Auxialiry-Assisted Inert C-H Functionalization in Natural Products Synthesis

Author:Liao Gang

Supervisor:shi bing feng


Degree Year:2018





In recent years,the transition metal catalyzed C-H bond functionalization has received widely concerned.Specific locations of C-H bonds are difficult to be functionalized,especially inert carbon positions,according to traditional synthesis methods.As a very practical and efficient strategy,transition metal catalyzed C-H bond functionalization has been applied to the synthesis of natural products and drug molecules by synthetic chemists.However,it is also a challenge to make use of this efficient synthesis strategy for the synthesis of natural molecules or drug molecules.Because inert C-H bonds have high barrier itself and it is difficult to recognize or functionalize specific C-H bonds in a large number of chemical bonds with similar chemical environments.Therefore,the direct group is needed to be introduced in the process of the direct functionalization of inert C-H bonds.The precise control of the site selectivity and stereoselectivity of the reaction provides strong guarantee for the synthesis of the target natural molecules or drug molecules.In this paper,the synthesis of natural compounds is guided by the inert C-H bond functionalization based on directing strategies.1.Hydroxyl-Directing Synthesis of Polycyclic Quinoline Derivatives Via Rh(III)-Catalyzed Cascade C-H Activation/Annulation/LactonizationWe have developed an efficient strategy for the one-step synthesis of tetracyclic pyrano[2,3,4-de]quinoline derivatives via a Rh(III)-catalyzed cascade C-H activation/annulation/lactonization.The reaction condition is mild and was found to be compatible with a wide range of functional groups.Different kinds of substituted alkynols,symmetrical alkyl acetylene,symmetrical aryl acetylene and heterocyclic acetylene can all be used as effective alkynylation reagents.This reaction provides a direct and atomic economic method for the synthesis of biologically important polycyclic quinoline by using readily available quinolin-4-ols and internal alkynes as starting materials2.Pd(Ⅱ)-catalyzed C(sp3)-H bond Alkoxycarbonylation for the Synthesis of Aspartic Acid and Glutamic Acid Derivatives with 8-Amino Quinoline as Directing GroupWith 8-amino quinoline as a bidentate directing group,we have developed the stereoselective alkoxycarbonylation of both methyl and methylene C(sp3)-H bonds with alkyl chloroformate through a Pd(Ⅱ)/Pd(Ⅳ)catalytic cycle.A broad range of aliphatic carboxamides and alkyl chloroformates are compatible with this protocol.Compared to the well-established C-H carbonylation with carbon monoxide via Pd(Ⅱ)/Pd(0)catalysis,the direct alkoxycarbonylation of unactivated C-H bonds provides a new mode of reaction.In addition,this process is scalable and the directing group could be easily removed under mild conditions with complete retention of configuration.3.Pd(Ⅱ)-catalyzed Stereoselective Alkynylations to the Synthesize(+)-Isoschizandrin and(+)-Steganone with amino acid as a transient chiral auxiliaryDibenzocyclooctadiene lignans are a common class of natural products that possess unique structural features and significant biological activity.We have developed Pd(Ⅱ)-catalyzed atroposelective C-H alkynylation strategy in natural product syntheses.tert-Leucine was used as a key catalytic transient chiral auxiliary.A broad range of enantiomerically enriched biaryl compounds were obtained in good yields(up to 99%)with excellent enantioselectivity(up to>99%ee).Gram-scale,stereocontrolled formal syntheses of(+)-isoschizandrin and(+)-steganone were achieved based on this method.These syntheses compare very favorably with previous syntheses in terms of step economy,overall yield,and stereocontrol.