Enantioselektivne sinteze jedinjenja značajnih za medicinu: oseltamivir-fosfat (tamifly), svainsonin i platenzimicin
oseltamivir phosphate (tamiflu), swainsonine and platensimycin
Author
Trajković, Miloš D.Mentor
Saičić, Radomir
Committee members
Ferjančić, Zorana
Bihelović, Filip

Matović, Radomir

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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 stereoc...enter,
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.