Asymmetric β-Arylation & β-Acylation Of Cyclopropanols Enabled By Photoredox And Nickel Dual Catalysis

Cyclopropanols,readily available from the Simmons-Smith reaction or the Kulinkovich protocol,are prone to various ring expansion and ring opening reactions due to the intrinsic strain in the three-membered ring system.As precursors of ketone homoenolates,cyclopropanols have attracted emerging interest as three-carbon synthons for new bonds formation and natural products synthesis in recent years.Despite these advances,the development of catalytic asymmetric strategies to access various enantioenriched βfunctionalized ketones through ring-opening of cyclopropanols has proven to be quite challenging yet highly desirable.Over the past decade,asymmetric photoredox dual catalysis has become one powerful and reliable tool for developing innovative synthetic methodologies,designing and constructing bioactive interesting molecules and valuable functional materials.As we all known,compared to racemic forms,chiral drugs are demonstrated with higher activity,lower side-effects and low toxicity.Therefore,the development of new catalytic system to realize efficient and concise enantioenriched β-functionalized reaction of cyclopropanols possesses broad prospects and positive significance.Chiral β-aryl ketones and chiral β-acyl ketones are widely seen in biologically active molecules and natural products.Encouraged by recent progress on photoredox/Nickel enantioselective dual catalysis,we envisioned that a photocatalytic system engaging a chiral nickel catalyst might serve as a general platform for enantioselective β-functionalization of cyclopropanols to access a series of value-added β-functionalized ketones in a stereoselective fashion.In this thesis,we have developed an enantioselective β-arylation of cyclopropanols enabled by asymmetric photoredox/Nickel dual catalysis.Based on this,we also studied enantioselective β-acylation of cyclopropanols.The first chapter reviewed the application of visible light photoredox asymmetric catalysis in the area of organic synthesis over the past decades.Strategies for the synthesis of cyclopropanols was discussed in order to illustrate the ease of access to these materials.Recent developments in β-functionalization of cyclopropanols was also summarized.The second chapter focuses on asymmetric β-arylation of cyclopropanols.Based on the strategy of photoredox and nickel dual catalysis,using cyclopropanols bearing a primary alcohol moiety and aryl bromides as substrates,chiral Ni(OAc)2/Py-(oxazoline)as catalyst,the method of asymmetric β-ary lation of cyclopropanols was accomplished at room temperature.This dual catalytic transformation features a broad substrate scope and good functional group tolerance.A broad range of substituted cyclopropanols bearing an electronwithdrawing or electron-donating group on the aryl moiety were well tolerated,Cyclopropanol with 2-naphthyl group also proceeded to afford the desired product.In addition,substrates with different heteroaryl moieties,such as 2-furyl,2-thiofuryl and 3thiofuryl groups,participated well to give the desired ketones in comparable yields and enantioselectivities.A wide variety of functional groups including ketones,aldehydes,cyanides and halides were well tolerated to provide the desired β-aryl ketones in satisfying results.Moreover.2-naphthyl substituted aryl bromide also successfully yielded the corresponding ketone.We applied this asymmetric protocol to the late-stage functionalization of bromides derived from complex bioactive molecules and found a number of complicated compounds,such as Fenofibrate,Lithocholic acid,Isoxepac and Ketoprofen derived bromides,all reacted well with the cyclopropanol,delivering the highly functionalized chiral ketones in 63-70%yields with up to 90%ee.To demonstrate the synthetical value of this asymmetric βarylation protocol,1 mmol scale reaction was carried out.providing the chiral ketone in 70%yield with 93:7 er.Then,further derivatization of the products was performed.Direct deprotection of TIPS group of ketone afforded the chiral primary alcohol in 88%yield.An enantioselective reduction of chiral ketone product,followed by deprotection of TIPS would generate chiral tri-hydroxy product in 82%yield with 96%ee.The absolute configuration of the tri-hydroxy product was determined as 1S,3S by X-ray diffraction.Br(?)nsted acid catalyzed stereospecific benzylic substitution occurred,furnishing the concise synthesis of a marine natural product ent-calyxolane B analog in 80%yield.Subjecting the chiral ketone product to the Wittig reagent,followed by deprotection of TIPS could generate y-hydroxy ene.Treatment of y-hydroxy ene with hydrochloride in 1.4-dioxane solution led to tetrahydrofuran derivative,which is a privileged structural unit in natural products and bioactive compounds.A number of control experiments were performed in order to gain insight into the reaction pathway.Both trans-and cis-cyclopropanols were subjected to the standard condition,producing the corresponding product in similar yield with the same enantioselectivity.TBS protected cyclopropanol failed to generate product,indicating the ring-opening process of cyclopropanols underwent a PECT pathway.The results of TEMPO radical quenching experiment and acrylonitrile radical probe experiment supported that the asymmetric photoredox/Nickel dual catalysis process involved a radical pathway.The third chapter focuses on asymmetric β-acylation of cyclopropanols.Based on the strategy of photoredox and nickel dual catalysis,using cyclopropanols and preformed or in situ generated anhydride as substrates,chiral nickel/ligand as catalyst,the method of asymmetric β-acylation of cyclopropanols was evaluated.The experimental results indicated that both alkyl or aryl anhydride can generate desired product with moderate to good yields.The β-acylation reaction can also be realized by using carboxylic acid and dimethyl pyrocarbonate to produce mixed anhydride in situ,which expands the range of substrates and cuts the costs.After preliminary screening,products with 24%ee can be obtained.These results lay a solid foundation for the further studies towards substrates structural modification and chiral ligands optimization.