Asymmetric Syntheses Of Naturally Occurring Bioactive β-Amino Alcohols

Natural products are important source for new drugs. Chiral vicinal amino alcohols constitute an important class of compounds which exist in many bioactive natural products and medicinal agents. They exhibit various bioactivities including anticancer activity, and also serve as versatile chiral auxiliaries in the asymmetric synthesis. However, they only exist in minute amount in the nature. Thus it is important to establish a facile method for the asymmetric synthesis ofβ-amino acids.(2S,3R)-2-Aminododecan-3-ol (â… ), which was isolated from the ascidian Clavelina oblonga, displays excellent antifungal activity. (2S,3R)-2-Aminotetradecan-3-ol (xestoaminol C,â…¡), which was collected from the secondary metabolites of sponges Xestospongia in Fiji by Jim(?)nez and Crews in 1990, is a inhibitor of reverse transcriptase and shows broad-spectrum activity against parasites and microbes. (2S,3R)-2-Aminooctadecan-3-ol (spisulosine,â…¢) was isolated from the clam Spisula polynyma and is a cytotoxic compound that inhibites the cell proferation. (2S,3R)-2-Aminooctadecan-1,3-diol (DHS,â…£) is an principal medium in vivo biosynthesis of sphingosine. These natural products contain the same (2S,3R)-configuration and the configuration at C-2 is the same as that of the naturalα-amino acids.This thesis contains two parts. The first part is about the asymmetric synthesis of naturally occurring chiral vicinal amino alcohols. We used the natural a-amino acids: L-alanine and L-serine as the chiral starting materials, and N-dibenzylated derivatives to improve the stereoselectivity of the Grignard addition to a-amino aldehydes. A one pot Swern oxidation-Grignard addition procedure was established to avoid possible racemization, In such a manner, the anti-diastereoselectivity of the Grignard addition is about 90% d.e., and the e.e of the products is up to 99%. Thus starting from L-alanine, the total syntheses of (2S,3R)-2-aminododecan-3-ol (â… ), xestoaminol C (â…¡) and spisulosine (â…¢) were accomplished in four steps respectively with overall yields of 40%. Starting from L-serine, the total syntheses of (2S,3R)-2-aminooctadecan-1,3-diol (DHS,â…£) was accomplished in five steps with an overall yield of 20%.The second part of the thesis is about the asymmetric synthesis of the aza-analog of prostaglandin: 8-aza-PGE₁. Prostaglandins (PGs) are lipids existing in minor amount in human body which exhibit significant physiological activity at hormone-like concentration. Much effort has been paid to the synthesis of PGs. The second theme of this thesis was to accomplish the chiral building blockâ…§. expecting to be useful for the synthesis of 8-aza-PGE₁. Starting from (S)-malic acid, compoundâ…¦was obtained in 3 steps with a total yield of 52%. Then N-alkylation ofâ…¦affordedâ…¦.