Synthesis Of Novel L-proline Derivatives And The Catalytic Effects On The Asymmetric Direct Aldol Reaction

Since2000, the early discovery of List and Barbas that L-proline was used as the catalyst for the enantioselective direct aldol reaction, asymmetric organic catalytic have been greatly developed and applied for highly enantioselective direct aldol reaction, Michael addition and Mannich reaction. Compared with the traditional chiral catalysts of enzyme and transition metal-chiral legend, the organocatalyst showed lots of advantages such as inexpensive, low toxicity and simply operation. However, the organocatalyst also owns some shortcomings as poor solubility, rigorous reaction condition and extra addition of additives et.al.To overcome the shortcomings, we designed and synthetized a series of L-proline derived organocatalysts containing pyridine-2,6-biformacyl.Commercial available L-proline and pyridine-2,6-dicarboxylic acid were taken as the starting materials, bifunctional L-prolinamide derivative organocatalysts were synthesized via the reduction of carboxyl, protection of amino and hydroxy, azidation et.al. These catalysts are (S)-N2-(pyrrolidin-2-ylmethyl)-N6-tosylpyridine-2,6-dicarboxamide,(S)-N2-(mesitylsulfonyl)-N6-(pyrrolidin-2-ylmethyl) pyridine-2,6-dicarboxamide and (S)-N2-((4-dodecylphenyl)sulfonyl)-N6-(pyrrolidin-2-ylmethyl)pyridine-2,6-dic ar-bo-xamide, all the organocatalysts and a part of important intermediates were confirmed by Infrared Spectroscopy (FT-IR) and Nuclear Magnetic Resonance (’H-NMR). Some synthesis processes were refined in order to improve catalytic activity and solubility of the catalysts.Catalystic performance were performed by the reactions between cyclohexanone and p-nitrobenzaldehyde; the results suggested that these catalysts could catalyze Aldol reaction efficiently, with ee up to85%, dr up to90:10. High yield and stereoselectivity were obtained under simple conditions that room-temperature, without additive or water. Universality study showed that these catalysts could well apply to multifarious ketones, but gave disappointing results when aldehyde varies. Additionally, reaction mechanism was preliminary discussed.