Primena taktičke kombinacije organokatalitičke aldolizacije i reduktivnog aminovanja na sintezu polihidroksilovanih alkaloida značajnih za medicinu

Abstract

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.