Proline-catalyzed aldol reactions

In the 1970s, two research groups discovered (and published) almost simultaneously their discoveries of two related intramolecular reactions: Zoltan Hajos and David Parrish at Hoffmann-La Roche[2][3] and Rudolf Wiechert et al at Schering AG.

Three decades later, Carlos Barbas and Benjamin List demonstrated that larger catalyst concentrates could enable a similar intermolecular reaction.

In 1971, Escher headed a research group at Schering AG examining reactions under non-biological conditions: (S)-Proline (47 mol%) and 1N perchloric acid in acetonitrile at 80 °C.

Their reaction sequence produced bicyclic ketol intermediates in good yield, which, to their surprise, exhibited circular dichroism corresponding to a large enantiomeric excess.

[2][3] A single-crystal X-ray diffraction study confirmed this hypothesis,[2][3] showing an axial methyl and equatorial hydroxyl group, as in digitoxigenin's CD-ring:[8][improper synthesis?

[10] Searching the literature, they noticed that Hajos et al had already identified a similar reaction, and began investigating whether simple enamines could substitute for their antibodies.

(S)-1-(2-pyrrolidinylmethyl)-pyrrolidine salts would forme the basis for the development of diamine organocatalysts that have proven effective in a wide variety or organocatalytic reactions.

The iminium hydroxide ion caused enolization of the side chain methyl ketone would be followed by ring closure to the above shown optically active bicyclic ketol product (see Figure 1.)

The virtual anomaly can be explained with a top side approach of the bulkier beta amino acids to the above triketone starting material of reflective symmetry.

The top side approach results in the formation of an enantiotopic carbinolamine to give the (−)-(3aR,7aR)-3a,4,7,7a-tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)-indanedione bicyclic ketol enantiomer identical to the one obtained with unnatural (R)-(+)-proline.

List in 2010[22] on the other hand is perplexed and surprised that Hajos rejected the enamine mechanism, certainly in light of earlier work by Spencer in 1965 on amine catalysed aldol reactions.

This is the same mechanism proposed by Barbas for aldolase antibodies reported by the group in 1995: This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami[17] is disputed by Barbas based on the lack of a non-linear effects[16] and supported by later studies of List based on reaction kinetics.

Sodiumborohydride reduction of the primarily formed aldol products gave the corresponding alcohols in good yield and excellent enantioselectivity in the ratio of PN/PO=>99:1 as shown in the Scheme below.