Pd(II)Pd(II)--Catalysed CyclisationsCatalysed Cyclisationsof Aminoalkenitolsof Aminoalkenitols
Dr. Peter SzolcsányiDepartment of Organic ChemistrySlovak University of Technology
Bratislava, Slovak Republic
Pd(II)-Catalysed chlorocyclisation and N,O-bicyclisation
of polyhydroxylated aminoalkenitols
Synthetic versatility of chloromethyl piperidines
Structural diversity of piperidine/azepine alkaloids
Where did the idea come from ?
P. Szolcsányi et al.: Tetrahedron: Asymmetry 2000, 11, 2579-2597.
Substrates for the screening
Preparation of substrates - D-gluco serie
Preparation of substrates - D-galacto serie
Pd(II)/CuCl2-catalysed chlorocyclisation-D-gluco serie
Entry Solvent Time & Temperature Isolated yield (after FLC)
HPLC ratio of L-ido / D-gluco (d.e.)
1 AcOH 48 hrs, 23oC 70% 19 / 1 (90%)2 DMF 24 hrs, 30oC 21% 8 / 1 (82%)
3 CH2Cl2 24 hrs, 30oC 65% 6 / 1 (71%)
4 THF 24 hrs, 30oC 60% 6 / 1 (71%)5 MeOH 24 hrs, 23°C 59% 5 / 1 (67%)6 Toluene 48 hrs, 30oC 56% 3 / 1 (33%)
Pd(II)/CuCl2-catalysed chlorocyclisation-D-galacto serie
Entry Solvent Catalyst & Additive(s) Time & Temperature
Chlorides/bicycle (yield after FLC)
HPLC ratio ofL-altro/D-gala
(d.e.)1 AcOH 0.1 eq. PdCl2, 3 eq. CuCl2, 3 eq. AcONa 24 hrs, 25oC 28% / 49% 19 / 1 (90%)2 DMF - detto - 19 hrs, 25oC 53% / 11% 15 / 1 (88%)3 CH2Cl2 - detto - 24 hrs, 29oC 36% / 8% 5 / 1 (67%)4 THF - detto - 24 hrs, 25oC 54% / 10% 2 / 1 (33%)5 Toluene - detto - 24 hrs, 29oC 43% / 9% 1 / 2 (33%)6 MeOH - detto - 24 hrs, 25oC 32% / 7% 1 / 3 (50%)7 AcOH 0.1 eq. PdCl2, 2 eq. CuCl2, 2 eq. AcONa 48 hrs, 30oC 35% / 52% 19 / 1 (90%)8 AcOH 0.1 eq. PdCl2, 1 eq. CuCl2, 1 eq. AcONa 48 hrs, 28oC 25% / 48% 19 / 1 (90%)9 AcOH 0.1 eq. PdCl2, 3 eq. CuCl2 24 hrs, 30oC 27% / 50% 19 / 1 (90%)10 AcOH 1 eq. PdCl2, 3 eq. AcONa 96 hrs, 28oC 0% / 0% -11 AcOH 0.1 eq. Pd(OAc)2, 2 eq. BQ, 3 eq. AcONa 24 hrs, 30oC - / 0% -
Mechanistic proposal of the Pd(II)/CuCl2-catalysedchloroaminocyclisation and bicyclisation
Synthesis of new analogues of iminoalditols
P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498-8502.
Conclusions
• We have found a novel Pd(II)-catalysed halocyclisation and/or bicyclisationWe have found a novel Pd(II)-catalysed halocyclisation and/or bicyclisation of aminoalkenitols providing chloromethyl-piperidines and/or of aminoalkenitols providing chloromethyl-piperidines and/or oxaoxa-- azabicyclo[3.2.1]octanesazabicyclo[3.2.1]octanes
• We have postulated the reaction mechanism explaining the observedWe have postulated the reaction mechanism explaining the observed chemoselectivitychemoselectivity
• Both transformations were developed intoBoth transformations were developed into effectiveeffective synthetic methodsynthetic methodologiesologies that were successfully that were successfully emploemployyeded in the total synthesis of new analogues of in the total synthesis of new analogues of glycosidase inhibitor 1-deoxynojirimycinglycosidase inhibitor 1-deoxynojirimycin
Acknowledgments
Generous support Prof. Dr. Tibor Gracza
HPLC Dr. Katarína Hroboňová
NMR Dr. Naďa Prónayová
IR Ms. Silvia Markusová
MALDI Dr. Ivan Špánik
Grant APVT-20-000904
Known precedents of Pd(II)/CuCl2-catalysedhaloaminocyclisation yielding 6-membered azacycles
Known reports on Pd(II)/Cu(II)-heterobimetallic complexes