organocatalytic aldol addition/reductive amination in synthesis of medicinally important polyhydroxylated alkaloids

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

Supplementary data for article: Marjanović-Trajković, J.; Ferjančić, Z.; Saičić, R. A Short Stereoselective Synthesis of (+)-Aza-Galacto-Fagomine (AGF). Tetrahedron 2017, 73 (18), 2630. https://doi.org/10.1016/j.tet.2017.03.052

Supplementary material for: [https://doi.org/10.1016/j.tet.2017.03.052]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2452]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3025

Supplementary data for the article: Marjanovic Trajkovic, J.; Milanovic, V.; Ferjancic, Z.; Saicic, R. N. On the Asymmetric Induction in Proline-Catalyzed Aldol Reactions: Reagent-Controlled Addition Reactions of 2,2-Dimethyl-1,3-Dioxane-5-One to Acyclic Chiral α-Branched Aldehydes. European Journal of Organic Chemistry 2017, 2017 (41), 6146–6153. https://doi.org/10.1002/ejoc.201701073

Supporting information for: [https://doi.org/10.1002/ejoc.201701073]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2410

Supplementary data for article: Marjanovic, J.; Ferjancic, Z.; Saicic, R. N. Organocatalyzed Synthesis of (-)-4-Epi-Fagomine and the Corresponding Pipecolic Acids. Tetrahedron 2015, 71 (38), 6784–6789. https://doi.org/10.1016/j.tet.2015.07.036

Supplementary material for: [https://doi.org/10.1016/j.tet.2015.07.036]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1951]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3389

Supplementary data for article: Marjanović-Trajković, J.; Ferjančić, Z.; Saičić, R. A Short Stereoselective Synthesis of (+)-Aza-Galacto-Fagomine (AGF). Tetrahedron 2017, 73 (18), 2630. https://doi.org/10.1016/j.tet.2017.03.052

Supplementary material for: [https://doi.org/10.1016/j.tet.2017.03.052]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2452]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3025

A short stereoselective synthesis of (+)-aza-galacto-fagomine (AGF)

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.This is the peer-reviewed version of the following article: Marjanović-Trajković, J.; Ferjančić, Z.; Saičić, R. A Short Stereoselective Synthesis of (+)-Aza-Galacto-Fagomine (AGF). Tetrahedron 2017, 73 (18), 2630. [https://doi.org/10.1016/j.tet.2017.03.052]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3026

Supplementary data for article: Marjanović-Trajković, J.; Divjakovic, V.; Matovic, R.; Ferjančić, Z.; Saičić, R. Double Asymmetric Induction in Organocatalyzed Aldol Reactions: Total Synthesis of (+)-2-Epi-Hyacinthacine A(2) and (-)-3-Epi-Hyacinthacine A(1). European Journal of Organic Chemistry 2013, 2013 (25), 5555–5560. https://doi.org/10.1002/ejoc.201300716

Supporting information for: [https://doi.org/10.1002/ejoc.201300716]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1389

Supplementary data for the article: Marjanovic Trajkovic, J.; Milanovic, V.; Ferjancic, Z.; Saicic, R. N. On the Asymmetric Induction in Proline-Catalyzed Aldol Reactions: Reagent-Controlled Addition Reactions of 2,2-Dimethyl-1,3-Dioxane-5-One to Acyclic Chiral α-Branched Aldehydes. European Journal of Organic Chemistry 2017, 2017 (41), 6146–6153. https://doi.org/10.1002/ejoc.201701073

Supporting information for: [https://doi.org/10.1002/ejoc.201701073]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2410

Supplementary data for article: Marjanović-Trajković, J.; Divjakovic, V.; Matovic, R.; Ferjančić, Z.; Saičić, R. Double Asymmetric Induction in Organocatalyzed Aldol Reactions: Total Synthesis of (+)-2-Epi-Hyacinthacine A(2) and (-)-3-Epi-Hyacinthacine A(1). European Journal of Organic Chemistry 2013, 2013 (25), 5555–5560. https://doi.org/10.1002/ejoc.201300716

Supporting information for: [https://doi.org/10.1002/ejoc.201300716]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1389

Organocatalyzed synthesis of (-)-4-epi-fagomine and the corresponding pipecolic acids

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.Peer-reviewed manuscript: [http://cherry.chem.bg.ac.rs/handle/123456789/3389]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3390