Part I. One-pot synthesis of secondary alcohols and one-pot asymmetric synthesis of secondary propargylic alcohols. Part II. Redox isomerization of secondary propargylic alcohols to enones. Part III. Synthesis study towards C9-C14 fragment of (+)-discodermolide. Part IV. Asymmetric synthesis of anti, anti-stereotriad building blocks for polypropionate natural products

• Main Author: Xie, Qiuzhe
• Format: Dissertation
• Language: English
• Subjects: chemistry, organic
• ISBN: 9780549914327; 0549914323

Part I. Chiral secondary propargyl alcohols are versatile building blocks for fine chemicals, pharmaceuticals, and natural products. A convenient method for asymmetric synthesis of secondary propargyl alcohols is highly demanded. Based on preliminary study, asymmetric synthesis of secondary propargyl alcohols in one-pot was designed and achieved by applying Zn-catalyzed enantioselective alkynylation directly with the aldehyde products of substitution reaction of methyl formate with nucleophiles. Various chiral alcohols with different substitutions have been synthesized successfully with good yield and high enantiomeric excess.
Part II. A convenient conversion of secondary propargyl alcohols to alpha,beta-enones is highly in demand because the diverse applications of alpha,beta-enones in synthesis and the facile access to propargyl alcohols. Recently, the transition metals such as Pd, Ru, Rh and Ir were used to catalyze the highly atom economical isomerization of propargyl alcohols to alpha,beta-enals and alpha,beta-enones. However, such isomerizations are less well studied compare with the well established isomerizations of allylic alcohols. In this project, Trost's two-metal (ruthenium, indium) catalysis system was carefully optimized to promote the isomerization of secondary propargyl alcohols to alpha,beta-enones, with tetraethylammonium hexafluorophosphate additive. To our knowledge, the first example of isomerization of dialkynyl alcohols to enynones catalyzed by a transition metal complex is reported here.
Part III. (+)-Discodermolide, a marine sponge natural product that stabilizes microtubules and maintains activity against multidrug resistant cell lines, is currently in clinical trials as an anticancer drug developed by Novartis Pharmaceuticals. Most of the completed total syntheses of (+)-discodermolide have relied on the Roche ester as the source of chirality and enantioselective chain extensions for construction of the building blocks. In our retro-synthetic plan towards (+)-discodermolide, the disconnections at C8-C9, C14-C15 generated three fragments. While my colleagues concentrated on the C1-C8 fragment and C15-C24 fragment, my work focuses on the synthesis of the C9-C14 moiety. The C9-C14 fragment was successful synthesized in 12 steps with 26.8% over all yield. The chirality source, (-)-N-methylephedrine, is inexpensive and the auxiliary is recoverable.
Part IV. Polypropionate subunits are present in a great number of biological active natural products such as antibiotics, antitumors, antifungals, or antiparasitics. A widespread strategy to synthesize these structures involves the disconnection of polypropionate chains into shorter subunits, such as stereotriad building blocks bearing alternate methyl and hydroxyl groups. Starting from inexpensive, commercially available achiral starting materials, a powerful protocol was developed to construct anti, anti-stereotriad building blocks. With further modifications, the (2R,3R,4R)-3-(tertbutyldimethylsilyloxy)-2,4,6-trimethylheptanoic acid (TBS-TMHEA) segment of Callipeltin A, the Segment B2 of Miyashita's total synthesis of Scytophycin C, and the TES-PMB protected piece of Paterson's synthesis approach of Aplyronines were synthesized from these stereotriads.