Synthesis of Farnesol Analogues through Cu(I)-Mediated Displacements of Allylic THP Ethers by Grignard Reagents

Abstract

The synthesis of a family of farnesol analogues, incorporating aromatic rings, has been achieved in high yields through the development of a regioselective coupling of allylic tetrahydropyranyl ethers with organometallic reagents. The allylic THP group is displaced readily by Grignard reagents in the presence of Cu(I) halides but is stable in the absence of added copper. Thus, an allylic THP group can fulfill its traditional role as a protecting group or serve as a leaving group depending on reaction conditions. An improved synthesis of (2E,6E)-10,11-dihydrofarnesol also has been accomplished using this methodology, and some preliminary studies on the reactivity and regioselectivity of THP ether displacements were conducted. The farnesol analogues reported herein may be useful probes of the importance of nonbonding interactions in enzymatic recognition of the farnesyl chain and allow development of more potent competitive inhibitors of enzymes such as farnesyl protein transferase.

A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro

“…The resulting product then was split and carried forward in three divergent directions. The 2-tetrahydro pyranyl (THP) protecting group of alcohol 10 was subjected to cop per-mediated Grignard displacement ( 24,25,28 ) with the corresponding biphenyl Grignard reagents to provide independently the ortho, meta, and para analogs 11, 12, and 13, respectively. Standard conversion of the free hydroxyl group to the allylic bromide was performed using PBr 3 .…”

Preparation of aromatic geraniol analogues via a Cu(I)-mediated Grignard coupling

“…A new sequence was investigated with another substrate in an attempt to improve the yield of the desired phenolalcohol 9 (Scheme 4). Using a modified Mechelke-Wiemer protocol, 8 the transmetalation of the lithium derivative of the O-protected 2-iodophenol 11 with magnesium bromide was performed at low temperature to give the Grignard intermediate and then with CuI to afford the intermediate organocuprate which was alkylated with geranyl 2-tetrahydropyranyl ether 12 to give 13 in 88% yield. Oxidation of the geranyl moiety with SeO 2 /SiO 2 , t-BuO 2 H and then with NaBH 4 reduction of the intermediate aldehyde using the optimized protocol described above gave the allylic alcohol 14 in 43% yield.…”

“…3 C-alkylation has been obtained by acid-catalyzed condensation of geraniol or farnesol with phenols in aprotic solvents in the presence of Lewis acids, 4 mineral acids such as p-toluenesulfonic acid, 5 Friedel-Crafts alkylation, 6 copper-induced isomerization to 2-alkenyl 2-lithiophenyl ethers, 7 or Cu(I)-mediated Grignard coupling of THP ethers. 8 As part of our continuing interest in phenolic oxidative coupling mediated for iodine hypervalent reagents, 9 we describe the preparation of 2-geranylphenolic intermediates that will be necessary for future studies on synthesis of cyclic isoprenoids.…”

Microwave assisted synthesis of benzophenone and acetophenone ethylene ketals

“…[3][4][5][6][7][8] We were seeking a simple and environmentally benign synthesis of benzophenone and acetophenone ethylene ketals. Most of the reported methods that avoided the drawbacks of the traditional protection methods (eg.…”