Studies On The Design And Synthesis Of New Alkyl-based Chiral Phoshoric Acid Catalysts

The last century was limited by the level of technological development.Organic chemists were unaware of that the attachment of four different groups on one carbon atom can produce two enantiomers with completely different biological activities.Until the 1960s,in order to treat women with severe morning sickness during pregnancy,a pharmaceutical company in West Germany developed a drug called the“Thalidomide”that can anti-pregnancy response.But after taking this medicine,it gave birth to a baby with deformed limbs.This has caused serious harm to many countries around the world.After this incident,according to some investigations,the scientists finally realized that,thalidomide,the main component of the drug,is a chiral compound with R and S configurations,in which the R configuration can resist pregnancy response,but the S configuration can lead to deformity.That is to say,compounds of different configurations have different biological activities.Based on this,the synthesis of chiral compounds with a single configuration has attracted widespread attention of organic chemists all over the world.Up to now,there are four main methods to obtain pure optical active chiral compounds,namely,chiral resolution,chiral pool,chiral auxiliaries and chiral catalysts.The first three methods have some drawbacks that are difficult to overcome.Chiral catalysts can overcome these deficiencies.Ideall,as long as the efficiency of the chiral catalysts is high,we can obtain unlimited amount of chiral compounds with single configuration.Bio-enzyme can catalyze the metabolism of human body.Therefore,early organic chemists tried to use enzymes to catalyze organic reactions to get enantiomeric excess compounds and they succeeded.Later,people discovered that metals can also act as catalysts to catalyze organic reactions.However,for a long time,the use of small molecular organic compounds as catalysts has been ignored.Until1990s,Fiske and Bredig used quinine and quinidine to catalyze the addition of cyanide to benzaldehyde.This attempt let us know that small organic molecules can also catalyze asymmetric reactions.Early reports on asymmetric reactions catalyzed by organic catalysts were relatively fragmented.Only some research groups published that an organic catalyst can catalyze an asymmetric reaction without systematically exploring the mechanism of the organic catalysts.Since the mechanism was unknown,we cannot reform and design new organic catalysts and new asymmetric reactions.Until 2000,the catalytic mechanism of enamines reported by the List group.And the catalytic mechanism of imines reported by the Macmillan group.The publication of these two papers opens the door to investigate the mechanism of organocatalysis.The value of understanding the general pattern of how catalysts activate substrates is that once these general mechanisms are established,we can design new asymmetric reactions via known activation mechanisms.In fact,more than 130organic catalytic reactions have been reported since 1998 are directly based on only five or six activation modes.That is to say,as far as it is concerned,the number of asymmetric reactions far exceeds activation mechanisms.And using known activation modes will make it easier to design new asymmetric reactions.For organic catalysis,there are five main catalytic mechanisms.They are enamine catalysis,hydrogen bonding catalysis,imine catalysis,SOMO（singly occupied molecular orbital）catalysis and counterion catalysis.The mechanism of enamine catalysis is that the catalysts containing amines interact with carbonyl groups（mainly in aldehydes and ketones）to form enamine intermediates,and at the same time the catalysts through hydrogen bonding or electrostatic attraction combine with electrophile.The mode of hydrogen bonding is that the catalysts can activate the substrates by forming hydrogen bonds.The electrophile which reacted with the nucleophile is activated by the formation of a hydrogen bond that lower the energy of LUMO（lowest unocccupied molecular orbital）of the electrophile.The imine catalytic mechanism is that the chiral amine interacts with theα,β-unsaturated aldehyde to form an imine,which reduces the energy of the LUMO.The catalytic mechanism of SOMO is based on that an electron-rich enamine transforms to an active radical cation by a single electron oxidation to react easily with a weak nucleophile to form an asymmetric alkylation product.The mechanism of counterion catalysis is that the chiral thiourea and the halide ion combine to form a complex.And then transient ion pair was formed by ionizing the weak C-Cl bond.The function of the thiourea-Cl complex is a chiral counterion.Almost all asymmetric reactions can now be explained by these five mechanisms.Organic catalysis can divide into organic base-mediated catalytic reactions and organic acid-mediated catalytic reactions.There are many types of organic acid catalysts,but it is undoubted that the chiral phosphoric acid catalysts are definitely the most dazzling star among them.The design of chiral phosphoric acid catalysts dated back to 1962.Sir Cornforth wanted to synthesize a catalyst with a rigid skeleton,a cavity to hold the substrate,and a chiral axis to control the chirality of the product.Therefore,he chose the phosphinic acid derivative as a candidate,which is the prototype of the chiral phosphoric acid catalysts.From the current chiral phosphoric acid catalysts（chiral PAs）,we can see that its structural characteristics are similar to those of phosphinic acid derivatives.It has a rigid backbone,a Bronsted acidic site and a Lewis basic site which can be used to activate substrates and substituents at the3,3’-position with a bulky groups providing chiral environment for asymmetric reactions.At the very beginning,the chiral PAs were used to resolve the racemic ammonia.Until 2004,Akiyama group and Terada group reported the catalytic asymmetric reactions catalyzed by chiral PAs independently.Their pioneering efforts opened the door to the application of chiral BINOL-derived PAs in asymmetric catalysis.Next in 2006,the Yamamoto group synthesized BINOL-derived N-phosphoramide catalysts,which are more acidic and can activate weak reactive substrates.The advantage of H₈-BINOL catalysts is that they have different solubility.The VANOL or VAPOL-derived PAs developed by the Wulff group has a larger chiral pocket compared with BINOL-derived PAs.It can provide a different chiral environment.List group developed another chiral PAs with a compact structure,namely imidodiphosphoric acids,which can be used to synthesize asymmetric spiroacetal compounds.Birman designed a spiro scaffold chiral PAs which are also widely used in a variety of asymmetric reactions.We know that realizing the modes of how chiral PAs activate substrates are important for designing new asymmetric reactions,so it is necessary to understand the activation mechanism of chiral PAs.In 2014,Reuping concluded the four existing activation modes.They are mono activation,dual activation,bifunctional activation,and counterion catalysis.The mono activation mechanism can be explained as the two mechanisms,that is ion pairing and hydrogen bonding for different catalysts and substrates.Dual activation can be clarified by the fact that one substrate is simultaneously activated by the acidic and basic sites of chiral PAs,or that the protonic acid of the chiral PAs simultaneously activates two different sites of one substrate.Bifunctional activation means that the protonic acid of the chiral PAs activates imine,in the meanwhile the basic site of chiral PAs need activate the nucleophile.The activation of counterion catalysis is achieved by forming a chiral ion pair that the anion formed by the chiral PAs and the cation formed by the substrates,at the same time the catalyst activates the nucleophile to make the nucleophile attack the more stable side of ion pair.By clarifying the activation modes of chiral PAs,these catalysts are now widely used in a variety of asymmetric reactions.Another important aspect for chiral PAs is to investigate how to synthesize the catalyst at low costs and high yields.So it is well known that a good design route can achieve twice the result with half the effort.The first to be studied is the BINOL-derived PAs,because such catalysts are the most widely used.The most classical step is to use a optical pure R or S binaphthol as a starting material.It can protect the phenolic hydroxyl groups by using Me I when ether as a solvent,and then the 3,3’-positions were substituted by bromine,iodine or boric acids under the condition of n Bu Li.Next,different coupling reactions such as Suzuki coupling,Kumada coupling and Sonogashira coupling can be used to introduce different aromatic groups to 3,3’-positions like anthracenyl,phenanthryl and2,4,6-isopropylphenyl.Methyl groups were removed at a low temperature using BBr₃in the presence of CH₂Cl₂as solvent.Lastly,POCl₃reacted with phenolic hydroxyl groups and then hydrolysis to obtain the corresponding chiral PAs.It must be noted here that in the early days,we did not know that the chiral PAs were easily complexed with metals in the silica gel,so they were directly used for the asymmetric catalytic reactions after purifying through columns.Later,List pointed out in his paper that chiral PAs can complex with metals such as Na,K,Mg,Ca and Al after purifying via columns.Therefore,as long as the catalysts are purified by silica gel column,washing with HCl is required.The metal ions are washed away to ensure the purity of the chiral PAs.The synthetic route of BINOL-derived N-phosphoramide catalysts is the same as the BINOL-derived chiral PAs,and it was only necessary to carry out the amidation reaction via using the parent phosphoric acid.The H₈-BINOL catalysts need to reduce the binaphthol moiety,and then did not need to protect the phenolic hydroxyl groups to introduce bromine or iodine directly into the 3.3’-positions,followed by coupling reactions to introduce aromatic groups into 3.3’-positions and finally corresponding PAs can be obtained by phosphorylation.The difficulty in the synthesis of VANOL or VAPOL-derived chiral PAs lies in the construction of the backbone of the catalysts.Taking VANOL as an example,starting from 1-naphthol,reacted with thionyl chloride in dichloroethane gave 4-chloro-1-Naphthol.Then,under reflux conditions,Al Cl₃was added to 4-benzene-1-naphthol in benzene,and3-phenyl-1-naphthol was obtained by rearrangement of dienone phenol.The oxidative coupling reaction gave a racemic VANOL backbone.The S and R enantiomers were well resolved by the use of a chiral resolution agent.Finally,the phosphoric acid catalysts of the VANOL scaffold is obtained by phosphorylation.The former steps of the synthesis of imidodiphosphoric acids were the same as the BINOL-phosphoric acid catalyst,except that the final step was to obtain BINOL phosphoramide and BINOL phosphoryl chloride,respectively,and then the phosphoramide reacted with phosphoryl chloride to obtain the final chiral PAs.The synthetic method of SPINOL catalyst is also similar to that of BINOL-phosphoric acid catalyst,and it also needs to go through five-steps.Its synthesis difficulty lies in the construction of the backbone of SPINOL,which needs to undergo condensation reaction,reduction reaction,spiro ring reaction,dehalogenation reaction and resolution.The steps are cumbersome.Although chiral PAs have been widely used in many asymmetric catalytic reactions,we have found a phenomenon in which these catalysts can enhance the enantioselectivity of most aromatic substrates,but for aliphatic substrate,ee values are very low.Therefore,in order to solve this problem,we try to design and synthesize some alkyl-substituted chiral PAs with steric hindrance groups at the end.We hope if these chiral PAs can generate non-covalent interactions with aliphatic substrates,it may have great potential value in improving enantioselectivies the ee values.To date,we have successfully designed and synthesized 12 distinct alkyl-based chiral PAs.For the synthesis of PA 1 to PA 4,the synthetic route is similar to the BINOL-derived PAs,except that the coupling reactions introduced different groups,such as alkynyl,allyl,neopentyl,and n-octyl groups.For PA 5 to PA 9,we have designed two routes,but the central idea is first to introduce alkynyl or propargyl alcohol groups into 3,3’-positions,then reduce the triple bond and hydroxyl groups,and finally obtain the corresponding phosphoric acid catalyst by phosphorylation demethylation.The synthesis of PA 10 was carried out by first introducing allyl groups into the 3,3’-positions,then making addition reaction to double bonds obtained mono amino-substituted compound.And finally We can receive PA 10 by amidation,deprotection,and phosphorylation.PA 11 and PA 12 were also prepared by first introducing allyl groups into the 3,3’-position’,followed by addition of HBr,substitution of Na N₃,click reaction,deprotection and phosphorylation.In the synthesis process,the starting materials that we use are readily available,and the yields of per step are high.Finally,we also used this new batch of catalysts to screen some asymmetric reactions by using aliphatic compounds as substrates.However,the enantioselectivity was not so good.There are two possible reasons.One may be the substituents at3,3’-positions are lack of rigidity.Another reason may be that the catalytic reactions we screened are limited.We hope to solve this problem in the future by synthesizing some more rigid alkyl based chiral PAs and screening more catalytic reactions.In summary,this thesis will discuss three major aspects.The first aspect is the development history of asymmetric catalysis,organic catalysis,and chiral phosphoric acid catalysis.The second aspect is that according to describe the activation mechanisms of organic catalysts and chiral PAs,we can explain the idea of how to design novel alkyl-substituted chiral PAs.The third aspect is a detailed description of the synthesis of several representative chiral PAs and the synthesis of new alkyl-substituted chiral PAs.