Biomimetic Organocatalytic C–C-Bond Formations
77
This catalytic cascade was first realized using propanal, nitrostyrene
and cinnamaldehyde in the presence of catalytic amounts of OTMSprotected diphenylprolinol ((S)-71, 20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst
(S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi
et al. 2005). The following hydrolysis liberates the catalyst, which is
now able to form the iminium ion of the α,β-unsaturated aldehyde C to
accomplish in the second step the conjugate addition of the nitroalkane
(Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol
condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8)
(Enders and Hüttl 2006).
After optimization of the reaction conditions, we carried out the
domino reaction in toluene between 0°C and room temperature; the reaction was finished between 16 hours and 3 days. Nearly stoichiometric
amounts of all three components were used (A:B:C =1.20:1.00:1.05).
Complete enantiocontrol (97% to ≥99% ee, except in one case only
79% ee) was obtained.
The best results concerning yield and selectivity were obtained with
20 mol% of the TMS-ether (S)-71, which is easily available from the
natural amino acid (S)-proline. Using the (R)-proline derived catalyst
(R)-71 affords the enantiomeric products ent-72 (Scheme 17).
The fact that the residues R
1 –R
3 of the precursors A, B and C can
be broadly varied demonstrates the high flexibility of our approach. R
1
of component A can bear simple to demanding residues as well as valuable functional groups (Scheme 17). R
2 is limited to aromatic and heteroaromatic substituents, due to the lower reactivity of the aliphatic nitroalkenes. The residue R
3 of component C allows the broadest diversity. Aliphatic as well as aromatic moieties are tolerated. Furthermore,
acrolein (R
3 = H) can be used, affording trisubstituted cyclohexene
carbaldehydes. The best yields were obtained with aromatic substituents
R
2 and R
3 (38%–60%). The replacement of R
3 by aliphatic residues
led to lower yields (25% and 29%), whereas sterically demanding aldehydes A had less influence on the yield. In contrast, the variation of
the residues had only a small impact on the diastereoselectivity (68:32-
77
This catalytic cascade was first realized using propanal, nitrostyrene
and cinnamaldehyde in the presence of catalytic amounts of OTMSprotected diphenylprolinol ((S)-71, 20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst
(S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi
et al. 2005). The following hydrolysis liberates the catalyst, which is
now able to form the iminium ion of the α,β-unsaturated aldehyde C to
accomplish in the second step the conjugate addition of the nitroalkane
(Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol
condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8)
(Enders and Hüttl 2006).
After optimization of the reaction conditions, we carried out the
domino reaction in toluene between 0°C and room temperature; the reaction was finished between 16 hours and 3 days. Nearly stoichiometric
amounts of all three components were used (A:B:C =1.20:1.00:1.05).
Complete enantiocontrol (97% to ≥99% ee, except in one case only
79% ee) was obtained.
The best results concerning yield and selectivity were obtained with
20 mol% of the TMS-ether (S)-71, which is easily available from the
natural amino acid (S)-proline. Using the (R)-proline derived catalyst
(R)-71 affords the enantiomeric products ent-72 (Scheme 17).
The fact that the residues R
1 –R
3 of the precursors A, B and C can
be broadly varied demonstrates the high flexibility of our approach. R
1
of component A can bear simple to demanding residues as well as valuable functional groups (Scheme 17). R
2 is limited to aromatic and heteroaromatic substituents, due to the lower reactivity of the aliphatic nitroalkenes. The residue R
3 of component C allows the broadest diversity. Aliphatic as well as aromatic moieties are tolerated. Furthermore,
acrolein (R
3 = H) can be used, affording trisubstituted cyclohexene
carbaldehydes. The best yields were obtained with aromatic substituents
R
2 and R
3 (38%–60%). The replacement of R
3 by aliphatic residues
led to lower yields (25% and 29%), whereas sterically demanding aldehydes A had less influence on the yield. In contrast, the variation of
the residues had only a small impact on the diastereoselectivity (68:32-