Synthesis Of Novel Bicyclo β-Lactamase Inhibitors And 1-Octacosanol

Theβ-lactam antibiotic is the most important class of antibiotic used in the clinical practice for the treatment of bacterial infections. They have immensed influence on protecting people's health and have saved millions of human lives since their first application in the 1940's. However, the development ofβ-lactam antibiotics resistant bacteria has raised a major challenge for the effectiveness ofβ-lactam antibiotics as a major class of antibacterial treatment drugs. The most important mechanism of this microbial resistance toβ-lactam antibiotics is that some bacterias produceβ-lactamase which hydrolytically destroyβ-lactam antibiotics within the body. Two methods for overcoming this growing problem of bacterial resistance involve either developing new antibiotics or designing new, broad-spectrum and effectiveβ-lactamase inhibitors to be used in combination with exsisting antibiotics. The later approach has been found to be an effective method and has enabled some very early generation of antibiotics still remain to be effective. Therefore there are growing interests in the development of effective inhibitors for the inhibition ofβ-lactamases.One of the results of this thesis is to prepare novel bicyclic lactams with potentialβ-lactamase inhibition properties. Since [2+2] cycloaddition of chlorosulfonyl isocyanate (CSI) with an alkene is a very effective method for the synthesis ofβ-lactams, we plan our synthesis of one class of bicyclic lactam targets such as (±)-95, (±)-96 by reacting the cyclic alkene (±)-91 obtainable from 2-adamantanone with CSI. The synthetic route to (±)-95,(±)-96 is shown in Schemeâ… . Another result of this thesis is to synthesize a second type of novel bicyclicβ-lactams such as 104, 113 starting from optically active (S)-(-)-α-pinene and (R)-(+)-α-pinene employing the same [2+2] cycloaddition strategy. Cycloaddition of (S)-(-)-α-pinene with CSI afforded 97 in 87% yield. Protection of the lactam amide by TBSCl led to compound 100, which was further acylated with ClCO₂Bn to give 101. Deprotection of the lactam amide by hydrogenation with cat. Pd/C in EtOAc and then TBAF in THF led to compound 103. This novel compound is to be converted to a water soluble bicyclicβ-lactam 104(Schemeâ…¡) forβ-lactamase inhibition testing.The same route from (R)-(+)-α-pinene led to compound 113 in 19.7% overall yield(Schemeâ…¢). The third result of this thesis is to synthesize a third type of novel bicyclicβ-lactams such as 122 starting from optically active (1R,5S)-(-)-myrtenol employing the same [2+2] cycloaddition strategy. Cycloaddition of protected (-)-myrtenol 117 with CSI afforded 118 in 62% yield. Deprotection of the lactam amide by hydrogenation with cat. Pd/C in methanol and oxidation of the hydroxy with Jones reagent led to compound 120. This novel compound is to be converted to a water soluble bicyclicβ-lactam 122(Schemeâ…£) forβ-lactamase inhibition testing. The second part of the thesis describes the synthesis of 1-octacosanol. 1-Octacosanol is a long chain aliphatic primary alcohol which possesses several important physiological functions such as toning up sinew, promoting physical force etc. The aim of this part of work is to exploit a practical route for the synthesis of this commercially important compound.Using decane-1,10-diol and 1-octadecanol as the starting materials,monobromination of decane-1,10-diol followed by THP protection of the hydroxy group give the compound 148 from which the corresponding Grignard reagent was formed and coupled with the Tosylate 150 prepared from 1-octadecanol in the presence of freshly prepared CuI.Final deprotection of the THP group afforded 1-octacosanol 130 in 61.4% overall yield(Schemeâ…¤).