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
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1、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 Concepts
2、Protecting 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 F
3、G 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 P
4、G 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
5、,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 gr
6、oup 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
7、 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.React
8、ion 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
9、.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 gro
10、up9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 wit
11、h 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.Pro
12、tection 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,oxid
13、ation,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 me
14、tal 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 conditio
15、n: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 protecti
16、on 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
17、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 u
18、sed 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 met
19、hoxymethy 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
20、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
21、,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 hyd
22、rolysis 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
23、 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,mesitoat
24、e 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:Protectin
25、g 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-OHPhCH2
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