Towards the diastereoselective synthesis of derivative of 11'-epi-brevipolide H.

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Towards the diastereoselective synthesis of derivative of 11’-epi-brevipolide H† Gullapalli Kumaraswamy,*a,c Neerasa Jayaprakash,a Dasa Rambabu,a Aniban Gangulyb and Rajkumar Banerjeeb,c An efficient diastereoselective synthesis of brevipolide H derivative is described. The approach features

Received 26th November 2013, Accepted 7th January 2014

the use of (i) catalytic asymmetric transfer hydrogenation, (ii) hydroxyl-directed cyclopropanation, and

DOI: 10.1039/c3ob42367k

(iii) substrate-controlled catalytic epoxidation and ring-closing metathesis. Remarkably, in this convergent synthesis process, stereogenic centers were installed through catalytic reactions with high stereocontrol,

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which greatly facilitates the synthesis of stereo-divergent derivatives.

Introduction Hyptis brevipes Piot is an invasive species which belongs to the genus Hyptis (Lamiaceae) and which is widely distributed in tropical regions around the world. Recently, the entire plant was selected for phytochemical evaluation, with several natural products 1a–f consequently isolated from this genus.1 Further investigation using a range of solvents extracts of 1a–f showed excellent biological activity, including (i) inhibitory activities against bacterial and fungal growth,2 (ii) DNA intercalation activity,3 and (iii) cytotoxicity against HT-291a and the MCF-7 human breast cancer cell line.1b In particular, a 70% aqueous methanol extract of 1e isolated from the Peruvian plant Lippia alva (Verbenaceae) was identified as an inhibitor of chemokine receptor 5 (CCR5, IC50 = 5.5, 6.0, and 7.2 µg mL−1) and hence is considered as having potential as an anti-HIV agent (Fig. 1).4 Additionally, compound 1d was found to be active in an enzyme-based ELISA NF-kB assay.1a The brevipolide A–J family possess a cyclopropyl motif linked to β-substituted cinnamylcarboxy-keto unit on one side and on the other side a hydroxymethine containing an unsaturated δ-lactone as core structural unit. Recently, Pereda-Miranda et al. also isolated brevipolides A–J (1a–1j) from a Hyptis brevipes plant; the relative configuration of all of these compounds, including C11 sterogenic center, was confirmed by a combination of X-ray diffraction a Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 607, India. E-mail: [email protected]; Fax: +91-40-27193275; Tel: +91-40-27193154 b Biomaterial group, Division of Lipid Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 607, India c Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi-110 001, India † Electronic supplementary information (ESI) available: Copies of 1H and 13 C NMR spectra. See DOI: 10.1039/c3ob42367k

This journal is © The Royal Society of Chemistry 2014

Fig. 1

Brevipolide family, 1a–j.

analysis, chiroptical measurements, chemical correlations, and Mosher ester derivatization with the assignments of 5R, 6S, 7S, 9S, and 11S.1b The intriguing structural features coupled with the diverse biological profiles showing significant activity prompted us to initiate studies of the synthesis the family of brevipolides in general and brevipolide H, 1e, in particular.

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Results and discussion With our sustained interest in developing catalytic enantioselective routes to bioactive molecules,5 herein we propose a flexible and scalable synthetic route that would provide sufficient quantities for the structure–activity studies necessary for further biological evaluations of these natural molecules. Primarily, the strategy relies on three key steps. These are (a) catalytic asymmetric transfer hydrogenation as the genesis of chirality, (b) hydroxyl-directed diastereoselective cyclopropanation, and (c) substrate-controlled catalytic epoxidation and ring-closing metathesis. The hypothesized retro-synthetic analysis indicates that brevipolide H can arise via the condensation of p-methoxycinnamic acid (3), with β-hydroxy cyclopropyl intermediate 2. The pivotal intermediate 2 would be ensured from cyclopropyl epoxy alcohol 4, which in turn can be realized via a substratecontrolled Charette modified Simmons-Smith cyclopropanation6 and the Vo-mediated epoxidation of the secondary allylic alcohol, 5. Stereogenic center 11 in 1e could be introduced through catalytic asymmetric transfer hydrogenation, which has the option of generating both enantiomers with a low level of catalyst loading.7 We chose the furyl moiety to generate a fivecarbon unit embedded with prochiral keto and with α,β-unsaturated functionality. Further, the α,β-unsaturated functionality will become a logical tool to achieve the intended hydroxyl cyclopropyl sub unit. Accordingly, a retro-synthetic analysis is delineated in Scheme 1. The synthesis commenced by ruthenium-catalyzed (0.5 mol%) asymmetric transfer hydrogenation of acetyl furan (6) employing a HCO2H–Et3N (5 : 2) azeotropic mixture to provide enantioenriched secondary alcohol in 98% yield with 95% ee;7b the subsequent protection of the secondary alcohol with PMB-Cl led to PMB-ether 7 in 93% yield. Then, NBS promoted furan oxidation of 7 under basic conditions resulted in the desired γ-keto α,β-unsaturated aldehyde 8 in moderate yield (65%).8 Reduction of the prochiral ketone and aldehyde of 8 under Luche conditions delivered the expected syn diol with a 97 : 3 diastereomeric ratio (as judged by its 1H NMR spectra)9 which upon the protection of the primary alcohol with TBDMSCl resulted in 5 in 86% isolated yield. With requisite secondary chiral allylic alcohol 5 in hand, we considered a Charette modified Simmons-Smith cyclopropanation. As anticipated, cyclopropanation resulted in syn-cyclopropyl carbinol 9 as the major diastereomer (95 : 5) in 90% yield.6,10 Alcohol 9 was converted into its MOM-ether followed by fluoride-induced deprotection of the silyl group, leading to cyclopropyl alcohol 10 in 97% yield. In order to generate α,β-unsaturated allylic alcohol 12, primary alcohol 10 was converted to aldehyde by employing a Swern oxidation followed by a two-carbon Wittig reaction, leading to α,β-unsaturated ester 11, which was subjected to DIBAL reduction resulting in 12 in 92% yield (Scheme 2). Initially, the epoxidation process was carried out under Sharpless conditions.11 The desired epoxy alcohol 4 was

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Scheme 1

Retro-synthesis analysis of brevipolide H.

produced in 88% yield with a 10 : 3 diastereomeric ratio (Scheme 3). With the same substrate, using a Vo-catalyzed12 epoxidation at ambient temperatures while stirring for 1 h gave the required product 4 as a 1 : 1 mixture. After considerable experimentation, it was found that the dropwise addition of TBHP to a refluxing benzene solution containing the Vo(acac)2 catalyst and substrate 12 furnished epoxy alcohol 4 in 85% yield with a 10 : 1 diastereomeric ratio. The specific rotation and spectral data (1H and 13C NMR) were in agreement with (+)-diethyl tartrate/Ti-mediated product 4; consequently, it was assumed that the epoxide was likely α-epoxy alcohol 4. Similarly, diastereomer 13 was generated with 10 : 1 diastereoselectivity in 89% yield by employing (−)-DIPT/Ti(OiPr)4 (Scheme 3). In order to convert epoxy alcohol 4 to a vicinal diol, the primary alcohol was converted to its tert-butyl carbonate derivative, and then BF3·Et2O promoted intramolecular oxacyclization13 provided the cyclic carbonate with secondary alcohol at a diastereomeric ratio of 9 : 1 as a separable isomer. The subsequent protection of the secondary alcohol of the major isomer with TBDMSCl under basic conditions led to 14 in 86% yield (more than three steps). Then, basic methanolysis of the cyclic carbonate gave diol 15, which after a sequential treatment with NaH and N-tosylimidazole resulted in terminal epoxide 16 in 97% yield14 (Scheme 4). Initially, we planned to open terminal epoxide 16 with vinylmagnesium bromide in the presence of Cu followed by


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Scheme 2

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Synthesis of cyclopropyl allylic alcohol 12.

Scheme 3

Synthesis of cyclopropyl epoxy alcohol 4 and 13.

Scheme 4

Synthesis of cyclopropyl unsaturated δ-lactone.


coupling of the resulting alcohol with acrylic acid and subsequent cross-metathesis. This was expected to deliver α,β-unsaturated δ-lactone 17. Nevertheless, opening with vinylmagnesium bromide in the presence of CuI is associated with poor reproducibility with varying yields of 17 (10–40%) (Scheme 4). Eventually, terminal epoxide 16 was converted to allylic alcohol in 95% yield by treating it with dimethyl sulphonium methylide.15 The resulting alcohol was then esterified with propionic acid using the Steglich protocol,16 resulting in 18 in 90% yield. Ring-closing metathesis17 followed by base-catalyzed isomerisation18 of the double bond furnished α,β-unsaturated δ-lactone19 19 in moderate yield (65%). Oxidative cleavage of the PMB group led to critical intermediate 2 in 71% isolated yield. At this juncture, in principle the C11 stereogenic center in 2 requires inversion to achieve natural molecule 1e. Accordingly, the secondary alcohol in 2 was subjected to Mitsunobu inversion. To our dismay, no trace of the required compound 2a was obtained.20 Although this was disappointing at this point, there was an option to generate ent-7 by employing an antipode ligand in a Noyori reduction using 6. Then, we advanced to synthesize not only the derivatives of brevipolide but also to determine the reaction course of the penultimate oxidation of hydroxyl, leading to keto functionality. Thus, esterification with p-methoxycinnamic acid under the Steglich conditions and subsequent Lewis acid-mediated deprotection of the MOM group resulted in 20 in 88% yield (Scheme 5). Finally, oxidation of the secondary alcohol using various oxidizing agents gave us cause for concern. None of the oxidizing agents we tried generated the anticipated keto functionality from alcohol 20 (Scheme 6). Eventually, we generated a derivative of brevipolide 22 from 20 via a fluoride-induced deprotection step, which was then evaluated for structure–activity studies.

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Scheme 5


Synthesis of the penultimate intermediate brevipolide.

Cytotoxicity studies

Scheme 6

Synthesis of brevipolide derivative.

Materials and methods Cell culture MCF-7 (human breast adenocarcinoma) and HEK-293 (human embryonic kidney) cells were purchased from the National Center for Cell Sciences (Pune, India). All of the cells were mycoplasma-free. HEK 293 cells were cultured in DMEM and MCF-7 cells were cultured in a RPMI 1640 medium which contained 10% fetal bovine serum (Lonza). 50 μg mL−1 of penicillin, 50 μg mL−1 of streptomycin, and 100 μg mL−1 of kanamycin were used as antibiotics. During the cell culturing process, a temperature of 37 °C was maintained inside the incubator with an atmosphere of 5% CO2 in air. Cultures at 85–90% confluence were used for all of the experiments. The cells were trypsinized before being counted and seeded in 96-well plates for viability studies. The cells were given time to adhere overnight before they were used in the experiments.

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The cytotoxicity studies of the compounds were estimated by 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assays. The cell was seeded at a density of 5000 cells per well in a 96-well plate. The experiments were usually conducted 12–14 h after seeding of the cells in the 96-well plates. Following treatment of a compound for 72 h, MTT was directly added to the media, and it was incubated at 37 °C for 2–3 h. The cells were then dissolved in a mixture of DMSO and methanol (50 : 50) to determine their viability. The results were expressed as percent viability = [A550(treated cells) − background/A550(untreated cells) − background] × 100. The IC50 values were calculated using Micrococal Origin 6.0 professional software. The cytotoxicity studies of compounds 20 and 22 were estimated in a cancer (MCF-7) cell line and in a non-cancer (HEK-293) cell line. The IC50 values are calculated in µM and are averages of triplicate data obtained in three different batches of experiments. The results in Table 1 indicate that dihydroxy compound 22 is four times more cytotoxic than 20 in MCF-7 cells. The high IC50 in HEK-293 cells for compounds 20 and 22 indicates that the cytotoxicity of both of these molecules is cancer-selective. Table 1 Cytotoxicity studies of compounds 20 and 22 against the MCF-7 cancer cell line

Entry

Compound

IC50 in MCF-7 (μM)

IC50 in HEK-293 (μM)

1 2

20 22

11.57 ± 0.034 2.8 ± 0.003

>50 >50

The IC50 values are calculated in µM. The results are averages of triplicate data obtained in three different batches of experiments.


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While comparing the IC50 values in cancer and non-cancer cells, it became clear that the therapeutic index for brevipolide derivative 22 (MCF-7 = 2.8 μM) is much better than 20. Remarkably, the dihydroxy derivative 22 is more toxic against MCF-7 human breast cancer cells than the naturally occurring molecule 1e (MCF-7 = 5.2 μM) (Fig. 1). Also, it can be proposed that a free hydroxyl group at C-6 and C-11 and a hydroxyl group or methoxy functionality in an aromatic nucleus are required for good activity.

Conclusion In conclusion, we accomplished a concise enantioselective route to a derivative of a brevipolide H natural product. The salient feature of this concise synthesis is the genesis of chirality through an asymmetric transfer hydrogenation reaction. Brevipolide derivative 22 is synthesized in 23 steps (the longest linear sequence) in 2.5% overall yield, starting from commercially available 2-acetylfuran (6). The advanced intermediates generated via this protocol by hydroxyl-directed cyclopropanation, substrate-controlled catalytic epoxidation and ringclosing metathesis would facilitate the synthesis of each representative member of the brevipolide family. Further, the initial reduction can produce either enantiomer with a low level of catalyst loading and hence is amenable for the preparation of diastereo-derivatives of this class of natural products.

Experimental section General information Reactions were conducted under inert atmosphere if argon is mentioned. Apparatus used for reactions were oven dried. THF was distilled from sodium benzophenone ketyl. 1H NMR spectra were recorded at 300, 400 & 500 MHz and 13C NMR 75 & 125 MHz in CDCl3. J values were recorded in hertz and abbreviations used are s – singlet, d – doublet, m – multiplet, br – broad. Chemical shifts (δ) are reported relative to TMS (δ = 0.0) as an internal standard. IR (FT-IR) spectra were measured as KBr pellets or as film. Mass spectral data were compiled using MS (ESI) or HRMS mass spectrometers. Optical rotations were recorded on a high sensitive polarimeter with 10 mm cell. (R)-1-(Furan-2-yl)ethanol (6a). To a solution of 6 (10 g, 90.9 mmol) in anhydrous EtOAc (80 mL) under argon was added a formic acid–triethylamine azeotropic mixture (5 : 2, 80 mL) followed by the addition of Ru-catalyst A (240 mg, 0.5 mol%) which was pre-dissolved in CH2Cl2 (20 mL). The resulting reaction mixture was heated to 40 °C for 15 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography eluting with 10% EtOAc–hexane to give 6a (R) (9.9 g,


Paper 7b 98%): colorless oil; [α]25 [α]23 D = +24.1 (c = 0.45, ethanol); [lit. D = −24.3 (c = 6.0, ethanol)] for the enantiomer of 98% ee. 1H NMR (300 MHz, CDCl3): δ 7.30–7.32 (m, 1H), 6.27 (dd, J = 3.0, 1.8 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H), 4.81 (dq, J = 6.0, 6.0 Hz, 1H), 2.26 (s, 1H), 1.5 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 157.5, 141.5, 109.9, 104.8, 63.2, 21.0; IR (KBr): 3462, 2985, 2935, 1668, 1149, 877, 731 cm−1. (R)-2-(1-(4-Methoxybenzyloxy)ethyl)furan (7). To an ice-cold suspension of oil-free NaH (2.9 g, 120.6 mmol), in DMF (100 mL) was added 6a (9.0 g, 80.4 mmol), and the reaction mixture was stirred at room temperature for 1 h. p-Methoxybenzyl chloride (13.0 mL, 96.5 mmol) was added to the mixture. After 2 h, water (150 mL) was added to it and the product was extracted with EtOAc twice. The combined extracts were washed with brine and dried over sodium sulphate, which was subjected to chromatography eluting with 10% EtOAc–hexane to furnish 7 (17.3 g, 93%): colorless oil. [α]25 D = +116.2 (c = 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1H), 7.25 (d, J = 9 Hz, 1H), 6.86 (d, J = 9 Hz, 1H), 6.34 (dd, J = 3.2 Hz, 1H), 6.27 (d, J = 3 Hz, 1H), 4.53 (q, J = 7.0 Hz, 1H), 4.46 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H), 3.79 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 158.9, 155.4, 130.2, 129.2, 113.6, 109.8, 106.9, 69.6, 69.2, 55.0, 19.7; IR (KBr): 1600, 1582, 1511, 1242, 818, 740 cm−1. (R,E)-5-(4-Methoxybenzyloxy)-4-oxohex-2-enal (8). A solution of 7 (15.0 g, 64.7 mmol) in acetone–H2O (150 mL, 10 : 1 v/v) was slowly added to a mixture of N-bromosuccinimide (11.5 mg, 64.7 mmol) and NaHCO3 (10.8 g, 129.4 mmol) in acetone–H2O (150 mL, 10 : 1 v/v) while stirring at −15 °C. The resulting reaction mixture was stirred at the same temperature for 1 h. After 30 min of stirring at −15 °C, furan (4.4 mL, 64.7 mmol) and pyridine (10.7 mL, 129.4 mmol) were added to the mixture. The resulting mixture was stirred at room temperature for 6 h and poured into 0.5 M CuSO4 solution (300 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined extracts were dried and evaporated to furnish a residue, which on chromatography (hexane–EtOAc 85 : 15) afforded aldehyde 8 (10.4 g, 65%): [α]25 D = +69.5 (c = 0.1, CHCl3); 1H NMR (300 MHz, CDCl3): δ 9.70 (d, J = 7.6 Hz, 1H), 7.15–7.26 (m, 3H), 6.77–6.85 (m, 3H), 4.51 (d, J = 11.3 Hz, 1H), 4.42 (d, J = 11.3 Hz, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.79 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 200.8, 192.8, 159.4, 139.5, 137.8, 129.6, 113.7, 79.6, 71.7, 54.9, 17.0; IR (KBr): 1690, 1610, 1511, 1250, 1112 cm−1. (4R,5R,E)-5-(4-Methoxybenzyloxy)hex-2-ene-1,4-diol (8a). Compound 8 (8.0 g, 32.3 mmol) was dissolved in MeOH (150 mL) and cooled to −100 °C. To this, CeCl3·7H2O (42.2 g, 129.2 mmol) was added and stirred for 10 min. Following NaBH4 (3.7 g, 96.9 mmol) was added in 3 portions and stirred for 2 h at the same temperature. The reaction was quenched by adding EtOAc (30 mL), warmed to rt, and added water (100 mL). The aqueous layer extracted 3 times with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and the solvent was removed under vacuum. The obtained oil was purified by column chromatography (hexane–EtOAc = 1 : 1). yielding alcohol 8a as colorless

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oil (7.9 g, 98%) (diastereomeric ratio 97 : 3 judged by 1H NMR 1 spectra). [α]25 D = −35.7 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.24–7.29 (m, 2H), 6.86–6.91 (m, 2H), 5.91–6.0 (m, 1H), 5.64–5.75 (m, 1H), 4.61 (d, J = 11.3 Hz, 1H), 4.38 (d, J = 11.3 Hz, 1H), 4.13–4.18 (m, 2H), 3.93–3.97 (m, 1H), 3.81 (s, 3H), 3.36–3.45 (m, 1H), 2.7 (bs, 1H), 1.74 (bs, 1H), 1.17 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 158.9, 132.3, 130.0, 129.1, 113.5, 77.6, 75.1, 70.5, 62.1, 54.9, 15.2; IR (KBr): 3399, 3362, 2985, 2922, 1585, 1462, 1301, 1217, 1149, 877, 772 cm−1; MS (ESI) m/z: 275 (M + Na)+. HRMS: calcd for C14H20O4Na 275.1253; found 275.1255. (2R,3R,E)-6-(tert-Butyldimethylsilyloxy)-2-(4-methoxybenzyloxy)hex-4-en-3-ol (5). Compound 8a (7.0 g, 27.8 mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0 °C. Imidazole (1.9 g, 27.8 mmol) was added followed by TBDMSCl (4.58 g, 30.58 mmol) and resulting contents were stirred for 6 h at room temperature. The reaction was quenched by adding H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer dried and filtered and evaporated to give a residue. The residue was subjected to chromatography (hexane–EtOAc 90 : 10) to furnish 5 (8.75 g, 86%) as colorless oil. [α]25 D = −45.5 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.24.7.29 (m, 2H), 6.85–6.91 (m, 2H), 5.88 (dt, J = 15.3, 4.5 Hz, 1H), 5.67 (dd, J = 15.3, 6.6 Hz, 1H), 4.6 (d, J = 11.1 Hz, 1H), 4.39 (d, J = 11.1 Hz, 1H), 4.20 (d, J = 4.3 Hz, 2H), 3.95 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.40 (q, J = 6.8 Hz, 2H), 3.36–3.44 (m, 1H), 2.81 (bs, 1H), 1.17 (d, J = 6.2 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 159.1, 132.3, 130.2, 129.2, 113.7, 78.1, 75.5, 70.7, 63.1, 55.0, 25.8, 15.5, −5.4; IR (KBr): 3384, 3019, 2935, 1667, 1598, 1530, 1370, 1215, 1149, 744, 667 cm−1; MS (ESI) m/z: 389 (M + Na)+. HRMS: calcd for C20H34O4NaSi 389.2118; found 389.2122. (1R,2R)-1-((1S,2S)-2-((tert-Butyldimethylsilyloxy)methyl)cyclopropyl)-2-(4-methoxybenzyloxy)propan-1-ol (9). Diiodomethane (4.0 mL, 49.2 mmol) was added slowly to a stirred solution of diethylzinc (24.6 mL, 3 equivalents, 1.0 M solution in hexane) in dry CH2Cl2 (100 mL) at −78 °C. After a white slurry was formed, a solution of 5 (3.0 g, 8.2 mmol) in CH2Cl2 (30 ml) was added dropwise. The resulting reaction mixture was stirred at 0 °C for 2 h, and allowed to warm to room temperature (∼2 h) and quenched with sat. NH4Cl followed by saturated sodium sulfite solution (20 mL). The reaction mixture was stirred for 10 minutes, then hydrochloric acid (0.5 N solution) was added to dissolve the resultant white precipitate. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL), washed with brine (50 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure to afford a crude residue that was purified by chromatography eluting with 10% EtOAc– hexane to furnish 9 (2.8 g, 90%) as colorless oil (diastereomeric ratio 95 : 5 judged by 1H NMR spectra). [α]25 D = −46.7 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.55 (d, J = 11.0 Hz, 1H), 4.43 (d, J = 11.0 Hz, 1H), 3.80 (s, 3H), 3.60–3.66 (m, 2H), 3.36 (dd, J = 7.7, 6.6 Hz, 1H), 3.08 (dd, J = 3.3, 3.3, Hz, 1H), 1.60 (bs, 1H), 1.25 (d, J = 6.6 Hz, 3H), 0.88 (s, 9H), 0.81–0.85 (m, 2H), 0.57 (m, 1H), 0.49 (m, 1H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3):

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δ 158.9, 130.4, 128.9, 113.5, 76.5, 76.3, 70.1, 65.6, 54.9, 25.7, 18.4, 18.0, 13.6, 7.6, −5.6; IR (KBr): 3384, 3019, 2935, 1598, 1530, 1370, 1215, 1149, 744, 667 cm−1; MS (ESI) m/z: 403 (M + Na)+. HRMS: calcd for C21H36O4NaSi 403.22751; found 403.22761. tert-Butyl(((1S,2S)-2-((1R,2R)-2-(4-methoxybenzyloxy)-1(methoxymethoxy)propyl )cyclopropyl )methoxy)dimethylsilane (9a). To a DCM solution (30 mL) of 9 (2.7 g, 7.1 mmol) at 0 °C was added dropwise EtN(i-Pr)2 (2.5 ml, 14.2 mmol) and MOMCl (0.8 ml, 10.65 mmol) sequentially. The reaction was allowed to reach room temperature and was stirred for 12 h. The reaction was quenched by adding sat. aq. NH4Cl solution (20 mL) and was extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulphate, filtered and the solvent was removed under vacuum. The thus obtained colorless oil was purified by column chromatography (silica gel, hexane–EtOAc 9 : 1), yielding 9a (2.8 g, 93%) as col1 orless oil. [α]25 D = +11.0 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.25–7.27 (m, 2H), 6.86 (d, J = 8.1 Hz, 2H), 4.81 (d, J = 6.5 Hz, 1H), 4.68 (d, J = 6.5 Hz, 1H), 4.56 (d, J = 11.3 Hz, 1H), 4.47 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.62 (ddd, J = 6.5, 5.7, 6.5 Hz, 1H), 3.45–3.53 (m, 2H), 3.37 (s, 3H), 2.95 (dd, J = 1.9, 5.7 Hz, 1H), 1.25 (d, J = 6.5 Hz, 3H), 0.91–0.97 (m, 2H), 0.88 (s, 9H), 0.57–0.64 (m, 1H), 0.52–0.57 (m, 1H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 158.5, 130.6, 128.8, 113.2, 95.3, 82.4, 76.1, 70.8, 65.3, 54.8, 25.5, 17.9, 16.9, 15.9, 8.3, −5.7; IR (KBr): 2930, 2887, 2851, 1613, 1581, 1467, 1219, 1201, 1096, 1037, 769, 668 cm−1; MS (ESI) m/z: 447 (M + Na)+. HRMS: calcd for C23H40O5NaSi 447.25372; found 447.25205. ((1S,2S)-2-((1R,2R)-2-(4-Methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)methanol (10). To a solution of 9a (2.5 g, 5.9 mmol) in THF (25 mL) at 0 °C was added TBAF (1.0 M solution in THF, 8.8 mL, 8.8 mmol). The resultant solution was stirred at room temperature for 5 h, and then saturated aqueous NH4Cl solution was added. The organic layer was concentrated under reduced pressure, and the residual aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 30% EtOAc–hexane) gave 10 (1.77 g, 97%) as a colorless oil: 1 [α]25 D = +8.5 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.24–7.29 (m, 2H), 6.85–6.90 (m, 2H), 4.81 (d, J = 6.5 Hz, 1H), 4.56–4.63 (m, 2H), 4.44 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.65–3.73 (m, 1H), 3.56–3.63 (m, 1H), 3.36 (s, 3H), 3.16–3.23 (m, 1H), 3.0 (dd, J = 4.5, 9.1 Hz, 1H), 1.75–1.82 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 0.98–1.07 (m, 1H), 0.64–0.71 (m, 1H), 0.54–0.60 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 158.9, 130.3, 129.1, 113.5, 95.1, 81.1, 76.4, 70.6, 66.0, 54.9, 18.2, 16.8, 15.1, 8.4; IR (KBr): 3362, 2985, 2935, 1618, 1505, 1462, 1370, 1230, 1149, 877, 731 cm−1; MS (ESI) m/z: 333 (M + Na)+. HRMS: calcd for C17H26O5Na 333.1672; found 333.1673. (E)-Ethyl 3-((1R,2S)-2-((1R,2R)-2-(4-methoxybenzyloxy)-1(methoxymethoxy)propyl)cyclopropyl)acrylate (11). Dimethylsulfoxide (1.0 mL, 13.8 mmol) was added to a solution of oxalyl chloride (0.9 mL, 11.0 mmol) dissolved in


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dichloromethane (20 mL) at −78 °C. After 20 min, a solution of alcohol 10a (1.7 g, 5.5 mmol) in dichloromethane was added. The reaction mixture was stirred for 25 min. Triethylamine (3.8 mL, 27.5 mmol) was added dropwise, followed by 10 min stirring at same temperature. Then, the mixture was warmed to 0 °C and stirred for 15 min. The reaction was quenched by adding 20 mL of water. The aqueous layer was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with water and brine (3 × 10 mL), dried over sodium sulphate, filtered, and concentrated under vacuum. The crude aldehyde was then immediately subjected to the next step. The above crude aldehyde was dissolved in dichloromethane (20 ml) and cooled to 0 °C. To this, ethyl (triphenylphosphoranylidene)acetate (1.9 g, 5.5 mmol) was added. The reaction mixture warmed to room temperature and stirred for 6 h. Then, dichloromethane was removed under vacuum, and the resulting crude residue purified by column chromatography (silica gel, 15% EtOAc–hexane) to give the desired product 11 as light yellow oil (1.65 g, 80% over two steps). [α]25 D = +42.1 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.22–7.27 (m, 2H), 6.84–6.87 (m, 2H), 6.46 (dd, J = 10.0, 15.5 Hz, 1H), 5.83 (d, J = 15.5 Hz, 1H), 4.79 (d, J = 6.8 Hz, 1H), 4.65 (d, J = 6.8 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.43 (d, J = 11.5 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.57–3.65 (m, 1H), 3.37 (s, 3H), 3.06 (dd, J = 4.7, 8.1 Hz, 1H), 1.43–1.53 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.06–1.14 (m, 1H), 0.88–0.97 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 166.8, 159.3, 152.1, 130.8, 129.5, 119.1, 113.9, 96.1, 81.7, 71.1, 60.3, 55.7, 55.4, 23.0, 19.1, 16.0, 14.5; IR (KBr): 2998, 2871, 2851, 1720, 1652, 1581, 1462, 1219, 1201, 1096, 1037, 775, 669 cm−1; MS (ESI) m/z: 401 (M + Na)+. HRMS: calcd for C21H30O6Na 401.1934; found 401.1925. ((1S,2S)-2-((1R,2R)-2-(4-Methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)methanol (12). To a cold suspension of the compound 11 (1.5 g, 4.0 mmol) in dry toluene (15 mL) at −78 °C, a solution of DIBAL-H (1 M in toluene, 8.0 mL, 8.0 mmol) was added dropwise. The resulting reaction mixture was stirred for 2 h at the same temperature. The reaction mixture was quenched with sodium potassium tartrate solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was separated and washed with water, brine and dried (Na2SO4). Evaporation of the solvent resulted in a residue which was purified by column chromatography (30% ethyl acetate–hexanes) to afford the title compound 12 (1.2 g, 1 92%) as colorless oil. [α]25 D = −28.0 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.23–7.29 (m, 2H), 6.85–6.89 (m, 2H), 5.67 (dt, J = 6.0, 15.1 Hz, 1H), 5.23 (dd, J = 9.1, 15.1 Hz, 1H), 4.81 (d, J = 6.8 Hz, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 4.1 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.56–3.66 (m, 1H), 3.37 (s, 3H), 2.98 (dd, J = 5.2, 9.1 Hz, 1H), 1.66 (bs, 1H), 1.26–1.35 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H), 0.98–1.05 (m, 1H), 0.85–0.91 (m, 1H), 0.69–0.75 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 158.9, 134.9, 130.8, 129.2, 127.3, 113.6, 95.7, 82.3, 77.4, 71.1, 63.4, 55.2, 21.2, 18.3, 16.0, 12.5; IR (KBr): 3394, 2995, 2820, 2851, 1641,


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1585, 1465, 1246, 1218, 1096, 1033, 772, 668 cm−1; MS (ESI) m/z: 359 (M + Na)+. HRMS: calcd for C19H28O5Na 359.1829; found 359.1831. ((2S,3S)-3-((1S,2S)-2-((1R,2R)-2-(4-Methoxybenzyloxy)-1(methoxymethoxy)propyl)cyclopropyl)oxiran-2-yl)methanol (4). Alcohol 12 (1.0 g, 3.0 mmol) and vanadyl acetyl acetonate (8 mg, 1 mol%) in 10 ml of refluxing benzene was added, dropwise 0.9 mL (3.0 mmol) of 3 M tert-butyl hydroperoxide. The initially colourless solution of alcohol in benzene turned bright green upon addition of the VO(acac)2. The colour faded as the reflux temperature was reached and then turned deep red as t-BuOOH was added. During the progress of the reaction, the deep red colour turns to yellow and then light green. After 1 h EtOAc and brine were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated to furnish a yellow oil which was purified over silica gel chromatography to give 4 (890 mg, 85%) as colorless oil (diastereomeric ratio 10 : 3 as separable isomers). [α]25 D = −20.0 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.17–7.22 (m, 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.57 (d, J = 7.2 Hz, 1H), 4.50 (dd, J = 7.2, 10.7 Hz, 1H), 4.36–4.41 (m, 1H), 3.77–3.82 (m, 4H), 3.51–3.59 (m, 1H), 3.29 (s, 3H), 2.92–2.98 (m, 1H), 2.81–2.89 (m, 1H), 2.68–2.72 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H), 0.93–1.03 (m, 1H), 0.74–0.83 (m, 1H), 0.58–0.68 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 159.0 130.8, 129.2, 113.7, 95.7, 81.6, 77.2, 71.0, 61.2, 58.0, 57.1, 56.4, 55.2, 29.7, 16.9, 16.3, 15.5, 7.7; IR (KBr): 3432, 2979, 2920, 2851, 1610, 1512, 1419, 1246, 1173, 1078, 1029, 750, 665 cm−1; MS (ESI) m/z: 375 (M + Na)+. HRMS: calcd for C19H28O6Na 375.17781; found 375.17773. ((2S,3S)-3-((1S,2S)-2-((1R,2R)-2-(4-Methoxybenzyloxy)-1(methoxymethoxy)propyl)cyclopropyl)oxiran-2-yl)methanol (4). To a DCM suspension of powdered molecular sieves (MS 4 Å) and (+)-DET (40 μL, 0.24 mmol) under N2 atmosphere at −20 °C was added Ti(Oi-Pr)4 (35 μL, 0.12 mmol). After 15 min, compound 12 (200 mg, 0.6 mmol,) in CH2Cl2 was added and 30 min later a 3.5 M solution of TBHP in toluene (0.4 mL, 1.2 mmol) was added. The resulting reaction mixture was stirred for 16 h. Then, the reaction mixture was quenched by the addition of a tartaric acid solution (15% in water), and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue obtained was dissolved in ether and washed with NaOH solution (15% in water). The organic phase was dried with Na2SO4 and purified by column chromatography (silica gel, 30% EtOAc–hexane) to give the desired product 4 as colorless oil (186 mg, 88%). (diastereomeric ratio 10 : 1 as separable isomers). [α]25 D = −20.0 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.17–7.22 (m, 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.57 (d, J = 7.2 Hz, 1H), 4.50 (dd, J = 7.2, 10.7 Hz, 1H), 4.36–4.41 (m, 1H), 3.77–3.82 (m, 4H), 3.51–3.59 (m, 1H), 3.29 (s, 3H), 2.92–2.98 (m, 1H), 2.81–2.89 (m, 1H), 2.68–2.72 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H), 0.93–1.03 (m, 1H), 0.74–0.83 (m, 1H), 0.58–0.68 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 159.0 130.8, 129.2, 113.7,

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95.7, 81.6, 77.2, 71.0, 61.2, 58.0, 57.1, 56.4, 55.2, 29.7, 16.9, 16.3, 15.5, 7.7; IR (KBr): 3432, 2979, 2920, 2851, 1610, 1512, 1419, 1246, 1173, 1078, 1029, 750, 665 cm−1; MS (ESI) m/z: 375 (M + Na)+. HRMS: calcd for C19H28O6Na 375.17781; found 375.17773. ((2R,3R)-3-((1S,2S)-2-((1R,2R)-2-(4-ethoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)oxiran-2-yl)methanol (13). To a DCM solution of powdered molecular sieves (4 Å MS) and (−)-DIPT (50 μL, 0.24 mmol) under N2 atmosphere at −20 °C was added Ti(Oi-Pr)4 (35 μL, 0.12 mmol). After 15 min compound 12 (200 mg, 0.6 mmol) in CH2Cl2 was added and stirred 30 min. Then, a 3.5 M solution of TBHP in toluene (0.4 mL, 1.2 mmol) was added and the resulting contents were stirred overnight. The reaction was quenched with a tartaric acid solution (15% in water), and the aqueous layer was extracted with CH2Cl2. The extracts were dried over Na2SO4, filtered and the organic solvent was evaporated under reduced pressure. The residue obtained was dissolved in ether and washed with NaOH solution (15% in water). The organic phase was dried over Na2SO4 and filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% EtOAc– hexane) to give the desired product 13 as colorless oil (186 mg, 89%) (diastereomeric ratio 10 : 1 as separable isomers). [α]25 D = +25.0 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.25–7.27 (m, 2H), 6.86–6.88 (m, 2H), 4.63–4.77 (m, 2H), 4.66–4.54 (m, 2H), 4.19–4.23 (m, 1H), 3.94–4.0 (m, 1H), 3.80 (s, 3H), 3.58–3.63 (m, 1H), 3.36 (s, 3H), 3.10–3.14 (m, 1H), 2.95–3.05 (m, 1H), 2.67–2.79 (m, 1H), 1.49 (s, 9H), 1.24 (d, J = 6.7 Hz, 9H), 0.95–1.0 (m, 1H), 0.80–0.90 (m, 1H), 0.63–0.73 (m, 2H); 13 C NMR (75 MHz, CDCl3): δ 159.1, 153.2, 131.6, 131.0, 129.1, 113.7, 95.5, 82.6, 80.8, 77.0, 70.6, 57.5, 56.8, 55.5, 54.8, 16.9, 15.9, 15.3, 7.5; IR (KBr): 3436, 2979, 2920, 2851, 1610, 1512, 1419, 1246, 1173, 1078, 1029, 751, 662 cm−1; MS (ESI) m/z: 375 (M + Na)+. HRMS: calcd for C19H28O6Na 375.17781; found 375.17773. tert-Butyl ((2S,3S)-3-((1S,2S)-2-((1R,2R)-2-(4-methoxybenzyloxy)-1-(methoxymethoxy)propyl )cyclopropyl )oxiran-2-yl )methyl carbonate (4a). To a toluene (10 mL) solution of epoxy alcohol 4 (900 mg, 2.6 mmol) under N2 atmosphere and at room temperature was added N-methylimidazole (0.3 mL, 3.9 mmol) followed by Boc anhydride (558 mg, 2.6 mmol). The reaction was stirred for 5 h at room temperature. The reaction mixture was treated with EtOAc and water (10 mL) and extracted with EtOAc (3 × 5 mL). The organic phase was dried and concentrated. The resulting residue was subjected to silica gel column chromatography afforded 1.0 g (93% yield) of 4a. 1 [α]25 D = −8.3 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.25–7.27 (m, 2H), 6.86–6.88 (m, 2H), 4.63–4.77 (m, 2H), 4.66–4.54 (m, 2H), 4.19–4.23 (m, 1H), 3.94–4.0 (m, 1H), 3.80 (s, 3H), 3.58–3.63 (m, 1H), 3.36 (s, 3H), 3.10–3.14 (m, 1H), 2.95–3.05 (m, 1H), 2.67–2.79 (m, 1H), 1.49 (s, 9H), 1.24 (d, J = 6.7 Hz, 9H), 0.95–1.0 (m, 1H), 0.80–0.90 (m, 1H), 0.63–0.73 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 159.1, 153.2, 131.6, 131.0, 129.1, 113.7, 95.5, 82.6, 80.8, 77.0, 70.6, 57.5, 56.8, 55.5, 54.8, 16.9, 15.9, 15.3, 7.5; IR (KBr): 2979, 2925, 2852, 1742, 1610, 1513, 1370, 1279, 1252, 1214, 1162, 1033, 855, 748, 667 cm−1;

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MS (ESI) m/z: 475 (M + Na)+. HRMS: calcd for C24H36O8Na 475.2302; found 475.2301. (R)-4-((S)-Hydroxy((1S,2S)-2-((1R,2R)-2-(4-methoxybenzyloxy)1-(methoxymethoxy)propyl)cyclopropyl)methyl)-1,3-dioxolan-2one (4b). A flame dried, argon purged 50 mL round-bottom flask was charged with epoxide 4a (800 mg, 1.8 mmol) and anhydrous CH2Cl2 (20 mL). The solution was cooled to −40 °C and a 0.2 M BF3·OEt2 solution (9 mL) was added in one portion. The solution was stirred vigorously at −40 °C for 15 min, then quenched with saturated NaHCO3 (15 mL). The aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was subjected to silica gel chromatography using hexanes–EtOAc (1 : 1) afforded 4b (450 mg, 65%) as colorless oil (diastereomeric ratio 9 : 1 as 1 separable isomers). [α]25 D = −53.3 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.16 (d, J = 9.1 Hz, 2H), 6.82 (d, J = 9.1 Hz, 2H), 4.64 (d, J = 11.1 Hz, 1H), 4.52 (d, J = 11.1 Hz, 1H), 4.45 (d, J = 5.1 Hz, 1H), 4.30 (d, J = 5.1 Hz, 1H), 4.21–4.24 (m, 1H), 3.86–3.91 (m, 1H), 3.74 (s, 3H), 3.59–3.66 (m, 2H), 3.44–3.49 (m, 1H), 3.28 (s, 3H), 3.02–3.05 (m, 1H), 1.17 (d, J = 6.2 Hz, 3H), 0.93–1.01 (m, 2H), 0.69–0.77 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 159.0, 155.2, 130.4, 129.4, 113.6, 95.3, 80.7, 78.1, 75.6, 73.8, 70.0, 66.1, 55.3, 55.1, 17.6, 16.1, 15.0, 9.0; IR (KBr): 3438, 2979, 2920, 2851, 1785, 1611, 1512, 1419, 1246, 1173, 1078, 1029, 750, 666 cm−1; MS (ESI) m/z: 393 (M + Na)+. HRMS: calcd for C20H28O8Na 393.1874; found 393.1877. (R)-4-((S)-(tert-Butyldimethylsilyloxy)((1S,2S)-2-((1R,2R)-2-(4methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)methyl)-1,3-dioxolan-2-one (14). Compound 4b (450 mg, 1.14 mmol) was dissolved in dry DMF (5 mL) and cooled to 0 °C. Imidazole (116 mg, 1.7 mmol) was added, followed by TBDMSCl (172 mg, 1.14 mmol) and the resulting reaction mixture stirred for 9 h at room temperature. The reaction was quenched by adding water (5 mL), and extracted with EtOAc. The organic layer was dried, filtered and evaporated to dryness. The resulting residue was purified by column chromatography (silica gel, 10% EtOAc–hexane) to give the desired product 14 as colorless oil (490 mg, 86%). [α]25 D = +13.0 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.21 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 4.72 (d, J = 7.1 Hz, 1H), 4.60 (d, J = 6.1 Hz, 1H), 4.51 (d, J = 11.1 Hz, 1H), 4.4–4.43 (m, 1H), 4.37 (d, J = 11.1 Hz, 1H), 4.0 (dd, J = 5.1, 8.1, Hz, 1H), 3.81 (s, 3H), 3.65–3.72 (m, 2H), 3.56 (dd, J = 3.1, 12.1 Hz, 1H), 3.35 (s, 3H), 3.11 (dd, J = 5.1, 8.1 Hz, 1H), 1.23 (d, J = 7.1 Hz, 3H), 1.06–1.12 (m, 1H), 0.95–1.0 (m, 1H), 0.87 (s, 9H), 0.75–0.83 (m, 2H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 159.1, 154.6, 130.2, 129.1, 113.7, 95.4, 81.2, 80.9, 79.9, 75.9, 70.7, 61.9, 55.4, 55.1, 25.6, 18.5, 14.6, 8.2, −5.6; IR (KBr): 3017, 2924, 2853, 1781, 1632, 1604, 1468, 1252, 1214, 1170, 1033, 779, 664 cm−1; MS (ESI) m/z: 510 (M + Na)+. HRMS: calcd for C26H42O8NaSi 533.2541; found 533.2538. (2R,3S)-3-(tert-Butyldimethylsilyloxy)-3-((1S,2S)-2-((1R,2R)-2(4-methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)propane-1,2-diol (15). A 25 mL round-bottom flask was charged with 14 (0.4 g, 0.78 mmol) and MeOH (10 mL). After


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dissolving, K2CO3 (860 mg, 6.24 mmol) was added and the reaction mixture was stirred vigorously at room temperature for 12 h. The reaction mixture was then taken up in CH2Cl2 (15 mL) and H2O (15 mL). The aqueous phase was extracted with additional CH2Cl2 (3 × 10 mL), The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo and the resulting residue purified by column chromatography over silica gel using hexanes–EtOAc (1 : 1) afforded 15 (285 mg, 75%) as colorless oil: [α]25 D = +13.0 (c = 0.45, CHCl3); 1 H NMR (300 MHz, CDCl3): δ 7.24–7.29 (m, 2H), 6.85–6.91 (m, 2H), 4.71 (d, J = 11.1 Hz, 1H), 4.61 (d, J = 11.1 Hz, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.45 (d, J = 5.1 Hz, 1H), 3.81 (s, 3H), 3.58–3.75 (m, 2H), 3.48–3.55 (m, 1H), 3.34–3.38 (m, 1H), 3.33 (s, 3H), 2.97–3.09 (m, 2H), 1.28 (d, J = 6.2 Hz, 3H), 0.92–1.06 (m, 2H), 0.88 (s, 9H), 0.63–0.72 (m, 1H), 0.54–0.60 (m, 1H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.1, 129.1, 113.7, 95.4, 81.1, 80.9, 79.9, 75.9, 70.9, 62.1, 55.4, 55.1, 25.6, 18.5, 14.6, 8.1, −5.5; IR (KBr): 3390, 3382, 2921, 2851, 1609, 1589, 1373, 1241, 1212, 1079, 770, 665 cm−1; MS (ESI) m/z: 507 (M + Na)+. HRMS: calcd for C25H44O7NaSi 507.28577; found 507.28582. tert-Butyl((S)-((1S,2S)-2-((1R,2R)-2-(4-methoxybenzyloxy)-1(methoxymethoxy)propyl)cyclopropyl)((R)-oxiran-2-yl)methoxy)dimethylsilane (16). Sodium hydride (60% suspension in mineral oil, 120 mg, 2.48 mmol) was added to a solution of diol 15 (300 mg, 0.62 mmol) in anhydrous THF (10 mL) at 0 °C. After 15 min at 0 °C, 1-( p-toluenesulfonyl)imidazole (165 mg, 0.74 mmol) was added. Stirring was continued for an additional 3 h at 0 °C, whereupon the ice bath was removed and stirring continued for 1 h at room temperature. EtOAc (10 mL) and saturated aqueous NH4Cl (10 mL) were added to the reaction mixture, and the layers were separated. The organic layer was further washed with brine (10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel using hexanes–EtOAc (9 : 1) afforded 16 (280 mg, 97%) as colorless oil: [α]25 D = −24.0 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.23–7.25 (m, 2H), 6.85–6.87 (m, 2H), 4.78 (d, J = 6.0 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.43 (d, J = 11.9 Hz, 1H), 3.80 (s, 3H), 3.62–3.67 (m, 1H), 3.36 (s, 3H), 3.10–3.13 (m, 1H), 3.05 (dd, J = 5.0, 8.0 Hz, 1H), 2.90–2.92 (m, 1H), 2.71–2.73 (m, 1H), 2.53–2.55 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H), 0.94–1.01 (m, 1H), 0.89 (s, 9H), 0.86–0.88 (m, 1H), 0.70–0.74 (m, 1H), 0.57–0.61 (1H, m), 0.09 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.0, 130.9, 128.9, 113.6, 95.7, 81.8, 77.4, 74.7, 70.8, 55.7, 55.2, 44.8, 29.6, 25.8, 18.7, 18.1, 15.6, 14.6, 7.0, −4.4, −4.9; IR (KBr): 2930, 2887, 1612, 1586, 1513, 1465, 1247, 1144, 1030, 913, 773, 669 cm−1; MS (ESI) m/z: 489 (M + Na)+. HRMS: calcd for C25H42O6NaSi 489.2778; found 489.2777. (1S,2R)-1-(tert-Butyldimethylsilyloxy)-1-((1S,2S)-2-((1R,2R)-2(4-methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)but-3-en-2-ol (16a). A solution of trimethylsulfonium iodide (614 mg, 3.0 mmol) in THF (10 mL) was cooled to −15 °C. n-BuLi (1.6 M in hexane, 1.8 mL, 2.8 mmol) was added dropwise and the resulting solution was stirred for 1 h at −15 °C. A THF


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(2 mL) solution of epoxide 16 (200 mg, 0.43 mmol) was added and a cloudy suspension was formed. The reaction was allowed to slowly warm to 25 °C over a period of 1 h and stirred for another 1 h. The reaction mixture was cooled in an ice/water bath and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (15% EtOAc–hexanes) gave 195 mg (95%) of 1 16a as a colorless oil: [α]25 D = −10.0 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.22–7.26 (m, 2H), 6.85–6.87 (m, 2H), 5.86–5.96 (m, 2H), 5.12–5.29 (m, 2H), 4.62–4.69 (m, 2H), 4.42–4.53 (m, 2H), 3.80 (s, 3H), 3.55–3.63 (m, 2H), 3.33–3.39 (m, 2H), 1.20 (d, J = 6.7 Hz, 3H), 0.85–0.99 (m, 11H), 0.57–0.64 (m, 2H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.1, 130.8, 113.5, 95.7, 81.8, 77.4, 74.7, 70.8, 55.7, 55.2, 44.8, 29.6, 25.8, 18.7, 18.1, 15.6, 14.6, 7.0, −4.4, −4.9; IR (KBr): 3360, 3010, 2951, 2930, 1650, 1521, 1459, 1414, 1267, 1095, 852, 665 cm−1; MS (ESI) m/z: 503 (M + Na)+. HRMS: calcd for C26H44O6NaSi 503.2799; found 503.2805. (1S,2R)-1-(tert-Butyldimethylsilyloxy)-1-((1S,2S)-2-((1R,2R)-2(4-methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)but-3-en-2-yl but-3-enoate (18). To a dry CH2Cl2 (3.5 mL) solution of above alcohol 16a (150 mg, 0.31 mmol) was added DCC (84 mg, 0.4 mmol), vinyl acetic acid (35 mg, 0.4 mmol) and DMAP (8 mg, 0.2 eq.) at room temperature. The resulting mixture was stirred for 16 h at ambient temperature, then diluted with CH2Cl2 (5 mL), filtered and quenched with water (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica chromatography (hexane–EtOAc = 95/5) to provide the title compound 18 (154 mg, 90%) as a colourless oil. [α]25 D = +23.6 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.24–7.28 (m, 2H), 6.85–6.88 (m, 2H), 5.86–5.96 (m, 2H), 5.12–5.29 (m, 4H), 4.62–4.69 (m, 2H), 4.53 (d, J = 11.3 Hz, 1H), 4.47 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.55–3.63 (m, 2H), 3.33–3.39 (m, 4H), 3.06–3.09 (m, 1H), 1.20 (d, J = 6.7 Hz, 3H), 0.85–0.99 (m, 11H), 0.57–0.64 (m, 2H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.9, 159.0, 137.2, 133.1, 129.1, 118.6, 117.6, 116.6, 113.6, 96.3, 80.5, 75.1, 72.9, 71.0, 55.2, 39.3, 29.7, 25.9, 16.8, 15.6, 14.9, 6.5, −4.3; IR (KBr): 2925, 2854, 1713, 1639, 1609, 1513, 1464, 1362, 1249, 1214, 1036, 1095, 835, 752, 667 cm−1; MS (ESI) m/z: 571(M + Na)+. HRMS: calcd for C30H48O7NaSi 571.3061; found 571.3062. (R)-6-((S)-(tert-Butyldimethylsilyloxy)((1S,2S)-2-((1R,2R)-2-(4methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)methyl)-3,6-dihydro-2H-pyran-2-one (18a). To a dry and degassed CH2Cl2 (15 mL) solution of 18 (100 mg, 0.18 mmol) was added Grubbs II catalyst (2 mg, 0.002 mmol, 1 mol%). The reaction mixture was refluxed for 16 h. After disappearance of the starting material (tlc), the reaction mixture was concentrated under reduced pressure. Purification of the residue by flash silica chromatography (hexane–EtOAc = 80/20) gave the title compound as a colourless oil (88 mg, 93%). [α]25 D = +47.8

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(c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.22–7.25 (m, 2H), 6.82–6.85 (m, 2H), 6.06–6.09 (m, 1H), 5.78–5.82 (m, 1H), 4.78–4.82 (m, 1H), 4.74 (d, J = 7.0 Hz, 1H), 4.55–4.62 (m, 2H), 4.39 (d, J = 11.1 Hz, 1H), 3.79 (s, 3H), 3.68–3.76 (m, 1H), 3.44–3.47 (m, 1H), 3.32–3.36 (m, 4H), 3.23 (dd, J = 3.1, 7.1 Hz, 1H), 3.11–3.13 (m, 2H), 3.02–3.09 (m, 2H), 1.23 (d, J = 6.7 Hz, 3H), 0.99–1.04 (m, 1H), 0.85 (s, 9H), 0.72–0.76 (m, 1H), 0.59–0.69 (m, 2H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 168.7, 159.0, 154.1, 130.8, 129.2, 123.6, 122.4, 113.4, 95.8, 86.2, 82.7, 80.9, 74.0, 70.4, 55.5, 55.2, 30.2, 29.6, 25.7, 17.9, 17.6, 15.7, 9.3, −4.2, −4.8; IR (KBr): 2925, 2851, 1732, 1639, 1513, 1461, 1303, 1250, 1210, 1031, 1089, 835, 749, 667 cm−1; MS (ESI) m/z: 543 (M + Na)+. HRMS: calcd for C28H44O7NaSi 543.2748; found 543.2747. (R)-6-((S)-(tert-Butyldimethylsilyloxy)((1S,2S)-2-((1R,2R)-2-(4methoxybenzyloxy)-1-(methoxymethoxy)propyl)cyclopropyl)methyl)-5,6-dihydro-2H-pyran-2-one (19). The above metathesis product 18a (80 mg, 0.15 mmol) dissolved in dry CH2Cl2 (1.0 mL) and was added DBU (2 mg, 10 mol%) at room temperature. The resulting reaction mixture was stirred for 16 h before it was concentrated under reduced pressure. Purification of the residue by flash silica column chromatography (hexane–EtOAc = 80 : 20) gave 19 as a colourless liquid (52 mg, 1 65%). [α]25 D = +45.8 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 7.21–7.24 (m, 2H), 6.84–6.86 (m, 2H), 6.77–6.81 (m, 1H), 5.94 (dd, J = 3.0, 10.0, 1H), 4.76 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.7 Hz, 1H), 4.53 (d, J = 11.3 Hz, 1 H), 4.39 (d, J = 11.1 Hz, 1H), 4.33 (dt, J = 4.0, 13.0 Hz, 1H), 3.79 (s, 3H), 3.65–3.69 (m, 1H), 3.53–3.56 (m, 1H), 3.35 (s, 3H), 3.09 (dd, J = 4.0, 7.0 Hz, 1H), 2.56–2.63 (m, 1H), 2.18–2.25 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), 1.02–1.10 (m, 1H), 0.83–0.91 (s, 10H), 0.63–0.70 (m, 2H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 164.0, 158.9, 145.7, 128.8, 120.9, 113.6, 95.7, 81.7, 80.5, 77.4, 73.6, 70.7, 55.4, 55.2, 29.7, 25.8, 24.5, 16.9, 15.5, 15.1, 8.4, −4.2; IR (KBr): 2926, 2854, 1712, 1639, 1513, 1461, 1303, 1247, 1210, 1031, 1095, 835, 749, 667 cm−1; MS (ESI) m/z: 543 (M + Na)+. HRMS: calcd for C28H44O7NaSi 543.27485; found 543.27481. (R)-6-((S)-(tert-Butyldimethylsilyloxy)((1S,2S)-2-((1R,2R)-2hydroxy-1-(methoxymethoxy)propyl)cyclopropyl)methyl)-5,6dihydro-2H-pyran-2-one (2). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (50 mg, 0.1 mmol) was added to a solution of CH2Cl2 (2 mL) of 19 (100 mg, 0.1 mmol) maintaining pH 7 ( phosphate buffer (0.2 mL)) at room temperature. Stirring was continued for 1 h at room temperature, whereupon the reaction was washed with H2O (3 mL) and saturated aqueous NaHCO3 (2 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane–EtOAc (1 : 1) to provide 47 mg (71%) as 1 colorless oil. [α]25 D = +42.2 (c = 0.45, CHCl3); H NMR (300 MHz, CDCl3): δ 6.88–6.91 (m, 1H), 5.98 (dd, J = 2.7, 10.0, 1H), 4.81 (d, J = 6.4 Hz, 1H), 4.62 (d, J = 6.4 Hz, 1H), 4.41 (dt, J = 3.6, 12.8 Hz, 1H), 3.74–3.79 (m, 1H), 3.35 (s, 3H), 2.82 (dd, J = 5.4, 8.2, 1H), 2.57–2.64 (m, 1H), 2.26–2.32 (m, 1H), 1.20 (d, J = 6.7 Hz, 3H), 1.02–1.06 (m, 1H), 0.92–0.96 (m, 1H), 0.84 (s, 9H), 0.70–0.73 (m, 1H), 0.63–0.66 (m, 1H), 0.06 (s, 3H), 0.04 (s, 3H);

1802 | Org. Biomol. Chem., 2014, 12, 1793–1803


C NMR (75 MHz, CDCl3): δ 164.0, 145.8, 125.8, 121.1, 95.6, 84.8, 80.3, 72.4, 70.2, 55.6, 29.7, 25.7, 19.5, 16.6, 15.5, 8.0, −4.4, −4.6; IR (KBr): 3362, 3018, 2955, 2935, 1711, 1620, 1529, 1441, 1214, 1095, 837, 667 cm−1; MS (ESI) m/z: 423 (M + Na)+. HRMS: calcd for C20H36O6NaSi 423.2173; found 423.2180. (E)-((1R,2R)-1-((1S,2S)-2-((S)-(tert-Butyldimethylsilyloxy)((R)6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)cyclopropyl)-1-hydroxypropan-2-yl) 3-(4-methoxyphenyl)acrylate (20). To a dry CH2Cl2 (1.0 mL) solution of above alcohol 2 (50 mg, 0.12 mmol) was added DCC (30 mg, 0.16 mmol, 1.3 eq.), p-methoxycinnamic acid (26 mg, 0.14 mmol, 1.2 eq.) and DMAP (5 mg, 0.2 eq.) at room temperature. The resulting mixture was stirred for 16 h at room temperature (until TLC analysis indicated complete conversion) before it was filtered and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was subjected to the next step. To a flask charged with MgBr2·OEt2 (280 mg, 1.09 mmol) were added dimethyl sulphide (1.5 mL) and a DCM solution (2.0 mL) of the above crude ester (51 mg, 0.09 mmol). The reaction mixture was heated at 40 °C for 6 h. Saturated aq. NaHCO3 (2 mL) was added and the water phase was extracted with EtOAc (3 × 3 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was subjected to column chromatography (EtOAc–hexane) to yield 44.5 mg (72%) as a colorless 1 oil. [α]25 D = +44.0 (c = 0.40, CHCl3); H NMR (300 MHz, CDCl3): δ 7.65 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.6 Hz, 4H), 6.32 (d, J = 15.6 Hz, 1H), 6.02 (dd, J = 9.4, 2.3 Hz, 1H), 5.05 (q, J = 6.2 Hz, 1H), 4.40 (dt, J = 3.9, 7.8 Hz, 1H), 3.84 (s, 3H), 3.74–3.76 (m, 1H), 3.21–3.25 (m, 1H), 2.58–2.66 (m, 1H), 2.30–2.37 (m, 1H), 1.36 (d, J = 6.3 Hz, 3H), 1.16–1.20 (m, 1H), 0.97–1.02 (m, 1H), 0.9 (s, 9H), 0.59–0.71 (m, 2H), 0.07 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 170.0, 164.0, 161.4, 145.6, 145.0, 129.8, 121.2, 115.4, 114.3, 80.4, 76.1, 73.8, 71.9, 55.3, 29.6, 25.7, 24.4, 17.2, 16.7, 6.0, −4.5.; IR (KBr): 3361, 3020, 2955, 2935, 1720, 1709, 1621, 1522, 1441, 1214, 1120, 1092, 831, 665 cm−1; MS (ESI) m/z: 539 (M + Na)+. HRMS: calcd for C28H40O7NaSi 539.24355; found 539.24328. (E)-((1R,2R)-1-Hydroxy-1-((1S,2S)-2-((S)-hydroxy((R)-6-oxo-3,6dihydro-2H-pyran-2-yl)methyl)cyclopropyl)propan-2-yl) 3-(4methoxyphenyl)acrylate (22). To a THF (2 mL) stirred solution of 20 (30 mg, 0.058 mmol) was added HF·pyridine (50 μL, 0.029 mmol) at room temperature, and the reaction mixture was refluxed for 6 h. The crude residue was subjected to column chromatography (EtOAc–hexane) to yield 19.1 mg 1 (85%) as a amorphous solid. [α]25 D = +14.0 (c = 0.30, CHCl3); H NMR (300 MHz, CDCl3): δ 7.62 (d, J = 15.6 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 4H), 6.30 (d, J = 15.6 Hz, 1H), 5.89 (dd, J = 9.4, 2.3 Hz, 1H), 5.01 (q, J = 6.2 Hz, 1H), 4.41 (dt, J = 3.9, 7.8 Hz, 1H), 3.81 (s, 3H), 3.72–3.78 (m, 1H), 3.20–3.24 (m, 1H), 2.56–2.64 (m, 1H), 2.31–2.35 (m, 1H), 1.34 (d, J = 6.3 Hz, 3H), 1.15–1.21 (m, 1H), 0.98–1.01 (m, 1H), 0.59–0.71 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 170.1, 164.2, 161.1, 145.5, 145.1, 129.7, 121.1, 115.3, 114.2, 80.3, 76.0, 73.7, 71.8, 55.1, 29.5, 24.2, 17.0, 16.6, 6.0; IR (KBr): ν = 3360, 3343, 3016, 2945, 2915, 1727, 1789, 1641, 1592, 1431, 1284, 1120, 1072, 838, 13


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662 cm−1; MS (ESI) m/z: 425 (M + Na)+. HRMS: calcd for C22H26O7Na 425.1435; found 425.1432.


Acknowledgements We are grateful to Dr Lakshimi Kantham, Director, IICT, for her constant encouragement. Financial support was provided by the DST, New Delhi, India (grant no. SR/S1/OC-08/2011), and ORGIN (CSC-0108) programme (CSIR) of XII Five year plan. UGC & CSIR (New Delhi) is gratefully acknowledged for awarding a fellowship to N. J., D.R and V. P.

Notes and references 1 (a) Y. Deng, M. J. Balunas, J.-A. Kim, Daniel D. Lantvit, Y.-W. Chin, H. Chai, S. Sugiarso, L. B. S. Kardono, H. S. Fong, J. M. Pezzuto, S. M. Swanson, E. J. Carcache de Blanco and A. Douglas Kinghorn, J. Nat. Prod., 2009, 72, 1165–1169; (b) G. A. Suárez-Ortiz, C. M. Cerda-García-Rojas, A. Hernández-Rojas and R. Pereda-Miranda, J. Nat. Prod., 2013, 76, 72–78. 2 M. P. Gupta, A. Monge, G. A. Karikas, A. Lopez de Cerain, P. N. Solis, E. de Leon, M. Trujillo, O. Suarez, F. Wilson, G. Montenegro, Y. Noriega, A. I. Santana, M. Correa and C. Sanchez, Int. J. Pharm., 1996, 34, 19–27. 3 E. Goun, G. Cunningham, D. Chu, C. Nguyen and D. Miles, Fitoterapia, 2003, 76, 592–596. 4 V. R. Hegde, H. Pu, M. Patel, P. R. Das, J. Strizki, V. P. Gullo, C. Chouan-C, A. V. Buevich and T.-M. Chan, Bioorg. Med. Chem. Lett., 2004, 14, 5339–5342. 5 (a) G. Kumaraswamy and M. Padmaja, J. Org. Chem., 2008, 73, 5198–5201; (b) G. Kumaraswamy, G. Ramakrishna, P. Naresh, B. Jagadeesh and B. Sridhar, J. Org. Chem., 2009, 74, 8468–8471; (c) G. Kumaraswamy, G. Ramakrishna and B. Sridhar, Tetrahedron Lett., 2011, 52, 1778– 1782; (d) G. Kumaraswamy, G. Ramakrishna, R. Raju and M. Padmaja, Tetrahedron, 2010, 66, 9814–9818; (e) G. Kumaraswamy, D. S. Ramakrishna and K. Santhakumar, Tetrahedron: Asymmetry, 2010, 21, 544–548; (f) G. Kumaraswamy and N. Jayaprakash, Tetrahedron Lett., 2010, 51, 6500–6502.


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