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.

<p>U radu je ostvarena sinteza četiri prirodna proizvoda, goniobutenolida A i B,<br />krasalaktona D i 3-deoksi-kardiobutanolida i 32 derivata i analoga polazeći iz<br />D-glukoze. Sinteza prirodnog stiril-laktona, kardiobutanolida&nbsp; i njegova 4<br />derivata je izvedena polazeći iz&nbsp; D-ksiloze.&nbsp; Ispitan je uticaj sintetizovanih<br />jedinjenja&nbsp; na inhibiciju rasta 10 tumorskih i jedne zdrave ćelijske linije.<br />Uspostavljene su i&nbsp; korelacije izmedju strukture i antiproliferativne aktivnosti&nbsp;(SAR) i ispitan je mehanzam antitumorskog dejstva.</p> / <p>Synthesis of four natural products: goniobutenolide A and B,&nbsp;crassalactone D, 3-deoxy-cardiobutanolide and their 32 analogues&nbsp;and derivatives is accomplished starting from&nbsp; D-glucose. Synthesis of natural styryl lactone cardiobutanolide and its four derivatives is &nbsp;achieved&nbsp; starting&nbsp; from&nbsp; D-xylose.&nbsp; Synthesized natural lactones, their analogues and derivatives were evaluated for their antiproliferative activity against ten malignant cell lines&nbsp; as well as against a single normal cell line. Influence of functional groups on antitumour activity was established by correlating structures of synthesized compounds&nbsp; with&nbsp; their&nbsp; biological&nbsp; activity (SAR).&nbsp; Also, mechanism of antitumour action was investigated.</p>