Asymmetric synthesis of isoquinuclidines by Diels–Alder reaction of 1,2-dihydropyridine utilizing a chiral Lewis acid catalyst

Abstract

The chiral isoquinuclidine derivative, 2-azabicyclo[2.2.2]octane ring system, endo-(7 R)- 3 was obtained in good yield with excellent diastereoselectivity (up to 92% de) by Diels–Alder reaction of 1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with N-acryloyl-(4 S)-4-benzyloxazolidin-2-one (4 S)- 2 using titanium-(2 R,3 R)-TADDOLate 4 as a chiral Lewis acid catalyst in toluene at 0 °C. On the other hand, endo-(7 S)- 3 was obtained in good yield with excellent diastereoselectivity (up to 97% de) by Diels–Alder reaction of 1 with (4 R)- 2 using Cu(OTf) 2/(4 S,4′ S)-bis(oxazoline) catalyst 8 as a chiral Lewis acid catalyst in dichloromethane at 0 °C. In these reactions, the choice of solvent and the combination of titanium-(2 R,3 R)-TADDOLate 4 {or Cu(II)/(4 S,4′ S)-bis(oxazoline) 8} and dienophile (4 S)- 2 {or (4 R)- 2} are very important. The stereochemistry of endo-(7 R)- 3 has been established to be (1 R,4 S,7 R) and the reaction mechanism is proposed.