Sulfur Ylides Involved Novel Cycloaddition Reactions

Sulfur ylides are neutral dipolar molecules.As a kind of powerful nucleophiles,they participate in cycloaddition reactions as 1C unit usually.The formally negatively charged carbanion attached to the sulfur with a formal positive charge directly can attack the electronphiles,then the sulfur group gains the electron and is removed.As a result,the cycloadditon products are obtained.In 1961,the Johnson-Corey-Chaykovsky reaction was reported,and from then on,more and more chiral sulfides based on different skeletons were synthesized.In general,three different pathways of sulfur ylides involved reactions are explored.Firstly,the sulfides could catalyze the cycloadditons directly;secondly,the sulfur ylides could be previously prepared and then take part in the cycloadditon reactions;thirdly,the sulfur ylides could be produced in situ by the metal-carbeen and sulfide and then participate in the reactions.Furthermore,a variety of sulfur ylides involved reaction types have been reported,such as the [2 + 1] cycloadditions with aldehydes,ketones,imines and electron deficient alkenes;[4 + 1] cycloadditions with ??-unsaturated aldehydes,ketones,imines and so on.Other types of cycloadditions,cascade reactions,domino reactions and [2,3]-s rearrangement with special substrates,have also been developed.This dissertation focused on novel cycloaddition reactions involved sulfur ylides,to construct a series of useful ring compounds.Azaoxyallyl cation intermediates,readily generated from a-halohydroxamates in the presence of bases,recently performed as versatile 3-units in [3 + 4] and [3 + 2] cycloaddition reactions with electron-rich dienes and indoles,respectively.Consequently,we postulated that the azaoxyallyl cations might have high potentials to be assembled with sulfur ylides in an unprecedented [3 + 1] cycloaddition manner,providing a convenient protocol to ?-lactams,which are a sort of key skeletons in a variety of biologically active compounds used in bacterial infections and other kind of diseases such as antifungal,anticancer and antiviral diseases.We investigated the cycloaddition reactions of azaoxyallyl cations generated in situ from a-halohydroxamates and sulfur ylides.A [3 + 1] formal cycloaddition reaction was observed for a-halohydroxamates bearing a-alkyl groups,and ?-lactams derivatives were obtained in fair to modest yields with excellent diastereoselectivity(>19:1 dr),while moderate enantioselectivity was realized by employing chiral sulfur ylides.In contrast,for a-halohydroxamates with a-aryl groups,an interesting [3 + 2] formal cycloaddition reaction occurred to give g-lactam derivatives with moderate to high yields(up to 85%),in which sulfur ylides with ketone groups performed as previously unreported 2C partners.Brief density functional theory(DFT)calculations were performed to clarify the regioselective cycloadditions.The key transition states for the formation of intermediates of [3 + 2] cycloaddition(TS1)and [3 + 1] cycloaddition(TS2),respectively,were calculated,and the Gibbs free energy of TS1 is 0.6 kcal/mol lower than that of TS2,suggesting that the five-membered ring system would be theoretically more favorable,which is consistent with the experimental results.4,5-Dihydrothiazoles and analogs are an important type of organosulfur compounds,which play significant roles in bioactive molecules.However,the asymmetric methods for the synthesis of 4,5-dihydrothiazoles are rare.It is reported that N-thioacyl imines could react with ketenes under the catalysis of tertiary amines in [4 + 2] cycloaddition reactions,which inspired us that the N-thioacyl imines could react with sulfur ylides in [4 + 1] cycloaddition reactions.So we used the a-amido sulfones and D-camphor devirated sulfur salts as substrates,and developed the asymmetric [4 + 1] cycloaddition reactions with the assistance of R-binol.This practical method allowed a facile access to 4S,5R-dihydrothiazoles in moderate to high yields with excellent diastereoselectivities(>19:1 dr)and good to excellent enantioselectivites(ee up to 98%).Fulvenes are the condensation product of cyclepentadiene and aldehydes or ketones,which bears an electronphilic exocyclic double bond.It is reported that fulvenes could participate in [6 + 2] cycloadditions with 1-isopropenylpyrrolidine,and in [6 + 3] cycloadditions with azomethine ylides.Accordingly,we postulated that fulvenes could be susceptible to attact by sulfur ylides in [6 + 1] cycloaddition reactions.Then we investigated the cycloaddition reactions of the fulvene produced by cyclepentadiene and benzaldehyde with the achiral stable ylide.As a result,an unexpected [2 + 1] cycloaddition reaction was observed,and the spiro[2.4]hepta-4,6-diene derivative was obtained in 74% yield with low dr.Moreover,some chiral ylides were tested in the reaction,and with the R-binol derivated sulfur salts the chiral product was produced in 70% yield,with dr 11:3 and ee 34%.Further screening of the reaction is still in progress.This reaction indicated that the olefin without electron withdrawing groups(EWG)could react with sulfur ylide as well.Besides,we investigated chiral tertiary amines catalyzed asymmetric [4 + 2] annulation reactions of g-butenolides and cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif,proceeding in a cascade Michael addition-Michael addition sequence to give complex fused tetracyclic architectures.Diastereodivergent cycloadducts could be produced by employing different Brfnsted base catalysts.Endo-type cycloadducts were obtained in high enantioselectivity(up to >99% ee)under the catalysis of modified cinchona alkaloid(DHQD)2PHAL.On the other hand,exo-type diastereomers could be produced catalyzed by ?-isocupreidine(?-ICD),though with moderate enantioselectivity.In conclusion,the strategy for constructing the cyclic products from the cycloaddition reactions with sulfur ylides and different kinds of electron-deficient substrates is of great use.In addition,different structures of the electron-deficient substrates indicated the different cycloaddition types,which could increase the interest of chemists.The large numbers of reports about this topic enrich the synthetic protocols,which might be useful for the total synthesis of natural or non-natural compounds.