Synthesis And Applications Of 1,4-Diketones And Y-Oxobutyramides Derived From Tartaric Acid

Abstract

The thesis entitled “Synthesis and applications of 1,4-diketones and γ-oxobutyramides derived from tartaric acid” is divided into two chapters. Chapter 1: Synthesis of TADDOL analogues by nucleophilic addition reactions and their application to the synthesis of α-methoxy arylacetic acid derivatives Synthesis of various TADDOL analogues by the addition of nucleophiles to 1,4-diketones derived from L-(+)-tartaric acid is presented in this chapter. It is found that the reduction of 1,4-Diketones 1a-d with K-Selectride pre-complexed with 18-crown-6 which is the optimized condition to attain better diastereoselectivity towards the C2-symmetric isomer 2a-d (Scheme 1). Addition of Grignard reagents to diketones 1a, 1eh is dependent on nature of Grignard reagents, solvent and temperature. (Structural formula) Scheme 1: Synthesis of TADDOL analogues Application of the synthesized TADDOL analogues in synthesis of enantiopure α-methoxy arylacetic acid derivatives is discussed. The C2-symmetric 1,4-diols 2a-d (TADDOL analogues) are utilized in the synthesis of enantiopure α-methoxy arylacetic acid derivatives as shown in scheme 2. Scheme 2: Synthesis of α-methoxy arylacetic acid derivatives. (SF) Both enantiomers of α-alkyl-α-methoxy arylacetic acids 13a-b and ent-13a are synthesized from the respective C2-symmetric diols 5a-b and 7a-b (scheme 3). (SF) Scheme 3: Synthesis of both enantiomers of α-alkyl-α-methoxy arylacetic acids. Chapter 2: Facile Synthesis of α,β-dihydroxy-γ-butyrolactones and jaspine B from γ-oxobutyramides derived from tartaric acid A short and efficient route for the synthesis of γ-alkyl/aryl-α,β-dihydroxy-γ-butyrolactones 15a-j is accomplished from γ-oxobutyramides 14a-l derived from tartaric acid. Key step includes a controlled addition of Grignard reagent and stereoselective reduction (Scheme 4). (sF) Scheme 4: Synthesis of α,β-dihydroxy-γ-butyrolactones and jaspine B. Utility of the γ-oxobutyramides is further exemplified in the synthesis of jaspine B 18 a cytotoxic anhydrophytosphingosine in 48% overall yield (Scheme 5). (SF) . Scheme 5: Synthesis of α,β-dihydroxy-γ-butyrolactones and jaspine B. Appendix: Serendipitous observation of polymorphism in TADDOL analogue induced by the presence of chiral impurity Polymorphism in one of the TADDOL analogues is serendipitously observed and demonstrated that the 2% impure diastereomer is responsible for the formation of one of the pol ymorphic crystals (Figure 1). (SF) Figure 1: Diastereomeric impurity induced polymorphism. (For structural formula pl see the pdf file)