Mitsunobu反应-三十张幻灯片的简短概述.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,The Mitsunobu Reaction,A thirty slide short overview,Scope and Power but also Headaches,Scope and Power,various acidic nucleophiles can be alkylated,tolerates a wide range of functional groups,works under mild reaction conditions,usually highly stereospecific,Part 1,Headaches,isolation of desired product from byproducts,Part 2,The Mitsunobu reaction is famous for its scope and power,but infamous for its seperation headaches.“,Reaction Mechanism,S,N,2 reaction,Nucleophilic attack proceeds under,total inversion of stereochemistry!,Under classical Mitsunobu reaction conditions the nucleophile has to have a pK,a,11-12 do not react in the presence of DEAD and PPh,3,!,However,a lot of nucleophiles fulfil this requirement and thus allow,a wide range of interesting alkylations.,But what if the nucleophile has a pK,a,11-12?,Part 1,The Classic Mitsunobu Approach,*,)of protonated form,pK,a,12,*,),pK,a,11-12?,Part 1,Other reagents than PPh,3,and DEAD are required!,*,)pKas of protonated form,Increased reactivity in the Mitsunobu reaction!,pK,a,12,pK,a,13,pK,a,14,pK,a,15,*,),A,zo,d,icarbonyl,d,i,p,iperidine,D,imethyl,h,exahydro-,t,etrazocin,d,ione,T,etra,m,ethyl-,a,zo,d,icarboxamide,D,i,e,thyl,a,zo,d,icarboxylate,Nitrogen Nucleophiles With pK,a,12,Tsunoda et al.,Tetrahedron Lett.,1994,35,5081.,Part 1,Tsunoda et al.,Tetrahedron Lett.,1995,36,2531.,Part 1,Carbon Nucleophiles with pK,a,12,Is this the limit?,No!,Part 1,Alternatives to Trialkylphosphines and Azodicarboxylates,These compounds can replace the trialkylphosphine and the azodicarboxylate!,But how?,Part 1,Mitsunobu Reaction With Very Weak Carbon Nucleophiles,Tsunoda et al.,Tetrahedron Lett.,1995,36,2531.,Part 1,Sterically Hindered Substrates,Only 17%!,What the hell,What is wrong?,The alcohol is sterically quite congested!,Try sterically less demanding trialkylphosphines and/or azo compounds!,pK,a,4.5,Part 1,Sterically Hindered Substrates:Some Very General Rules,concerning the azo compound:,Good choice for the reaction of,sterically congested sec.alcohols,with various nucleophiles.,Tsunoda et al.,Tetrahedron Lett.,1995,34,2529.,and concerning the trialkylphosphine:,Hillier et al.,Org.Lett.,2004,6,573.,basicity and nucleophilicity,Sometimes its worthy to try different phosphines.,Availibility of Reagents,Part 1,The Headache of the Mitsunobu Reaction,Purification!,Part 2,Seperation of product from byproducts,can cause unwanted headaches.,In a single synthesis the purification might be done successfully by chromatography,but for parallel chemistry the purification difficulties are a significant drawback.,BUT:There are some painkillers“on the market.,Polymer-supported reagents,Disadvantages of polymer-supported Mitsunobu reactions:,chromatography still neccessary,large excess of polymer-supported reagent required(5 equiv.),much slower than solution phase reaction,Part 2,Vederas et al.,J.Am.Chem.Soc.,1989,111,3973.,Tunoori et al.,Tetrahedron Lett.,1998,39,8751.,filtration,then,chromatography,Using polymer-supported reagents simultaneously?,Part 2,But reactions between isolated polymer beads do not readily occur!,Would require a single filtration,and possibly no chromatography!,Polymer-supported reagents,Much faster reaction with soluble polymers but still time consuming work-up,and chromatographic purification neccessary.,Part 2,Mitsunobu Reagents Attached to Soluble Polymers,Alternatively to polymer-support PPh,3,a soluble polymeric form was introduced.,Janda et al.,Chem.Rev.,2002,102,3325.,A larger library of Mitsunobu products was synthesized,and purified by this method.,Lan et al.,J.Comb.Chem.,2003,5,660.,Part 2,Capture of Byproducts with Scavenger Resins,2.filtration to remove polymer DECH,4.filtration to remove,3.treatment of remaining mixture with,80%yield,95%purity,Part 2,Water Soluble Triphenylphosphines,Work-up has limitations for products containing acid or base labile groups!,References in:R.Dembinski,Eur.,J.Org.Chem.,2004,5,2763.,For acidic work-up:,For basic work-up:,Part 2,Water Soluble Azodicarboxylates,For acidic work-up:,For acidic/basic work-up:,Again,work-up has limitations for products containing acid or base labile groups!,References in:D.P.Curran et al.,Chem.Eur.,J.,2004,10,3130.,Successful Use of Water Soluble Reagents,Part 2,extracts into aqueous or,disappears in the air,68%yield,94%purity,Also successfully applied in parallel chemistry.,Kiankarimi et al.,Tetrahedron Lett.,1999,40,4497.,Only extractive work-up,no chromatography at all!,Part 2,Availibility of Reagents,Part 2,Fluorophilic Reagents,Fluorous solid phase extraction:,Loading the crude mixture onto fluorous silica gel,Eluation of the non-fluorinated product with a fluorophobic solvent(e.g.MeOH),highly pure product,Eluation of F-TPPO and F-DECH with fluorophilic solvents(e.g.THF)mixture of pure byproducts,Succesful application in combinatorial chemistry!,W.Zhang,Tetrahedron,2003,59,4475.,Commercially available!,5 g/500$,Commercially available!,5 g/430$,Modified Phosphanes:,Modified Azadicarboxylates:,Curran et al.,Tetrahedron,2002,58,3855.,Conclusion,The Mitsunobu reaction indeed is a very versatile alkylation reaction.,It is far more than a method for esterification.,If the combination PPh,3,/DEAD is not working,remember to check,the pK,a,of the nucleophile and maybe try commercially,available alternatives.,If the purification causes headaches,check out available,modified reagents.,Literature,O.Mitsunobu,Synthesis,1981,1-28,R.Jason Herr,Albany Molecular Research,Tech.Reports,1999,3,1-36.,(Valentine Jr.,J.H.Hillhouse,Synthesis,2003,317-334.,R.Dembinski,Eur.J.Org.Chem.,2004,2763-2772.,S.Dandapani,D.P.Curran,Chem.Eur.J,.,2004,10,3130-3138.,D.H.Valentine Jr.,J.H.Hillhouse,Synthesis 2003,3,317-334.,And a lot of cross references out of these papers.,Oyo Mitsunobu,