Synthesis of hydroxylated long-chain alkanoic acids by olefin cross-metathesis reactions

Hydroxylated long-chain alkanoic acids 4 are interesting molecules whose presence is crucial in many biological processes.[1] For instance, both enantiomers of 9-hydroxystearic acid (9-HSA) were able to inhibit the enzymatic activity of HDAC1, HDAC2 and HDAC3 histone deacetylases, the (R)-isomer resulting more active.[2] In another application, HSAs and their derivatives were studied as low molecular weight organogelators (LMOGs), compounds that, even at low concentrations, are able to incorporate large volume of organic solvent, producing viscoelastic semisolid materials (organogels).[3] (R)-12-Hydroxystearic acid (12-HSA), easily derivable from extracts of castor bean, is one of the most useful organogelators.[4] Unfortunately, a small number of chiral non racemic hydroxyalcanoic acids are available on a large scale from natural sources, therefore, the construction of this class of compounds seems an attractive challenge. We have already successfully employed a ring closing metathesis (RCM) reaction for the synthesis of lactone precursors of chiral non racemic 7- and 8-hydroxystearic acids (7- and 8-HSA).[5] Since different types of chiral non racemic macrocyclic lactones were formed in this reaction, resulting in a poor total yield of the desired compounds, we decided to investigate the CM reaction as a possible alternative route to RCM. (Figure 1) Using easily available chiral non racemic allylic or homoallylic alcohols 1 [5],[6] and unsaturated methyl esters 2, having different lengths of the carbon chains (value of x, y and z), a wide class of chiral non racemic hydroxyalcanoic acids 4 may be obtained. In the present work different methyl esters 3 will be synthetized by CM reactions using both allylic (R = H, y = 0) and homoallylic (R = H, y = 1) alcohols as starting compounds in order to obtain the highest yields. Acetylated starting compounds 1 (R = Ac, y = 1) will be also considered.