Study On Desymmetric Reduction Of Cyclic Diketones And Its Application In Total Synthesis Of Toxicodenane A

The desymmetric enantioselective reduction of cyclic 1,3-diketones plays an important role in the total synthesis of many natural products,and it is an important strategy which often used by lots of chemists to construct the key chiral centers in complex compounds when designing synthesis routes.The chiral 3-hydroxyl ketones obtained by this reaction are important building blocks in synthetic chemistry.The reported desymmetric enantioselective reduction methods include Corey-Bakshi-Shibata reduction(CBS reduction),enzyme-catalyzed reduction,and transition-metal-catalyzed hydrogenation.However,these methods usually have one or several disadvantages,such as limited substrate scope,low to moderate diastereoselectivity,and poor stability of catalysts towards air and moisture.Therefore,it is of great significance to develop a new method of desymmetric enantioselective reduction and to apply it to the synthesis of natural products and drugs.This thesis includes two parts:Part ?:Desymmetric enantioselective reduction catalyzed by P-chiral phosphinamidesWe have designed and developed a new method for desymmetric enantioselective reduction of cyclic 1,3-diketones,and successfully obtained 3-hydroxyl ketones with all-carbon chiral quaternary carbon by this method.In the newly developed method,P-chiral phosphinamide was used as organocatalyst and catecholborane as reducing agent.After careful optimization of conditions,the target product was obtained with high enantioselectivity and diastereoselectivity.The results of substrate scope showed that this method was widely applicable to 1,3-cyclopentadione and 1,3-cyclohexadione substrates,and the yield of the target product was up to 71%,the enantioselectivity was up to 98%,and the diastereoselectivity was up to 99:1.The reaction could be scaled up to gram scale without affecting the reaction results.All reactants and reagents were added in one pot,which made the operation convenient.Notably,the catalyst could be recovered and reused without affecting its catalytic effect.Based on a detailed study of the reaction mechanism,we proposed a working model via bifunctional catalytically active intermediate.The results provide useful information for the design and development of new asymmetric reactions catalyzed by P-chiral phosphinamides.Part ?:Enantioselective total synthesis of Toxicodenane AToxicodenane A is a naturally occurring sesquiterpenoid which possesses a unique oxatricyclo[7,2,1,0]dodecane framework and bears four stereocenters including an all-carbon quaternary center.So far,no enantioselective total synthesis of Toxicodenane A has been reported.We used P-chiral phosphinamide catalyzed desymmetric enantioselective reduction of cyclic 1,3-cyclohexanedione to obtain the key chiral 3-hydroxyl ketone building block.The construction of the oxygen-bridged tricyclic skeleton was achieved through highly stereo-controlled Grignard reaction,selective protection of secondary hydroxyl group,Lewis-acid-mediated intramolecular transacetalation and Prins cyclization cascade reaction as key steps.Starting from the tricyclic intermediate,the target product was obtained through three steps involving ozonation,Wittig reaction,and removal of the hydroxyl protection group.Consequently,a novel synthesis strategy was developed to achieve the enantioselective total synthesis of Toxicodenane A and its epimer 8,11-epi-Toxicodenane A via a route of nine linear steps.