Rapid Library Synthesis of Amphiphiles Based On a Dioxinone Scaffold and Identification of Nonlamellar Liquid Crystals

Abstract

Linear and branched amphiphiles with different lengths of lipids and different numbers of hydroxyl groups were rapidly synthesized based on a dioxinone scaffold. The liquid crystalline (LC) properties of the synthesized amphiphiles in excess water were investigated by polarizing optical microscopy and small-angle X-ray scattering (SAXS) analysis. Novel β-keto ester based amphiphiles that formed non-lamellar, inverted LC phases were identified.

Key words

multicomponent reaction - combinatorial chemistry - alkylation - nucleophilic addition - palladium

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• 18 General Procedure for the Preparation of Alkylated Dioxinones: To a stirred solution of alcohol 1, 2, or 3 (1.00 equiv) in anhyd THF was added a solution of PBr₃ (0.400 equiv) in anhyd THF dropwise at 0 °C under an argon atmosphere. After being stirred at the same temperature for 30 min, the reaction mixture was poured into H₂O, also at 0 °C. The aqueous layer was extracted with two portions of Et₂O. The combined extract was washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was used in the next reaction without further purification. To a stirred solution of (i-Pr)₂NH (2.40 equiv) in anhyd THF was added n-BuLi (1.60 M solution in hexane, 2.20 equiv) dropwise at –78 °C under an argon atmosphere. After being stirred at 0 °C for 30 min, 2,2,6-trimethyl-1,3-dioxin-4-one (7; 2.00 equiv) in anhyd THF was added dropwise at –78 °C under an argon atmosphere. After being stirred at 0 °C for 30 min, CuBr·Me₂S (1.00 equiv) in anhyd THF was added at –78 °C under an argon atmosphere. After being stirred at 0 °C for 30 min, crude alkyl bromide 4, 5, or 6 in anhyd THF was added dropwise at –78 °C under an argon atmosphere. After being stirred at 0 °C, the reaction mixture was poured into sat. aq NH₄Cl at 0 °C. The aqueous layer was extracted with three portions of Et₂O. The combined extract was washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give products 8, 9, or 10 as a mixture of isomers. General Procedure for the Preparation of β-Keto Esters: To stirred solutions of dioxinone 7, 8, 9, or 10 (1.00 equiv), solutions of alcohol 11, 12, or 13 in anhyd toluene were added at r.t. under an argon atmosphere. After being stirred at 130 °C, the reaction mixtures were cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give products 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 as a mixture of E- and Z-isomers. General Procedure for the Preparation of Branched Lipids: To stirred solutions of β-keto ester 14, 15, 16, 17, or 18 (1.00 equiv) and geranylmethylcarbonate (24; 1.0 or 2.5 equiv) in anhyd THF were added Pd₂(dba)₃ (0.0250 equiv) and dppe (0.100 equiv) at r.t. under an argon atmosphere. After being stirred at 60 °C, the reaction mixtures were cooled, filtered through Celite and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give products 25, 26, 27, 28, 29, 30, 31, 32, or 33 as a mixture of E- and Z-isomers. General Procedure for Acidic Deprotection: To a stirred solution of protected alcohols (1.00 equiv) in THF–H₂O (4:1) was added TFA (1.10–2.00 equiv) at r.t. under an argon atmosphere. After being stirred at 50 °C or 60 °C, the reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the desired amphiphiles. 48 (major isomer): ¹H NMR (400 MHz, CDCl₃): δ = 5.15 (quint, J = 4.8 Hz, 1 H), 5.02–5.09 (m, 4 H), 4.88 (t, J = 6.6 Hz, 2 H), 3.79 (d, J = 4.8 Hz, 4 H), 3.66–3.73 (br, 8 H), 3.48 (br, 2 H), 2.76–2.88 (br, 4 H), 2.58 (br s, 4 H), 2.46 (t, J = 7.3 Hz, 2 H), 2.23 (dt, J = 7.3, 7.3 Hz, 2 H), 1.93–2.05 (m, 12 H), 1.67 (s, 9 H), 1.59–1.60 (m, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 207.7, 171.8, 139.2, 136.5, 131.6, 131.4, 124.1, 123.9, 122.4, 117.7, 81.1, 72.2, 67.9, 63.5, 62.4, 62.2, 39.9, 39.7, 39.3, 30.2, 26.7, 26.5, 25.6, 22.2, 17.7, 16.3, 16.0. FT-IR (KBr): 3405, 2926, 1710, 1445, 1377, 1277, 1217, 1124, 1050, 833 cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd. for C₄₃H₇₃O₉: 733.5255; found: 733.5240.