| Summary: | 博士 === 國立清華大學 === 化學系 === 99 === This thesis consists of two parts. The first part was concerned with application of chiral 1,3-dioxolan-4-ones 36, derived from (1S)-(+)-N,N-diisopropyl-10-camphorsulfonamide 29, in enantioselective formal synthesis of precursor of (-)-quinic acid 65a and LdT 96. In the second part, discovering high potent Cathepsin S inhibitors based on skeleton of core structure 144 is described.
I. (a) Enantioselective formal synthesis of precursor of (-)-quinic acid: Asymmetric Diel-Alder reaction of dienophile 88, derived from 1,3-dioxolan-4-ones 59, with 1,3-butadiene afforded precursors of glycolic acid 69 derivatives, 93, 94 in 39% yield. The diastereoselective ratio of Diel-Alder reaction is 4.9 : 1. On the other hand, A seven-step synthesis, including diastereoselective alkylation and ring-closing metathesis reactions, of precursor of (-)-quinic acid 65a from 1,3-dioxolan-4-ones 36 has been achieved in 33% overall yield.
(b) Enantioselective formal synthesis of precursor of LdT: Aldol reaction of the enolate of 1,3-dioxolan-4-one 36 with alpha-trimethylsilyl acrolein 131 afforded corresponding product 130. A three-step synthesis of precursor of LdT 123 from aldol adduct 130 has been furnished in 37% overall yield.
II. Discovery of potent Cathepsin S inhibitors: Synthesis of various core structure 144 derivatives and alpha-ketoamide 179 for inhibition of Cathepsin S. Unfortunately, those compounds has low IC50 value of Cathepsin S.
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