α-Amino Acids Based Stereoselective Synthesis of Biologically Important Natural Products and Natural Product-like Molecules

Abstract

An eminent role has been played by natural products in the discovery and development of new drugs. A major part of the drugs present in the market is natural products or natural product-derived. The two main synthetic devices towards the drug development are Targetoriented synthesis (TOS) and Diversity-oriented synthesis (DOS) for creating structurally diverse compounds that cover the harmaceutically relevant chemical space in an optimal way. On the other hand, an over-proportionally large number of drugs or lead structures also originate from compounds isolated from natural sources. So, the development of new synthetic routes for the natural products can not be denied. Towards this perspective, the use of naturally occurring amino acids is well known because of their easy availability in chirally pure form. Again, they have at least two functional groups (amino and carboxylic acid groups) and by chemical transformations of these, they can be renovated to a broad range of biologically important compounds. The thesis entitled “α-Amino Acids Based Stereoselective Synthesis of Biologically Important Natural Products and Natural Product-like Molecules” describes the synthesis of chiral heterocycles, bioactive natural products and natural product-like molecules and related diversity from natural amino acids as the chiral synthones. The present investigations have been carried out by the author under the supervision of Dr. Gautam Panda, Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226001, UP, India. The work embodied in this thesis has been organized under six chapters:

Chapter 1: Amino Acids as Chiral Synthon: Application to the Synthesis of Chiral Heterocycles, Bioactive Natural Products and related Diversity In the ‘Chapter 1’ a brief over view on synthesis of chiral heterocycles, natural products and related diversity from different amino acids has been presented.

Chapter 2: An Approach Towards The Total Synthesis of (+)-Epiquinamide and (+)-α-Conhydrine From Garner Aldehyde ‘Chapter 2’ of this thesis describes the total synthesis of (+)-Epiquinamide and (+)-α- Conhydrine starting from L-Serine derived Garner aldehyde. Stereoselective nucleophilic addition, ring closing metatheis (RCM) and hydrogenation are the key steps among the reaction sequences.

Chapter 3: A New Route to 1,4-Oxazepanes and 1,4-Diazepanes from Garner Aldehde In this ‘Chapter 3’ a short stereoselective synthetic route towards 1,4-Oxazepanes and 1,4-Diazepanes has been described starting from L-Garner aldehyde and using inter molecular reductive amination to couple two different amino acids. Chapter 4: Formal Total Synthesis of Antimalarial Natural Product (–)- Raphidecursinol B and All Stereoisomers

‘Chapter 4’ presents the formal total synthesis of Antimalarial Natural Product (–)- Raphidecursinol B and All Other Stereoisomers of an advanced synthetic intermediate. Sharpless asymmetric dihydroxylation and Mitsunobu reactions are among the key steps of the synthetic sequence.

Chapter 5: Stereoselective Approach to Aminocyclopentitols from Garner Aldehyde In this ‘Chapter 5’ different synthetic routes towards glycosidase inhibitors, aminocyclopentitols have been described using L- and D-Garner aldehyde as the starting materials and ring closing metathesis reaction as one of the key steps of the reaction sequence.

Chapter 6: A Diversity Oriented synthetic Approach towards Conduramines, Valienamine, Validamine and Lycoricidine The ‘Chapter 6’ deals with the several synthetic approaches towards four important natural products: Conduramines, Valienamine, Validamine and Lycoricidine. The starting point of all the syntheses is L-Garner aldehyde. Nucleophillic addition, ring clossing metathesis and oxidative cleavage are the vital steps to synthesize some common intermediates which will be used to achieve the target molecules. Brief summary, experimental procedures, spectra of some of the important compounds and appropriate literature citations are given in the text of each chapter of the thesis. The compound number of each chapter of the thesis is given separately.