In the early 1970, the first L-proline-catalyzed aldol cyclization was appeared (Scheme 3). After nearly 25 years, the expected transition state for the reaction has been illustrated (Scheme 4).

Scheme 3 . L -Proline-Catalyzed Robinson Annulation Through Aldol Reaction

Scheme 4. Expected Transition State

10.1.1 Intermolecular Aldol Reaction

The enantioselective aldol reaction is one of the most powerful methods for the construction of chiral polyol. The first intermolecular direct enantioselective aldol reaction catalyzed by L-proline appeared employing acetone and 4-nitrobenzaldehyde as the substrates (Scheme 5). This result sparked high interest from several groups in further investigating proline-catalyzed direct asymmetric aldol reactions. Subsequently, modified chiral proline derived catalysts L1-3 has been developed to enhance the selectivity of the reaction.

Scheme 5. First L-Proline Catalyzed Direct Aldol Reaction