The thesis entitled “Total synthesis of bio-active natural products microcarpalide, synargentolide A, jaspine B and anamarine.” demonstrates the utility of chiral pool tartaric acid as the source in the synthesis of bio-active natural products. The thesis was divided into four sections. Section I of the thesis deals with the enantiodivergent synthesis of microcarpalide from tartaric acid. Microcarpalide is a 10-membered lactone of polyketide origin isolated from the fermentation broths of an unidentified endophytic fungi, found to be weekly cytotoxic to mammalian cells and acts as a microfilament discrupting agent. Stereoselective approach for the synthesis of ()-microcarpalide is described from D- and L-tartaric acids, while enantiodivergent approach for the synthesis of both enantiomers is described from L-tartaric acid using ring closing metathesis as the Scheme 2: Enantiodivergent total synthesis of microcarpalide. In section II of the thesis, stereoselective synthesis of synargentolide A is described. Synargentolide A is a polyhydroxy -lactone, isolated from Syncolostemon argenteus, which was founf to exhibit cytotoxic and antitumor properties. Stereoselective synthesis of synargentolide A was accomplished, starting from L-tartaric acid employing, Keck and Brown allylations and ring closing metathesis, as the key steps. Scheme 3: Stereoselective total synthesis of ()-synargentolide A. Section III of the thesis deals with the synthesis of ()-jaspine B. Pachastrissamine (jaspine B), is an anhydrophytoshingosine derivative, isolated from marine sponges Pachastrissa and Jaspis speces. Pachastrissamine was shown to exhibit cytotoxicity (IC 50 0.01 g/mL) against P388, A549, HT29, and MEL28 cell lines. Enantioselective synthesis of jaspine B is accomplished from L-tartaric acid employing, Keck allylation, acid mediated formation of tetrahydrofuran, and olefin cross metathesis as the key reactions. In section IV of the thesis, enantioselective synthesis of ()-anamarine is described. Anamarine is a polyhydroxy -lactone isolated from the flowers and leaves of Peruvian hyptis, possessing cytotoxicity against human tumor cell lines. Enantioselective synthesis of -anamarine is accomplishedelaboration of hitherto unknown -keto phosphonate derived from tartaric acid amide. In an appendix for the thesis, enantiodivergent synthesis for 4-siloxy-pent-2-enone was described. The usefulness of asymmetric aldol reaction is exemplifiedin this section. hydroxy amide synthesized from crotonaldehyde is suitably elaborated to the diene which on RCM yielded 4-silyloxycyclopent-2-enone. Further synthetic modification of this compound afforded the other enantiomer. Scheme 6: Enantiodivergent synthesis of hydroxy cyclopentenones. (For structural formula pl the abstract pdf file)

First chapter of the thesis describes the desymmetrization of the bis-dimethyl amide 1 derived from tartaric acid with vinyl Grignard reagents and subsequent reduction of the resultant -keto amides 2a-c to the -hydroxy amides 3a-c. Application of the -hydroxy amides 3a-c in the total synthesis of bio-active natural products such as gabosines, crassalactone C and anamarine is described in the subsequent sections. In section A of the first chapter, application of the -hydroxy amides 3a-b to the total synthesis of gabosine A 4, gabosine F 5 and gabosine H 6 was described. Key strategy in the synthesis was the use of ring closing metathesis (RCM) reaction. Incidentally, the total synthesis of gabosine H 6 was not only accomplished for the first time but the synthesis also ascertained the absolute stereochemistry of the natural product. During the course of the synthesis of gabosine A 4, an unprecedented formation of a unique 14-membered macrocycle 7 was observed. Incisive studies were conducted to elucidate the reaction sequence for the formation of the macrocyle 7. It was found that the formation of the macrocycle 7 was through a tandem cross-metathesis/intramolecular hetero Diels-Alder reaction. Section B of chapter 1 delineated the utility of the -hydroxy amide 3a in the total synthesis of (–)-crassalactone C 8a. Crassalactone C 8a is a cinnamoyl derivative of styryllactone natural product goniofufurone and was found to possess marginal in vitro cytotoxic activity. Pivotal strategies in the synthesis include the use of bis-cinnamoyl ester 10a in the ring closing metathesis reaction which also evades the selective cinnamoylation of the benzylic hydroxy group. Section C of Chapter 1 deals with the total synthesis of (+)-anamarine 11. While the - hydroxy amide 3a was employed to synthesize an important intermediate 12 enroute to the synthesis of anamarine, to mitigate the number of steps in the synthesis, the -hydroxy amide 13 was employed for the synthesis of (+)-anamarine 11. Key reactions in the total synthesis include the use of 1,3-dithiane as a surrogate for the methyl group, Brown’s allylation and ring closing metathesis. In second chapter of the thesis, formal total synthesis of iriomoteolide 3a 16 is presented. Iriomoteolide 3a 16 is a unique 15-membered marine macrolide isolated by Tusda’s group from the Amphidinium strain HYA024, with impressive in vitro cytotoxic activity against human lymphoma cell line DG-75 (IC50 0.08 g/mL) and Raji cells (IC50 0.05 g/mL). Salient features of the synthesis include the synthesis of the chiral aldehyde 19 from the oxazolidinone 17 and the use of -keto phosphonate 20 derived from D-(–)-tartaric acid in the Horner-Wadsworth-Emmons olefination reaction to construct the C1-C10 fragment 23 of iriomoteolide 3a 16. Synthesis of the C10-C18 fragment 29 was accomplished from the butyrolactone 24 using Keck allylation and olefin cross metathesis reactions as key steps. Ring closing metathesis of the ester 30, followed by selective deprotection of the primary TBS group afforded the key intermediate 31, the transformation of which to iriomoteolide 3a 16 is known in literature.