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An evolution of a synthetic route leading to a successful enantioselective total synthesis of monoterpenoid indole alkaloid (+)-alstonlarsine A is represented. The unique 9-azatricyclo[4.3.1.03,8]decane core was assembled through an efficient domino sequence comprising enamine formation in situ, followed by intramolecular dearomative inverse-electron-demand Diels Alder reaction. The preparation of the tricyclic dihydrocyclohepta[b]indole key intermediate via the intramolecular Horner–Wadsworth–Emmons reaction required a development of a new general method for the introduction of the phosphonoacetate moiety into the indole C-2 position, through copper-carbenoid insertion. The modular nature of the represented synthetic approach makes it suitable for the synthesis of analogues with different substituents’ patterns.

A tactical combination of either (S)- or (R)-proline catalyzed aldol reaction followed by intramolecular reductive amination enabled the synthesis of a chiral pyrrolidine derivative with 3 contiguous stereocenters in only 2 synthetic steps, starting from achiral precursors. This product, obtainable in both enantiomeric forms, was further exploited as a common intermediate in total syntheses of the biologically active iminosugars: ( + )-swainsonine, (–)-swainsonine, ( + )-8-epi-swainsonine, and ( + )-dideoxy-imino-lyxitol.

An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels–Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2)-H bond functionalization, combined with intramolecular Horner–Wadsworth–Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.

Indole alkaloid (+)-rauvomine B1 contains cyclopropane ring incorporated in the unprecedented 6/5/6/6/3/5 hexacyclic structure ornate with six stereocenters, making this compound a challenging synthetic task. Our strategy for (+)-rauvomine B total synthesis proceeds via a key tetracyclic intermediate, which could be efficiently prepared from commercially available N-Boc-(S)- tryptophan in 4 steps: 1) homologization to homotryptophan 2) aldol reaction 3) Pictet Spengler reaction 4) elimination. This efficient route also enabled several other members of macroline/sarpagine indole alkaloids to be synthesized from this common intermediate, via unified strategy.

Jedan od ključnih koraka u okviru planirane totalne sinteze (+)-alstonlarsina A1 je intramolekulska Horner-Wadsworth-Emmons-ova (HWE) reakcija za zatvaranje cikloheptenskog prstena. Nedavno izolovani monoterpenski indolski alkaloid (+)- alstonlarsin A poseduje jedinstvenu kavezastu strukturu, kao i biološki interesantnu osobinu da se ponaša kao inhibitor DRAK2 enzima. Stoga je razvijena nova metodologija za funkcionalizaciju indola u položaju 2, kako bi se sintetisao odgovarajući 2- fosfonoacetatni indolski prekursor. Ova metodologija se zasniva na efikasnoj intramolekulskoj bakar-karbenoidnoj inserciji, čime je omogućena kasnija HWE reakcija i dobijanje kondenzovanih indolskih derivata sa kondenzovanim petočlanim, šestočlanim, sedmočlanim i osmočlanim prstenom., One of the key steps in our efforts toward the total synthesis of (+)-alstonlarsine A1 – a recently isolated monoterpenoid indole alkaloid possessing a unique cage-shaped structure and acting as Drak2 inhibitor – was an intramolecular Horner-Wadsworth-Emmons (HWE) reaction for the formation of the cycloheptene ring. To achieve this transformation, a new methodology for indole C-2 functionalization was developed aiming to synthesize the 2-phosphonoacetate indole precursor. The represented methodology relied on an efficient intermolecular copper carbenoid insertion, thus allowing a subsequent formation of indole derivatives with condensed 5-, 6-, 7- and 8-membered rings via HWE reaction.

An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels–Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2)-H bond functionalization, combined with intramolecular Horner–Wadsworth–Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.

Over the past two decades, organocatalytic aldol reaction emerged as a powerful method for the enantioselective carbon–carbon bond formation, often offering more efficient, economical and environmentally friendly synthesis of chiral molecules. On the other hand, reductive amination is one of the most important reactions in synthesis of biologically active compounds and drug candidates. Coupling these two reactions results in a powerful combination that allows for a rapid, stereoselective access to substituted, highly functionalized five- and six-membered N-heterocycles. This minireview illustrates the applicability of this approach as the key feature in syntheses of various iminosugars – a class of polyhydroxylated alkaloids with a range of interesting biological activities and high pharmacological potential.

A chiral-pool-based synthesis of the platensimycin core was achieved using (S)-lactic acid as an inexpensive starting material. The cyclohexenone ring was closed in a Mukaiyama–Michael domino sequence, while the quaternary stereocenter was created by a highly stereoselective decarboxylative allylation. The spirobicyclic skeleton was constructed by a RCM reaction. A new silver(I)-promoted cyclization reaction of Δ 6 - and Δ 7 -α-iodoketones was developed and applied for the pivotal carbon–carbon bond formation. The scope and limitations of this methodology are also presented.

Two new analogues of alstoscholarisine A, containing a phenyl or butyl substituent at the C-19 position, have been prepared in racemic form from the known skatole derivative. The syntheses of these compounds were accomplished in 13 steps, with a late-stage formation of the C-19 stereocenter. These derivatives are expected to have significantly changed biological activity, compared to alstoscholarisine A – a potent neuroactive natural product.

Majarova reakcija (MR) je spontana reakcija izmeĊu karbonilne i amino grupe iod velikog je znaĉaja u hemiji hrane. Proteini modifikovani u MR imaju poboljšanetehno-funkcionalne osobine i nalaze primenu u prehrambenoj industriji. TakoĊe,strukture Majarovih proizvoda modifikovanih proteina imaju brojne efekte naalergenost proteina hrane.Predmet rada ove disertacije bilo je ispitivanje efekata MR indukovaneultrazvukom ili sušenjem raspršivanjem na fiziĉko-hemijske i tehno-funkcionalneosobine kravlje surutke i kamiljeg mleka, kao i efekata intenzivnog glikovanja u MR naimunološke osobine glavnog alergena kravljeg mleka, β-laktoglobulina (BLG).Kombinovana primena ultrazvuka i makromolekulskog nagomilavanja jeznaĉajnije ubrzala MR i glikovanje proteina nego sam ultrazvuĉni tretman.Makromolekulsko nagomilavanje, preko ubrzavanja MR, povećava oksidativnepromene na proteinima i formiranje struktura sliĉnih amiloidima. Visoko glikovaniproteini surutke su pokazali poboljšanu rastvorljivost u širokom pH i temperaturnomopsegu, kao i povećanu antioksidativnu moć.U kamiljem mleku u prahu sušenom raspršivanjem više temperature (230 °C –250 °C) su rezultirale većim stepenom MR u odnosu na niže temperature sušenja (190°C – 210 °C). Poboljšanje tehno-funkcionalnih osobina proteina kamiljeg mleka uprahu, kao što su antioksidativna moć i rastvorljivost, je pozitivno koreliralo sastepenom MR.Glikovanje BLG u MR, dovelo je do njegovog smanjenog transporta kroz modelsistem intestinalne barijere, povećanog preuzimanja od strane dendritskih ćelija,smanjenog luĉenja citokina u mešovitoj kulturi dendritskih ćelija sa CD4+ T-ćelijama, ido smanjene aktivacije bazofila, ukazujući da modifikovanje BLG u MR znaĉajnomenja njegovu sudbinu u procesima koji odreĊuju alergenost proteina mleka., Maillard reaction (MR) is a spontaneous reaction between carbonil and aminogroup, and it is of high importance in food chemistry. Proteins modified in MR possessimproved techno-functional properties and they have application in food industry. MRproducts of food proteins exert numerous effects on food proteins allergenicity.The subject of this doctoral dissertation was to examine the effects of MRinduced by ultrasound or spray-drying on phisyco-chemical and techno-functionalproperties of cow whey proteins and camel milk proteins, as well as the effects of MRon immunologic properties of major cow milk allergen, β-lactoglobulin (BLG).Combined application of ultrasound and macromolecular crowding enhancedMR to a greater extent than ultrasound treatment alone. Macromolecular crowdingindirectly, by enhancing MR, intensified oxidative modifications of whey proteins andformation of amyloid-like structures. Highly glycated proteins exhibited improvedsolubility in wide pH range, thermal stability and antioxidative power.Upon spray-drying treatment of camel milk, higher temperatures (230 °C – 250°C) induced higher degree of MR compared to lower drying temperatures (190 °C – 210°C). Improvement of techno-functional properties of camel milk proteins, such asantioxidative power and solubility, strongly correlated with the degree of MR.Intensive glycation of BLG in MR reduced its transport through the modelsystem of intestinal barrier, increased uptake by dendritic cells and decreased cytokineproduction in dendritic cells/CD4+ T-cells coculture, as well as reduced basophilactivation, indicating that modification of BLG in MR alters its fate in processescrucially involved in allergenicity of milk proteins.

Majarova reakcija (MR) je spontana reakcija izmeĊu karbonilne i amino grupe i od velikog je znaĉaja u hemiji hrane. Proteini modifikovani u MR imaju poboljšane tehno-funkcionalne osobine i nalaze primenu u prehrambenoj industriji. TakoĊe, strukture Majarovih proizvoda modifikovanih proteina imaju brojne efekte na alergenost proteina hrane. Predmet rada ove disertacije bilo je ispitivanje efekata MR indukovane ultrazvukom ili sušenjem raspršivanjem na fiziĉko-hemijske i tehno-funkcionalne osobine kravlje surutke i kamiljeg mleka, kao i efekata intenzivnog glikovanja u MR na imunološke osobine glavnog alergena kravljeg mleka, β-laktoglobulina (BLG). Kombinovana primena ultrazvuka i makromolekulskog nagomilavanja je znaĉajnije ubrzala MR i glikovanje proteina nego sam ultrazvuĉni tretman. Makromolekulsko nagomilavanje, preko ubrzavanja MR, povećava oksidativne promene na proteinima i formiranje struktura sliĉnih amiloidima. Visoko glikovani proteini surutke su pokazali poboljšanu rastvorljivost u širokom pH i temperaturnom opsegu, kao i povećanu antioksidativnu moć. U kamiljem mleku u prahu sušenom raspršivanjem više temperature (230 °C – 250 °C) su rezultirale većim stepenom MR u odnosu na niže temperature sušenja (190 °C – 210 °C). Poboljšanje tehno-funkcionalnih osobina proteina kamiljeg mleka u prahu, kao što su antioksidativna moć i rastvorljivost, je pozitivno koreliralo sa stepenom MR. Glikovanje BLG u MR, dovelo je do njegovog smanjenog transporta kroz model sistem intestinalne barijere, povećanog preuzimanja od strane dendritskih ćelija, smanjenog luĉenja citokina u mešovitoj kulturi dendritskih ćelija sa CD4+ T-ćelijama, i do smanjene aktivacije bazofila, ukazujući da modifikovanje BLG u MR znaĉajno menja njegovu sudbinu u procesima koji odreĊuju alergenost proteina mleka., Maillard reaction (MR) is a spontaneous reaction between carbonil and amino group, and it is of high importance in food chemistry. Proteins modified in MR possess improved techno-functional properties and they have application in food industry. MR products of food proteins exert numerous effects on food proteins allergenicity. The subject of this doctoral dissertation was to examine the effects of MR induced by ultrasound or spray-drying on phisyco-chemical and techno-functional properties of cow whey proteins and camel milk proteins, as well as the effects of MR on immunologic properties of major cow milk allergen, β-lactoglobulin (BLG). Combined application of ultrasound and macromolecular crowding enhanced MR to a greater extent than ultrasound treatment alone. Macromolecular crowding indirectly, by enhancing MR, intensified oxidative modifications of whey proteins and formation of amyloid-like structures. Highly glycated proteins exhibited improved solubility in wide pH range, thermal stability and antioxidative power. Upon spray-drying treatment of camel milk, higher temperatures (230 °C – 250 °C) induced higher degree of MR compared to lower drying temperatures (190 °C – 210 °C). Improvement of techno-functional properties of camel milk proteins, such as antioxidative power and solubility, strongly correlated with the degree of MR. Intensive glycation of BLG in MR reduced its transport through the model system of intestinal barrier, increased uptake by dendritic cells and decreased cytokine production in dendritic cells/CD4+ T-cells coculture, as well as reduced basophil activation, indicating that modification of BLG in MR alters its fate in processes crucially involved in allergenicity of milk proteins.

Ispitana je dvostruka asimetrična indukcija u aldolnim reakcijama između dioksanona ihiralnih acikličnih α-supstituisanih aldehida katalizovanih prolinom, i tom prilikom jeutvrđeno da je stereohemijski ishod ove reakcije kontrolisan reagensom, sa dobrimstepenom dijastereoselektivnosti. Sa cikličnim aldehidima stereokontrola nijezadovoljavajuća.Takođe, kombinacijom organokatalizovane aldolizacije i reduktivnog aminovanja,sintetisano je šest biološki aktivnih jedinjenja: (+)-2-epi-hiacintacin A2, (–)-3-epihiacintacinA1, 1-deoksi-galaktonodžirimicin (DGJ), 2,5-dideoksi-2,5-imino-D-altritol(DIA), (–)-4-epi-fagomin i (+)-aza-galaktofagomin. Pored ovih iminošećera, istimpristupom sintetisano je još tri molekula - pipekolinska kiselina, 3-hidroksipipekolinskakiselina i 4-deoksifagomin - koji predstavljaju sintetički značajne intermedijere zadobijanje drugih biološki aktivnih jedinjenja. U svim sintezama kao ključna reakcijakorišćena je asimetrična aldolna adicija 2,2-dimetil-1,3-dioksan-5-ona (dioksanona) naodgovarajući aldehid katalizovana prolinom i praćena reduktivnim aminovanjem.Formirana su dva nova stereocentra primenom principa katalitičke asimetrične sinteze ijedan dijastereoselektivnim reduktivnim aminovanjem., Double asymmetric induction was investigated in proline-catalyzed aldol additionsbetween dioxanone and chiral α-substituted aldehydes, and it was found that, withacyclic aldehydes, the stereochemical outcome of this reaction was controlled by areagent, with a good level of diastereoselectivity. Stereocontrol with cyclic aldehydes isnot satisfactory.Six biologically active compounds as well as some significantly useful intermediateswere synthesized by a combination of organocatalytic aldol addition and reductiveamination: (+)-2-epi-hyacinthacine A2, (–)-3-epi-hyacinthacine A1, 1-deoxygalactonojirimycin(DGJ), 2,5-dideoxy-2,5-imino-D-altritol (DIA), (–)-4-epi-fagomine and (+)-aza-galacto-fagomine. In addition to these iminosugars, three other molecules -pipecolic acid, 3-hydroxypipecolic acid and 4-deoxyfagomine - are synthesized byapplying this tactical combination on the same way, and they are significantintermediates in synthesis of other biologically active compounds. Proline-catalyzedasymmetric aldol addition of 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) to thecorresponding aldehyde, followed by reductive amination, was used as the keytransformation in all syntheses. Two new stereocentres were formed in these reactionsusing the principle of catalytic asymmetric synthesis and one by diastereoselectivereductive amination.

Ispitana je dvostruka asimetrična indukcija u aldolnim reakcijama između dioksanona i hiralnih acikličnih α-supstituisanih aldehida katalizovanih prolinom, i tom prilikom je utvrđeno da je stereohemijski ishod ove reakcije kontrolisan reagensom, sa dobrim stepenom dijastereoselektivnosti. Sa cikličnim aldehidima stereokontrola nije zadovoljavajuća. Takođe, kombinacijom organokatalizovane aldolizacije i reduktivnog aminovanja, sintetisano je šest biološki aktivnih jedinjenja: (+)-2-epi-hiacintacin A2, (–)-3-epihiacintacin A1, 1-deoksi-galaktonodžirimicin (DGJ), 2,5-dideoksi-2,5-imino-D-altritol (DIA), (–)-4-epi-fagomin i (+)-aza-galaktofagomin. Pored ovih iminošećera, istim pristupom sintetisano je još tri molekula - pipekolinska kiselina, 3-hidroksipipekolinska kiselina i 4-deoksifagomin - koji predstavljaju sintetički značajne intermedijere za dobijanje drugih biološki aktivnih jedinjenja. U svim sintezama kao ključna reakcija korišćena je asimetrična aldolna adicija 2,2-dimetil-1,3-dioksan-5-ona (dioksanona) na odgovarajući aldehid katalizovana prolinom i praćena reduktivnim aminovanjem. Formirana su dva nova stereocentra primenom principa katalitičke asimetrične sinteze i jedan dijastereoselektivnim reduktivnim aminovanjem., Double asymmetric induction was investigated in proline-catalyzed aldol additions between dioxanone and chiral α-substituted aldehydes, and it was found that, with acyclic aldehydes, the stereochemical outcome of this reaction was controlled by a reagent, with a good level of diastereoselectivity. Stereocontrol with cyclic aldehydes is not satisfactory. Six biologically active compounds as well as some significantly useful intermediates were synthesized by a combination of organocatalytic aldol addition and reductive amination: (+)-2-epi-hyacinthacine A2, (–)-3-epi-hyacinthacine A1, 1-deoxygalactonojirimycin (DGJ), 2,5-dideoxy-2,5-imino-D-altritol (DIA), (–)-4-epi-fagomine and (+)- aza-galacto-fagomine. In addition to these iminosugars, three other molecules - pipecolic acid, 3-hydroxypipecolic acid and 4-deoxyfagomine - are synthesized by applying this tactical combination on the same way, and they are significant intermediates in synthesis of other biologically active compounds. Proline-catalyzed asymmetric aldol addition of 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) to the corresponding aldehyde, followed by reductive amination, was used as the key transformation in all syntheses. Two new stereocentres were formed in these reactions using the principle of catalytic asymmetric synthesis and one by diastereoselective reductive amination.

Hiralni, polisupstituisani derivati pirolidina, dobijeni cikloadicionim reakcijama azometinskih ilida, proučavani su kao organokatalizatori u Michael-ovoj reakciji aldehida/ketona i vinil-sulfona. Pod optimalnim reakcionim uslovima, u kojima se koristilo 10 mol % katalizatora u vlažnom metilen-hloridu prinosi reakcija su generalno bili dobri dok je enantioselektivnost varirala dostižući 52 %. Razvijen je efikasan biokatalizator za asimetričnu Michael-ovu adiciju acetaldehida na β- nitrostiren na bazi celih ćelija koja eksprimira 4-oksalokrotonat tautomerazu (4-OT). Utvrđen je optimalan odnos supstrata i biokatalizatora. Kada je kao supstrat korišćen β-nitrostiren dobijena je odlična enantioselektivnost (e.e. >99%) uz prinos reakcije do 60%. Biokatalizator je manje efikasan sa p-hlor-, o-hlor- i p-fluor-β-nitrostirenom gde su dobijeni prinosi od 38%, 51%, 31% i e.e. 84%, 88%, 94%..., Chiral, polysubstituted pirrolydines derivatives, obtained via cycloaddition reactions of azomethine ylides, were studied as organocatalysts in the Michael reaction of aldehydes/ketones and vinylsulphones. Under optimised reaction conditions employing 10 mol % of the catalyst in wet CH2Cl2, the yields of the products were generally good while the enantioselectivity varied, reaching up to 52 %. A novel whole cell system based on recombinantly expressed 4-oxalocrotonate tautomerase (4-OT) was developed and shown to be an effective biocatalyst for the asymmetric Michael addition of acetaldehyde to β-nitrostyrenes. Optimal ratio of substrates and biocatalyst was determined. Excellent enantioselectivity (>99% ee) and product yields of up to 60% were obtained with β-nitrostyrene substrate. The biocatalyst exhibited lower reaction rates with pchloro-, o-chloro- and p-fluoro-β-nitrostyrenes with product yields of 38%, 51%, 31% and ee values of 84%, 88% and 94% respectively...

A catalytic asymmetric synthesis of (+)-aza-galacto-fagomine (AGF) - the most promising compound for the pharmacological chaperone therapy of Krabbe disease was accomplished in six steps, in 14% overall yield. The synthesis hinges on the combination of organocatalyzed aldolization and reductive hydrazination.

Sintetisali smo biblioteku od 18 derivata (R)-3-hidroksioktanske kiseline,monomera bakterijskog polimera poli(hidroksialkanoata). Sva jedinjenja suokarakterisana i testirana je njihova antimikrobna i antiproliferativna aktivnost. Kakobismo ispitali značaj konfiguracije na hiralnom centru polazne kiseline za njenubiološku aktivnost, sintetisan je (S)-metil-3-hidroksioktanoat. U okviru teze je ispitanamogućnost konjugacije 3-hidroksialkanskih kiselina različite dužine lanca i hemijskisintetisane 3-hlordekanske kiseline na antikancerski peptid kao i uticaj na promenubiološke aktivnosti peptida., We have synthesized a library of 18 derivatives from (R)-3-hydroxyoctanoicacid, monomer of bacterial polymer poly(hydroxyalkanoate). All compounds werecharacterized and tested for their antimicrobial and anti-proliferative activity. In order toexamine the significance of the configuration of the chiral center of the starting acid inthe biological activity, (S)-methyl-3-hydroxyalkanoate was synthesized. Within the PhDthesis the possibility of conjugation 3-hydroxy alkanoic acids of different chain lengthand chemically synthesized 3-chloro octanoic acid with anticancer peptide wasinvestigated, and impact of conjugation in changing biological activity of the peptide.

Razvijene su dve enantioselektivne formalne sinteze oseltamivir-fosfata i totalna enantioselektivna sinteza svainsonina. U prvoj sintezi oseltamivir-fosfata kao ključne reakcije korišćene su enantioselektivna aldolna adicija hiralnog borovog enolata na hiralni aldehid, čime su formirana dva nova stereocentra i aldolna kondenzacija kojom je nagrađen cikloheksenski prsten. U drugoj sintezi oseltamivir-fosfata kao ključne reakcije korišćene su alilovanje hiralnog aldehida u vodenim uslovima i ciklizaciona metateza za formiranje cikloheksenskog skeleta. Na osnovu rezultata do kojih se došlo u sintezi oseltamivira, razvijena je enantioselektivna sinteza Garner-ovog aldehida, koja se zasniva na transfer-hidrogenolizi odgovarajućeg tioestra. Totalna enantioselektivna sinteza svainsonina počiva na taktičkoj kombinaciji organokatalizovane aldolne adicije i reduktivnog aminovanja, čime se formira pirolidinski skelet sa tri definisana stereocentra, dok je piperidinski prsten zatvoren primenom još jedne reakcije reduktivnog aminovanja. U okviru sintetičke studije platenzimicina ostvaren je prodor prema formalnoj sintezi oksatetracikličnog Nicolaou-ovog intermedijera, gde je uspešno napravljen spiro-biciklični intermedijer. Kao ključne reakcije za sintezu ovog jedinjenja iskorišćene su Mukaiyama–Michael-ova reakcija, praćena 6–endo-trig ciklizacijom, dekarboksilativno alilovanje i ciklizaciona metateza., Two enantioselective formal syntheses of oseltamivir phosphate and the enantioselective total synthesis of swainsonine have been accomplished. The key reactions in the first synthesis of oseltamivir phosphate were enantioselective aldol additions of boron enolate to chiral aldehyde, that formed two new stereocenters, and aldol condensation for the construction of cyclohexene ring. In the second synthesis of oseltamivir phosphate, the pivotal steps were allylation of chiral aldehydes under aqueous conditions and ring closing metathesis for the formation of cyclohexene ring. Based on the results for the first synthesis of oseltamivir, a new enantioselective synthesis of Garner aldehyde was developed, that hinges on the transfer hydrogenation of the corresponding thioester. Total enantioselective synthesis of swinsonine was based on the tactical combination of organocatalyzed aldol addition and reductive amination for the formation of the pyrrolidine skeleton with three contiguous stereocenter, followed by the piperidine ring formation by a second reductive amination. Within a synthetic study on platensimycin, a breakthrough towards formal synthesis of oxatetracyclic Nicolaou's intermediate was achieved, by successfully synthesizing the spirobicyclic intermediate. The key steps in the synthesis of this compound were Mukaiyama-Michael's reaction followed by 6-endo-trig cyclisation, decarboxylative allylation and ring closing metathesis.

The enantioselective synthesis of 4-epi-fagomine was accomplished starting from dioxanone and Cbz-protected benyzlamine, in 4 steps, with 18% overall yield. The key feature of this synthetic approach is the tactical combination of reactions: organocatalyzed aldolization/reductive amination, which allows for a quick formation of heterocyclic rings with defined absolute configuration of all stereogenic centers. Two hydroxypipecolic acids and a reduced fagomine analogue were also synthesized.

Razvijen je nov pristup sintezi petočlanih i šestočlanih prstenova, zasnovan na kombinaciji organokatalize i katalize kompleksima prelaznih metala. Organokatalizovana Tsuji-Trost-ova reakcija omogućuje 5-egzo- i 6-egzo-ciklizacije aldehida koji u pogodnom položaju poseduju alilnu funkcionalnu grupu, uz nastajanje karbocikličnih i N-heterocikličnih prstenova. Moguća je i katalitička asimetrična varijanta reakcije, kojom se dobijaju vinilciklopentanski derivati optičke čistoće više od 98% ee. Nova reakcija je upotrebljena kao ključni korak u totalnoj sintezi prirodnog proizvoda (+)-alokainske kiseline i njenog strukturnog analoga. Ciklizacije aldehida koji poseduju stereocentar odigravaju se stereoselektivno i kontrolisane su supstratom, a stereohemijski ishod ciklizacija može se predvideti računarskim metodama.

Razvijen je nov pristup sintezi petočlanih i šestočlanih prstenova, zasnovan na kombinaciji organokatalize i katalize kompleksima prelaznih metala. Organokatalizovana Tsuji-Trost-ova reakcija omogućuje 5-egzo- i 6-egzo-ciklizacije aldehida koji u pogodnom položaju poseduju alilnu funkcionalnu grupu, uz nastajanje karbocikličnih i N-heterocikličnih prstenova. Moguća je i katalitička asimetrična varijanta reakcije, kojom se dobijaju vinilciklopentanski derivati optičke čistoće više od 98% ee. Nova reakcija je upotrebljena kao ključni korak u totalnoj sintezi prirodnog proizvoda (+)-alokainske kiseline i njenog strukturnog analoga. Ciklizacije aldehida koji poseduju stereocentar odigravaju se stereoselektivno i kontrolisane su supstratom, a stereohemijski ishod ciklizacija može se predvideti računarskim metodama.

Intermolecular Nozaki-Hiyama-Kishi coupling between alkenylchromium(III) reagents, derived from either (E)-(2-bromoethenyl)benzene or (E)-1-iodo-1-pentadecene, and the conformationally rigid Garner's aldehyde resulted in the stereoselective formation of Felkin-type allylic alcohols in good yields, thus providing an easy access to sphingosines. In addition, when the protecting group in the Garner's aldehyde was changed (from Boc to N-octanoyl), a reversal of stereoselectivity was observed in the reaction with (E)-1-pentadecenylchromium(III), probably as the result of hydrophobic interactions between the long carbon chains of the reaction partners.

Enantioselective synthesis of (+)-swainsonine was achieved in 9 steps, with 24% overall yield. The key feature of the synthesis is the tactical combination of reactions: organocatalyzed aldolization/reductive amination, which allows for a rapid construction of highly functionalized heterocyclic systems. In a similar way (+)-8-epi-swainsonine was synthesized (7 steps, 28%).

The stereodivergent synthesis of two hyacinthacine analogues, which relies on an organocatalyzed aldol addition, is described. The aldol addition of dioxanone to an -N-carbobenzyloxy-substituted chiral aldehyde, promoted by both (R)- and (S)-proline, proceeds in reasonable yields with acceptable diastereomeric ratios. The success of the reaction may be due to the use of an acyclic aldehyde acceptor, which allows reagent control of the stereochemical outcome of the key aldolization step in both the matched and mismatched cases.

The formal synthesis of (-)-oseltamivir phosphate (Tamiflu (TM)) was accomplished starting from (S)-pyroglutamic acid. The synthesis comprised two carbon-carbon bond forming reactions, the first one being a diastereoselective, indium-mediated allylation of a pyroglutamic aldehyde derivative. However, attempts to effect the second carbon-carbon bond formation - cyclohexene ring closure - using an enol-exo aldolization of a dialdehyde resulted in the formation of a product with the opposite regioselectivity. This shortcoming could be overcome by using a reaction sequence of Mannich methylenation/ring-closing metathesis, which provided the desired regioisomer in high yield.

A synthetic sequence has been developed for the preparation of 9,10- di-O-diacetyl-4-desmethylene-4β-(3-butenyl)-4α-hydroxy-5-O-mesyltaxicin I- -1,2-carbonate 3, an intermediate in an attempted synthesis of a cyclobutane paclitaxel analogue. A series of reactions of 3 were investigated, including the protection of the sterically hindered C-4α-hydroxy group and the oxidative cleavage of the terminal double bond. Cyclization of 13 to the cyclobutane-containing intermediate failed due to the unexpected instability of the dimethylsilane protecting group under basic conditions., Razvijena je sintetička sekvenca za dobijanje 9,10-di-O-acetil-4-desmetilen-4β-(3-butenil)-4α-hidroksi-5-O-meziltaksicin I-1,2-karbonata (3), intermedijera u pokušanoj sintezi ciklobutanskog analoga paklitaksela. Ispitivana je mogućnost dalje hemijske transformacije jedinjenja 3, kao što je zaštita sterno izrazito zaštićene C-4α hidroksilne grupe i oksidativna fragmentacija terminalne dvostruke veze. Ciklizacija jedinjenja 13 nije dala željeni rezultat - intermedijer sa ciklobutanovim prstenom, što je posledica neočekivane nestabilnosti DMS-zaštitne grupe u baznim reakcionim uslovima.

The design, synthesis and biological evaluation of a novel C, D-spirolactone analogue of paclitaxel is described. This is the first paclitaxel analogue without an oxetane D-ring that shows a significant cytotoxic effect (activity one order of magnitude lower than paclitaxel). More importantly, its cytotoxicity is a result of a different mechanism of action, involving mTOR inhibition-dependent autophagy instead of G(2)/M cell cycle arrest-dependent apoptosis.

The design, synthesis and biological evaluation of a novel C, D-spirolactone analogue of paclitaxel is described. This is the first paclitaxel analogue without an oxetane D-ring that shows a significant cytotoxic effect (activity one order of magnitude lower than paclitaxel). More importantly, its cytotoxicity is a result of a different mechanism of action, involving mTOR inhibition-dependent autophagy instead of G(2)/M cell cycle arrest-dependent apoptosis.