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