SYNTHESIS OF SOME VITAMIN D ANALOGUES

Abstract

1. The most fruitful approach to the synthesis of vitamin D secosterols involves functionalisation of existing photolysis steroid of the molecules latter to provitamin D and furnishes the desired secosteroids. Though this approach is shorter than total synthesis, its considerable length and overall poor yield are problems requiring solutions. The objective of the present work is to find ways to improve the existing methods 118,119,120 of synthesising 1- hydroxyergocalciferol ( 1 HEC) and 1- hydroxycholecalciferol (1 HCC). 2. The metabolism of natural vitamin D and the clinical applications of its many metabolites were reviewed. The general approaches to the chemical synthesis of vitamin D secosterols were surveyed and discussed. 3. A general scheme to synthesise provitamin D2 from ergosterol (Chart 9, p. 61) was proposed. The scheme served as a framework upon which methods to prepare certain key intermediary compounds could be investigated and improved. Any improvement in the yields of these compounds could conceivably improve the overall yield of other reported schemes of synthesis which share the same, or analogous intermediary compounds. 4. For each of the proposed reaction step, reviews were made of the reported methodologies and the mechanism of reaction. This information led to the choice of the most suitable method for each reaction step. 5. The following steps of the proposed scheme were investigated. Ergosterol (35) was oxidised via Oppenauer oxidation to ergosterone (36), which underwent acid catalysed isomerisation to isoergosterone (J.2). Oxidation of 37 with DDO gave ergosta-1,4,6,22- tetraenone ( 38). Acetylation of the tetraenone 38 afforded an enolic ester 55 which on reduction with large excess of calcium borohydride gave the 1, 5, 7, 22- tetraen-3B-ol (56). Prior to oxiranation, the important 5, 7-diene system in 56 was protected as a PTAD adduct (57), and the C-3 hydroxyl function derivatised as an alkylsilyl ether (58) . The oxiranation of 58 was found to be stereoselective with respect to the C-22, instead of the C-1, olefinic bond. Further exploration along the proposed scheme was abandoned. 6. The structure of all compounds prepared in the present work were elucidated from spectral data and confirmed by elemental analysis. Wherever possible, spectral data of each compound were compared with those of similar or analogous compounds reported in the literature. 7. The present work has achieved its objective in two ways: ( a ) Increase in yields have been made by improvement of some of the reported procedures. For example, in the three-step synthesis of the tetraenone (38) from ergosterol, an overall yield of 43% was achieved. This is significantly better than the 14% yield obtained by Lam et al120 (b) Where part of the existing route is unreliable because of some inherent weakness, alternative by-pass has been designed which circumvents the difficulty. Thus the way in which the tetraenone 38 was transformed to the 1, 5, 7, 22-tetraen-3B-ol ( 56) in the present work is unique. It avoids the necessity of isolating an unstable intermediary compound, a 1,5,7-trien-3-one (e.g. 26 Chart 5) which forms part of the synthetic route of Guest and Williams: 19 It is postulated that li could tautomerise back to the more conjugated, and hence more stable trienone (20 Chart 5). This could well account for the capricious yield of the former as reported by Kaneko et al118 The present alternative approach of first acetylating the enolic tautomer of 38, followed by reduction of the ester with 10 times excess of calcium borohydride, gave 56 with an overall yield of 78%. The estimated overall best yield reported by Guest and Williams for similar transformation (i.e. 20 to 27, Chart 5) was only 40%. Besides, the new method has the added advantage of reproducibility. 8. It is hoped that when these findings are applied to industry, it may be possible to manufacture cheaper 1- hydroxylated vitamin D compounds, thus resulting in a wider usage of these compounds in the treatment of vitamin D deficiency syndrome.