Compound 2a

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Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

General Procedure 2: A dry vial or round bottomed flask containing a stir bar was charged with ligand 3f (105 mg, 0.301 mmol), sealed with a rubber septum and flushed with nitrogen for 10 min. The septum was pierced with a short needle and the ligand was dried azeotropically three times with benzene (0.5 mL) under heating (using a sandbath at 50-60 °C) and stirring in a well-vented fume hood (vacuum can be used, but care should be taken to avoid mechanical losses of the foaming solution). Meanwhile, a dry vial was charged with the appropriate substrate 1 (0.134 mmol), sealed with a rubber septum and flushed with nitrogen for 10 min. Separately, a solution of MeOH in THF (110 µL/mL, 2.72M) was prepared under nitrogen. The aforementioned azeotroped ligand was cooled to room temperature and the needle was removed, the ligand was dissolved in THF (0.3 mL), and SmI₂ (0.1M in THF, 2.95 mL, 0.295 mmol) was added dropwise with gentle stirring, during which the solution turned to a deep green colour. MeOH in THF (110 µL of 2.72M solution, 0.295 mmol) was added dropwise, the green solution was stirred at room temperature for 1 min then slowly cooled to –70 °C using an immersion cooler (fast cooling typically results in the detrimental precipitation of an unidentified solid). The nitrogen flushed substrate 1 was dissolved in THF (1 mL) and the substrate solution was added dropwise to the chiral Sm(II) reagent solution at –70 °C. The mixture was then slowly warmed to the appropriate temperature and stirred until full conversion of the starting material was evident by TLC. The reaction was quenched by opening to air and stirred until complete discolouration was observed. Saturated aqueous sodium thiosulfate (0.5 mL) was added, the mixture was diluted with CH₂Cl₂ (10 mL) and poured into a saturated aqueous solution of sodium potassium tartrate (15 mL). Layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 x 5 mL). The combined organic layers were washed with brine (2 mL), dried over MgSO₄ and concentrated. The crude mixture was purified by column chromatography (hexane/EtOAc mixtures) to afford the title compound 2 and recycled ligand 3f.

Prepared according to general procedure 2 described above from methyl 2-acetyl-2-(but-3-en-1-yl)hex-5-enoate 1a (30 mg, 0.134 mmol). After a reaction time of 30 h at –50 °C, the crude product (ca. 30:1 dr according to ¹H NMR analysis) was purified by column chromatography (hexane/EtOAc 98:2 to 96:4 to elute the product, then 80:20 to elute ligand 3f) to afford diastereopure 2a as a colorless oil (25 mg, 82%, er: 89:11). The minor cis diastereomer was separated at this stage. ¹H NMR (400 MHz, CDCl₃) δ5.82–5.71 (m, 1 H, CH=CH₂), 5.00 (d, 1 H, J = 17.0 Hz, CH=CH_cisH_trans), 4.94 (d, 1 H, J = 10.3 Hz, CH=CH_cisH_trans), 3.72 (s, 3 H, CO₂CH₃), 3.46 (s, 1 H, OH), 2.40–2.31 (m, 1 H, CHCH₂CH_aH_bCCO₂CH₃), 2.05–1.83 (m, 5 H, CH₂CH=CH₂ + CH₃CH + CH_aH_bCH₂CH=CH₂ + CH₃CHCH_aH_b), 1.56–1.41 (m, 2 H, CH_aH_bCH₂CH=CH₂ + CHCH₂CH_aH_bCCO₂CH₃), 1.16–1.08 (m, 1 H, CH₃CHCH_aH_b), 1.06 (s, 3 H, CH₃COH), 0.94 (d, 3 H, J = 6.5 Hz, CH₃CH); ¹³C NMR (100 MHz, CDCl₃) δ177.9 (CO₂CH₃), 138.3 (CH=CH₂), 114.7 (CH=CH₂), 82.3 (COH), 59.0 (CCO₂CH₃), 52.0 (CO₂CH₃), 43.3 (CH₃CH), 33.6 (CH₂CH₂CH=CH₂), 30.3 (CH₂CCO₂CH₃), 30.0 (CH₂CH=CH₂), 27.8 (CH₃CHCH₂), 17.6 (CH₃COH), 14.6 (CH₃CH); IR ν_max (neat/cm^-1): 3480, 2954, 2873, 2346, 1722, 1641, 1449, 1378, 1324, 1278, 1199, 1123, 1064, 994, 910, 811; HRMS (ESI) calcd for C₁₃H₂₂O₃Na, [M+Na]⁺: 249.1461, found 249.1454. [α]²²_D = +15.3 (c = 0.35, CH₂Cl₂).

Enantiomeric purity of the product (major diastereomer) was determined by GC analysis (Chiraldex^® G-TA 30 m x 0.25 mm column, isothermal run at 100 °C, flow rate = 1.0 mL/min, retention time: 104.8 min (major), 108.6 min (minor); er: 89:11.