Synthesis and biological evaluation of sapinofuranones A,B and 1,2,3-triazole-sapinofuranone hybrids as cytotoxic agents

Abstract

The total synthesis of sapinofuranones A,B and ent-sapinofuranones A,B and L-factor has been described. A series of novel 1,2,3-triazole-sapinofuranone hybrids were efficiently synthesized employing a click chemistry approach. These sapinofuranones and 1,2,3-triazole-sapinofuranone hybrids were further evaluated for their cytotoxic activity against four human cancer cell lines (A549, MDA-MB-231, DU145 and HepG2). Most of them revealed cytotoxic effects against cancer cells at the micromolar range. From a structure–activity relationship (SAR) perspective, it was noticed that the combination of triazole moiety to the lactone ring is playing modest role in exhibiting the cytotoxic effect. This is the first report on the synthesis and in vitro cytotoxic evaluation of 1,2,3-triazole-sapinofuranone hybrids.

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Introduction

Two butanolide natural products, sapinofuranones A and ent-sapinofuranones B (1 and 3), were isolated by Evidente and co-workers in 1999 from the liquid cultures of the phytotoxic fungus, Sphaeropsis sapinea.¹ The structures of 1 and 3 were determined based on spectroscopic and chemical methods, as 4-[(2Z,4E)-1-hydroxy-2,4-hexadienyl]butan-4-olides, which are epimers at C-1 of the side chain. The absolute stereochemistry of this chiral center, determined by Mosher's method analysis, proved to be S and R in 1 and 3, respectively. An NMR J-based configuration analysis² has also been used for the stereochemical determination of sapinofuranone A. Later, (S,S)-sapinofuranone B (2) was isolated from Acremonium strictum.³ The structure of 2 was further established by chemical correlation with the known L-factor 5, which is a reduced form of 2, isolated from Streptomyces griseus. L-Factor [(4S,5S)-5-hydroxydecan-4-olide]^4–8 is an autoregulator in the biosynthesis of the anthracycline antibiotic, leukaemomycin. The mode of action of L-factor is mediated by an interaction with RNA polymerase, and that L-factor may regulate the synthesis of β-galactosidase by affecting transcription termination. Two methods are already precedent in the literature on the synthesis of sapinofuranone A by application of regiodivergent enantioselective silylation of chiral diols⁹ and the other from D-ribose.¹⁰

Total synthesis of sapinofuranone B has been achieved by two groups.^11,12 In continuation to our ongoing research program aimed at developing enantioselective synthesis and biological studies of naturally occurring lactones and their structural hybrids, we have accomplished the stereoselective synthesis of sapinofuranones A,B, ent-sapinofuranones A,B, L-factor and 1,2,3-triazole-sapinofuranone hybrids from key intermediates by employing Noyori reduction and the Mitsunobu reaction to generate new chiral centers using the commercially available starting material, D-mannitol. It has been recognized in the past few years that a number of lactones (sesquiterpene lactones, styryl lactones)¹³ and other derivatives obtained from natural sources have exhibited interesting biological activities, in addition 1,2,3-triazoles are important class of heterocyclics with a chemical scaffold having interesting biological properties. Several therapeutically active compounds containing 1,2,3-triazoles have been reported to function as antitumor, antimicrobials, anti-HIV agents, and kinase inhibitors.^14,15 In continuation with our efforts in the area of γ-lactones, and considering the biological importance of these lactones and 1,2,3-triazole derivatives as anticancer agents, we have designed a new drug scaffold and report herein the synthesis of a novel 1,2,3-triazole-sapinofuranone hybrids and further examined their cytotoxic activities.

Results and discussion

Our retrosynthetic analysis of sapinofuranones A,B and ent-sapinofuranones A,B and L-factor suggested that the 5-hydroxy γ-lactones with different stereochemistry at C4 and C5, could serve as a useful intermediates to the total synthesis of all five target compounds (Scheme 1). We anticipated that the configurations at C-4 and C-5 could be inverted to allow ready access to each of these related synthetic targets.

Scheme 1 Retrosynthetic analysis of targets 1, 2, 3, 4 and 5.

The synthesis of sapinofuranones started with the known aldehyde 13 prepared from D-mannitol according to the literature protocol.¹⁶ The metalated propargylic ether (obtained by treating 14 with n-BuLi) was coupled with aldehyde 13 to afford a functionalized propargylic alcohol 15 as a diastereomeric mixture in 75 : 25 ratio, which were easily separated by silica gel column chromatography (Scheme 2). The newly created chiral center in the major isomer was confirmed by Mosher ester analysis (see ESI†) and found to have anti-stereochemistry.¹⁷ The triple bond in compound 15 was reduced to give a saturated 1,4-diol compound 16 and further protected as the di-PMB ether 17. Acetonide deprotection using 50% TFA in DCM and followed by NaIO₄ treatment of the resulting diol gave aldehyde 18, which was used without further purification for the next step.

Scheme 2 Synthesis of key intermediates.

The key intermediate, propargylic alcohol 12 could be obtained from aldehyde 18 by successive transformations, reduction of aldehyde, conversion into the corresponding chloro compound 19 and treatment with n-BuLi.¹⁸ Silylation of the free hydroxy group in 12 followed by deprotection of the di-PMB groups using DDQ gave another key diol intermediate 10, which was utilized further for the synthesis of sapinofuranones A and B (1 and 2) as shown in Schemes 3 and 4.

Scheme 3 Synthesis of sapinofuranone A (1).

Scheme 4 Synthesis of sapinofuranone B (2) and L-factor (5).

Accordingly, as anticipated TEMPO/BAIB oxidation of 1,4-diol 10 gave rise to the TBS protected γ-lactone 20 (Scheme 3). TBS deprotection was achieved using TBAF to give 5-hydroxy γ-lactone 6.¹⁹ This was subjected to Sonogashira coupling with trans-1-bromo-1-propene using CuI, Pd(Ph₃P)₂Cl₂ and triethylamine to furnish the coupled product 21 and then the triple bond was partially reduced with Zn, Cu(OAc)₂/AgNO₃ catalytic system²⁰ in MeOH and H₂O which furnished cis olefin that could afford the target, sapinofuranone A (1).

To access the target sapinifuranone B (2), the stereochemistry of the key intermediate 10 at C4 has to be inverted. As shown in Scheme 4, the primary hydroxyl was converted into its benzoate 22 and then inversion of the secondary hydroxy group was achieved under Mitsunobu reaction conditions followed by hydrolysis to afford the inverted alcohol 24. As described above in Scheme 3, TEMPO/BAIB oxidation, TBS removal, Sonogashira coupling with trans-1-bromo-1-propene gave lactone 26. Partial reduction of triple bond in compound 26 using the Zn, Cu(OAc)₂/AgNO₃ catalytic system in MeOH and H₂O furnished sapinofuranone B (2), whereas, treatment of 26 with Pd/C afforded L-factor (5).

An oxidation/reduction protocol was used to allow ready access to synthetic targets, ent-sapinofuranones B and A (3 and 4) from 12 (Scheme 5).

Scheme 5 Synthesis of ent-sapinofuranone B (3).

Accordingly, the oxidation of intermediate compound 12 to keto compound 27 was achieved using IBX. Asymmetric reduction with (S,S)-Noyori was performed to afford compound 28 with the opposite stereochemistry at C5-position.²¹ Subsequently, the secondary hydroxy group was silylated and subsequent removal of the di-PMB groups using DDQ gave the 1,4-diol 11. This was utilized for the synthesis of ent-sapinofuranones B and A (3 and 4).

The synthesis of ent-sapinofuranone B (3) was accomplished in an identical manner to that used for the synthesis sapinofuranone A from 10 (Scheme 3). TEMPO/BAIB oxidation and the TBS removal gave the lactone 8, and further Sonogashira coupling and partial reduction of the triple bond by use of the same reagents and conditions as those described for the conversion of 6 into 1, gave ent-sapinofuranone B (3).

The synthesis of ent-sapinofuranone A (4) was also accomplished in an identical manner as used for sapinofuranone B from 10 (Scheme 4). Benzoyl chloride treatment of 11 afforded the benzoate 32, which was converted into the C-4 inverted stereoisomer 34 under Mitsunobu reaction conditions followed by hydrolysis, TEMPO/BAIB oxidation and TBS removal to give lactone 9, and further Sonogashira coupling and partial reduction of the triple bond, by use of the same reagents and conditions as those described for the conversion of 7 into 2, gave ent-sapinofuranone A (4) (Scheme 6).

Scheme 6 Synthesis of ent-sapinofuranone A (4).

The synthetic route to the 1,2,3-triazole-sapinifuranone hybrids is outlined in Scheme 7. The 5-hydroxy-lactones (6–9), having the terminal alkynyl group were subjected to click reactions with various benzylazides, affording 1,2,3-triazole-sapinifuranone hybrids in high yields.

Scheme 7 Synthesis of 1,2,3-triazole-sapinofuranone hybrids.

Since drug resistance limits the effectiveness of many anticancer agents, development of a new class of anticancer agents for patients with drug-resistant cancer is potentially valuable. Thus, all the synthesized sapinofuranones A,B, ent-sapinofuranones A,B, L-factor and series of 1,2,3-triazole-sapinofuranone hybrids were subjected to cytotoxicity evaluation against the four human cancer cell lines A549 (human alveolar adenocarcinoma epithelial cells, ATCC no. CCL-185), MDA-MB-231 (human breast adenocarcinoma cells, ATCC no. HTB-26), DU145 (human prostate cancer cells (ATCC no. HTB-81)) and HepG2 (human liver adenocarcinoma cells (ATCC no. HB-8065)).

The cancer cell viability after treatments with the test compounds were measured using a colorimetric MTT assay.

The IC₅₀ values of sapinofuranones A,B and their structural hybrids against A549, MDA-MB-231, DU145 and HepG2 cancer cells were determined and summarized in Table 1. Most of the compounds revealed cytotoxic effects against these cancer cells in micromolar range of 15.6–33.4 μM, while the 1,2,3-triazole-sapinofuranone hybrids were found to be slightly promising than the natural compounds.

Table 1 In vitro cytotoxicity of sapinofuranones and 1,2,3-triazole-sapinofuranone hybrids against different cancer cell lines

Compd	IC50 values in (μM)
	A549	DU145	MDA-MB-231	HepG2
6a	20.8 ± 0.28	22.2 ± 0.32	21.6 ± 0.33	22.8 ± 0.32
6b	19.2 ± 0.24	28.6 ± 0.28	21.3 ± 0.24	19.5 ± 0.14
6c	—	30.2 ± 0.26	33.4 ± 0.44	—
6d	22.1 ± 0.18	19.5 ± 0.32	17.6 ± 0.52	20.5 ± 0.28
7a	—	—	—	—
7b	15.6 ± 0.25	19.3 ± 0.31	18.9 ± 0.34	19.2 ± 0.42
7c	32.5 ± 0.32	18.8 ± 0.17	16.6 ± 0.16	20.8 ± 0.26
7d	26.4 ± 0.36	—	32.5 ± 0.32	—
8a	16.9 ± 0.42	15.2 ± 0.16	18.2 ± 0.24	23.4 ± 0.23
8b	—	—	25.3 ± 0.22	30.2 ± 0.18
8c	25.1 ± 0.14	18.9 ± 0.22	17.3 ± 0.28	22.4 ± 0.32
8d	—	—	—	—
9a	—	—	—	—
9b	—	—	—	—
9c	—	—	—	—
9d	—	—	—	—
1	24.4 ± 0.51	27.1 ± 0.32	30.2 ± 0.24	29.8 ± 0.35
2	21.2 ± 0.38	21.6 ± 0.28	18.9 ± 0.18	20.8 ± 0.44
3	22.8 ± 0.42	22.7 ± 0.12	21.5 ± 0.14	28.1 ± 0.24
4	22.5 ± 0.32	23.4 ± 0.22	21.6 ± 0.16	26.9 ± 0.36
5	31.2 ± 0.16	21.3 ± 0.34	22.8 ± 0.28	20.2 ± 0.12
Doxorubicin	0.8 ± 0.26	0.6 ± 0.11	0.7 ± 0.08	0.8 ± 0.09

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Compounds 1, 2, 3, 4 and their triazole hybrids showed moderate activity against all the four cancer cell lines (A549, MDA-MB-231, DU145 and HepG2), except 7a and 8d which were practically inactive; while compound 4 itself showed cytotoxicity towards all the cancer cell lines; however, its structural hybrids were inactive. Compound 5 also showed similar moderate activities. From a structure–activity relationship (SAR) perspective, it was noticed that the combination of triazole moiety to the lactone ring is playing a modest role in increasing the cytotoxic effect. Further, the chirality of these derivatives also played a key functional role on the cytotoxicity towards all the cancer cell lines; nevertheless, it was observed that the electron withdrawing and donating groups present on the triazole ring may not be playing an active role. These results suggest that the in vitro cytotoxicity of natural lactones and their structural hybrids against different cancer cell lines has provided information on the structural requirements for further improving the potency and selectivity of these compounds.

Conclusions

The total synthesis of sapinofuranones A,B, ent-sapinofuranones A,B, L-factor and series of 1,2,3-triazole-sapinofuranone hybrids were synthesized in high yields and screened for cytotoxicity against four human tumour cell lines. Most of the compounds revealed cytotoxic effect against these cancer cells at the micromolar range of 15.6–33.4 μM, while the 1,2,3-triazole-sapinofuranone hybrids were found to be more promising than the natural compounds.

Experimental section

Chemistry

General. All reactions were performed under inert atmosphere. All glassware apparatus used for performing the reactions were oven/flame dried. Anhydrous solvents were distilled prior to use: THF from Na and benzophenone; CH₂Cl₂ from CaH₂; MeOH from Mg. Commercial reagents were used without purification. Column chromatography was carried out by using silica gel (60–120 mesh) unless otherwise mentioned. Analytical thin layer chromatography (TLC) was run on silica gel 60 F₂₅₄ pre-coated plates (250 μm thickness). Optical rotations [α]_D were measured on a polarimeter and given in 10⁻¹ deg cm² g⁻¹. Infrared spectra were recorded in CHCl₃ (or) KBr (as mentioned) and reported in wavenumber (cm⁻¹). Mass spectral data were obtained using MS (EI) ESI, HRMS mass spectrometers. High resolution mass spectra (HRMS) [ESI+] were obtained using either a TOF or a double focusing spectrometer. ¹H NMR spectra were recorded at 300, 400, 500 and ¹³C NMR spectra were obtained at 75, 100, 125 MHz in CDCl₃ solution unless otherwise mentioned. Chemical shifts are reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in Hertz (Hz). The following abbreviations were used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.

Biology

In vitro cytotoxicity assay. The cell lines used for testing the in vitro cytotoxicity included A549 derived from human alveolar adenocarcinoma epithelial cells (ATCC no. CCL-185), MDA-MB-231 derived from human breast adenocarcinoma cells (ATCC no. HTB-26), DU145 derived from human prostate cancer cells (ATCC no. HTB-81) and HepG2 derived from human liver adenocarcinoma cells (ATCC no. HB-8065), which were all obtained from the American Type Culture Collection, Manassas, VA, USA. All tumour cell lines were maintained in a modified DMEM medium supplemented with 10% fetal bovine serum, along with 1% non-essential amino acids except L-glutamine, 0.2% sodium hydrogen carbonate, 1% sodium pyruvate and 1% antibiotic mixture (10 000 units penicillin and 10 mg of streptomycin per mL). The cells were washed and re-suspended in the above medium and then 100 mL of this suspension was seeded into a 96-well bottom plate. The cells were kept at 37 °C in a humidified CO₂ incubator (Model Galaxy 170S, Eppendorf AG, Hamburg, Germany) under a 5% CO₂ atmosphere. After incubation for 24 h, the cells were treated for 2 days with the test compounds at concentrations ranging from 0.1–100 μM in DMSO (1% final concentration) and were assayed at the end of the second day. Each assay was performed with two internal controls: (1) an IC₀ with the cells only, and (2) an IC₁₀₀ with the media only. After incubation for 48 h, the cells were subjected to an MTT colorimetric assay (5 mg mL⁻¹).²² The effects of the different test compounds on the viability of the tumour cell lines were measured at 540 nm using a multimode reader (Infinite® M200Pro, Tecan, Switzerland). Doxorubicin was used as positive control for comparison purpose and 1% DMSO as a vehicle control. In order to account for the toxicity of DMSO, the values obtained for the DMSO control were subtracted from those of the test compounds. Dose–response curves were plotted for the test compounds and controls after correction by subtracting the background absorbance from that of the blanks. The cytotoxicity of the compounds indicated by IC₅₀ values (50% inhibitory concentration) were calculated from the plotted absorbance data for the dose–response curves. Statistical analysis was performed using GraphPad PRISM software version 3.0 (GraphPad Software, Inc, La Jolla, CA, USA). IC₅₀ values (in μM) are expressed as the mean ± S.D of four independent experiments. All experimental data were compared using student's t-test. In all comparisons, p < 0.05 was considered statistically significant.
(R)-4-(Benzyloxy)-1-((4S,4′R,5S)-2,2,2′,2′-tetramethyl-[4,4′-bi(1,3-dioxolan)]-5-yl)but-2-yn-1-ol (15). nBuLi (2.5 M in hexanes, 41.6 mL, 104.12 mmol) was added to a solution of alkyne 14 (15.23 g, 104.12 mmol) in THF (30 mL) at −78 °C. After stirring for 5 min, the reaction mixture was warmed to −20 °C and stirred for 30 min. The mixture was cooled back to −78 °C and a solution of the crude aldehyde 13 (20.0 g, 87.46 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred for 2 h at −78 °C, and then the mixture was quenched with saturated aqueous NH₄Cl solution (40 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried with Na₂SO₄, and concentrated under reduced pressure. The residue (75 : 25 dr, 29.74 g, 92% yield) was separated by column chromatography (20% EtOAc/hexane) to afford 15 (23.21 g, 61.72 mmol, 71% yield) as a single diastereomer as a colourless liquid. [α]²⁰_D = +12.4 (c 0.88, CHCl₃); IR (neat) ν_max: 3445, 2987, 1514, 1372, 1249, 1070, 844, 758 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.37–7.27 (m, 5H), 4.61 (s, 2H), 4.60–4.55 (m, 1H), 4.24 (d, J = 1.6 Hz, 2H), 4.22–4.19 (m, 1H), 4.14–4.06 (m, 2H), 4.02–3.97 (m, 1H), 3.87 (t, J = 7.7 Hz, 1H), 3.06 (brs, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 137.2, 128.3 (2C), 127.9 (2C), 127.7, 110.3, 109.8, 84.2, 82.3, 82.2, 78.9, 76.6, 71.4, 67.4, 63.9, 57.2, 27.1, 26.9, 26.5, 25.0 ppm; HRMS: calcd for C₂₁H₂₈O₆Na [M + Na]⁺ 399.1778; found 399.1784.
(R)-1-((4S,4′R,5S)-2,2,2′,2′-Tetramethyl-[4,4′-bi(1,3-dioxolan)]-5-yl)butane-1,4-diol (16). To a solution of 15 (22.32 g, 59.36 mmol) in anhyd. MeOH (100 mL) was added a 100 mg of 10% Pd/C and the resulting mixture was stirred under balloon H₂ atmosphere at r.t. for 4 h. After completion, the catalyst was filtered and then washed with EtOAc (3 × 40 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (50% EtOAc/hexane) to afford the diol 16 (16.36 g, 56.41 mmol, 95% yield) as a colorless gummy liquid. [α]²⁰_D = +10.1 (c 0.27, CHCl₃); IR (neat) ν_max: 3430, 2987, 1373, 1215, 1069, 846, 769 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.20 (dd, J = 8.7, 6.1 Hz, 1H), 4.08 (ddd, J = 11.4, 5.8, 3.3 Hz, 1H), 4.02 (dd, J = 8.5, 5.3 Hz, 1H), 3.5–3.63 (m, 5H), 2.90 (brs, 1H), 2.08–1.88 (m, 2H), 1.81–1.71 (m, 2H), 1.60–1.52 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 110.2, 109.1, 82.9, 81.0, 76.3, 72.8, 67.8, 62.9, 30.7, 28.8, 26.8, 26.7, 26.3, 25.0 ppm; HRMS: calcd for C₁₄H₂₇O₆ [M + H]⁺ 291.1802; found 291.1805.
(4S,4′R,5S)-5-((R)-1,4-Bis((4-methoxybenzyl)oxy)butyl)-2,2,2′,2′-tetramethyl-4,4′-bi(1,3-dioxolane) (17). To a suspension of NaH (60%, 4.11 g, 170.12 mmol) in anhyd. THF (50 mL) was added dropwise a solution of diol 16 (15.51 g, 53.56 mmol) in THF (25 mL) at 0 °C. To this mixture TBAI (30 mg) and PMBBr (18.3 mL, 127.12 mmol) were added sequentially and stirring was continued for 2 h at this temperature and 6 h at r.t. The mixture was quenched by the addition of crushed ice flakes until a clear solution (biphasic) formed. The mixture was extracted with EtOAc (2 × 60 mL). The organic extracts were washed with H₂O (1 × 50 mL) and brine (1 × 50 mL) and dried over anhyd. Na₂SO₄. Evaporation of the solvent followed by column chromatography (10% EtOAc/hexane) afforded the pure 17 (26.1 g, 49.24 mmol, 92% yield) as a pale yellow liquid. [α]²⁰_D = +13.0 (c 0.44, CHCl₃); IR (neat) ν_max: 2987, 1613, 1514, 1248, 1066, 1036, 846, 770 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.31–7.21 (m, 4H), 6.92–6.82 (m, 4H), 4.58 (d, J = 11.3 Hz, 1H), 4.50 (d, J = 11.3 Hz, 1H), 4.40 (s, 2H), 4.17–4.02 (m, 3H), 3.96–3.87 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.62–3.54 (m, 1H), 3.45–3.33 (m, 2H), 1.84–1.54 (m, 4H), 1.39 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 159.1, 159.0, 130.6, 130.5, 129.5 (2C), 129.1 (2C), 113.7 (2C), 113.6 (2C), 109.6, 109.4, 80.8, 78.5, 78.2, 77.1, 72.4, 71.6, 69.9, 66.9, 55.2 (2C), 27.2, 27.1, 26.5 (2C), 25.5, 25.3 ppm; HRMS: calcd for C₃₀H₄₆O₈N [M + NH₄]⁺ 548.3217; found 548.3225.
(R)-1-((4S,5S)-5-((R)-1,4-Bis((4-methoxybenzyl)oxy)butyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol. A solution of acetonide 17 (25.48 g, 48.07 mmol) and CF₃CO₂H (50% aq solution, 56.62 mL, 48.07 mmol) in CH₂Cl₂ (460 mL) was stirred at 0 °C for 1 h. The mixture washed with aq. saturated NaHCO₃ (40 mL), water, brine and dried over anhydrous Na₂SO₄. Removal of the organic solvent on a rotary evaporator and column chromatography (50% EtOAc/hexane) on silica gel gave diol as colourless oil (19.32 g, 39.42 mmol, 82%). [α]²⁰_D = +3.2 (c 0.48, CHCl₃); IR (neat) ν_max: 3429, 2987, 1613, 1514, 1248, 1077, 1035, 819, 758 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.31–7.21 (m, 4H), 6.92–6.82 (m, 4H), 4.62 (d, J = 10.8 Hz, 1H), 4.45 (s, 2H), 4.36 (d, J = 10.8 Hz, 1H), 3.92–3.69 (m, 10H), 3.68–3.42 (m, 4H), 1.97–1.88 (m, 1H), 1.85–1.72 (m, 3H), 1.35 (s, 3H), 1.33 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 159.6, 159.1, 130.5, 130.1 (2C), 129.2 (2C), 128.6, 113.9 (2C), 113.7 (2C), 109.3, 80.6, 79.7, 79.2, 72.8, 72.5, 70.9, 69.9, 63.9, 55.2 (2C), 26.8, 26.7, 26.2, 23.5 ppm; HRMS: calcd for C₂₇H₃₉O₈ [M + H]⁺ 491.2639; found 491.2644.
((4S,5S)-5-((R)-1,4-Bis((4-methoxybenzyl)oxy)butyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol. The diol (18.6 g, 37.59 mmol) was dissolved in H₂O/THF (1 : 5, 120 mL) and NaIO₄ (12.12 g, 56.93 mmol) was added at 0 °C. After completed the reaction water was added. The aqueous layer was extracted with Et₂O. The organic layer was dried over anhydrous Na₂SO₄ and solvent was removed under reduced pressure. Without purification the crude aldehyde was subjected to next step. The crude aldehyde was dissolved in MeOH (2 mL). To this solution (cooled in a 0 °C bath) was added NaBH₄ (3.7 g, 99.0 mmol). The bath was allowed to warm to ambient temperature until TLC showed completion of the reaction MeOH was removed, followed by aqueous saturated NH₄Cl and ethyl acetate were added. The phases were separated. The organic layer was washed with water and brine before being dried over anhydrous NaSO₄. The solvent was removed by rotary evaporation and the oily residue was chromatographed on silica gel (30% EtOAc/hexane) to afford the alcohol titled (14.15 g, 30.76 mmol, 80% over 2 steps) as a colorless viscous liquid. [α]²⁰_D = −2.6 (c 0.44, CHCl₃); IR (neat) ν_max: 3448, 2934, 1612, 1514, 1248, 1083, 1035, 820, 769 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.31–7.19 (m, 4H), 6.92–6.82 (m, 4H), 4.56 (d, J = 10.9 Hz, 1H), 4.46 (d, J = 10.9 Hz, 1H), 4.43 (s, 2H), 4.02–3.92 (m, 1H), 3.86–3.77 (m, 7H), 3.69 (dq, J = 16.1, 11.6, 4.6 Hz, 2H), 3.59–1.39 (m, 3H), 1.84–1.64 (m, 4H), 1.38 (s, 6H). ¹³C NMR (125 MHz, CDCl₃): δ 159.2, 159.0, 130.5, 129.8, 129.6 (2C), 129.1 (2C), 113.7 (2C), 113.6 (2C), 108.8, 79.8, 78.8, 78.7, 72.4, 71.6, 69.8, 63.4, 55.1 (2C), 27.2, 26.9, 26.8, 24.5 ppm; HRMS: calcd for C₂₆H₃₇O₇ [M + H]⁺ 461.2533; found 461.2536.
(4S,5R)-4-((R)-1,4-Bis((4-methoxybenzyl)oxy)butyl)-5-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (19). To the solution of above alcohol (13.82 g, 30.04 mmol) in CCl₄ (90 mL) were added triphenylphosphine (15.46 g, 60.08 mmol) and sodium bicarbonate (12.45 g, 90.12 mmol) and the mixture was heated to reflux for 10 h. The reaction mixture was then cooled to room temperature and filtered. The solid residue was washed with EtOAc (2 × 30 mL) and the combined filtrates were washed with water (1 × 20 mL), brine (1 × 20 mL), and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (10% EtOAc/hexane) to obtain the pure product 19 (12.78 g, 26.73 mmol, 89%) as colorless oil. [α]²⁰_D = +0.4 (c 0.48, CHCl₃); IR (neat) ν_max: 2936, 1612, 1514, 1248, 1080, 820, 770 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.28–7.19 (m, 4H), 6.91–6.84 (m, 4H), 4.55 (d, J = 11.1 Hz, 1H), 4.46 (d, J = 11.1 Hz, 1H), 4.42 (s, 2H), 4.10 (ddd, J = 9.1, 6.1, 3.0 Hz, 1H), 3.85 (t, J = 6.5 Hz, 1H), 3.80 (s, 6H), 3.75 (dd, J = 11.7, 8.5 Hz, 1H), 3.57–3.52 (m, 2H), 3.48–3.42 (m, 2H), 1.82–1.60 (m, 4H), 1.42 (s, 3H), 1.39 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 159.2, 159.0, 130.5, 130.0, 129.5 (2C), 129.2 (2C), 113.8 (2C), 113.7 (2C), 109.5, 79.2, 79.1, 78.8, 72.4, 71.8, 69.8, 55.1 (2C), 45.7, 27.4, 27.1, 26.9, 24.8 ppm; HRMS: calcd for C₂₆H₃₅O₆ClNa [M + Na]⁺ 501.2014; found 501.2022.
(3S,4R)-4,7-Bis((4-methoxybenzyl)oxy)hept-1-yn-3-ol (12). To a stirred solution of the chloride 19 (12.51 g, 26.17 mmol) in THF (60 mL), was added nBuLi (33.5 mL, 2.5 M in hexane, 83.74 mmol) dropwise at −78 °C. The solution was stirred at −78 °C for 30 min. After completion of the reaction (monitored by TLC), it was quenched with saturated solution of NH₄Cl (40 mL) and diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (30% EtOAc/hexane) to afford 12 (8.64 g, 22.50 mmol, 86%) as a colorless liquid. [α]²⁰_D = +13.2 (c 0.32, CHCl₃); IR (neat) ν_max: 3422, 2935, 1612, 1513, 1248, 1083, 1034, 820, 755 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.30–7.22 (m, 4H), 6.91–6.83 (m, 4H), 4.56 (ABq, J = 12.9 Hz, 2H), 4.48–4.44 (m, 1H), 4.42 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.56–3.51 (m, 1H), 3.46–3.40 (m, 2H), 2.54 (brs, 1H), 2.47 (d, J = 2.1 Hz, 1H), 1.79–1.59 (m, 4H). ¹³C NMR (125 MHz, CDCl₃): δ 159.3, 159.0, 130.5, 130.0, 129.5 (2C), 129.2 (2C), 113.8 (2C), 113.7 (2C), 81.8, 80.5, 74.3, 72.5, 72.1, 69.8, 63.8, 55.1 (2C), 26.7, 25.7 ppm; HRMS: calcd for C₂₃H₂₈O₅Na [M + Na]⁺ 407.1829; found 407.1829.
(((3S,4R)-4,7-Bis((4-methoxybenzyl)oxy)hept-1-yn-3-yl)oxy)(tert-butyl)dimethylsilane. To an ice-bath cooled solution of 12 (3.5 g, 9.11 mmol) and imidazole (1.21 g, 18.2 mmol) in anhyd CH₂Cl₂ (20 mL) was added a solution of TBSCl (1.64 g, 10.93 mmol) in anhyd CH₂Cl₂ (5 mL). The mixture was stirred at 0 °C for 3 h, then diluted with H₂O (10 mL) and extracted with Et₂O (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried with anhyd Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (10% EtOAc/hexane) to give titled compound (4 g, 8.03 mmol, 88%) as yellowish oil. [α]²⁰_D = +37.5 (c 1.92, CHCl₃); IR (neat) ν_max: 2931, 1613, 1514, 1248, 1096, 837, 778 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.31–7.21 (m, 4H), 6.90–6.81 (m, 4H), 4.77 (d, J = 10.9 Hz, 1H), 4.49 (d, J = 10.9 Hz, 1H), 4.42–4.36 (m, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.51–3.35 (m, 3H), 2.42 (d, J = 2.1 Hz, 1H), 1.81–1.53 (m, 4H), 0.91 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 159.1, 159.0, 130.7 (2C), 129.6 (2C), 129.2 (2C), 113.7 (2C), 113.6 (2C), 83.7, 81.7, 73.4, 72.8, 72.4, 70.0, 65.7, 55.2 (2C), 27.7, 25.8, 25.7 (3C), 18.1, −4.6, −5.1 ppm; HRMS: calcd for C₂₉H₄₂O₅SiNa [M + Na]⁺ 521.2699; found 521.2697.
(4R,5S)-5-((tert-Butyldimethylsilyl)oxy)hept-6-yne-1,4-diol (10). To a solution of the tbs protected compound (3.76 g, 7.55 mmol) in CH₂Cl₂ (40 mL) and buffer (4 mL), DDQ (4.1 g, 18.12 mmol) was added at 0 °C and allowed to stir for 2 h at room temperature. The reaction mixture was quenched with solid NaHCO₃ and filtered. The solid residue was washed with CH₂Cl₂ (2 × 30 mL) and the combined filtrates were washed with water (1 × 20 mL), brine (1 × 20 mL), and dried over anhydrous Na₂SO₄ and the solvent evaporated to give the crude product which was purified by column chromatography (60% EtOAc/hexane) to provide the desired compound 10 (1.61 g, 6.24 mmol, 82%) as a colourless oil. [α]²⁰_D = +45.3 (c 0.96, CHCl₃); IR (neat) ν_max: 3419, 2930, 1253, 1091, 838, 778, 656 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.28 (dd, J = 1.9, 4.2 Hz, 1H), 3.75–3.60 (m, 2H), 2.75 (bs, 1H), 2.44 (d, J = 2.1 Hz, 1H), 1.83–1.66 (m, 3H), 1.64–1.53 (m, 1H), 0.90 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 82.1, 74.4, 74.3, 66.7, 62.6, 29.1, 28.8, 25.6 (3C), 18.0, −4.6, −5.2 ppm; HRMS: calcd for C₁₃H₂₇O₃Si [M + H]⁺ 259.1724; found 259.1726.
(R)-5-((S)-1-((tert-Butyldimethylsilyl)oxy)prop-2-yn-1-yl)dihydrofuran-2(3H)-one (20). To a stirred solution of diol 10 (0.385 g, 1.51 mmol) in anhyd CH₂Cl₂ (5 mL) were added sequentially PhI(OAc)₂ (0.586 g, 1.82 mmol) and TEMPO (0.065 g, 0.38 mmol). After stirring the reaction mixture at 25 °C for 4 h, sat. aq Na₂S₂O₃ (5 mL) was added, and the mixture was extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with sat. aq NaHCO₃ (5 mL) and brine (3 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was subjected to column chromatography (20% EtOAc/hexane) to afford the lactone 20 (0.350 g, 1.38 mmol, 92%) as a color less liquid; [α]²⁰_D = +61.5 (c 0.51, CHCl₃); IR (neat) ν_max: 2955, 2857, 1783, 1170, 1066, 837, 781 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.64 (t, J = 2.3 Hz, 1H), 4.61–4.57 (m, 1H), 2.66–2.56 (m, 1H), 2.52–2.40 (m, 3H), 2.32–2.22 (m, 1H), 0.90 (s, 9H), 0.16 (s, 3H), 0.12 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.2, 81.0, 80.8, 74.6, 64.3, 28.2, 25.5 (3C), 21.3, 17.9, −5.1, −5.4 ppm; HRMS: calcd for C₁₃H₂₃O₃Si [M + H]⁺ 255.1411; found 255.1438.
(R)-5-((S)-1-Hydroxyprop-2-yn-1-yl)dihydrofuran-2(3H)-one (6). To a stirred solution of compound 20 (0.274 g, 1.08 mmol) in dry THF, tetra butyl ammonium fluoride (1 M solution in THF, 1.3 mL, 1.30 mmol) was added slowly at 0 °C. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (40% EtOAc/hexane) to yield the product 6 (0.130 g, 0.93 mmol, 86%) as a colorless liquid. [α]²⁰_D = +29.6 (c 0.38, CHCl₃); IR (neat) ν_max: 3288, 1768, 1189, 1056, 941, 684 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 4.73–4.59 (m, 2H), 2.79–2.63 (m, 1H), 2.62–2.19 (m, 4H), 1.94 (bs, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 177.7, 81.3, 79.8, 75.3, 63.5, 28.1, 21.6 ppm; MS (ESI): m/z = 141 [M + H]⁺.
(R)-5-((S,E)-1-Hydroxyhex-4-en-2-yn-1-yl)dihydrofuran-2(3H)-one (21). To a stirred mixture of Pd(PPh₃)₂Cl₂ (0.008 g, 0.011 mmol) and CuI (0.007 g, 0.33 mmol) in Et₃N (1 mL) were added solutions of trans-1-bromopropene (0.027 g, 0.22 mmol) in Et₃N (1 mL) and acetylene compound 6 (0.019 g, 0.11 mmol) in Et₃N (1 mL) under argon. After 6 h, the reaction mixture was filtered through Celite and filtrate was concentrated. Silica gel column chromatography (15% EtOAc/hexane) of the crude product gave 21 (0.022 g, 0.12 mmol, 89%) as pale yellow oil: [α]²⁰_D = +62.3 (c 0.31, CHCl₃); IR (neat) ν_max: 3422, 1773, 1170, 1054, 1020, 955, 773, 618 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 6.20 (dq, J = 6.6, 15.8 Hz, 1H), 5.49 (dt, J = 1.8, 15.8 Hz, 1H), 4.77–4.71 (m, 1H), 4.66 (ddd, J = 2.6, 5.2, 7.9 Hz, 1H), 2.90 (bs, 1H), 2.77–2.63 (m, 1H), 2.57–2.24 (m, 3H), 1.79 (dd, J = 1.7, 6.8 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.5, 141.7, 109.4, 85.8, 82.8, 81.4, 64.4, 28.1, 21.8, 18.6 ppm; HRMS: calcd for C₁₀H₁₃O₃ [M + H]⁺ 181.0859; found 181.0851.
(R)-5-((S,2Z,4E)-1-Hydroxyhexa-2,4-dien-1-yl)dihydrofuran-2(3H)-one (1). A solution of alkyne 21 (0.011 g, 0.061 mmol) dissolved in MeOH : H₂O (3 : 2 mL) was added to the suspension of activated Zn (0.100 mg) and the reaction mixture was heated to 60 °C until complete conversion of alkyne to alkene occurred (as judged by TLC). The metal was removed by filtration, washed with MeOH (5 mL) and the combined solution was concentrated to 1/3 of the original volume. Ethyl acetate was added and the organic layer carefully washed with H₂O. The organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuum. Silica gel chromatography of the crude product using (25% EtOAc/hexane) as an eluent gave the compound 1 (0.010 g, 0.054 mmol, 91%) as a light yellow liquid. [α]²⁰_D = +69.8 (c 0.98, CHCl₃); IR (neat) ν_max: 3421, 2924, 1770, 1460, 1260, 1186, 1018, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.36–6.26 (m, 1H), 6.15 (t, J = 11.0 Hz, 1H), 5.83 (dq, J = 6.7, 13.8 Hz, 1H), 5.20 (dd, J = 8.4, 11.0 Hz, 1H), 4.87 (dd, J = 3.1, 8.4 Hz, 1H), 4.52 (dd, J = 3.1, 7.4 Hz, 1H), 2.68–2.42 (m, 2H), 2.26–2.11 (m, 2H), 1.80 (dd, J = 1.8, 6.8 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.3, 133.9, 133.1, 126.0, 123.6, 82.2, 68.5, 28.5, 21.3, 18.3 ppm; HRMS: calcd for C₁₀H₁₅O₃ [M + H]⁺ 183.1021; found 183.1026.
(4R,5S)-5-((tert-Butyldimethylsilyl)oxy)-4-hydroxyhept-6-yn-1-yl benzoate (22). Anhydrous Et₃N (1.1 mL, 8.137 mmol), BzCl (0.9 mL, 7.751 mmol), and 20 mg of DMAP were added to a solution of 10 (1.00 g, 3.875 mmol), in dry CH₂Cl₂ under N₂ atmosphere at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture quenched with saturated NaHCO₃ solution, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with water followed by brine solution. The organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (30% EtOAc/hexane) to give the corresponding compound 22 (1.22 g, 3.732 mmol, 86%) yield as a colorless liquid. [α]²⁰_D = +49.72 (c 0.32, CHCl₃); IR (neat) ν_max: 3489, 2929, 1718, 1276, 1114, 1028, 839, 778 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 8.07–8.01 (m, 2H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H), 4.43–4.33 (m, 2H), 4.31 (dd, J = 2.1, 4.4 Hz, 1H), 3.71–3.65 (m, 1H), 2.34 (d, J = 4.6 Hz, 1H), 2.09–1.99 (m, 1H), 1.92–1.76 (m, 2H), 1.72–1.63 (m, 1H), 0.90 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 166.6, 132.8, 130.3, 129.5 (2C), 128.3 (2C), 81.9, 74.5, 73.9, 66.8, 64.8, 28.3, 25.7 (3C), 25.0, 18.1, −4.5, −5.1 ppm; HRMS: calcd for C₂₀H₃₀NaO₄Si [M + Na]⁺ 385.1806; found 385.1820.
(3S,4R)-7-(Benzoyloxy)-3-((tert-butyldimethylsilyl)oxy)hept-1-yn-4-yl 4-nitrobenzoate (23). To a stirred solution of 22 (0.98 g, 2.70 mmol), triphenylphosphine (1.42 g, 5.414 mmol), and P-nitrobenzoic acid (0.91 g, 5.414 mmol) in dry THF (15 mL) at 0 °C was added diethyl azodicarboxylate (1.06 mL, 5.414 mmol) via syringe. After half an hour, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 15 mL). The solvent was evaporated followed by flash chromatography (10% EtOAc/hexane) afforded 23 (1.21 g, 2.374 mmol, 87%) as a pale yellow oil. [α]²⁰_D = −2.5 (c 0.39, CHCl₃); IR (neat) ν_max: 2862, 1731, 1706, 1514, 1248, 1099, 1034, 821, 719 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 8.29 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 9.0 Hz, 2H), 8.05–7.99 (m, 2H), 7.59–7.52 (m, 1H), 7.46–7.38 (m, 2H), 5.26 (ddd, J = 3.3, 5.8, 9.1 Hz, 1H), 4.61 (dd, J = 2.1, 5.8 Hz, 1H), 4.38 (t, J = 6.4 Hz, 2H), 2.46 (d, J = 1.9 Hz, 1H), 2.22–2.14 (m, 1H), 2.07–1.80 (m, 3H), 0.85 (s, 9H), 0.16 (s, 3H), 0.08 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 166.4, 164.1, 150.5, 135.3, 132.8, 130.8 (2C), 130.1, 129.5 (2C), 128.3 (2C), 123.5 (2C), 81.5, 76.5, 74.5, 64.3, 64.0, 29.6, 25.9, 25.5 (3C), 24.8, 17.9, −4.7, −5.2 ppm; HRMS: calcd for C₂₇H₃₃NaO₇NSi [M + Na]⁺ 534.1918; found 534.1923.
(4R,5S)-5-((tert-Butyldimethylsilyl)oxy)hept-6-yne-1,4-diol (24). The compound 23 (1.02 g, 1.996 mmol) was dissolved in MeOH (15 mL), and K₂CO₃ (1.38 g, 9.980 mmol) was added at rt. After stirring for 2 h, K₂CO₃ was filtered and sat. NH₄Cl aq. was added to the mixture. After evaporation of MeOH, the residue was extracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated in vacuo. Column chromatography (60% EtOAc/hexane) provided 24 (0.463 g, 1.793 mmol, 79%) as a colorless viscous liquid. [α]²⁰_D = +27.0 (c 0.28, CHCl₃); IR (neat) ν_max: 3311, 2954, 2930, 1253, 1090, 961, 838, 779 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.14 (dd, J = 1.9, 7.1 Hz, 1H), 3.75–3.57 (m, 3H), 2.87 (bs, 1H), 2.46 (d, J = 2.1 Hz, 1H), 2.37 (bs, 1H), 1.93–1.85 (m, 1H), 1.79–1.73 (m, 2H), 1.54–1.46 (m, 1H), 0.92 (s, 9H), 0.19 (s, 3H), 0.16 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 82.4, 74.9, 74.4, 66.9, 62.8, 29.2, 29.0, 25.7 (3C), 18.1, −4.5, −5.1 ppm; HRMS: calcd for C₁₃H₂₇O₃Si [M + H]⁺ 259.1724; found 259.1727.
(S)-5-((S)-1-((tert-Butyldimethylsilyl)oxy)prop-2-yn-1-yl)dihydrofuran-2(3H)-one (25). The procedure was the same as described above for the conversion of 10 leading to 20, except that 24 (0.385 g, 1.492 mmol) was employed to replace 10, giving 25 (0.342 g, 1.346 mmol, 90%) as colorless oil; [α]²⁰_D = +33.7 (c 0.39, CHCl₃); IR (neat) ν_max: 2955, 2931, 1783, 1256, 1170, 1112, 838, 780 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.55–4.49 (m, 2H), 2.68–2.60 (m, 1H), 2.53–2.45 (m, 1H), 2.44 (d, J = 1.8 Hz, 1H), 2.37–2.22 (m, 2H), 0.90 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 176.8, 80.8 (2C), 74.6, 64.8, 27.9, 25.6 (3C), 22.7, 18.1, −4.7, −5.1 ppm; HRMS: calcd for C₁₃H₂₃NaO₃Si [M + Na]⁺ 277.1230; found 277.1232.
(S)-5-((S)-1-Hydroxyprop-2-yn-1-yl)dihydrofuran-2(3H)-one (7). The procedure was the same as described above for the conversion of 20 leading to 6, except that 25 (0.289 g, 1.131 mmol) was employed to replace 20, giving 7 (0.142 g, 1.014 mmol, 89%) as colourless liquid; [α]²⁰_D = +18.7 (c 0.10, CHCl₃); IR (neat) ν_max: 3415, 2924, 1769, 1460, 1187, 952, 655 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.63–4.58 (m, 1H), 4.49 (dd, J = 2.3, 5.2 Hz, 1H), 2.66 (ddd, J = 5.8, 10.2, 16.0 Hz, 1H), 2.60–2.52 (m, 2H), 2.42–2.33 (m, 1H), 2.29–2.22 (m, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 176.8, 81.1, 80.0, 75.3, 64.3, 28.1, 23.2 ppm; MS (ESI): m/z = 163 [M + Na]⁺.
(S)-5-((S,E)-1-Hydroxyhex-4-en-2-yn-1-yl)dihydrofuran-2(3H)-one (26). The procedure was the same as described above for the conversion of 6 leading to 21, except that 7 (0.03 g, 0.214 mmol) was employed to replace 6, giving 26 (0.033 mg, 0.183 mmol, 87%) as colourless oil; [α]²⁰_D = +9.6 (c 0.27, CHCl₃); IR (neat) ν_max: 3407, 2924, 2853, 1774, 1460, 1185, 956, 646 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 6.20 (dq, J = 6.8, 15.8 Hz, 1H), 5.48 (d, J = 15.8 Hz, 1H), 4.65–4.53 (m, 2H), 2.72–2.45 (m, 2H), 2.42–2.14 (m, 2H), 1.79 (dd, J = 1.5, 6.8 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 176.7, 141.7, 109.4, 85.8, 83.1, 81.4, 65.0, 28.1, 23.3, 18.6 ppm; HRMS: calcd for C₁₀H₁₃O₃ [M + H]⁺ 181.0859; found 181.0861.
(S)-5-((S,2Z,4E)-1-Hydroxyhexa-2,4-dien-1-yl)dihydrofuran-2(3H)-one (2). The procedure was the same as described above for the conversion of 21 leading to 1, except that 26 (0.014 g, 0.077 mmol) was employed to replace 21, giving 2 (0.013 g, 0.071 mmol, 92%) as colourless oil; [α]²⁰_D = +19.8 (c 0.45, CHCl₃); IR (neat) ν_max: 3422, 2923, 2853, 1772, 1187, 1031, 823, 755 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 6.40–6.31 (m, 1H), 6.19 (t, J = 11.0 Hz, 1H), 5.84 (dq, J = 6.7, 13.8 Hz, 1H), 5.31 (t, J = 10.2 Hz, 1H), 4.59 (dd, J = 5.5, 8.8 Hz, 1H), 4.50–4.43 (m, 1H), 2.70–2.45 (m, 2H), 2.29–2.01 (m, 2H), 1.81 (d, J = 6.8 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.1, 133.6, 133.5, 126.0, 123.9, 82.8, 69.8, 28.3, 23.5, 18.2 ppm; HRMS: calcd for C₁₀H₁₅O₃ [M + H]⁺ 181.1021; found 183.1018.
(S)-5-((S)-1-Hydroxyhexyl)dihydrofuran-2(3H)-one (5). To a solution of 15 (0.010 g, 0.055 mmol) in anhyd MeOH (2 mL) was added a catalytic amount of 10% Pd/C and the resulting mixture was stirred under H₂ atmosphere at r.t. for 3 h. After completion, the catalyst was filtered and then washed with EtOAc (3 × 3 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (50% EtOAc/hexane) to afford the compound 5 (0.009 g, 0.048 mmol, 90%) as a colourless liquid. [α]²⁰_D = +30 (c 0.27, CHCl₃); IR (neat) ν_max: 3442, 2931, 1767, 1373, 1189, 1055, 830, 769 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.41 (ddd, J = 4.5, 7.5, 11.9, 1H); 3.56 (dt, J = 4.5, 9.1, 1H); 2.64–2.48 (m, 2H); 2.28–2.18 (m, 1H); 2.17–2.07 (m, 1H); 1.58–1.45 (m, 3H); 1.43–1.26 (m, 5H); 0.88 (t, J = 7.2, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.2; 82.9; 73.6; 32.9; 31.6; 28.6; 25.0; 24.0; 22.5; 13.9 ppm. HRMS: calcd for C₁₀H₁₈NaO₃ [M + Na]⁺ 209.1148; found 209.1158.
(R)-4,7-Bis((4-methoxybenzyl)oxy)hept-1-yn-3-one (27). Alcohol 12 (4.8 g, 12.51 mmol) in dry CH₃CN (25 mL) was added to a solution of IBX (4.21 g, 15.01 mmol) in CH₃CN. The mixture was stirred at 80 °C for 1 h and then filtered through a Celite pad and washed with ether. The combined organic filtrates were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20% EtOAc/hexane) to afford keto compound 27 as a yellow coloured liquid (4.26 g, 11.15 mmol, 89%). [α]²⁰_D = +23.0 (c 0.49, CHCl₃); IR (neat) ν_max: 2924, 2854, 1721, 1610, 1513, 1248, 1102, 757 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.29–7.20 (m, 4H), 6.90–6.83 (m, 4H), 4.65 (d, J = 11.2 Hz, 1H), 4.39 (ABq, J = 11.7, 14.2 Hz, 2H), 4.33 (d, J = 11.2 Hz, 1H), 3.93–3.88 (m, 1H), 3.82–3.79 (m, 6H), 3.45–3.38 (m, 1H), 1.96–1.86 (m, 1H), 1.85–1.62 (m, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 189.1, 159.4, 159.0, 130.4, 129.8 (2C), 129.2 (3C), 113.8 (2C), 113.7 (2C), 83.9, 81.5, 79.9, 72.4, 72.1, 69.1, 55.2 (2C), 28.6, 25.3 ppm; MS (ESI): m/z = 405 [M + Na]⁺.
(3R,4R)-4,7-Bis((4-methoxybenzyl)oxy)hept-1-yn-3-ol (28). To a mixture of propargyl ketone 27 (4.08 g, 10.68 mmol) in formic acid (4.91 mL, 106.8 mmol) and triethylamine (9.1 mL, 64.08 mmol) were added at room temperature an aliquant amount of the stock solution of the RuCl[(N-(tosyl)-1,2-diphenylethylenediamine)(p-cymene)] complex 0.1 M in CH₂Cl₂ (2.13 mL, 0.213 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with saturated aqueous NaHCO₃ solution, and extracted with CH₂Cl₂, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (40%, EtOAc/hexane) to afford chiral propargyl alcohol 28 (3.82 g, 9.942 mmol, 93%) as a light yellow coloured liquid. [α]²⁰_D = −0.9 (c 0.48, CHCl₃); IR (neat) ν_max: 3422, 2935, 2864, 1612, 1513, 1248, 1083, 1034, 820, 755 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.29–7.23 (m, 4H), 6.90–6.84 (m, 4H), 4.64 (d, J = 10.9 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 4.42 (s, 2H), 4.30 (td, J = 2.1, 5.6 Hz, 1H), 3.80 (s, 6H), 3.58–3.54 (m, 1H), 3.47–3.39 (m, 2H), 2.48 (d, J = 2.3 Hz, 1H), 1.80–1.65 (m, 4H). ¹³C NMR (125 MHz, CDCl₃): δ 159.3, 159.0, 130.5, 130.0, 129.6 (2C), 129.2 (2C), 113.8 (2C), 113.7 (2C), 82.8, 81.0, 73.9, 72.9, 72.5, 69.8, 64.3, 55.2 (2C), 27.6, 25.4 ppm; HRMS: calcd for C₂₃H₂₈O₅Na [M + Na]⁺ 407.1829; found 407.1832.
(((3R,4R)-4,7-Bis((4-methoxybenzyl)oxy)hept-1-yn-3-yl)oxy)(tert-butyl)dimethylsilane (29). The procedure was the same as described above for the conversion of 12 leading to 12a, except that 28 (3.51 g, 9.140 mmol) was employed to replace 12, giving 29 (4.21 mg, 8.453 mmol, 92%) as colourless oil; [α]²⁰_D = −2.53 (c 0.31, CHCl₃); IR (neat) ν_max: 2934, 1623, 1514, 1250, 1096, 836, 778 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.28–7.22 (m, 4H), 6.88–6.83 (m, 4H), 4.66 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.42–4.37 (m, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.44–3.34 (m, 3H), 2.41 (d, J = 2.1 Hz, 1H), 1.88–1.76 (m, 2H), 1.65–1.54 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 159.1, 159.0, 130.7, 130.6, 129.5 (2C), 129.2 (2C), 113.7 (4C), 83.1, 81.1, 73.8, 72.9, 72.4, 70.1, 65.7, 55.2 (2C), 27.1, 25.8, 25.7 (3C), 18.2, −4.7, −5.0 ppm; HRMS: calcd for C₂₉H₄₂O₅SiNa [M + Na]⁺ 521.2694; found 521.2707.
(4R,5R)-5-((tert-Butyldimethylsilyl)oxy)hept-6-yne-1,4-diol (11). The procedure was the same as described above for the conversion of 12a leading to 10, except that 29 (3.99 g, 8.012 mmol) was employed to produce compound 11 (1.78 g, 6.899 mmol, 86%) as colourless oil; [α]²⁰_D = −32.3 (c 0.42, CHCl₃); IR (neat) ν_max: 3394, 2930, 2859, 1253, 1090, 838, 776 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 4.15 (dd, J = 1.9, 7.1 Hz, 1H), 3.76–3.56 (m, 3H), 2.47 (d, J = 2.1 Hz, 1H), 1.94–1.86 (m, 1H), 1.81–1.73 (m, 2H), 1.56–1.46 (m, 1H), 0.93 (s, 9H), 0.19 (s, 3H), 0.16 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 82.4, 74.9, 74.4, 66.9, 62.7, 29.2, 29.0, 25.7 (3C), 18.1, −4.5, −5.1 ppm; HRMS: calcd for C₁₃H₂₇O₃Si [M + H]⁺ 259.1724; found 259.1726.
(R)-5-((R)-1-((tert-Butyldimethylsilyl)oxy)prop-2-yn-1-yl)dihydrofuran-2(3H)-one (30). The procedure was the same as described above for the conversion of 10 leading to 20, except that 11 (0.387 g, 1.500 mmol) was employed to replace 10, giving 30 (0.336 g, 1.322 mmol, 88%) as colourless oil; [α]²⁰_D = −37.3 (c 0.41, CHCl₃); IR (neat) ν_max: 2965, 2932, 1773, 1252, 1170, 1114, 838, 780 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.55–4.50 (m, 2H), 2.70–2.61 (m, 1H), 2.54–2.46 (m, 1H), 2.44 (d, J = 1.8 Hz, 1H), 2.37–2.22 (m, 2H), 0.91 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 176.8, 80.8 (2C), 74.6, 64.7, 27.8, 25.5 (3C), 22.7, 18.0, −4.8, −5.2 ppm; HRMS: calcd for C₁₃H₂₂NaO₃Si [M + Na]⁺ 277.1230; found 277.1241.
(R)-5-((R)-1-Hydroxyprop-2-yn-1-yl)dihydrofuran-2(3H)-one (8). The procedure was the same as described above for the conversion of 20 leading to 6, except that 30 (0.262 g, 1.031 mmol) was employed to replace 20, giving 8 (0.13 g, 0.928 mmol, 90%) as colourless oil; [α]²⁰_D = −20.17 (c 0.12, CHCl₃); IR (neat) ν_max: 3400, 2925, 1769, 1189, 1051, 952, 665 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.65–4.59 (m, 1H), 4.50 (dd, J = 2.3, 5.2 Hz, 1H), 3.61 (bs, 1H), 2.67 (ddd, J = 5.8, 10.2, 16.0 Hz, 1H), 2.61–2.52 (m, 2H), 2.42–2.33 (m, 1H), 2.30–2.21 (m, 1H). ¹³C NMR (125 MHz, CDCl₃): δ 177.2, 81.4, 80.1, 75.1, 64.1, 28.1, 23.2 ppm; MS (ESI): m/z = 158 [M + NH₄]⁺.
(R)-5-((R,E)-1-Hydroxyhex-4-en-2-yn-1-yl)dihydrofuran-2(3H)-one (31). The procedure was the same as described above for the conversion of 6 leading to 21, except that 8 (0.023 g, 0.164 mmol) was employed to replace 6, giving 31 (0.026 g, 0.144 mmol, 87%) as colourless oil; [α]²⁰_D = −12.5 (c 0.30, CHCl₃); IR (neat) ν_max: 3417, 2925, 2854, 1774, 1467, 1185, 958, 758 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 6.20 (dq, J = 6.8, 15.8 Hz, 1H), 5.49 (d, J = 15.8 Hz, 1H), 4.62–4.56 (m, 2H), 2.72–2.48 (m, 2H), 2.40–2.16 (m, 2H), 1.79 (dd, J = 1.5, 6.8 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 176.8, 141.7, 109.4, 85.7, 83.1, 81.5, 65.0, 28.1, 23.3, 18.6 ppm; HRMS: calcd for C₁₀H₁₃O₃ [M + H]⁺ 181.0859; found 181.0862.
(R)-5-((R,2Z,4E)-1-Hydroxyhexa-2,4-dien-1-yl)dihydrofuran-2(3H)-one (3). The procedure was the same as described above for the conversion of 21 leading to 1, except that 31 (0.013 g, 0.072 mmol) was employed to replace 21, giving 3 (12 mg, 0.0695 mmol, 89%) as colourless oil; [α]²⁰_D = −20.6 (c 0.52, CHCl₃); IR (neat) ν_max: 3421, 2924, 2854, 1772, 1455, 1186, 1042, 990, 754 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 6.43–6.28 (m, 1H), 6.20 (t, J = 10.9 Hz, 1H), 5.85 (dq, J = 6.8, 13.6 Hz, 1H), 5.41–5.23 (m, 1H), 4.58 (dd, J = 5.6, 8.9 Hz, 1H), 4.52–4.41 (m, 1H), 2.71–1.93 (m, 4H), 1.81 (d, J = 6.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 177.0, 134.0, 133.8, 126.0, 123.9, 82.8, 70.1, 28.4, 23.7, 18.4 ppm; HRMS: calcd for C₁₀H₁₄NaO₃ [M + H]⁺ 205.0840; found 205.0843.
(4R,5R)-5-((tert-Butyldimethylsilyl)oxy)-4-hydroxyhept-6-yn-1-yl benzoate (32). The procedure was the same as described above for the conversion of 10 leading to 22, except that 11 (1.00 g, 3.875 mmol) was employed to replace 10, giving 32 (1.20 g, 3.310 mmol, 85%) as colourless oil; [α]²⁰_D = −12.4 (c 0.6, CHCl₃); IR (neat) ν_max: 3450, 2955, 2929, 1718, 1276, 1114, 1028, 839, 779 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 8.07–8.02 (m, 2H), 7.57–7.52 (m, 1H), 7.45–7.40 (m, 2H), 4.38 (t, J = 6.5 Hz, 2H), 4.15 (dd, J = 2.1, 6.8 Hz, 1H), 3.68–3.62 (m, 1H), 2.54 (bs, 1H), 2.44 (d, J = 2.1 Hz, 1H), 2.09–1.99 (m, 1H), 1.95–1.83 (m, 2H), 1.64–1.54 (m, 1H), 0.91 (s, 9H), 0.18 (s, 3H), 0.15 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 166.6, 132.7, 130.3, 129.5 (2C), 128.2 (2C), 82.4, 74.5 (2C), 66.9, 64.7, 28.6, 25.7 (3C), 25.0, 18.1, −4.5, −5.2 ppm; HRMS: calcd for C₂₀H₃₀NaO₄Si [M + Na]⁺ 385.1806; found 385.1812.
(3R,4R)-7-(Benzoyloxy)-3-((tert-butyldimethylsilyl)oxy)hept-1-yn-4-yl 4-nitrobenzoate (33). The procedure was the same as described above for the conversion of 22 leading to 23, except that 32 (0.98 g, 2.707 mmol) was employed to replace 22, giving 33 (1.20 g, 2.348 mmol, 87%) as colourless oil; [α]²⁰_D = −1.3 (c 0.25, CHCl₃); IR (neat) ν_max: 2872, 1721, 1706, 1514, 1248, 1099, 1034, 821, 719 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.28 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H), 7.71–7.68 (m, 1H), 7.58–7.50 (m, 2H), 7.45–7.39 (m, 2H), 5.32–5.26 (m, 1H), 4.63 (dd, J = 2.2, 4.1 Hz, 1H), 4.40–4.32 (m, 2H), 2.45 (d, J = 2.2 Hz, 1H), 2.17–1.83 (m, 4H), 0.85 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 166.4, 164.2, 150.6, 135.4, 132.9, 130.8 (2C), 130.2, 129.5 (2C), 128.3 (2C), 123.5 (2C), 81.5, 77.3, 74.4, 64.3, 64.2, 25.8, 25.5 (3C), 24.8, 17.9, −4.6, −5.3 ppm; HRMS: calcd for C₂₇H₃₃NaO₇NSi [M + Na]⁺ 534.1918; found 534.1924.
(4R,5R)-5-((tert-Butyldimethylsilyl)oxy)hept-6-yne-1,4-diol (34). The procedure was the same as described above for the conversion of 23 leading to 24, except that 16 (1.0 g, 1.956 mmol) was employed to replace 23, giving 34 (0.420 g, 1.628 mmol, 83%) as colorless oil; [α]²⁰_D = −33.5 (c 0.12, CHCl₃); IR (neat) ν_max: 3421, 1612, 1513, 1247, 1175, 820, 757 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.30 (dd, J = 1.9, 4.2 Hz, 1H), 3.78–3.63 (m, 3H), 2.65 (bs, 1H), 2.45 (d, J = 2.1 Hz, 1H), 1.83–1.71 (m, 3H), 1.63–1.59 (m, 1H), 0.91 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 81.9, 74.3 (2C), 66.6, 62.7, 29.1, 28.7, 25.6 (3C), 18.0, −4.6, −5.2 ppm; MS (ESI): m/z = 281 [M + Na]⁺.
(S)-5-((R)-1-((tert-Butyldimethylsilyl)oxy)prop-2-yn-1-yl)dihydrofuran-2(3H)-one (35). The procedure was the same as described above for the conversion of 10 leading to 20, except that 34 (0.37 g, 1.434 mmol) was employed to replace 10, giving 35 (0.333 g, 1.311 mmol, 91%) as colourless oil; [α]²⁰_D = −55.4 (c 0.41, CHCl₃); IR (neat) ν_max: 2955, 2931, 1783, 1466, 1170, 1112, 1030, 838, 780 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.64 (t, J = 2.3 Hz, 1H), 4.61–4.57 (m, 1H), 2.66–2.56 (m, 1H), 2.54–2.40 (m, 3H), 2.33–2.21 (m, 1H), 0.90 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 177.1, 81.0, 80.7, 74.6, 64.3, 28.1, 25.4 (3C), 21.2, 17.9, −5.2, −5.4 ppm; HRMS: calcd for C₁₃H₂₃O₃Si [M + H]⁺ 255.1411; found 255.1438.
(S)-5-((R)-1-Hydroxyprop-2-yn-1-yl)dihydrofuran-2(3H)-one (9). The procedure was the same as described above for the conversion of 20 leading to 6, except that 35 (0.26 g, 1.023 mmol) was employed to replace 20, giving 9 (0.128 g, 0.914 mmol, 89%) as colourless oil; [α]²⁰_D = −26.3 (c 0.36, CHCl₃); IR (neat) ν_max: 3402, 2926, 1768, 1189, 1055, 807, 666 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 4.73–4.59 (m, 2H), 2.77–2.64 (m, 1H), 2.59–2.46 (m, 2H), 2.43–2.26 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 177.7, 81.3, 79.8, 75.2, 63.5, 28.1, 21.6 ppm; MS (ESI): m/z = 163 [M + Na]⁺.
(S)-5-((R,E)-1-Hydroxyhex-4-en-2-yn-1-yl)dihydrofuran-2(3H)-one (36). The procedure was the same as described above for the conversion of 6 leading to 21, except that 9 (0.019 g, 0.135 mmol) was employed to replace 6, giving 36 (0.021 g, 0.116 mmol, 88%) as colourless oil; [α]²⁰_D = −56.3 (c 0.36, CHCl₃); IR (neat) ν_max: 3418, 2925, 2854, 1774, 1467, 1185, 1042, 952, 759 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 6.30–6.15 (m, 1H), 5.56–5.45 (m, 1H), 4.80–4.72 (m, 1H), 4.68 (ddd, J = 2.6, 5.2, 7.9 Hz, 1H), 2.90 (bs, 1H), 2.79–2.63 (m, 1H), 2.59–2.26 (m, 3H), 1.81 (dd, J = 1.7, 6.8 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.5, 141.7, 109.4, 85.9, 82.8, 81.4, 64.5, 28.1, 21.8, 18.6 ppm; HRMS: calcd for C₁₀H₁₃O₃ [M + H]⁺ 181.0859; found 181.0864.
(S)-5-((R,2Z,4E)-1-Hydroxyhexa-2,4-dien-1-yl)dihydrofuran-2(3H)-one (4). The procedure was the same as described above for the conversion of 21 leading to 1, except that 36 (0.01 g, 0.055 mmol) was employed to replace 21, giving 4 (0.009 g, 0.049 mmol, 90%) as colourless oil; [α]²⁰_D = −66.5 (c 0.89, CHCl₃); IR (neat) ν_max: 3420, 2925, 2856, 1770, 1456, 1185, 1048, 954, 757 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 6.35–6.27 (m, 1H), 6.15 (t, J = 11.0 Hz, 1H), 5.84 (dq, J = 6.7, 13.5 Hz, 1H), 5.21 (dd, J = 8.7, 10.8 Hz, 1H), 4.88 (dd, J = 3.1, 8.4 Hz, 1H), 4.53 (td, J = 3.0, 10.1 Hz, 1H), 2.67–2.45 (m, 2H), 2.30–2.14 (m, 2H), 1.81 (dd, J = 1.2, 6.6 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 177.4, 133.8, 133.0, 126.0, 123.8, 82.3, 68.5, 28.5, 21.3, 18.3 ppm; HRMS: calcd for C₁₀H₁₄NaO₃ [M + H]⁺ 205.0840; found 205.0849.

General procedure for the preparation of triazole-hybrids. 10 mL round-bottom flask equipped with a stirring bar, 2-azidochlorobenzene (0.046 g, 0.156 mmol) was dissolved in t-butanol (1 mL). Lactone 6 (0.02 g, 0.142 mmol) was added to the flask, followed by CuSO₄·5H₂O (0.007 g, 0.028 mmol), Na ascorbate (0.027 g, 0.135 mmol), and H₂O (1 mL). The mixture was stirred at room temperature for 6 h and then diluted with t-butanol (3 mL). The aqueous layer was separated and back extracted with CH₂Cl₂ (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. Chromatography of the crude material on a short silica gel plug by sequential elution with 10% EtOAc in hexanes followed by EtOAc, gave 6a (0.040 g, 0.129 mmol, 91% yield) as an off-white solid.
(R)-5-((S)-(1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (6a). Compound 6a (0.040 g, 0.129 mmol, 91%) was prepared via the general procedure as an off-white solid. mp 160–162 °C. [α]²⁰_D = +15.9 (c 0.12, CHCl₃); IR (neat) ν_max: 3401, 2925, 2854, 1771, 1445, 1256, 1184, 1051, 752 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.68 (s, 1H), 7.51–7.41 (m, 1H), 7.38–7.16 (m, 3H), 5.66 (s, 2H), 5.15 (dd, J = 2.8, 4.7 Hz, 1H), 5.06–4.95 (m, 1H), 2.63–2.37 (m, 2H), 2.29–2.02 (m, 2H). ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 177.4, 147.6, 133.0, 131.9, 129.9, 129.8, 129.4, 127.1, 122.4, 81.6, 67.2, 51.0, 28.1, 20.6 ppm; HRMS: calcd for C₁₄H₁₄ClN₃NaO₃ [M + Na]⁺ 330.0616; found 330.0645.
(R)-5-((S)-(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (6b). Compound 6b (0.043 g, 0.122 mmol, 86%) was prepared via the general procedure as an off-white solid, mp 182–183 °C. [α]²⁰_D = + 4.3 (c 0.49, CHCl₃); IR (neat) ν_max: 3379, 2925, 2854, 1771, 1442, 1183, 1029, 751 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.66 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.38–7.10 (m, 3H), 5.65 (s, 2H), 5.22 (d, J = 2.6 Hz, 1H), 5.03–4.91 (m, 1H), 2.63–2.39 (m, 2H), 2.36–1.98 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 177.8, 146.9, 133.7, 133.2, 130.5, 130.4, 128.2, 123.5, 122.5, 81.8, 67.8, 53.9, 28.4, 21.4 ppm; HRMS: calcd for C₁₄H₁₅BrN₃O₃ [M + H]⁺ 352.0291; found 352.028.
(R)-5-((S)-Hydroxy(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (6c). Compound 6c (0.039 g, 0.128 mmol, 90%) was prepared via the general procedure as a colourless solid, mp 158–160 °C. [α]²⁰_D = +29.4 (c 0.12, CHCl₃); IR (neat) ν_max: 3264, 2965, 2930, 1760, 1515, 1250, 1178, 1011, 820, 762 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.59 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.45 (ABq, J = 14.5, 21.3 Hz, 2H), 5.17–5.08 (m, 1H), 5.05–4.94 (m, 1H), 3.81 (s, 3H), 2.56–2.34 (m, 2H), 2.27–1.99 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 177.5, 159.4, 147.6, 129.3 (2C), 126.2, 121.8, 114.0 (2C), 81.6, 67.2, 54.9, 53.2, 28.1, 20.7 ppm; HRMS: calcd for C₁₅H₁₈N₃O₄ [M + H]⁺ 304.1292; found 304.1302.
(R)-5-((S)-Hydroxy(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (6d). Compound 6d (0.040 g, 0.126 mmol, 88%) was prepared via the general procedure as a pale yellow solid, mp 176–177 °C. [α]²⁰_D = +3.2 (c 0.37, CHCl₃); IR (neat) ν_max: 3389, 2925, 2854, 1768, 1523, 1348, 1185, 1052, 757 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 8.22 (d, J = 8.7 Hz, 2H), 7.66 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 5.64 (ABq, J = 15.4, 20.0 Hz, 2H), 5.19 (d, J = 3.6 Hz, 1H), 4.99–4.92 (m, 1H), 2.57–2.41 (m, 2H), 2.27–2.11 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 177.7, 148.1, 147.6, 141.3, 128.6 (2C), 124.3 (2C), 122.6, 81.7, 67.8, 53.2, 28.3, 21.6 ppm; HRMS: calcd for C₁₄H₁₄N₄NaO₅ [M + Na]⁺ 341.0856; found 341.086.
(S)-5-((R)-(1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (9a). Compound 9a (0.037 g, 0.121 mmol, 85%) was prepared via the general procedure as an off-white solid, mp 160–162 °C. [α]²⁰_D = −15.8 (c 0.12, CHCl₃); IR (neat) ν_max: 3409, 2927, 1770, 1445, 1257, 1185, 1050, 752 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.68 (s, 1H), 7.48–7.40 (m, 1H), 7.40–7.15 (m, 3H), 5.66 (s, 2H), 5.15 (dd, J = 2.8, 4.7 Hz, 1H), 5.01 (ddd, J = 2.8, 5.0, 7.9 Hz, 1H), 2.63–2.37 (m, 2H), 2.29–2.03 (m, 2H). ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 177.4, 147.6, 133.0, 131.9, 129.9, 129.8, 129.4, 127.1, 122.4, 81.5, 67.2, 51.0, 28.1, 20.6 ppm; HRMS: calcd for C₁₄H₁₄ClN₃NaO₃ [M + Na]⁺ 330.0616; found 330.0615.
(S)-5-((R)-(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (9b). Compound 9b (0.042 g, 0.119 mmol, 83%) was prepared via the general procedure as an off-white solid, mp 181–183 °C. [α]²⁰_D = −4.6 (c 0.48, CHCl₃); IR (neat) ν_max: 3382, 2926, 2854, 1771, 1441, 1255, 1183, 1050, 749 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.65 (s, 1H), 7.62 (dd, J = 1.2, 8.0 Hz, 1H), 7.35–7.10 (m, 3H), 5.65 (s, 2H), 5.21 (d, J = 2.6 Hz, 1H), 5.02–4.92 (m, 1H), 2.60–2.42 (m, 2H), 2.29–2.01 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 177.9, 147.0, 133.7, 133.2, 130.5, 130.4, 128.2, 123.5, 122.6, 81.9, 67.8, 53.9, 28.4, 21.3 ppm; HRMS: calcd for C₁₄H₁₄BrN₃NaO₃ [M + Na]⁺ 374.0111; found 374.0097.
(S)-5-((R)-Hydroxy(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (9c). Compound 9c (0.037 g, 0.122 mmol, 86%) was prepared via the general procedure as a colourless solid, mp 159–161 °C. [α]²⁰_D = −20.8 (c 0.48, CHCl₃); IR (neat) ν_max: 3281, 2924, 2853, 1759, 1515, 1462, 1250, 1175, 1106, 762 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.50 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.45 (ABq, J = 14.5, 21.3 Hz, 2H), 5.19–5.12 (m, 1H), 4.98–4.89 (m, 1H), 3.81 (s, 3H), 2.59–2.42 (m, 2H), 2.29–2.12 (m, 2H). ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 177.5, 160.0, 146.8, 129.7 (2C), 126.2, 121.2, 114.5 (2C), 81.7, 68.0, 55.3, 53.8, 28.3, 21.6 ppm; HRMS: calcd for C₁₅H₁₇O₄N₃Na [M + Na]⁺ 326.1111; found 326.1110.
(S)-5-((R)-Hydroxy(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (9d). Compound 9d (0.041 g, 0.129 mmol, 89%) was prepared via the general procedure as a pale yellow solid, mp 175–177 °C. [α]²⁰_D = −2.7 (c 0.56, CHCl₃); IR (neat) ν_max: 3379, 2923, 2854, 1768, 1522, 1348, 1185, 1051, 756 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 8.21 (d, J = 8.7 Hz, 2H), 7.66 (s, 1H), 7.40 (d, J = 8.7 Hz, 2H), 5.63 (ABq, J = 15.4, 19.7 Hz, 2H), 5.18 (d, J = 3.5 Hz, 1H), 4.98–4.92 (m, 1H), 2.54–2.41 (m, 2H), 2.26–2.10 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 177.7, 148.1, 147.5, 141.3, 128.6 (2C), 124.3 (2C), 122.6, 81.7, 67.9, 53.2, 28.3, 21.6 ppm; HRMS: calcd for C₁₄H₁₄N₄NaO₅ [M + Na]⁺ 341.0856; found 341.0862.
(S)-5-((S)-(1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (7a). Compound 7a (0.036 g, 0.117 mmol, 82%) was prepared via the general procedure as an off-white solid, mp 162–164 °C. [α]²⁰_D = +38.1 (c 0.10, CHCl₃); IR (neat) ν_max: 3411, 2925, 2854, 1771, 1445, 1183, 1050, 915, 752 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.75 (s, 1H), 7.49–7.40 (m, 1H), 7.38–7.12 (m, 3H), 5.66 (ABq, J = 15.4, 19.7 Hz, 2H), 4.96–4.77 (m, 2H), 2.70–2.21 (m, 4H). ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 177.4, 147.8, 132.9, 131.9, 129.9, 129.7, 129.3, 127.0, 122.3, 81.7, 68.2, 50.8, 27.9, 23.2 ppm; HRMS: calcd for C₁₄H₁₅ClN₃O₃ [M + H]⁺ 308.0796; found 308.0808.
(S)-5-((S)-(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (7b). Compound 7b (0.044 g, 0.125 mmol, 87%) was prepared via the general procedure as an off-white solid, mp 188–190 °C. [α]²⁰_D = +18.2 (c 0.43, CHCl₃); IR (neat) ν_max: 3379, 2924, 2854, 1770, 1442, 1184, 1050, 750 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.43–7.10 (m, 3H), 5.68 (s, 2H), 4.99–4.75 (m, 2H), 2.71–2.14 (m, 4H). ¹³C NMR (125 MHz, CDCl₃): δ 177.3, 146.9, 133.6, 133.3, 130.6, 130.5, 128.2, 123.6, 122.6, 81.9, 68.9, 54.0, 28.3, 23.6 ppm; HRMS: calcd for C₁₄H₁₄BrN₃NaO₃ [M + Na]⁺ 374.0111; found 374.0133.
(S)-5-((S)-Hydroxy(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (7c). Compound 7c (0.033 g, 0.107 mmol 83%) was prepared via the general procedure as a colourless solid, mp 168–169 °C. [α]²⁰_D = +28.6 (c 0.16, CHCl₃); IR (neat) ν_max: 3262, 2966, 2840, 1760, 1515, 1250, 1176, 1054, 820, 763 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.56 (s, 1H), 7.22 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.42 (s, 2H), 4.93 (d, J = 4.3 Hz, 1H), 4.80–4.70 (m, 1H), 3.79 (s, 3H), 2.67–2.15 (m, 4H). ¹³C NMR (125 MHz, CDCl₃): δ 177.2, 159.9, 146.9, 129.7 (2C), 126.2, 121.9, 114.5 (2C), 81.8, 69.0, 55.3, 53.8, 28.3, 23.6 ppm; HRMS: calcd for C₁₅H₁₇N₃NaO₄ [M + Na]⁺ 326.1111; found 326.1121.
(S)-5-((S)-Hydroxy(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (7d). Compound 7d (0.039 g, 0.122 mmol, 87%) was prepared via the general procedure as a pale yellow solid, mp 171–173 °C. [α]²⁰_D = +13.6 (c 0.42, CHCl₃); IR (neat) ν_max: 3388, 2924, 2853, 1769, 1523, 1348, 1222, 1184, 1052, 757 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 8.22 (d, J = 8.8 Hz, 2H), 7.84 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 5.68 (s, 2H), 4.99–4.76 (m, 2H), 2.72–2.24 (m, 4H). ¹³C NMR (100 MHz, CDCl₃ + DMSO-d₆): δ 177.0, 148.2, 147.2, 141.6, 128.2 (2C), 123.5 (2C), 122.6, 81.6, 68.1, 52.3, 27.8, 23.1 ppm; HRMS: calcd for C₁₄H₁₅N₄O₅ [M + H]⁺ 319.1037; found 319.1035.
(R)-5-((R)-(1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (8a). Compound 8a (0.039 g, 0.127 mmol, 90%) was prepared via the general procedure as an off-white solid, mp 162–164 °C. [α]²⁰_D = −53.7 (c 0.13, CHCl₃); IR (neat) ν_max: 3403, 2925, 2854, 1770, 1445, 1256, 1185, 1051, 752 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.76 (s, 1H), 7.50–7.41 (m, 1H), 7.39–7.13 (m, 3H), 5.66 (ABq, J = 15.4, 17.0 Hz, 2H), 4.96–4.78 (m, 2H), 2.69–2.20 (m, 4H). ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 176.9, 147.9, 132.8, 132.0, 129.9, 129.7, 129.3, 127.0, 122.3, 81.7, 68.2, 50.8, 27.9, 23.2 ppm; HRMS: calcd for C₁₄H₁₄O₃N₃ClNa [M + Na]⁺ 330.0615; found 330.0616.
(R)-5-((R)-(1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)dihydrofuran-2(3H)-one (8b). Compound 8b (0.043 g, 0.122 mmol, 85%) was prepared via the general procedure as a off-white solid, mp 189–191 °C. [α]²⁰_D = −23.3 (c 0.36, CHCl₃); IR (neat) ν_max: 3382, 2926, 2854, 1771, 1441, 1183, 1049, 915, 749 cm⁻¹; ¹H NMR (400 MHz, CDCl₃ + DMSO-d₆): δ 7.80 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.43–7.08 (m, 3H), 5.66 (s, 2H), 5.00–4.75 (m, 2H), 2.74–2.13 (m, 4H). ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 177.2, 148.3, 134.3, 132.9, 130.3 (2C), 128.1, 123.2, 122.9, 82.0, 68.5, 53.5, 28.3, 23.6 ppm; HRMS: calcd for C₁₄H₁₅O₃N₃Br [M + H]⁺ 352.0291; found 352.0281.
(R)-5-((R)-Hydroxy(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (8c). Compound 8c (0.038 g, 0.125 mmol, 88%) was prepared via the general procedure as a colourless solid, mp 167–169 °C. [α]²⁰_D = −18.3 (c 0.21, CHCl₃); IR (neat) ν_max: 3263, 2925, 2853, 1760, 1516, 1250, 1178, 1027, 820, 763 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.56 (s, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 5.43 (s, 2H), 4.94 (d, J = 4.4 Hz, 1H), 4.81–4.71 (m, 1H), 3.80 (s, 3H), 2.67–2.19 (m, 4H). ¹³C NMR (125 MHz, CDCl₃): δ 177.5, 159.9, 147.0, 129.7 (2C), 126.1, 122.0, 114.5 (2C), 81.9, 68.8, 55.3, 53.8, 28.3, 23.6 ppm; HRMS: calcd for C₁₅H₁₇O₄N₃Na [M + Na]⁺ 326.1111; found 326.1110.
(R)-5-((R)-Hydroxy(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)dihydrofuran-2(3H)-one (8d). Compound 8d (0.038 g, 0.119 mmol, 83%) was prepared via the general procedure as a pale yellow solid, mp 172–173 °C. [α]²⁰_D = −15.5 (c 0.36, CHCl₃); IR (neat) ν_max: 3403, 2924, 2853, 1769, 1522, 1348, 1183, 1050, 758 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 8.21 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 5.69 (s, 2H), 4.98–4.74 (m, 2H), 2.69–2.19 (m, 4H). ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 177.2, 148.4, 147.5, 141.6, 128.4 (2C), 123.7 (2C), 122.7, 81.8, 68.4, 52.6, 28.1, 23.4 ppm; HRMS: calcd for C₁₄H₁₅N₄O₅ [M + H]⁺ 319.1037; found 319.1027.

Mosher ester method.
(R)-4-(Benzyloxy)-1-((4S,4′R,5S)-2,2,2′,2′-tetramethyl-[4,4′-bi(1,3-dioxolan)]-5-yl)but-2-yn-1-yl (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (15a). ¹H NMR (500 MHz, CDCl₃): δ 7.60–7.53 (m, 2H), 7.41–7.27 (m, 8H), 5.93 (dt, J = 1.7, 3.2 Hz, 1H), 4.55 (s, 2H), 4.20 (d, J = 1.7 Hz, 2H), 4.18 (dd, J = 2.9, 7.6 Hz, 1H), 4.15–4.10 (m, 2H), 4.03–3.91 (m, 2H), 3.59 (d, J = 1.0 Hz, 3H), 1.45 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H) ppm.
(R)-4-(Benzyloxy)-1-((4S,4′R,5S)-2,2,2′,2′-tetramethyl-[4,4′-bi(1,3-dioxolan)]-5-yl)but-2-yn-1-yl (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (15b). ¹H NMR (500 MHz, CDCl₃): δ 7.61–7.51 (m, 2H), 7.43–7.27 (m, 8H), 5.87 (dt, J = 1.7, 3.3 Hz, 1H), 4.58 (s, 2H), 4.23 (d, J = 1.7 Hz, 2H), 4.20 (dd, J = 1.7, 12.0 Hz, 1H), 4.11–4.05 (m, 2H), 3.98–3.88 (m, 2H), 3.61 (d, J = 1.0 Hz, 3H), 1.44 (s, 3H), 1.34 (s, 6H), 1.26 (s, 3H) ppm.

Newly created stereogenic center in compound 15 bearing the hydroxyl group was assigned by the syntheses of both the (S)- and (R)-MTPA esters of 15 were achieved using MTPA acid with DCC as the coupling reagent. The chemical shifts of both the (S)- and (R)-MTPA esters of 15 were assigned by ¹H NMR. From the equation given in Fig. 1, the Δδ values were calculated for as many protons as possible. The carbon chain bearing protons showing Δδ negative values should be placed on the left hand side of the model (Fig. 1) whilst that where Δδ has positive values should be placed on the right hand side. From this the center was found to have the R-configuration which thus tentatively establishes the absolute stereochemistry of 15 (Fig. 2).

Fig. 1 Sapinofuranones and L-factor.

Fig. 2 Δδ = (δS − δR) × 10³ for (S)- and (R)-MTPA esters of 15.

Acknowledgements

KSNR thank CSIR, New Delhi for the award of fellowship. GS and KSNR thank CSIR, New Delhi for financial support as part of XII Five Year plan programme under title ORIGIN (CSC-0108).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra21939j

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