1982, found: 229.2002.

(E)-1-(tert-Butyldimethylsilyloxy)-5-isopropylhepta-3,6-dien-2-one (12)

To a stirred solution of alcohol 11 (5.5 g, 24.12 mmol) in THF (30 mL), TBAF (1.0 M in THF, 24.12 mL, 24.12 mmol) was added and stirring was continued for 3 h. The mixture was quenched with saturated aq NH4Cl (30 mL) and extracted with Et2O (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and partially concentrated in vacuo. The crude volatile was directly used in the next steps. To the above solution of alcohol and NaHCO3 (2.03 g, 24.12 mmol) in DCM (50 mL), Dess–Martin periodinane (7.16 g, 16.88 mmol) was added. Stirring was continued for 1 h at 0 °C, and the mixture was quenched with saturated aq Na2S2O3 (5 mL). The aqueous phase was extracted with DCM (3 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and partially concentrated in vacuo. The residue was used directly in the next step. To a solution of ketophosphonate 13 (3.57 g, 12.06 mmol) in THF (50 mL), Ba(OH)2·8H2O (5.318 g, 16.88 mmol) was added and stirred for 30 min at room temperature. A solution of aldehyde in wet THF (20 mL, THF/H2O = 40:1) was added, and the reaction was stirred for 12 h. The crude reaction mixture was diluted with DCM (50 mL) and quenched with saturated aq NaHCO3 (30 mL). The solution was stirred until two layers were clearly visible. The organic layer was collected and washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified using column chromatography (SiO2, hexane/EtOAc = 9:1) to afford enone 12 (2.96 g, 65%) in three steps as a clear oil. Rf = 0.5 (hexane/ethyl acetate = 9:1); 1H NMR (400 MHz, CDCl3): δ 6.84 (dd, J = 15.8, 8.1 Hz, 1H), 6.36–6.25 (m, 1H), 5.64 (ddd, J = 17.1, 10.3, 8.3 Hz, 1H), 5.06–4.88 (m, 2H), 4.26–4.17 (m, 2H), 2.55 (dt, J = 8.1, 4.0 Hz, 1H), 1.77–1.61 (m, 1H), 0.86–0.78 (m, 15H), 0.04 to −0.06 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 198.7, 149.1, 137.5, 125.4, 116.8, 68.8, 54.2, 31.9, 25.81, 20.2, 19.9, 18.4, −5.4; IR (KBr): νmax = 2956, 2861, 1698, 1624, 1466, 1254, 1105, 839, 778, 673 cm–1; MS (ESI): m/z 283 (M + H)+; HRMS (ESI): m/z calcd for C16H30O2SiNa (M + Na)+: 305.1913, found: 305.1915.

1-(tert-Butyldimethylsilyloxy)-5-isopropylhept-6-en-2-one (4)

A solution of enone 12 (2.6 g, 9.22 mmol) in dry degassed toluene (30 mL) was transferred via a syringe to a flask containing Stryker’s reagent (5.42 g, 2.78 mmol; transferred into the flask inside a glovebox). The resulting orange-brown solution was stirred for 1 h at room temperature. The reaction mixture was exposed to air, few drops of water were added, and stirring was continued for 1 h. The crude mixture was filtered through a pad of celite utilizing Et2O as eluent. The solvent was removed under reduced pressure, followed by purification via flash column chromatography (SiO2, hexane/EtOAc = 95:5) to afford ketone 4 (2.49 g, 95%) as a clear oil. Rf = 0.5 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3): δ 5.42 (ddd, J = 17.1, 10.2, 9.4 Hz, 1H), 5.00–4.79 (m, 2H), 4.14 (s, 2H), 2.51–2.22 (m, 2H), 1.78–1.59 (m, 2H), 1.52–1.33 (m, 2H), 0.91–0.72 (m, 15H), 0.17 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 211.4, 140.2, 116.1, 69.4, 50.6, 36.7, 31.8, 25.8, 25.2, 20.6, 19.1, 18.3, −5.5; IR (KBr): νmax = 2954, 2863, 1726, 1436, 1105, 1012, 844, 699 cm–1; MS (ESI): m/z 307 (M + Na)+; HRMS (ESI): m/z calcd for C16H32O2SiNa (M + Na)+: 307.2069, found: 307.2071.

Dimethyl 3-(tert-Butyldimethylsilyloxy)-2-oxopropylphosphonate (13)10

n-BuLi (9.41 mL of a 2.5 M solution in hexane, 23.52 mmol) was added to a solution of methyl dimethylphosphonate (2.92 g, 23.52 mmol) in anhydrous THF (30 mL) at −78 °C and stirring was continued for 30 min. Methyl glycolate TBS ether (4.00 g, 19.6 mmol) in THF (10 mL) was added to the above reaction mixture. After 1 h, the reaction mixture was quenched with aq NH4Cl (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexane = 1:1) to give ketophosphonate 13 colorless oil (3.84 g, 66.19%). Rf = 0.5 (EtOAc/hexane = 2:1); 1H NMR (400 MHz, CDCl3): 4.17 (s, 2H), 3.72–3.65 (m, 6H), 3.11 (d, J = 22.5 Hz, 2H), 0.85–0.78 (m, 9H), 0.03 to −0.03 (m, 6H); MS (ESI): m/z 297 (M + H)+.

(E)-6-(3-Isopropylpent-4-enyl)-2,2,3,3,10,14,16,16,17,17-decamethyl-14-vinyl-4,15-dioxa-3,16-disilaoctadec-10-en-7-yn-6-ol (14)

n-BuLi (2.5 M in n-hexane, 4.0 mL, 10.14 mmol) was added to a solution alkyne 3 (2.96 g, 10.14 mmol) in anhydrous THF (40 mL) at −40 °C, and the whole mixture was stirred for 15 min at −40 °C and for 20 min at −10 °C. After cooling the mixture again to −40 °C, the above ketone 4 (4.2 g, 8.45 mmol) was added to the reaction mixture, stirring was continued for 30 min, and saturated NH4Cl (aq) was added to the mixture and extracted with EtOAc. The solvent was evaporated under reduced pressure and purified by SiO2 column chromatography (EtOAc/hexane = 1:9) to give 14 (4.68 g, 80%) as a colorless oil. Rf = 0.4 (hexane/ethyl acetate = 9:1); 1H NMR (400 MHz, CDCl3): δ 5.76 (ddd, J = 15.7, 10.7, 5.0 Hz, 1H), 5.57–5.41 (m, 1H), 5.27 (td, J = 7.3, 1.4 Hz, 1H), 5.07 (dd, J = 17.3, 1.6 Hz, 1H), 4.97–4.80 (m, 3H), 3.61–3.38 (m, 2H), 2.84–2.74 (m, 2H), 2.67 (t, J = 11.0 Hz, 1H), 2.06–1.82 (m, 2H), 1.72–1.51 (m, 7H), 1.45–1.32 (m, 4H), 1.26–1.18 (m, 3H), 0.84–0.76 (m, 24H), 0.06 to −0.10 (m, 12H); 13C NMR (100 MHz, CDCl3): δ 145.5, 140.7, 129.6, 126.0, 115.5, 111.7, 83.3, 82.4, 75.4, 71.4, 71.2, 70.1, 50.9, 43.5, 36.5, 36.4, 31.7, 31.6, 28.8, 27.3, 26.4, 26.3, 25.9, 25.8, 22.7, 20.6, 18.9, 18.3, 15.9, −2.0, −5.3, −5.4; IR (KBr): νmax = 2956, 2863, 1467, 1255, 1117, 1046, 842, 777 cm–1; MS (ESI): m/z 599 (M + Na)+; HRMS (ESI): m/z calcd for C34H64O3SiNa (M + Na)+: 599.4292, found: 599.4287.

(E)-10-(tert-Butyldimethylsilyloxy)-2-(3-isopropylpent-4-enyl)-6,10-dimethyldodeca-6,11-dien-3-yne-1,2-diol (15)

To a solution of 14 (4.3 g, 7.25 mmol) in THF (40 mL), TBAF (1.0 M in THF, 8.94 mL, 8.94 mmol) was added and stirred for 2.5 h. The reaction mixture was quenched with aq NH4Cl solution (20 mL) and extracted with EtOAc (3 × 10 mL). The solvent was evaporated under reduced pressure and purified by SiO2 column (EtOAc/hexane = 1:9) to give 15 (3.09 g, 90%) as a colorless oil. Rf = 0.5 (hexane/ethyl acetate = 2:1); 1H NMR (500 MHz, CDCl3): δ 5.76 (ddd, J = 15.5, 10.7, 4.9 Hz, 1H), 5.47 (dddd, J = 17.1, 10.2, 9.3, 4.6 Hz, 1H), 5.27 (td, J = 7.3, 1.3 Hz, 1H), 5.07 (dd, J = 17.3, 1.6 Hz, 1H), 4.97–4.84 (m, 3H), 3.55 (d, J = 11.0 Hz, 1H), 3.41 (s, 1H), 2.81 (s, 2H), 2.43 (d, J = 9.3 Hz, 1H), 2.06–1.85 (m, 3H), 1.73–1.48 (m, 7H), 1.45–1.35 (m, 4H), 1.23 (s, 3H), 0.83–0.80 (m, 12H), 0.77 (dd, J = 6.8, 1.4 Hz, 3H), 0.02 to −0.04 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 145.5, 140.47, 129.3, 126.3, 115.8, 111.7, 83.9, 82.7, 82.7, 75.4, 72.1, 72.0, 70.1, 70.0, 50.7, 43.5, 36.2, 36.1, 31.7, 31.7, 28.7, 27.4, 26.3, 25.9, 22.7, 20.6, 18.9, 18.8, 18.3, 15.9, −2.1; IR (KBr): νmax = 3480, 2928, 2860, 1732, 1464, 1377, 1255, 1046, 775 cm–1; MS (ESI): m/z 485 (M + Na)+; HRMS (ESI): m/z calcd for C28H50O3SiNa (M + Na)+: 485.3427, found: 485.3427.

(E)-tert-Butyl(8-(4-(3-isopropylpent-4-enyl)furan-2-yl)-3,7-dimethylocta-1,6-dien-3-yloxy)-dimethylsilane (16a)

To a solution of propargylicdiol 15 (2.5 g, 5.4 mmol) in DCM (20 mL), AgNO3 (1.09 g, 6.48 mmol) was added at room temperature and stirring was continued for 2 h. The reaction mixture was diluted with water, extracted with DCM (20 mL), washed with brine, and dried over anhydrous Na2SO4. The crude mixture was subjected to silica gel column chromatography (EtOAc/hexane = 0.5:9.5) to afford the furan 16a (2.15 g, 90%). Rf = 0.4 (hexane/ethyl acetate = 9.5:0.5); 1H NMR (400 MHz, CDCl3): δ 7.05 (t, J = 2.9 Hz, 1H), 5.90–5.79 (m, 2H), 5.57 (ddd, J = 17.1, 10.2, 9.4 Hz, 1H), 5.25–4.90 (m, 5H), 3.22 (s, 2H), 2.39 (ddd, J = 10.1, 7.1, 4.1 Hz, 1H), 2.23 (ddd, J = 14.8, 13.1, 8.0 Hz, 1H), 2.13–1.96 (m, 2H), 1.80 (ddd, J = 14.0, 9.5, 4.5 Hz, 1H), 1.70–1.61 (m, 2H), 1.61–1.57 (m, 3H), 1.47 (dddd, J = 15.0, 13.3, 8.0, 4.2 Hz, 3H), 1.33–1.27 (m, 4H), 0.88 (d, J = 2.4 Hz, 9H), 0.87–0.82 (m, 6H), 0.09–0.03 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 154.4, 145.6, 140.6, 137.1, 131.5, 127.0, 126.0, 115.7, 111.6, 107.5, 75.5, 50.2, 43.6, 38.6, 32.1, 31.6, 27.4, 25.9, 23.0, 22.8, 20.6, 18.9, 18.3, 15.8, −2.0; IR (KBr): νmax = 2927, 2859, 1774, 1734, 1254, 1120, 999, 838, 775 cm–1; MS (ESI): m/z 445 (M + H)+; HRMS (ESI): m/z calcd for C28H49O2Si (M + H)+: 445.3502, found: 445.3509.

(E)-8-(4-(3-Isopropylpent-4-enyl)furan-2-yl)-3,7-dimethylocta-1,6-dien-3-ol (2)

To a solution of furan 16a (1.3 g, 2.92 mmol) in THF (15 mL), TBAF (1.0 M in THF, 5.84 mL, 5.84 mmol) was added, heated at 60 °C for 4 h, quenched with aq NH4Cl solution (10 mL), and extracted with EtOAc (3 × 10 mL). Removal of the solvent under reduced pressure and purification by SiO2 column (EtOAc/hexane = 1:9) gave 2 (886 mg, 92%) as a colorless oil. Rf = 0.5 (hexane/ethyl acetate = 8:2); 1H NMR (400 MHz, CDCl3): δ 7.06 (dd, J = 4.5, 1.0 Hz, 1H), 5.98–5.85 (m, 2H), 5.57 (ddd, J = 17.1, 10.2, 9.3 Hz, 1H), 5.30–5.15 (m, 2H), 5.09–5.02 (m, 2H), 4.95 (ddd, J = 17.1, 2.2, 0.7 Hz, 1H), 3.23 (s, 2H), 2.39 (dddd, J = 15.0, 10.0, 5.0, 1.0 Hz, 1H), 2.28–1.98 (m, 3H), 1.86–1.74 (m, 1H), 1.69–1.61 (m, 2H), 1.59 (s, 6H), 1.45 (dtd, J = 13.3, 10.0, 5.0 Hz, 1H), 1.28 (s, 3H), 0.85 (dd, J = 16.0, 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 154.1, 144.9, 140.5, 137.2, 132.3, 126.5, 126.0, 115.7, 111.7, 107.7, 73.4, 50.2, 41.8, 38.5, 32.0, 31.5, 27.9, 22.9, 22.8, 20.6, 18.9, 15.9; IR (KBr): νmax = 3449, 3076, 2964, 2873, 1765, 1642, 1419, 1377, 1116, 901, 762 cm–1; MS (ESI): m/z 353 (M + Na)+; HRMS (ESI): m/z calcd for C22H34O2 (M + H)+: 353.2621, found: 353.2607.

(E)-8-(4-(3-Isopropylpent-4-enyl)furan-2-yl)-3,7-dimethylocta-1,6-dien-3-yl Acetate (16b)

To a solution of alcohol 2 (30 mg, 0.09 mmol) in pyridine (1 mL), 4-dimethylaminopyridine (13 mg, 0.11 mmol) and acetic anhydride (11 μL, 0.11 mmol) were added and stirring was continued for 48 h at 60 °C. The mixture was poured into water. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with saturated aqueous CuSO4 solution, water, and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography with EtOAc/hexane (5:95) to give acetate (24 mg, 72%). Rf = 0.6 (hexane/ethyl acetate = 9:1); 1H NMR (500 MHz, CDCl3): δ 6.99 (d, J = 0.9 Hz, 1H), 5.91 (dt, J = 17.5, 7.3 Hz, 1H), 5.81 (s, 1H), 5.50 (ddd, J = 17.1, 10.2, 9.4 Hz, 1H), 5.18–5.10 (m, 1H), 5.10–5.02 (m, 2H), 4.98 (dd, J = 10.2, 2.3 Hz, 1H), 4.88 (ddd, J = 17.1, 2.2, 0.6 Hz, 1H), 3.16 (d, J = 11.8 Hz, 2H), 2.37–2.27 (m, 1H), 2.20–2.10 (m, 1H), 1.99–1.90 (m, 5H), 1.86–1.77 (m, 1H), 1.78–1.66 (m, 2H), 1.61–1.51 (m, 5H), 1.47 (s, 3H), 1.43–1.32 (m, 1H), 0.81 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 154.1, 141.7, 140.5, 137.1, 132.3, 126.0, 125.9, 115.7, 113.1, 107.7, 82.8, 50.2, 39.6, 38.5, 32.0, 31.6, 23.5, 22.9, 22.4, 22.2, 20.6, 18.9, 15.8; IR (KBr): νmax = 2962, 2876, 1769, 1737, 1457, 1249, 1116, 1006, 924 cm–1; MS (ESI): m/z 395 (M + Na)+; HRMS (ESI): m/z calcd for C24H36O3SiNa (M + Na)+: 395.2562, found: 395.2572.

Acknowledgments

S.Z.M. and C.R.R. acknowledge the Council of Scientific and Industrial Research (CSIR), New Delhi, for research fellowship and financial support as part of the 12th Five Year Plan Project under title ORIGIN (CSC-108) (IICT/Pubs./2018/044).

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02328.

  • Copies of 1H and 13C NMR spectra of all new compounds and explored RCM conditions (Table S1) (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao8b02328_si_001.pdf (1.1MB, pdf)

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