Unless otherwise stated, all reactions were conducted in oven-dried glassware under an atmosphere of dry argon. Tetrahydrofuran was distilled over sodium/benzophenone ketyl under argon. Acetonitrile, dichloromethane, DMSO, DMF and toluene were distilled over calcium hydride under argon. All other reagents were used as received. Chromatographic purifications refer to flash chromatography on silica gel. 1H NMR spectra were measured at 250, 300, 360 or 400 MHz using CDCl3 as solvent using residual chloroform (7.26 ppm) as an internal reference. 13C NMR spectra were measured at 62.5, 75 or 90 MHz using residual chloroform (77.1 ppm) as an internal reference. High-resolution mass spectrometry (HRMS) analyses were conducted with electro spray ionization (ESI).

6-Triisopropylsilyloxyhex-1-en-3-one (16): A solution of oxalyl chloride (0.49 mL, 5.75 mmol, 1.5 equiv) in dichloromethane (12 mL) was cooled to −78 °C and DMSO (0.82 mL, 11.49 mmol, 3 equiv) was added over 5 min. After 15 min, a solution of the alcohol 15 [35] (1.044 g, 3.83 mmol) in dichloromethane (5 mL) was added over 5 min. The reaction mixture was stirred for 30 min at −78 °C before addition of triethylamine (2.7 mL, 19.15 mmol, 5 equiv). The cooling bath was removed and the solution was allowed to warm to rt in 30 min. It was then poured into diethyl ether (50 mL) and the solution was successively washed with saturated aqueous CuSO4 solution (4 × 12.5 mL), saturated aqueous NH4Cl solution (3 × 12.5 mL), dried (MgSO4), filtered and concentred under reduced pressure to give a brown oil (1.021 g, 99%). Rf: 0,59 (10% AcOEt/cyclohexane); 1H NMR (300 MHz, CDCl3) δ 6.32 (dd, J = 17.7, 10.2 Hz, 1H), 6.19 (dd, J = 17.7, 1.5 Hz, 1H), 5.78 (dd, J = 10.2, 1.5 Hz, 1H), 3.68 (t, J = 6 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.86–1.77 (m, 2H), 1.00 (m, 21H) ppm; 13C NMR (75 MHz, CDCl3) δ 200.8, 136.7, 127.9, 62.4, 35.9, 27.2, 18.0, 12.0 ppm; HRMS (m/z): [M + Na]+ calcd 293.1907; found, 293.1898.

(3Z)-3-Diethylphosphoryloxy-6-triisopropylsilyloxyhexa-1,3-dien (17): A 0.5 M solution of potassium hexamethyldisilazide in toluene (4.4 mL, 2.22 mmol, 1.2 equiv) was added to a cooled (−78 °C) solution of diethyl chlorophosphate (0.27 mL, 1.85 mmol) in anhydrous THF (7 mL). A solution of the enone 16 (500 mg, 1.85 mmol) in THF (6 mL) was then slowly added. The solution was stirred 30 min at −78 °C, then 1 h at 0 °C and then 1 h at rt, before being poured in diethyl ether (35 mL). The solution was washed with 5% aqueous ammonia solution (18 mL). The aqueous layer was extracted with diethyl ether (3 × 35 mL) and the combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure to give a brown oil. Purification by column chromatography (25% AcOEt/cyclohexane) gave the enol phosphate 17 as a yellow oil (200 mg, 26%). Rf: 0.47 (30% AcOEt/cyclohexane); 1H NMR (360 MHz, CDCl3) δ 6.15 (dd, J = 17.3, 10.8 Hz, 1H), 5.47 (d, J = 17.3 Hz, 1H), 5.29 (dt, J = 7.2, 1.4 Hz, 1H), 5.08 (d, J = 10.8 Hz, 1H), 4.15–4.12 (m, 4H), 3.71 (t, J = 6.5 Hz, 2H), 2.48 (2dt, J = 7.2, 6.5 Hz, 2H), 1.31 (dt, J = 6.8, 1.1 Hz, 6H), 1.01 (m, 21H) ppm; 13C NMR (90 MHz, CDCl3) δ 146.2, 131.9, 118.0, 114.2, 64.4, 62.4, 30.0, 18.0, 16.2, 12.0 ppm; HRMS (m/z): [M + H]+ calcd 407.2377; found, 407.2359.

(6R)-tert-Butyl 5-(diethoxyphosphoryloxy)-6-(2-((triisopropylsilyl)oxy)ethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate (10b): A solution of the enol phosphate 17 (420 mg, 1.03 mmol) in chloroform (1.8 mL) was added to a solution of the Wightman reagent 6 (981 mg, 2.06 mmol, 2 equiv), calcium carbonate (206 mg, 2.06 mmol, 2 equiv) and water (40 µL, 2.06 mmol, 2 equiv) in isopropanol (1.8 mL). The mixture was stirred at rt for 30 h. Water (0.75 mL) was added and the solution stirred for additional 1 h. The pH was adjusted to 8 by addition of saturated aqueous NaHCO3 solution (1,6 mL), and a solution of Boc2O (899 mg, 4.12 mmol, 4 equiv) in chloroform (0.8 mL) was added. The solution was stirred at rt for 64 h and poured into a mixture of water (37 mL) and dichloromethane (74 mL); the layers were separated and the aqueous layer extracted with dichloromethane (3 × 74 mL). The combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure. Purification of the crude product by column chromatography (30% AcOEt/cyclohexane) gave the cycloadduct 10b as a yellow oil (404 mg, 73%). Rf: 0.42 (30% AcOEt/cyclohexane); 1H NMR (360 MHz, CDCl3) δ 5.69 (m, 1H), 4.57 (broad d, J = 9.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 4H), 4.12–4.00 (m, 2H), 3.99–3.82 (m, 2H), 2.03–1.85 (m, 2H), 1.47 (s, 9H), 1.34 (t, J = 7.2 Hz, 6H), 1.05 (m, 21H) ppm; 13C NMR (90 MHz, CDCl3) δ 154.8, 146.8, 105.1, 81.7, 75.2, 64.8, 59.3, 43.7, 33.7, 28.4, 18.1, 16.2, 12.1 ppm; HRMS (m/z): [M + Na]+ calcd 560.2779; found, 560.2775; [α]20D : +5.8 (c 1.0, CH2Cl2); ee: 8% (Whelk-O1, 1 mL/min, 95:5 hexane/EtOH, tr (R) = 14.9 min, tr (S) = 16.2 min).

(6R)-tert-Butyl 5-oxo-6-(2-((triisopropylsilyl)oxy)ethyl)-1,2-oxazinane-2-carboxylate (11b): A solution of the cycloadduct 10b (404 mg, 0.751 mmol) in anhydrous THF (12 mL) was cooled to 0 °C and a 3 M solution of Red-Al® in toluene (1 mL, 3 mmol, 4 equiv) was rapidly added. After stirring 30 min at 0 °C, the reaction was hydrolyzed by addition of an saturated aqueous NH4Cl solution (4 mL). The solution was concentred under reduced pressurre, the residue taken up with dichloromethane (10 mL) and filtered, washing with dichloromethane (3 × 5 mL). The filtrate was concentred under reduced pressure to give a yellow oil (300 mg) consisting in a mixture of the ketone 11b and the over-reduced alcohol. This mixture was carried into the next step without further purification.

DMSO (0.16 mL, 2.241 mmol, 3 equiv) was added dropwide to a cooled (−78 °C) solution of oxalyl chloride (0.1 mL, 1.121 mmol, 1.5 equiv) in dichloromethane (3.4 mL). After stirring 15 min at −78 °C, a solution of the crude product from reduction reaction (300 mg) in dichloromethane (2 mL) was added dropwise. After 30 min at −78 °C, triethylamine (0.52 mL, 3.735 mmol, 5 equiv) was added. The colling bath was removed and the solution stirred at rt for 40 min, before being poured into diethyl ether (45 mL). The solution was succesively washed with saturated aqueous CuSO4 solution (4 × 10 mL) and saturated aqueous NH4Cl solution (3 × 10 mL), then dried (MgSO4), filtered and concentred under reduced pressure. The residue was purified by filtration through a short plug of silica gel, eluting with ethyl acetate. Concentration under reduced pressure gave the pure ketone 11b as an orange oil (255 mg, 84% over two steps). Rf: 0.29 (10% AcOEt/cyclohexane); 1H NMR (250 MHz, CDCl3) δ 4.49 (dd, J = 8.3, 3.8 Hz, 1H), 4.18–4.08 (m, 1H), 3.94 (m, 4H), 2.67 (t, J = 7.0 Hz, 2H), 2.16–2.03 (m, 1H), 1.99–1.85 (m, 1H), 1.51 (s, 9H), 1.05 (m, 21H) ppm; 13C NMR (90 MHz, CDCl3) δ 206.6, 154.9, 85.1, 82.3, 59.0, 45.0, 36.5, 32.2, 28.4, 18.1, 12.1 ppm; HRMS (m/z): [M + Na]+ calcd 424.2490; found, 424.2480; [α]D20 +37.4 (c 0.5, CH2Cl2).

(5S,6R)-5-Ethyl-6-ethynyl-5,6-dihydro-2H-pyran-2-one (21): Caesium fluoride (290 mg, 1.91 mmol, 1.3 equiv) was added to a solution of the lactone 18 [6] (327 mg, 1.47 mmol) in anhydrous acetonitrile (15 mL). The solution was stirred at rt; after 2 h 20 min, additional CsF (112 mg, 0.74 mmol, 0.5 equiv) was added. After a total time of 3 h 30 min, the solution was partioned between diethyl ether (70 mL) and water (35 mL). The layers were separated, the organic layer was washed with saturated aqueous NaCl solution (35 mL). The combined aqueous layers were extracted with diethyl ether (2 × 70 mL). The organic layers were combined, dried (MgSO4), filtered and concentred under reduced pressure. Purification of the residue by column chromatography (25% Et2O/pentane) gave 21 as a yellow oil (171 mg, 77%). Rf: 0.33 (30% Et2O/pentane); 1H NMR (250 MHz, CDCl3) δ 6.79 (dd, J = 9.8, 3.5 Hz, 1H), 6.05 (dd, J = 10.0, 2.0 Hz, 1H), 5.16 (dd, J = 4.8, 2.3 Hz, 1H), 2.68–2.59 (m, 1H), 2.56 (d, J = 2.0 Hz, 1H), 1.86–1.62 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (90 MHz, CDCl3) δ 162.5, 148.8, 120.3, 77.4, 76.6, 70.7, 38.7, 22.6, 10.9 ppm; HRMS (m/z): [M + Na]+ calcd 173.0573; found, 173.0572; [α]D20 +132.0 (c 1.0, CH2Cl2).

(2R,3S,6RS)-3-Ethyl-2-ethynyl-6-methoxy-3,6-dihydro-2H-pyran (19): This compound was prepared according to reference [18].

A solution of the lactone 18 (1.23 g, 5.53 mmol) in anhydrous dichloromethane (10 mL) was cooled to −78 °C and a solution of DIBAL-H in toluene (1.2 M, 6 mL, 7.19 mmol, 1.3 equiv) was added dropwise. The reaction mixture was stirred at −78 °C for 30 min then poured into a NaHCO3 solution (5 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure. The residue (1.3 g) was redissolved in anhydrous methanol (25 mL) and paratoluenesulfonic acid hydrate (53 mg, 0.277 mmol, 0.05 equiv) was added. After stirring 1 h at rt, solid K2CO3 (1.53 g, 11.06 mmol, 2 equiv) was added and the mixture stirred overnight at rt. Diethyl ether (50 mL) was added and the solution washed with water (2 × 50 mL). The organic layer was dried (MgSO4), filtered and carefully concentred under reduced pressure. Purification by column chromatography (5% Et2O/pentane), gave 19 as a colourless oil (866 mg, 94%, 91/9 mixture of stereoisomers). Analytical data were in agreement with literature data [18].

(2R,3S,6RS)-3-Ethyl-2-((E)-2-iodovinyl)-6-methoxy-3,6-dihydro-2H-pyran (20): This compound was prepared according to reference [18].

A solution of the alkyne 19 (300 mg, 1.80 mmol) dans in anhydrous dichloromethane (4.2 mL) was added dropwise to a suspension of Cp2ZrHCl (696 mg, 2.70 mmol, 1.5 equiv) in anhydrous dichloromethane (9 mL). After stirring at rt for 15 min, a solution of iodine (777 mg, 3.06 mmol, 1.7 equiv) in anhydrous dichloromethane (9 mL) was added dropwise until a light brown solution was obtained. The reaction mixture was hydrolyzed by successive addition of a saturated aqueous Na2S2O3 solution (25 mL) and water (9 mL). The layers were separated and the organic layer was washed with water (9 mL). The combined aqueous layers were back-extracted with diethyl ether (2 × 40 mL). The combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure. Purification of the residue by column chromatography (2.5% Et2O/pentane) gave 20 as a yellowish oil (347 mg, 65%, 91:9 mixture of steroisomers). Analytical data were in agreement with literature data [18].

Coupling reaction between vinyl iodide 20 and ketone 11b: A solution of the vinyl iodide 20 (283 mg, 0.962 mmol, 1.8 equiv) in anhydrous toluene (2 mL) was cooled to −78 °C, and a n-butyllithium solution (2.3 M in hexanes, 0.39 mL, 0.909 mmol, 1.7 equiv) was added dropwise. The solution was stirred for 30 min at −78 °C then a solution of ketone 11b (215 mg, 0.535 mmol, 1 equiv) in toluene (3.8 mL) was slowly added. The reaction was stirred at −78 °C for 45 h than slowly warmed to rt over 20 h. The reaction as quenched by addition of a saturated aqueous NH4Cl solution (3.8 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2 × 8 mL) and diethyl ether (2 × 8 mL). The combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure. Purification of the residue by column chromatography (20 to 30% AcOEt/cyclohexane) gave the coupling product 23 as an orange oil, which was carried into the next step without further characterization (140 mg, 46%).

Product 23 was redissolved in 96% EtOH (3.9 mL) and pyridinium para-toluenesulfonate (17 mg, 0.066 mmol, 0.25 equiv) was added. The reaction mixture was stirred at rt for 24 h then neutralized by addition of a few drops of a saturated sodium hydrogen carbonate solution. The solvents were removed under reduced pressure and the residue partioned between ethyl acetate (5 mL) and water (2.5 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (3 × 5 mL) and diethyl ether (5 mL). The combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure to give the crude lactol 24 which was immediately engaged into the next reaction.

A solution of the above lactol (147 mg, 0.265 mmol) in acetone (6 mL) was cooled to 0 °C and a solution of the Jones reagent (2.2 M in water, 0.14 mL, 0.31 mmol, 1.15 equiv) was added. After stirring 15 min at 0 °C, the reaction was quenched by addition of a saturated aqueous sodium hydrogen carbonate solution (9 mL) and isopropanol (1.5 mL). The solvents were removed under reduced pressure and the residue partioned between ethyl acetate (11 mL) and water (5.5 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2 × 11 mL) and diethyl ether (2 × 11 mL). The combined organic layers were dried (MgSO4), filtered and concentred under reduced pressure. Purification of the residue by column chromatography (25 to 40% AcOEt/cyclohexane) gave first the protected lactone 25 as a sticky yellow oil (42 mg, 29% over two steps), further elution with 100% AcOEt gave the unprotected alcohol 26 (18 mg, 17%).

tert-Butyl (6R)-5-((E)-2-((2S,3S)-3-ethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)vinyl)-5-hydroxy-6-(2-((triisopropylsilyl)oxy)ethyl)-1,2-oxazinane-2-carboxylate (25): Data for 25: Rf: 0.10 (30% AcOEt/cyclohexane); 1H NMR (360 MHz, CDCl3) δ 6.97 (dd, J = 9.7, 5.5 Hz, 1H), 6.05 (d, J = 9.7 Hz, 1H), 5.95 (dd, J = 15.5, 4.2 Hz, 1H), 5.82 (dd, J = 15.5, 1.4 Hz, 1H), 5.02 (ddd, app td, J = 4.2, 4.2, 1.4 Hz, 1H), 3.99–3.90 (m, 3H), 3.76–3.69 (m, 1H), 3.55 (td, J = 13.1, 2.7 Hz, 1H), 2.44–2.37 (m, 1H), 1.90–1.70 (m, 2H), 1.67–1.57 (m, 3H), 1.49 (s, 9H), 1.45–1.39 (m, 1H), 1.05 (m, 21H), 0.93 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (62,5 MHz, CDCl3) δ 163.9, 155.1, 150.1, 135.5, 125.1, 121.0, 82.6, 81.8, 79.8, 70.8, 59.0, 42.3, 39.4, 35.9, 31.3, 28.4, 21.8, 18.1,12.0,11.1 ppm; HRMS (m/z): [M + Na]+ calcd 576.3327; found, 576.3330; [α]D20 +86.3 (c 1.1, CH2Cl2).

tert-Butyl (6R)-5-((E)-2-((2S,3S)-3-ethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)vinyl)-5-hydroxy-6-(2-hydroxyethyl)-1,2-oxazinane-2-carboxylate (26): Data for 26: Rf: 0.38 (80% AcOEt/cyclohexane); 1H NMR (400 MHz, acetone-d6) δ 7.09 (dd, J = 10.0, 5.2 Hz, 1H), 6.02 (dd, J = 15.6, 5.5 Hz, 1H), 5.97 (dd, J = 10.0, 1.2 Hz, 1H), 5.85 (dd, J = 15.6, 1.2 Hz, 1H), 5.06 (ddd, J = 5.5, 4.0,1.2 Hz, 1H), 4.27 (s, exchangeable with D2O, 1H), 3.96–3.91 (m, 2H), 3.74–3.66 (m, 2H), 3.63–3.59 (m, 1H), 2.61–2.53 (m, 1H), 1.95–1.83 (m, 2H), 1.73–1.67 (m, 1H), 1.67–1.55 (m, 2H), 1.49 (s, 9H), 1.47–1.38 (m, 1H), 0.94 (t, J = 7.6 Hz, 3H) ppm; 13C NMR (100 MHz, acetone-d6) δ 163.83, 156.0, 151.0, 137.2, 126.1, 121.2, 84.0, 81.8, 80.7, 71.1, 59.5, 42.7, 40.0, 36.3, 31.3, 28.4, 22.2, 11.2 ppm; HRMS (m/z): [M + Na]+ calcd 420.1993; found, 420.1970.