Synthesis Of The Novel Phosphinothiourea Organocatalysts And Their Applications In Morita-Baylis-Hillman Reaction

The Morita-Baylis-Hillman (MBH) reaction is an atom-economic carbon-carbon bond-forming reaction. The asymmetric MBH reaction could be catalyzed by chiral tertiary phosphine or tertiary amine to provide the chiralα-methylene-β-hydroxycarbonyl derivative which was a valuable intermediate in organic synthesis. However, the slow reaction rate, low chemical yields and low enantioselectivity are the shortcomings. Therefore the development of highly effective chiral catalyst to enhance the enantioselectivity plays a significant role in the exploration of the asymmetric MBH reaction.This dissertation focused on the design and synthesis of novel phosphinothiourea organocatalysts and their application in enantioselective Morita-Baylis-Hillman reaction. The main contents are as followed:1. A series of novel chiral bifunctional phosphinothioureas were designed and synthesized from cyclohexene oxide as starting matiral. At first, cyclohexene oxide reacted with NaN3 to provide azido-cyclohexanol. And in the present of PPh3, azido-cyclohexanol was transformed into 7-azabicyclo [4.1.0] heptane with evolving N2 in the mixture. Then, the trans-1-amino-2-(diphenylphosphino)-cyclohexane was obtained from the reaction of 7-azabicyclo [4.1.0] heptane and HPPh2 in the present of CF3SO3H. (1R,2R) and (1S,2S)-1-amino-2-diphenylphosphino cyclohexane were obtained via the optical resolution of the racemic trans-1-amino-2-diphenylphosphino cyclohexane with chiral tartaric acid. Finally, (1R,2R) or (1S,2S)-2-amino-1-(diphenylphosphino)-cyclohexane condensed with the corresponding isothiocyanate to afford the phosphinothiourea organocatalysts. In total, we have successfully synthesized 18 novel chiral bifunctional phosphinothioureas. Moreover, the single crystal of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(diphenylphosphino)cyclo-hexyl)thiourea (42c) was obtained and the X-ray analysis further confirmed its structure.2. The chiral bifunctional phosphinothiourea was firstly applied as organocatalyst in the enantioselective MBH reaction of MVK and aromatic aldehydes. The result indicated 42a displayed highly efficient for this reaction. And in the present of 10 mol% 42a, the MBH reaction could complete in a short reaction time (15 min-3 h) with up to 92% yield and up to 94% ee. Comparising to the previous reports on the enantioselective MBH reaction of MVK and aromatic aldehydes, this is the best result. 3. We have developed the first phosphinothiourea-catalyzed enantioselective MBH reaction with commercially available simple acrylates as Michael donor. The MBH adducts were obtained in up to 96% yield and up to 77% ee using 8 mol% 42k under mild reaction conditions.4 The chiral bifunctional phosphinothioureas were applied in the enantioselective intermolecular aza-MBH reaction. Unfortunately, the chemical yields and enantioselectivity were rather low.5. The chiral bifunctional phosphinothioureas were firstly applied in the enantioselective intramolecular MBH reaction ofω-formyl-enone. Rate acceleration was observed in alcohol solvents. With 3 mol% of 42c as organocatalyst in t-BuOH, the intramolecular MBH reaction could be carried out at room temperature to provide the desired products in up to 98% ee and up to 98% yields.6. To explore more efficient organocatalysts for the enantioselective intramolecular MBH reaction ofω-formyl-enone, the saccharide scaffolds were introduced into the chiral bifunctional phosphinothiourea. We found the chiral phosphinothiourea 42o based on mannose displayed higher effective than phosphinothiourea 42c. It is noteworthy that the intramolecular MBH reaction could proceed under mild conditions to generate the desired products in up to 99% yields and up to> 99% ee with 2 mol% of 42o. To be best of our knowledge, this is the best result of the enantioselective intramolecular MBH reaction.