A Stereoselective and Highly Practical Synthesis of Cytosolic Phospholipase A2 Substrate, 2-S-Arachidonoyl-1-O-hexadecyl-sn-2-thioglycero-3-O-phosphocholine
Abstract
The substrate 1 of cytosolic phospholipase A2 (cPLA2) is an ether-type thiophospholipid with arachidonic acid at the C-2 position and is required for the chromogenic assay for reliable and convenient high throughput screening. The original method of synthesis of 1 has significant problems, resulting in extremely low overall yield and purity. We developed a novel and highly practical method of preparing sufficient quantities of pure 1 for assay. Our synthetic sequence is started with commercially available 1,2-O-isopropylidene-sn-grycerol (5) and is based on the following key steps: trityl migration reaction of 10 with boron trifluoride etherate to form 13, phosphocholine-forming reaction of 13 to yield 15, and efficient conversion of 15 into 1 by deprotection of a trityl group and condensation with arachidonic acid. Our method offers a practical means of large-scale production of 1 with excellent high chemical purity, because of the introduction of arachidonic acid at the last step of the synthetic sequence.
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