Organic Catalytic Stereoselective Construction Of Spirothiazolone Or Fused Pyrazolone With Multiple Chiral Centers

Heterocyclic compound,one of the most important basic skeletons of naturally occurring and synthetic molecules,has exhibited a wide range of biologically activities,such as antibacterial,antiviral,anti-inflammatory,antitumor activities and so on.In view of the wide applications of opictally active heterocycles in the field of drug discovery,the development of efficient mothods for the stereocontrolled construction of novel heterocyclic scaffold have drawn much attention from synthetic organic chemists.In this thesis,we mainly focused on the stereocontrolled construction of novel heterocyclic skeletons with potential bioactivity via oragnocatalyzed asymmetric cascade reactions.(1)As a sulfur-containing lactam,thiazolinone is the core structure of a great number of bioactive natural occurring and synthetic compounds.Consequently,the development of asymmetric methods to access thiazol-4-one derivatives with a quaternary stereo center at the C-5 position has thus given rise to considerable interest.Although there are many asymmetric synthesis methods to access thiazol-4-ketone derivatives with quaternary carbon chiral centers at the C-5 position,up to date,no example of thiazol-4-ketone as sulfur-containing nucleophiles applied to the synthesis of optically active spiro-thiazol-4-ketone derivatives has been reported.In this part of the work,we have developed an organocatalyzed asymmetric three-component reaction of thiazol-4-ones,acrolein and nitroolefins,which provides an efficient approach to access optically active spiro thiazol-4-ones.Under the catalysis of a bifunctional squaramide derived from L-tert-leucine,the reactions of a wide range of thiazol-4-ones,acrolein and nitroolefins took place smoothly to generate the corresponding spirothiazolone derivatives bearing four continuous stereogenic centers in good yields with high levels of enantioselectivity.This transformation features atomic economy,good functional group tolerance,easy accessibility of starting materials,simple operation,mild reaction conditions as well as high diastereo-and enantioselectivity.Mechanistic study revealed that the reaction starts with the formation of an enol by bifunctional squaramide promoted via Michael addition of thiazolone to nitroolefin.Then,a nitro aldehyde intermediate was formed under the catalysis of catlayst through a subsequent Michael addition of the enol intermediate to acrolein.The subsequent spontaneous cyclization process occurs by means of intramolecular nucleophilic attack of the nitro-bearing carbon to the aldehyde carbonyl functionality(Henry reaction)with the aid of squaramide catalyst affording the desired spiro thiazolones.(2)Over the past two decades,the privileged structures-based diversity-oriented synthesis has become a powerful and highly efficient tool for discovering biologically active small molecule.In view of the interesting application of pyrano[4,3-b]-pyranone and pyrano[2,3-c]pyrazolone in the field of drug discovery,the fused ring system composing of a 3,4-dihydropyrano[4,3-b]pyran-5(2H)-one skeleton and a pyrano-[2,3-c]-pyrazol-6(1H)-one skeleton will be an important structural motif that has potential among biological activities and synthetic applications.As a result,we have developed a chiral bifunctional squaramide catalyzed enantioselective formal [3+3] annulation of 4-hydroxy-2H-pyrano[2',3':4,5]pyrano[2,3-c]pyrazole-2,5(7H)-diones and(E)-2-nitroallyl acetates,which provides an efficient approach to stereo-controlled construction of fused polycyclic 3,4-dihydropyrano[4,3-b]pyran 5(2H)-one scaffold.Under the catalysis of a bifunctional squaramide derived from(1R,2R)-1,2-diphenyltheane-1,2-diamine,a wide range of novel fused polycyclic 3,4-dihydropyrano-[4,3-b]pyran-5(2H)-one derivatives with two adjacent stereogenic centers are obtained in acceptable yields with high anti-selectivity and moderate to excellent enantioselectivities.Representative transformation of the annulation product to other synthetic valuable compound is achieved without any loss of stereochemical integrity.The reaction is believed to proceed via a Michael addition-elimination-Michael addition reaction sequences with the aid of bifunctional squaramide catalyst.Firsly,an enolate is formed via the deprotonation of 4-hydroxy-2H-pyrano[2',3':4,5]-pyrano[2,3-c]-pyrazole-2,5(7H)-diones by the tertiary amine group.Simultaneously,nitroallylic acetate was activated via a bidentate H-bond interaction between the nitro group and the squaramide moiety.Then the enol anions are added to the nitro olefin by Michael addition to obtain the intermediate.Finally,in the presence of bifunctional quadryl-amide catalyst,the molecular nucleophilic substitution reaction occurred in a similar dual-activation way,and the optically active polycyclic 3,4-dihydropyrano-[4,3-b]-pyran-5(2H)-ones derivatives were obtained.