A Diastereoselective Synthetic Approach towards the Synthesis of Berkeleylactone F and Its 4-epi-Derivative

Abstract

A diastereoselective approach to the synthesis of berkeleylactone F is presented. The synthetic strategy is initiated with commercially available (R)-glycidol, 1,6-heptadiyne, and (R)-(+)-methyl lactate. The key feature of the approach is directional functionalization at both terminals of 1,6-heptadiyne.

Key words

macrolide - epoxide - ring opening - heptadiyne

Publication History

Received: 27 August 2020

Accepted after revision: 14 September 2020

Article published online:
07 October 2020

• References and Notes

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• 13 Synthesis of (S)-1-(Benzyloxy)deca-4,9-diyn-2-ol (4): To a solution of 1,6-heptadiyne (0.5 mL, 4.57 mmol, 1.0 equiv) in anhydrous THF (10 mL) at –78 °C under argon was added n-BuLi (4.6 mL, 4.6 mmol, 1.0 M in hexane 1 equiv). The resulting mixture was stirred for 30 min at this temperature and a solution of epoxide 3 (250 mg, 1.52 mmol, 0.33 equiv, dissolved in anhydrous THF, 5 mL) was added dropwise, followed by rapid addition of BF₃·Et₂O (freshly distilled, 0.6 mL, 6.66 mmol, 1.45 equiv) The reaction mixture was stirred for 1.5 h and then quenched with saturated aqueous NH₄Cl solution and extracted with Et₂O (3 × 20 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude material was purified by column chromatography on silica gel (10% EtOAc in pet ether (PE)) to give pure alcohol 4 (0.88 g, 3.43 mmol 75%) as a yellow oily liquid. TLC: R_f 0.76 (10% EtOAc in PE). IR: 1096, 1428, 1633, 2115, 2946, 3453 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.71 (p, J = 7.0 Hz, 2 H), 1.99 (t, J = 2.6 Hz, 1 H), 2.28–2.33 (m, 4 H), 2.42–2.46 (m, 2 H), 3.52 (dd, J ₁,₂ = 3.92 Hz, J ₁,₃ = 9.52 Hz, 1 H), 3.61 (dd, J ₁,₂ = 6.68 Hz, J ₁,₃ = 9.52 Hz, 1 H), 3.92–3.98 (m, 1 H), 4.59 (s, 2 H), 7.30–7.40 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.5, 17.8, 23.9, 27.7, 68.8, 69.2, 72.9, 73.4, 76.4, 81.4, 83.5, 127.8, 128.3, 137.9. HRMS: m/z [M + Na]⁺ calcd for C₁₇H₂₀O₂Na: 279.1361; found: 279.1361.
• 14 Synthesis of (5S,14S,15R)-5-((Benzyloxy)methyl)-15,17,18,18-pentamethyl-2,4,16-trioxa-17-silanonadeca-7,12-diyn-14-ol (6): (R)-(+)-Methyl lactate (1.0 g, 9.60 mmol, 1 equiv), was dissolved in anhydrous DMF (5 mL), and imidazole (1.06 g, 15.57 mmol, 1.6 equiv) was added. The solution was cooled in an ice bath and TBSCl (1.45 g, 9.60 mmol, 1 equiv) was added slowly in portions. After the completion of addition, the ice bath was allowed to melt gradually overnight. After 18 h, the reaction mixture was diluted with water (3 mL) and hexanes (10 mL). The aqueous phase was separated and extracted with hexanes (60 mL), and the combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation to afford the TBS ether (1.6 g, 7.33 mmol, 76%) as a colorless liquid, which was used without purification. The above prepared TBS protected (R)-(+)-methyl lactate (1.00 g, 4.58 mmol, 1 equiv), in hexanes (20 mL), was cooled to –78 °C, DIBAL-H (4.7 mL, 1.0 M in hexanes, 4.7 mmol, 1.0 equiv) was added dropwise and the mixture was stirred for 45 minutes at –78 °C. The reaction mixture was then quenched by addition of MeOH (1.0 mL) and stirred for 15 min at –78 °C. The cold solution was transferred to a round-bottom flask containing saturated aqueous Rochelle salt (10 mL) and the resulting mixture was vigorously stirred for 30 min. The aqueous phase was separated and extracted with hexanes, and the combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the aldehyde (0.70 g, 3.66 mmol, 80%) as a colorless liquid. To a solution of compound 5 (0.90 g, 3.0 mmol, 1 equiv) in anhydrous THF (15 mL), n-BuLi (.3.0 mL, 3.0 mmol, 1 M in THF, 1 equiv) was added dropwise at –78 °C. The solution was stirred for 30 min at the same temperature and then freshly prepared aldehyde was added to the reaction mixture dropwise (0.70 g, 3.66 mmol, 1.2 equiv over 30 mins) and the mixture was stirred for 2.5 h. The reaction mixture was quenched with saturated aqueous NH₄Cl and the organic phase was separated and evaporated under reduced pressure. The aqueous layer was extracted with EtOAc and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated by rotary evaporation. Column chromatographic purification (10% EtOAc in PE) of the resultant crude residue provided pure alcohol 6 (1.20 g, 2.45 mmol, 80%) as a pale-yellow liquid. TLC: R_f 0.67 (5% EtOAc in PE). IR: 1252, 1494, 1628, 2245, 2985, 3470 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.11 (s, 3 H), 0.12 (s, 3 H), 0.92 (s, 9 H), 1.24 (d, J = 6.24 Hz, 3 H), 1.59 (brs, 1 H), 1.68 (p, J = 6.43 Hz, 2 H), 2.24–2.37 (m, 4 H), 2.48–2.53 (m, 2 H), 3.41 (s, 3 H), 3.62–3.64 (m, 2 H), 3.86–3.94 (m, 2 H), 4.28 (m, 1 H), 4.59 (s, 2 H), 4.77 (s, 2 H), 7.30–7.37 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = –4.7, –4.4, 17.9, 22.2, 25.8, 27.9, 55.5, 67.1, 71.2, 71.6, 73.4, 74.8, 78.6, 80.9, 85.8, 95.9, 127.6, 127.6, 128.4S, 138.2. HRMS: m/z [M + Na]⁺ calcd for C₂₈H₄₄O₅SiNa: 511.7212; found: 511.7211.