The thesis titled “Stereoselective synthesis of bio-active styryllactones” comprises an introduction about styryllactones and three sections delineating the results and discussion about the synthesis of styryllactones and experimental section. Trees of the genus Goniothalamus of the plant family Annonaceae in South East Asia has been known for a long time for their proven use in folk medicine. The research group of McLaughlin isolated and characterized a series of styryllactones, possessing significant to marginal cytotoxic activity against human tumor cell lines. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis. Classification of these styryllactones is based on the structural characteristics of the six different skeletons as shown in Figure 1. It was proposed by Shing et al. that the bio-synthesis of styryllactones 1-7 occur via the shikimic acid pathway. This proceeds through the formation of cinnamic acid from phenylalanine, followed by the incorporation of two acetate–malonate units activated as co-enzyme A, generating the styryl-pyrone, goniothalamin 9 a key styryllactone, which on further hydroxylation/oxidation leads to the formation of other styryllactones Section 1: Stereoselective synthesis of styryllactones containing furanofurone, pyrano-pyrone and styryl-pyrone structural units. In this section of the thesis, stereoselective total synthesis of furano-furone, pyrano-pyrone and styryl-pyrone type styryllactones (+)-7-epi-goniofufurone 1, (+)-goniofufurone 2, (+)goniopypyrone 3, (+)-goniotriol 4, (+)-9-deoxygoniopypyrone 5 and (+)-goniodiol 6 is discussed. It is anticipated that the masked tetrol 13, comprising an alkene tether and four contiguous hydroxy groups installed with definite configuration would serve as the intermediate for the synthesis of styryllactones 1-6. It is relied on exploiting the hydroxy directed lactonization via the oxidation of alkene in 13, and subsequent elaboration to styryllactones 1-6. Bis-dimethylamide 10, derived from D-(−)-tartaric acid was identified as the suitable precursor for the synthesis of 13. Synthesis of masked tetrol 13 is accomplished from 10 involving a combination of selective Grignard additions and a stereoselective reduction (Scheme 2). Section 2: Stereoselective synthesis of styryllactones containing tetrahydrofuran and furano-pyrone structural units This section deals with stereoselective synthesis of natural antitumor tetrahydrofuran containing natural product (+)-goniothalesdiol 8. Key features of the synthesis include a FeCl3 mediated formation of THF 15 with very high selectivity (Scheme 3). THF 15 is further elaborated into the furano-pyrone type styryllactones (+)-altholactone 7 and (−)-etharvensin 16 in good yields (Scheme 3). Section 3: Stereoselective total synthesis of (+)-cardiobutanolide Recently, a new styryllactone cardiobutanolide 20 was isolated from the stem bark of Goniothalamus cardiopetalus, together with four known styryllactones by Hisham et al. Stereoselective total synthesis of this natural product from D-(−)-tartaric acid is described in this section. Key features of the synthesis include the elaboration of the γ-hydroxy butyramide 17 obtained from the bis-dimethylamide 10, involving a combination of the addition of 1,3-dithian-2-yllithium and stereoselective reduction (Scheme 4). (For structural formula pl see the pdf file)

<p>U&nbsp; radu&nbsp; su&nbsp; ostvarene&nbsp; vi&scaron;efazne&nbsp; sinteze&nbsp; većeg&nbsp; broja&nbsp; analoga&nbsp; prirodnih&nbsp; stiril-laktona&nbsp; (+)-goniofufurona&nbsp; i&nbsp; 7-epi-(+)-goniofufurona&nbsp; polazeći&nbsp; iz&nbsp; D-glukoze.<br />Ispitana&nbsp; je&nbsp; in&nbsp; vitro&nbsp; citotoksičnost&nbsp; sintetizovanih&nbsp; analoga&nbsp; prema&nbsp; devet<br />malignih&nbsp; i&nbsp; jednoj&nbsp; zdravoj&nbsp; ćelijskoj&nbsp; liniji.&nbsp; Uspostavljeni&nbsp; su&nbsp; korelacioni&nbsp; odnosi<br />izmedju&nbsp; strukture&nbsp; i&nbsp; antiproliferati vne&nbsp; aktivnosti&nbsp; sintetizovanih&nbsp; proizvoda, pored&nbsp; toga&nbsp; uradjeni&nbsp; su&nbsp; i&nbsp; dodatni&nbsp; biolo&scaron;ki&nbsp; testovi&nbsp; koji&nbsp; se&nbsp; odnose&nbsp; na dokazivanje&nbsp; mehanizma&nbsp; citotoksičnog&nbsp; dejstva&nbsp; pomenutih&nbsp; stiril-laktona&nbsp; i analoga.</p> / <p>Multistep&nbsp; synthesis&nbsp; of&nbsp;&nbsp; a&nbsp; number&nbsp; of&nbsp; natural&nbsp; styryl&nbsp; lactones&nbsp;goniofufurone&nbsp; and&nbsp; 7-epi-goniofufurone&nbsp; analogues&nbsp; was&nbsp; achieved&nbsp;starting&nbsp; f rom&nbsp; D-glucose.&nbsp; In&nbsp; vitro&nbsp; cytotoxicity&nbsp; of&nbsp; newly&nbsp; synthetized analogues&nbsp; against&nbsp; nine&nbsp; human&nbsp; tumour&nbsp; cell&nbsp; lines&nbsp; and&nbsp; against&nbsp; a single normal cell line was evaluated. Structure-activity relationships were&nbsp; established&nbsp; for&nbsp; both&nbsp; natural&nbsp; products&nbsp; and&nbsp; analogues.&nbsp; Some additional&nbsp; biological&nbsp; tests&nbsp; related&nbsp; to&nbsp; the&nbsp; cell mechanisms&nbsp; underlying the&nbsp; cytotoxicity&nbsp; of&nbsp;&nbsp; the&nbsp; mentioned&nbsp; styryl&nbsp; lactones&nbsp; and&nbsp; analogues, were also carried out.</p>

<p>U radu je ostvarena enantiodivergentna totalna sinteza oba enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C polazeći iz D-glukoze. Ključne faze u sintezi 7-epi-(+)-goniofufurona bile su stereoselektivna adicija fenilmagnezijum bromida na aldehidnu grupu pogodno za&scaron;tićene dialdoze, i stereospecifično formiranje furano-laktonskog prstena ciklokondenzacijom odabranog hemiacetalnog derivata sa Meldrum-ovom kiselinom. Sinteza (+)-goniofufurona i (+)-krasalaktona C zahtevala je inverziju konfiguracije na C-5<br />u zajedničkom intermedijeru, koja je efikasno ostvarena u uslovima Mitsunobu-ove reakcije, ili alternativno oksidacijom benzilne hidroksilne grupe u prohiralni keton, uz naknadnu stereoselektivnu redukcijom sa borohidridom. Sličan pristup je zatim primenjen za sintezu neprirodnih (&minus;)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (&minus;)-goniofufurona (oksetani 36 i ent-36), kao i odgovarajućih 7-deoksigenovanih derivata (31 i ent-31). Takodje je razvijena i prva totalna sinteza prirodnog (+)-krasalaktona B (3) i alternativna sinteza (+)-krasalaktona C (4) polazeći iz D-glukoze. Selektivni pristup molekulima 3, odnosno 4 omogućen je promenom uslova za TBDPS deprotekciju u finalnom intermedijeru 53. Osnovna karakteristika pomenutih pristupa je njihova generalnost i fleksibilnost. Na taj način je omogućena sinteza serije analoga i derivata (+)-goniofufurona, ili 7-epi-goniofufurona, uključujući i do sada nepoznate 7-epi-(+)-krasalaktone B (6) i C (7), 5,7-di-O-cinamoil derivate 8 i 9, 5,7-di-O-izopropilidenske derivate 5 i 10, kao i vi&scaron;e lipofilnih derivata (jedinjenja 26, 30, 33, 65, ent-30 i ent-33). Konačno, u drugom delu rada, ispitan je uticaj sintetizovanih stiril-laktona na rast odabranih tumorskih ćelijskih linija in vitro.</p> / <p> Enantiodivergent total syntheses of both (+)- and (&minus;)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from D-glucose. The key steps of the synthe-sis of 7-epi-(+)-goniofufurone were a stereo-selective addition of&nbsp;<br /> phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum&rsquo;s acid. The synthesis of (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was applied to the synthesis of the unnatural enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, two novel, conformationally constrained analogues of both (+)- and (&minus;)-goniofufurone (oxetanes 34 and ent-34). as well as the corresponding 7-deoxygenated derivatives (31 and ent-31). We have also developed the first total synthesis of (+)-crassalactone B (2) and an alternative synthesis of (+)-crassalactone C (3) starting from D-glucose. Finally, the synthesized styryl-lactones were evaluated for their antiproliferative activity against a panel of human tumor cell lines.</p>