Compound 21b

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Compound data: 1H NMR

Compound data: 13C NMR

Compound data: Crystallographic data

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

To an oven-dried round-bottomed flask was added zinc powder (2.30 g, 35.0 mmol, 25 equiv) and LiCl (300 mg, 7.00 mmol, 5.0 equiv) with a large bore vacuum adapter with Teflon lined seal for addition of liquids via syringe. The flask and solids were then carefully flame-dried under high vacuum (using a vacuum/N₂ double manifold) by repeated heating and cooling cycles with swirling of the solids to avoid the solids from clumping. After the final cycle of heating, the solids were allowed to cool for 3 min under N₂, and then anhydrous THF (20.0 mL) was slowly and carefully added with vigorous stirring. After addition of THF, 1,2-dibromoethane (0.12 mL, 1.40 mmol, 1.00 equiv) was added which sometimes led to an exotherm simultaneous with rapid gas evolution, which needs to be controlled. Pressure fluctuations generated upon addition of 1,2-dibromoethane were controlled by momentarily switching the manifold from N₂ to vacuum. [Note: If gas evolution was not observed upon addition of 1,2-dibromoethane, a heat gun was employed to initiate gas evolution]. The solution was allowed to cool at ambient temperature over ~5 min before being further cooled to 0 ºC. A solution of keto lactone (–)-9 (215 mg, 1.40 mmol, 1.00 equiv) in THF (1.00 mL) was added dropwise by syringe followed by slow addition of allyl chloride 19 (Harvey, N. L., Krysiak, J., Chamni, S., Cho, S. W., Sieber, S. A. and Romo, D. Chem. Eur. J., 2015, 21, 1425-1428) (2.22 g, 14.0 mmol, 10.0 equiv) in THF (4.0 mL) via syringe pump at a rate of 1.0 mL/h. During this time, the reaction mixture was allowed to slowly warm to ambient temperature (23 ºC). The reaction mixture was then quenched with saturated NH₄Cl solution (100 mL). The organic phase was separated and the aqueous phase was further extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (200 mL), dried with MgSO₄, and concentrated under reduced pressure. Purification by automated flash chromatography (5→60% EtOAc/hexanes) afforded dimethyl cyclohexenol lactone 21b (318 mg, 82% yield) as an inseparable mixture of two diastereomers (1:1 dr, based on ¹H-NMR analysis of the crude mixture). White crystalline solid, m.p. 161.2-163.7 ºC (recrystallized from pentane); TLC (EtOAc/hexanes, 1:1 v/v), R_f = 0.44; Absolute stereochemistry was assigned based on X-ray analysis using anomalous dispersion (Supplementary Fig. 3). ¹H NMR (500 MHz, CDCl₃) δ 5.89 (ddd, J = 9.9, 6.3, 2.1 Hz, 1H), 5.52 (dd, J = 10.2, 1.8 Hz, 1H), 4.24 (dt, J = 9.0, 4.5 Hz, 1H), 3.93 (dd, J = 8.9, 4.3 Hz, 1H), 2.75 (tt, J = 12.0, 6.1 Hz, 1H), 2.64 (q, J = 5.5 Hz, 1H), 2.14 – 2.02 (m, 1H), 2.05 – 1.92 (m, 1H), 1.86 – 1.64 (m, 4H), 1.63 – 1.50 (m, 1H), 1.45 – 1.21 (m, 3H), 1.10 (dtd, J = 13.6, 2.7, 1.3 Hz, 1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 178.67, 178.63, 130.28 (2), 130.23 (2), 75.46, 75.44, 72.09, 71.97, 43.47, 43.42, 42.90, 42.85, 39.04 (2), 38.25 (2), 33.23, 33.22, 32.34, 32.33, 30.91 (2), 30.59, 30.58, 27.25, 27.19, 25.98 (2), 22.16 (2), 18.79, 18.69; IR (thin film): 3518, 2951, 2867, 1766 cm^–1; HRMS (ESI+) m/z calcd for C₁₇H₂₇O₃ [M+H]⁺: 279.1960, found: 279.1963.