Direct Catalytic Asymmetric Synthesis of Disubstituted 4-Oxocyclohexanecarbaldehydes from Acetone and Cinnamaldehyde Derivatives.

A first catalytic asymmetric reaction of acetone with cinnamaldehyde for the synthesis of disubstituted 4-oxocyclohexanecarbaldehyde is developed. A variety of substituted cinnamaldehydes are successfully tested under the optimized reaction conditions. Both the enantiomers of the same diastereomeric products are achieved in good yield and diastereoselectivity with an excellent enantioselectivity by changing the enantiomer of one of the two chiral catalysts. The practicality of this methodology is demonstrated by the gram-scale synthesis.

Enantioselective Total Synthesis of Potent 9ß-11-Hydroxyhexahydrocannabinol.

The first total synthesis of potent cannabinoid, 9ß-11-hydroxyhexahydrocannabinol, is achieved through a proline-catalyzed inverse-electron-demand Diels-Alder reaction. Using this asymmetric catalysis, the cyclohexane ring is constructed with two chiral centers as a single diastereomer with 97% ee. The creation of the third chiral center and benzopyran ring is demonstrated with the elegant synthetic strategies. This mild and efficient synthetic methodology provides a new route for the asymmetric synthesis of the other potent hexahydrocannabinols.

Stereodivergent Synthesis of Chiral Paraconic Acids via Dynamic Kinetic Resolution of 3-Acylsuccinimides.

A direct N-heterocyclic carbene (NHC) catalysis of maleimides with alkyl aldehydes is established for the synthesis of 3-acylsuccinimides. The first dynamic kinetic resolution of 3-acylsuccinimides is accomplished through asymmetric transfer hydrogenation. These two catalytic methodologies are utilized for the synthesis of each enantiomer of trans-paraconic acids in three steps and cis-paraconic acids in four steps with good yields and high stereoselectivities. This stereodivergent synthetic methodology is applied for the synthesis of seven bioactive paraconic acid natural products.

Catalytic Asymmetric Synthesis of 3,4-Disubstituted Cyclohexadiene Carbaldehydes: Formal Total Synthesis of Cyclobakuchiols A and C.

The first catalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electron-demand Diels-Alder reaction is described. A variety of arylacetaldehydes and α,ß,γ,δ-unsaturated aldehydes are tested under the mild reaction conditions catalyzed by l-proline to obtain the trans diastereomeric products with good yields and high enantioselectivities. The scope of this methodology is further extended to the asymmetric synthesis 3,4-disubstituted cyclohexane carbaldehydes and their derivatives. The practicality of this method is demonstrated by the gram-scale synthesis. This methodology is successfully applied for the formal total synthesis of cyclobakuchiol A, an antipyretic and anti-inflammatory agent, and cyclobakuchiol C.