Studies towards the total synthesis of cis-oseltamivir phosphate and asymmetric synthesis of cisy–butyrolactone-lactam derivatives / Zurhana Mat Hussin

Oseltamivir phosphate (Tamiflu) is the prodrug of a potent viral neuraminidase inhibitor and has been utilized as an effective treatment and preventative for influenza A and influenza B. Due to the concerns about a potential pandemic influenza outbreak and the limited availability of (-)-shikimic acid, organic chemists have shown significant interest in synthesising oseltamivir using alternative synthetic approaches. In this study, we embark on developing a synthetic target molecule, a novel structure of cis-oseltamivir phosphate, cis 1d as a new potential anti-influenza drug starting from simple, cheap and commercially available starting materials, in part A. In this part, the intermediate towards formation of cis-oseltamivir phosphate, (1S,6R)-3cyano-6-hydroxy-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)carbamate 16 was synthesised from 1,4-cyclohexadiene 5 via a novel and new sequence synthetic route. A unique feature of this synthesis is that the intermediate was synthesised from a readily available cyclohexene ring system by sequentially inserting substituents; an amino group at the carbon-1 position, a hydroxy group at the carbon-6 position, a pentaneyloxy group at the carbon-5 position, and a cyano group at the carbon-3 position sequentially through 8 reaction steps. The synthesis of the carbon-1 substituent involved epoxidation of 1,4-cyclohexadiene 5 and catalytic asymmetric ring opening by the salen complex and TMSN3 to afford azide 8. The formation of carbon-6 hydroxyl group was achieved after one pot reduction and amine protection of azide 8. The allylic position of olefin at the carbon-5 was an active site for constructing a pentaneyloxy group via allylic oxidation of compound 10 using SeO2 in the presence of TBHP and etherification of compound 12 with 3-pentanol. The cyano group at the carbon-3 position in compound 16 was successfully developed after the treatment of compound 13 by epoxidation of olefin, ring opening by TMSCN and elimination reaction. Then there were two more steps left, the Mitsonubu reaction and hydrolysis to targeted cis 1d. To further expand the use of selected synthetic steps and products from Part A, compounds 10 and 13 were utilized to construct an intermediate compound for Geismann-Waiss lactone (GWL) synthesis. In part B, the synthesis of cis γ-butyrolactone-lactam derivatives as potential GWL’s intermediates were examined. The oxidative cleavage of alkene by ruthenium tetraoxide, lactonization and lactamization on compounds 10 and 13 successfully produced compounds 18 and 19 in good yield. As conclusion, we have developed eight (8) reaction steps to afford compound 16 in part A and two new compounds of 18 and 19 in part B.