The search for new amphiphiles: synthesis of a modular, high-throughput library

Summary Amphiphilic compounds are used in a variety of applications due to their lyotropic liquid-crystalline phase formation, however only a limited number of compounds, in a potentially limitless field, are currently in use. A library of organic amphiphilic compounds was synthesised consisting of glucose, galactose, lactose, xylose and mannose head groups and double and triple-chain hydrophobic tails. A modular, high-throughput approach was developed, whereby head and tail components were conjugated using the copper-catalysed azide–alkyne cycloaddition (CuAAC) reaction. The tails were synthesised from two core alkyne-tethered intermediates, which were subsequently functionalised with hydrocarbon chains varying in length and degree of unsaturation and branching, while the five sugar head groups were selected with ranging substitution patterns and anomeric linkages. A library of 80 amphiphiles was subsequently produced, using a 24-vial array, with the majority formed in very good to excellent yields. A preliminary assessment of the liquid-crystalline phase behaviour is also presented.


Synthesis of double-chain tails Prop-2-yn-1-yl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (2) [1]
To a stirred solution of 2,2-bis(hydroxymethyl)propionic acid (1.0 equiv) in DMF (5 mL/mmol) was added KOH (1.1 equiv). After stirring for 2 h at 100 °C, propargyl bromide (1.0 equiv) was added dropwise over 30 min. The solution was heated at 80 °C for 18 h, before the reaction mixture was cooled, filtered and concentrated in vacuo. The crude product was diluted with ether and subsequently washed with brine and sat. aq. NaHCO 3 solution. The organic fragment was dried over MgSO 4 and concentrated in vacuo to give the title compound (4.06 g, 69%) without the need for further purification. Spectroscopic data matched with the literature data.

General procedure A
To a stirred solution of carboxylic acid (2.5 equiv) and DMAP (0.2 equiv) in DCM at r.t. (5 mL/mmol) was added diisopropylcarbodiimide (2.2 equiv). Once dissolved, diol 2 (1.0 equiv) was added and stirring continued for 18 h. The reaction mixture was then diluted with DCM and washed with 1.0 M aq. HCl, sat. aq. NaHCO 3 solution and brine, dried over MgSO 4

and concentrated in vacuo
to give the crude material.

General procedure B
To a stirred solution of carboxylic acid (3.5 equiv) and DMAP (0.3 equiv) in DCM at rt (5 mL/mmol) was added diisopropylcarbodiimide (3.3 equiv). Once dissolved, propargyl amide 15 (1.0 equiv) was added and stirring continued for 18 h. The reaction was then diluted with DCM and washed with 1.0 M aq. HCl, sat. aq. NaHCO 3 solution and brine, dried over MgSO 4 and concentrated in vacuo to give the crude product.

Synthesis of sugar head groups
(2S,3R,4S,5R)-tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (31) [2] To a stirred suspension of anhydrous sodium acetate (4.36 g, 53.2 mmol) in acetic anhydride (25 mL) heated at reflux was added D(+)-xylose (2.0 g, 13.3 mmol). The reaction mixture was heated for 3 h before cooling to 100 °C and immediately transferred to an ice-water mixture and stirred vigorously until a gum formed. After decanting the aqueous portion, the gum was dissolved in DCM and washed successively with sat. aq. NaHCO 3 solution and brine. The organic layer was dried over MgSO 4 anhydrous and concentrated in vacuo. The title compound (4.05g, 97%) was obtained as a white solid and was used in subsequent reactions without further purification.

Preliminary SAXS analysis
The internal liquid crystalline structure was determined using small-angle X-ray scattering. Each amphiphile was dispensed into a 96-well plate and an excess of water (70% w/v) was added to each well using a Mosquito ® liquid dispensing robot. The samples were equilibrated under controlled conditions of temperature and humidity for 5 days before SAXS analysis was carried out. Samples were analysed within the 96-well plate using a bespoke sample holder at the SAXS beamline at the Australian Synchrotron. The resulting diffraction patterns were analysed using the IDL-based AXcess software package [5] and the number and distribution of reflections used to assign the mesophase.