高等有机化学保护基省公共课一等奖全国赛课获奖课件.pptx

5 Synthesis strategy Protection Groups/10/10/10/101第1页Content/10/10/10/10 Introduction and Concept2.4.12.4.23 Protecting Groups for Alcohol32.4.3 Protecting Groups for Carbonyls Protecting Groups for Amines2.4.52.4.4Summary and Homework2.4.6 Protecting Groups for Diols2第2页1.Introduction and ConceptsProtecting GroupProtection and deprotection Protection -transforms the interfering FG into a different one Deprotection -transform the new FG back into the original group at a later stage of the synthesisOne practical solution is to temporarily block a reactive position by transforming it to a new FG that will not interfere with the desired Transformation.This new blocking group is Protecting Group.Nucleophilic species Grignard reagentKetone-aldehydeacids,bases and nucleophiles Alcohol-amineSynthetic targets many problemsmore than one FGcompetitive reaction3第3页/10/10Other uses of the PG1.The PG can be used to provide directing effects,influence solubility,and other physical properties,make it easier to isolate or crystallize.2.As a pro-drug in pharmaceutical industry,3.Solid-phase attachment,tagging molecules(fluorescence tagging)The use of the protecting groupwhen and how 1)Avoided step,but it can not be avoided,2)Planning the order of a synthesis for insertion of a given FG can minimize the use of PG.3)The PG must be relatively inert and easy to unmask in high yield.1.Introduction and ConceptsIntroduce,removeBlock unblock Protect deprotect Mask Unmask 4第4页An perfect protecting group must lBe easily obtained,stable and no-toxicitylNot introduce the stereo-center to the molecularlIntroduce and remove in high yieldlBe easily isolated from the system after the cleavage/10/10Summary:Protecting when alcohols,aldehydes,ketones,amines,double or triplex bonds and other active groups are with competitive reactions.1.Introduction and Concepts5第5页lEther,relatively inert,but uneasily removedlacyclic acetals or ketals lesters,much inert but easily removed/10/10So the key problems for Protection Groups is 1.Reaction conditions for introduce2.circumstance conditions for stable3.Reaction conditions for removed 2.Protection Groups for Alcohols6第6页lReaction conditions lMethyl ethers are most inert PG and stable to strong bases,nucleophiles,organometallics,ylids,hydrogenation,oxidizing agents,reducing agents,pH 1 to 14lMethyl group can be cleaved with HI,BBr3 lApply to phenolic-OH3.Protection Groups for Alcohols 3.1 methyl ether protecting group7第7页/10/108Mechanism for the BBr3 cleaveExample 1CoQ103.Protection Groups for Alcohols 3.1 methyl ether protecting group第8页(-)-cyclindrocylophane JACS,122,4984A C-C dimer,3.Protection Groups for Alcohols 3.1 methyl ether protecting group9第9页3.Protection Groups for Alcohols 3.1 methyl ether protecting group10第10页lReaction conditions lbenzyl ethers are more stable to a wide range of reagents,strong bases,nucleophiles,organometallics,carbanions,oxidizing agents,reducing agents,pH 14 lBenzyl group can be cleaved by hydrogenolysis with Pd/ClApply to sugar and amino acid3.Protection Groups for Alcohols 3.2 benzyl ether protecting group11第11页/10/10Example:(+)-Himbacine:piperidine alkaloid,isolated from the Australian pine,has become a leading compound for a possible new drug candidate for the treatment of Alzheimers dementia.3.Protection Groups for Alcohols 3.2 benzyl ether protecting group12第12页/10/10Example 23.Protection Groups for Alcohols 3.2 benzyl ether protecting group13第13页/10/10Reaction conditions Tert-butyl ethers are stable to pH 1-14,strong bases,nucleophiles,organometallics,carbanions,catalyst hydrogenation,oxidation,dissolving metal reductioncleaved condition:sensitive to acidApply to steroid OH group and 3.Protection Groups for Alcohols 3.3 tert-butyl ether protecting group14第14页/10/10Reaction conditions stable to pH 5-14,strong bases,nucleophiles,carbanions,catalyst hydrogenation,oxidation,dissolving metal reductioncleaved condition:strong base and than acid,or Rh-P complex3.Protection Groups for Alcohols 3.4 allyl ether protecting group 15第15页/10/10Reaction conditions Stable to pH 5-14,strong bases,nucleophiles,carbanions,catalyst hydrogenation,oxidation,dissolving metal reductionCleaved condition:weak acid hydrolysis Applied to:primary alcohol because of bulkySelectivity of Primary alcohol3.Protection Groups for Alcohols 3.5 tribenzyl methyl ether for PG 16第16页/10/10 All are alkyl ether protecting groupSimilar problems arise in molecules containing several OH moieties,that require protection and de-protection in a specific order.Alternative ether protecting groups have to developed that show greater selectivity in reactions with acids or Lewis acids.So substitute methyl and alkyl ether have been developed.3.Protection Groups for Alcohols Summary17第17页/10/10Reaction conditions Stable to bases,catalyst hydrogenation,oxidation,dissolving metal reduction and organometallic(RMgX,RLi,LiAlH4),pH 4-14Cleaved condition:acid and weak acid hydrolysis Applied to:phenol -OH3.Protection Groups for Alcohols 3.6 methoxymethy ether(MOM acetals)as Protecting Group18第18页/10/10Note:MOM was first used in JACS 1972,formed with a base,MOM sensitive to acid,key removing condition is 50%AcOH/H2O or HCl/CH3OH,Dowex Resin is an acid resin,not only remove MOM but also acetonide;Last step JOC 1999,64,4485 anti-tumor compound,alkaloid,from Amaryllidaceous plant.3.Protection Groups for Alcohols 3.6 methoxymethy ether(MOM acetals)as Protecting Group19第19页/10/10Reaction conditions Stable to bases,catalyst hydrogenation,oxidation,dissolving metal reduction and organometallic(RMgX,RLi,LiAlH4),pH 4-14Cleaved condition:acid and weak acid hydrolysis Applied to:phenol -OH3.Protection Groups for Alcohols 3.7 tetrahydropyranyl ether(THP acetal)as Protecting Group20第20页/10/10Example 1吡揉比星3.Protection Groups for Alcohols 3.7 tetrahydropyranyl ether(THP acetal)as Protecting Group21第21页/10/103.Protection Groups for Alcohols 3.7 tetrahydropyranyl ether(THP acetal)as Protecting Group22第22页/10/10Silyl ether,an extremely important for the protection of OH having the generation structure OSiR3,/10/10Reaction conditions:organo-base,Stable to:oxidation,not stable to organometallics,nucleophiles,hydrolysis Relative stability depends on steric factorCleaved condition:aqueous base or acid,but the rate of hydrolysis for 2nd silyl ether 1st silyl ether steric factor Applied to:phenol -OH3.Protection Groups for Alcohols 3.8 Silyl ether as Protecting Group23第23页Polyphenoltea polyphenol3.Protection Groups for Alcohols 3.8 Silyl ether as Protecting Group24第24页/10/10/10/10Reaction conditions:acetic hydride or acetyl chloride in the presence of pyridine and triethylamineStable to:nucleophilic acyl substitution,hydrolysis and reduction,pH 1-8,organometallics,catalyst hydrolysis,borohydrolysis,Lewis acid,oxidizing agentCleaved condition:hydrolysis with baseApplied to:all -OH groupsAcetate,benzoate,mesitoate Pivalate(新戊酸酯）3.Protection Groups for Alcohols 3.9 ester as Protecting Group25第25页/10/10/10/10Acetate,benzoate,3.Protection Groups for Alcohols 3.9 ester as Protecting Group26第26页3.Protection Groups for Alcohols 3.9 ester as Protecting Group27第27页/10/10Example 1Target comp.(d)MeOH,H+Note:Protecting when OH-and C=O are in the same Molecular flowing by Grignard Reaction.Example analysis?28第28页Protected GroupReactant Protecting GroupIntroduce conditionsStability toCleaving conditionsNote pHNuRMOxi.Red.H2/Cat.El.-OHMeI or Me2SO4-OMeBase or Base/Et4N+I1-14YYYYYYHI,BBr3 most inert,phenolic-OHPhCH2Cl-OBnBase 14YYYYNYH2/Cat.Apply to sugar and amino acidtert-butyl-Cl-OBu-tH+1-14YYYYYYAcid,CF3COOHsteroid OH CH2=CHCH2Cl-OAllBase 5-14YYYYYYStrong B&A,RhRPh3CCl-OTrWeek base5-14YNYYYYweak acid primary alcohol as of bulky-OHCH3OCH2X-OMOMStrong base NaH4-14YYYYYYAcid or week acidphenol -OHDi-hydropyran-OTHPH+4-14YYYYYYAcid or week acidphenol -OHSummary29第29页Protect-ed GroupReactant Protecting GroupIntroduce conditionsStability toCleaving conditionsNote pHNuRMOxi.Red.H2/Cat.El.-OHTMSCl,-OSiMe3Week Base or organo-baseNNNYNNNAqu.base or acid,Short term Prot.TESCl-OSiEt3Week Base or organo-baseS.SSYSSSAqu.base or acid,TBDMSCl,-OSiMe2ButWeek Base or organo-baseM.S.M.S.M.S.YM.S.M.S.M.S.Aqu.base or acid,Relative stability depends on steric factorthe rate of hydrolysis for 2nd silyl ether 1st silyl ether -OHAc2O,AcCl-OAcamine1-8YYYNYYBase and acid Hydr.or Common usedPhCOCl-O-Bzamine1-11M.S.M.S.M.S.YYYBasic hydrolysis or LiAlH4Summary30第30页Reaction conditions:a ketone with an acid catalyst to form 1,3-dioxolane or acetonide Stable to:base but not to acid(pH 4-12),organometallics,nucleophiles,catalytic hydrogenation,hydride,oxidizing agent Cleaved condition:aqueous HCl or p-toluenesulfonic acid in methanol,Applied to:carbohydrates 4.Protection Groups for Diols 31第31页4.Protection Groups for Diols 32第32页4.Protection Groups for Diols 33第33页JACS 122,66244.Protection Groups for Diols 34第34页The conversion of carbonyl to ketal and acetal using alcohol and diol reactionThe variation of this reaction use thiol or dithiol reaction to generate dithioketals or dithioacetolsAlcohols were protected as ketals and acetales by reaction with ketones and aldehydes,Carbonyl will be protected as the ketals and acetals by reaction with alcohols.The group,the reaction,the cleaving reaction are same,the difference is which FG is the object of attention and isolation.Note:Protection:Carbonyls,nucleophilic acetyl additions,oxygen-stabilized carbocation,Carbonyls,nucleophilic acetyl additions,oxygen-stabilized carbocation,5.Protecting Groups Carbonylsaldehydes and ketones5.Protecting Groups Carbonylsaldehydes and ketones35第35页Reaction conditions:a ketone with an acid catalyst to form 1,3-dioxolane or acetonide Stable to:pH 4-12 but sensitive to aqueous acid and lewis acid.organometallics,nucleophiles,catalytic hydrogenation,hydride,oxidizing agent Cleaved condition:aqueous HCl or p-toluenesulfonic acid or trifluoroacetic acid or oxalic acid(HOOC-COOH),Applied to:any aldehyde and ketones5.Protecting Groups Carbonylsaldehydes and ketones5.Protecting Groups Carbonylsaldehydes and ketones36第36页5.1 ketals and acetals as the protection groups for carbonyls5.1 ketals and acetals as the protection groups for carbonylsMethanol and ethanol are the most common ones used.Because:1.The yields of product are high2.Lower molecular weight of alcohol byproducts are easy removed3.Simple singlet NMR spectrumCorilin JOC 1999,64,24685.Protecting Groups Carbonylsaldehydes and ketones5.Protecting Groups Carbonylsaldehydes and ketones37第37页5.1 ketals and acetals as the protection groups for carbonyls5.1 ketals and acetals as the protection groups for carbonylsCyclic ketals or cyclic acetals 1,3-dioxolanes or 1,3-dioxanes 芳(香)族聚酮,hot compounds in anti-biotics,Fredericamycin A，a unique quinone antitumor antibiotic,was isolated from a new strain of Streptomyces griseus at the Frederick Cancer Research Center in Frederick,MD,in 1981.JACS 1994,116,9921,63卷 7期 化学通报,5.Protecting Groups Carbonylsaldehydes and ketones5.Protecting Groups Carbonylsaldehydes and ketones38第38页39第39页5.2 dithioketals and dithioacetals as the protection groups for carbonyls5.2 dithioketals and dithioacetals as the protection groups for carbonylsVariatation method,selectivity of protection,sulfur analogs,dithioketals dithioketals and dithioacetalsand dithioacetals,more flexibility,Reaction conditions:Stable to:acid(pH 1-12).organometallics,nucleophiles,catalytic hydrogenation,hydride,oxidizing agent（CrO3 可氧化）Cleaved condition:HgCl2 and AgNO3 but not reaction with other Lewis acidApplied to:5.Protecting Groups Carbonylsaldehydes and ketones5.Protecting Groups Carbonylsaldehydes and ketones40第40页5.2 dithioketals and dithioacetals as the protection groups for carbonyls5.2 dithioketals and dithioacetals as the protection groups for carbonyls11-hydroxyjasionone Corey 5.Protecting Groups Carbonylsaldehydes and ketones5.Protecting Groups Carbonylsaldehydes and ketones41第41页Amine,ammonium,amide,lone pair of electrons on nitrogen,basic activity,oxidation,Protection,ammonium salt,good leaving group for substitution and elimination reaction,so not a good protection group.Three protection methodConversion of primary,secondary amine to terary amine(benzyl or trialkylsilyl)Conversion to amide（Boc,Fmoc Chapter 3)Conversion to sulfonamide6.Protecting Groups for amines6.Protecting Groups for amines42第42页6.1 N-alkyl and N-silyl protecting groupReaction conditions:Stable to:acid and base(pH 4-12).organometallics,nucleophiles,hydride,but reaction with lewis acid(as a Lewis base)Cleaved condition:hydrogenlysis by catalyst hydrogenation or dissolving metals H2 and Pd on Carbon,Na/NH3Applied to:6.Protecting Groups for amines6.Protecting Groups for amines43第43页6.1 N-alkyl and N-silyl protecting groupHiv-1 protease inhibitors,JOC 1999,64,49806.Protecting Groups for amines6.Protecting Groups for amines44第44页6.2 N-acyl protecting groupsAmides are common protecting groups for amine.N-acylamine are known as acetamide derivatives (N-COMe,N-Ac)Reaction of Acetic anhydride or acetyl chloride with amine in the present of base,(pyridine or trimethylamine)will generate the acetamide.Acetamide are sensitive with strong acid or base but Stable in the pH range 1-12,can react with organometallic and nucleophiles(RLi does not react very well,but RMgBr does)Boc(t-butoxycarbonyl),Fmoc(9-fluorenylmethoxycabonyl 9-芴基甲氧基羰基)are currently used,Chapter 36.Protecting Groups for amines6.Protecting Groups for aminesFmoc-protection45第45页6.Protecting Groups for amines6.Protecting Groups for aminesCbz-protectionBoc-protection6.2 N-acyl protecting groups46第46页H+6.Protecting Groups for amines6.Protecting Groups for amines47第47页Protect-ed GroupReactant Protecting GroupIntroduce conditionsStability toCleaving conditionsNote pHNuRMOxi.Red.H2/Cat.E.DiolsAcetone Cylic ketals H+4-14YYYYYYAcid or week acidB(OH)3HB-(OR)2OH-4-14YYYYYYAcid or week acidPhCHOC=OalcoholsDiolsKetalsAcetls H+Dithiols dithioketals1-12YYY/NYYYHgCl2 and AgNO3-NH2PhCH2ClamineAcetyl acidamideCBZ-ClBoc2OFboc2OCbzBOCFBOCN-Carbamate H+Ammonium Carb-amate,-NH-CO-OR carbonate RO-CO-OR SummarySummary48第48页You should know When are protecting groups needed?Be careful How many protecting groups?Roll up what do they apply to?Conditions,stability,and so on You should have this skill How to analysis why the chemist used the specific protection group for a synthesis?Reference,database,You must know the reactions alkylation on Oxygen,Nitrogen,Carbonyl,and carbon A lot of protection group,different uses,specific selection,variation methodsSummarySummary49第49页In each of the following,give the major product.If there is no reaction,indicated by N.R.HomeworkHomework50第50页In each of the following,discuss the relative merits of protecting functional groups or finding the chemo-selective reagent for 1)reduction with hydride 2)Catalytic hydrogenation 3)reaction with MeMgBrAnd also read the book organic synthesis chapter 7HomeworkHomework51第51页Example 3Note:1.Protecti