[4+1] Cyclizations to Enantiopure Multifunctional Cyclopentanes from d-Glucose Using Formyl Dianion Synthons

In memory of Albert Jakob Eschenmoser

Abstract

The [4+1] cyclization of a sugar-based epoxytosylate with various C1 dianion equivalents provide highly functionalized homochiral cyclopentane derivatives. For these, a follow-up chemistry was developed to provide various cyclopentane building blocks as starting points for natural product syntheses. The [4+1] domino protocol relies on a 1,4-Brook rearrangement, which is essential for generating the second carbanion.

Key words

Brook rearrangements - cyclizations - domino reactions - ex-chiral pool synthesis - prostaglandins

• References and Notes

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• 9 [4+1] Cyclization Protocols towards Cyclopentanols 12 and 13: Cyclopentanol (12): Under a nitrogen atmosphere, the (bis-methylsulfanyl-methyl)trimethylsilane 4a (4.40 g, 24.4 mmol, 1.4 equiv) was dissolved in anhydr. THF (75 mL) and cooled to –78 °C. At this temperature, n-BuLi (2.5 M in hexane, 9.8 mL, 24.4 mmol, 1.4 equiv) was added slowly. Over a period of 2 h, the solution was warmed to 0 °C and kept at this temperature for an additional 1 h. The pale-yellow solution (indicating carbanion formation) was again cooled to –78 °C and a solution epoxyalkyl-p-tosylate 9 (6.21 g, 17.4 mmol, 1.0 equiv) in anhydr. THF (50 mL) was slowly added by using a syringe pump. The reaction mixture spontaneously became intense orange-yellow. Stirring was continued at 0 °C for 12 h, during which time the mixture became green. Subsequently, stirring was continued for another 3 h at room temperature, and the color changed to orange, which was taken as an indication that epoxide 9 was completely consumed. The reaction mixture was again cooled to 0 °C, and solid TBAF (6.31 g, 20.0 mmol, 1.15 equiv) was added in small portions to cleave the resulting silyl ether, which was accompanied by the occurrence of an intense orange color. After warming to room temperature over a period of 15 minutes, diethyl ether and water were added to the reaction mixture and stirring was continued for an additional 30 min. After phase separation, the organic phase was washed once each with water and brine. The organic phase was dried over Na₂SO₄, concentrated in vacuo and the crude product was purified by column chromatographic purification (silica; petroleum ether/ethyl acetate 5:1 to 2:1) to yield the title compound 12 (4.23 g, 14.5 mmol, 83%) as white solid; mp 110 °C; R_f = 0.33 (petroleum ether/ethyl acetate 2:1); [α]_D ²⁰ +46.7° (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃, CHCl₃ = 7.26 ppm): δ = 5.86 (d, J = 3.6 Hz, 1 H, 7-H), 5.03 (d, J = 3.6 Hz, 1 H, 6-H), 4.80 (dd, J = 5.3, 4.7 Hz, 1 H, 4-H), 4.42 (dddd, J = 10.6, 6.0, 4.7, 3.0 Hz, 1 H, 3-H), 2.72 (d, J = 5.3 Hz, 1 H, 5-H), 2.32 (dd, J = 13.0, 6.0 Hz, 1 H, 2-H), 2.29 (d, J = 10.6 Hz, 1 H, OH), 2.10 (s, 3 H, SMe), 2.05 (s, 3 H, SMe), 1.71 (dd, J = 13.0, 10.6 Hz, 1 H, 2-H´), 1.52 (s, 3 H, acetonide), 1.37 (s, 3 H, acetonide). ¹³C NMR (100 MHz, CDCl₃, CDCl₃ = 77.0 ppm): δ = 112.3 (q, acetonide), 106.5 (t, C-7), 85.3 (t, C-6), 83.9 (t, C-4), 72.2 (t, C-3), 62.2 (q, C-1), 58.4 (t, C-5), 43.7 (s, C-2), 27.6 (p, acetonide), 27.0 (p, acetonide), 13.0 (p, SMe), 12.9 (p, SMe). HRMS (ESI-QTOF): m/z [M + Na]⁺ calcd. for C₁₂H₂₀O₄NaS₂: 315.0701; found: 315.0696. Cyclopentanol (13): The synthesis of 13 was carried out as described above for the preparation of cyclopentanol 12. The reagents [1,3]dithiane-2-yl-trimethylsilane 4b (1.35 mL, 7.30 mmol, 1.3 equiv) and n-BuLi (2.5 M in hexane, 2.7 mL, 6.7 mmol, 1.2 equiv) were reacted with epoxytosylate 9 (2.00 g, 5.61 mmol, 1.0 equiv). After hydrolysis in the presence of TBAF (2.0 g, 6.45 mmol, 1.15 equiv), dithiane 13 (1.30 g, 4.26 mmol 76%) was obtained as a white solid; mp 112 °C; R_f = 0.20 (petroleum ether/ethyl acetate = 2:1); [α]_D ²⁰ +24.0° (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃, CHCl₃ = 7.26 ppm): δ = 5.82 (d, J = 3.6 Hz, 1 H, 7-H), 5.06 (d, J = 3.6 Hz, 1 H, 6-H), 4.83 (dd, J = 5.3, 4.7 Hz, 1 H, 4-H), 4.39 (dddd, J = 10.6, 10.5, 6.1, 4.7 Hz, 1 H, 3-H), 3.16 (d, J = 5.3 Hz, 1 H, 5-H), 2.96-2.79 (m, 4 H, dithiane), 2.52 (dd, J = 13.0, 6.1 Hz, 1 H, 2-H), 2.36 (d, J = 10.6 Hz, 1 H, OH), 2.12-1.95 (m, 2 H, dithiane), 1.85 (dd, J = 13.0, 10.5 Hz, 1 H, 2-H´), 1.53 (s, 3 H, acetonide), 1.37 (s, 3 H, acetonide). ¹³C NMR (100 MHz, CDCl₃, CDCl₃ = 77.0 ppm): δ = 112.3 (q, acetonide), 106.5 (t, C-7), 85.3 (t, C-6), 83.9 (t, C-4), 71.8 (t, C-3), 59.3 (t, C-5), 51.2 (q, C-1), 46.5 (s, C-2), 28.2 (s, dithiane), 28.0 (s, dithiane), 27.6 (p, acetonide), 27.0 (p, acetonide), 24.8 (s, dithiane). HRMS (ESI-LCT): m/z [M + Na + acetonitrile]⁺ calcd for C₁₅H₂₃NO₄NaS₂: 368.0966; found: 368.0965. The configuration of the newly formed stereogenic center was determined by NOE measurements after alcohol 14 was transformed into the corresponding pivaloate ester. For details see the Supporting Information.
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