Asymmetric Construction of Highly Functionalized Cyclobutanones Bearing Three Contiguous Stereogenic Centers by an Amino Acid Salt-Catalyzed Desymmetrization Reaction

Abstract

We report an amino acid salt-catalyzed direct desymmetrization of 3-substituted cyclobutanones through a direct aldol reaction under mild reaction conditions. The developed method provides an array of highly functionalized cyclobutanones bearing three contiguous stereogenic centers in high yields and stereoselectivities with varied functional-group compatibility. Furthermore, the obtained adducts can be smoothly converted into polyfunctional 1,4-butyrolactones with maintained enantioselectivity.

Key words

amino acid salts - desymmetrization - cyclobutanones - asymmetric catalysis - aldol reaction

Publication History

Received: 13 February 2022

Accepted after revision: 17 May 2022

Article published online:
13 July 2022

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• 11 Ethoxy 3-Oxocyclobutanecarboxylates 4a–s; General Procedure: A clean and dry Schlenk tube was charged with catalyst 1f (2.5–10 mol %) and the appropriate oxo ester 3 (0.2 mmol, 1 equiv) in anhyd DMA (0.3 mL), and the mixture was stirred vigorously at 0 °C or r.t. for 20 min. Subsequently, the appropriate cyclobutanone 2 (1.0 mmol, 5 equiv) was added and the resulting mixture was stirred at 0 °C or r.t. for 72–140 h until the reaction was complete. The mixture was then purified by flash column chromatography [silica gel, PE–EtOAc (10:1 to 8:1)]. Ethyl 2-[(2E)-1-Hydroxy-1-(isopropoxycarbonyl)-3-phenylprop-2-en-1-yl]-3-oxocyclobutanecarboxylate (4a) Prepared according to the general procedure and purified by flash column chromatography [silica gel, PE–EtOAc (10:1)] as a colorless liquid; yield: 64.1 mg (89%, 94% ee, dr 96:4); [α]_D ²⁶ –71.7 (c 0.605, EtOAc). HPLC [Daicel CHIRALPAK AD-H, hexane–i-PrOH (97:3), 1.0 mL/ min, 25 °C]: t _R (major) = 19.202 min, t _R (minor) = 21.953 min. ¹H NMR (500 MHz, CDCl₃): δ = 7.37 (d, J = 7.4 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 2 H), 7.26–7.23 (m, 1 H), 6.89 (d, J = 15.8 Hz, 1 H), 6.11 (d, J = 15.7 Hz, 1 H), 5.18 (m, 1 H), 4.19 (m, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 3.73 (s, 1 H), 3.36–3.24 (m, 2 H), 3.15 (m, 1 H), 1.35 (d, J = 6.3 Hz, 3 H), 1.30 (d, J = 6.3 Hz, 3 H), 1.09 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃) : δ = 202.5, 173.9, 172.1, 136.1, 131.8, 128.6, 128.1, 126.8, 126.5, 75.4, 71.5, 69.9, 61.3, 49.1, 30.0, 21.7, 21.6, 14.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₅O₆: 361.1646; found: 316.1650. Ethyl 2-[(2E)-3-(2-Fluorophenyl)-1-hydroxy-1-(isopropoxycarbonyl)prop-2-en-1-yl]-3-oxocyclobutanecarboxylate (4b) Prepared according to the general procedure and purified by flash column chromatography [silica gel, PE–EtOAc (10:1)] as a colorless liquid; yield: 67.4 mg (89%, ee 91%; dr 94:6), [α]_D ²⁶ –100.4 (c 0.544, EtOAc). HPLC [Daicel CHIRALPAK AD-H, hexane–i-PrOH (95:5), 1.0 mL/min, 25 °C]: t _R (major) = 14.812 min, t _R (minor) = 17.445 min. ¹H NMR (500 MHz, CDCl₃): δ = 7.39 (t, J = 7.6 Hz, 1 H), 7.23 (m, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.03 (m, 2 H), 6.22 (d, J = 15.9 Hz, 1 H), 5.19 (m, 1 H), 4.18 (d, J = 6.8 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.71 (s, 1 H), 3.38–3.25 (m, 2 H), 3.15 (m, 1 H), 1.35 (d, J = 6.2 Hz, 3 H), 1.30 (d, J = 6.2 Hz, 3 H), 1.11 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 202.4, 173.9, 172.0, 161.5, 159.5, 129.5, 129.4, 129.3, 129.3, 128.2, 128.1, 124.7, 124.6, 124.1, 124.1, 124.0, 123.9, 115.9, 115.7, 75.6, 71.5, 69.9, 61.3, 49.1, 30.0, 21.7, 21.6, 13.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₃FNaO₆: 401.1371; found: 401.1384.