1、The Mitsunobu reactions,Contents,A Whirlwind Tour of Current Mitsunobu Chemistry1. Alcohol Inversions2. Other Nucleophiles3. Carbon-Carbon Bond Formation4. Alternative Reagents-Azodicabonyl Portion5. Alternative Reagents-Trisubstituted Phosphine Portion6. Some Alternatives to Mitsunbu Chemistry Refe
2、rences Acknowledgements,Alcohol Inversion,mechanism,Alcohol Inversion,When a secondary alcohol substrate was used, the esterification reaction was shown to proceed with a net inversion of stereochemi- stry at the alcohol carbon.,Alcohol Inversion,In cases where no nucleophile was added to the reacti
3、on mixture, or when the betaine was not able to abstract the proton of the nucleophilic precursor (pKa13),the hydrazine portion of the reagent was shown to react with the alcohol substrate(Scheme 3),Alcohol Inversion-Intermolecular,The alcohol inversion and hydrolysis procedure may be easily carried
4、 out in the presence of sensitive functionality(scheme 5),Alcohol Inversions,Smith and coworkers,Alcohol Inversions,1991, Eli Lilly chemists Martin and Dodge,Alcohol Inversions,PNBA was also useful in preventing the elimination side reaction.,Alcohol Inversions,Tsunoda and coworkers found that the u
5、se of TMAD and Bu3P was more tolerant of sterically congested alcohols, resulting in consistently better yields than the PPh3/DEAD,Alcohol Inversions,The Mitsunobu reaction has also entered the area of solid-phase synthesis.,Alcohol Inversion-Intramolecular,Synthesis of lactones, a valuable precurso
6、r to amino acids,Alcohol Inversions,Synthesis of bis-lactones,Alcohol Inversions,Other Oxygen Nucleophiles,Alcohol Inversions,cyclizations,Alcohol Inversions,The use of TMAD was shown to enhance the reactivity of these nucleophiles of larger pKa,leading to higher overall yields,Alcohol Inversions,N-
7、hydroxyphthalimide was also an excellent nucleo- phile for the inthemolecular Mitsunobu reaction,Alcohol Inversions,Oximes serve as oxygen nucleophiles,Alcohol Inversions,Preparation of sulfonates,Preparation of sulfonates,Other nucleophiles,Nitrogen NucleophilesSulfonamides as Nucleophiles,Other nu
8、cleophiles,Application 1 - the synthesis of natural product Sarain A,Other nucleophiles,Application 2 - the synthesis of Boc-protected amines or amine hydrochloride.,Other nucleophiles,Application 3- Nitroarylsulfonamides as good leaving moiety.,Other nucleophiles,Other applications Fmoc protected s
9、ulfonamidesAmides and Imides as nucleophiles,Other nucleophiles,Hydroxylamines as nucleophiles,Other nucleophiles,Provide a propargyl hydrazine,Other nucleophiles,The preparation of guanidines.,Other nucleophiles,Two method of the formation of azide,Other nucleophiles,Synthesis of lysine and arginin
10、e analogs,Other nucleophiles,Secondary and tertiary benzylamines with activated aryl substrates,Other nucleophiles,Sulfur nucleophiles thioester,Other nucleophiles,Aryl thiols as nucleophiles,Other nucleophiles,HalogenationsSynthesis of the alkyl halogens,Other nucleophiles,Synthesis of the intermed
11、iate of the marine natural products astins A,B and C,Other nucleophiles,ZnCl2 as catalyst,Carbon-Carbon Bond Formations,Lithium cyanide as nucleophilesLimitation: primary alcohols and sterically unencumbered secondary substrates,Carbon-Carbon Bond Formations,Methanetricarboxylate as nucleophile,Carb
12、on-Carbon Bond Formations,C-alkylation of monosubstituted Meldrums acids,Carbon-Carbon Bond Formations,Preparation of -nitrocyclopropanes,Carbon-Carbon Bond Formations,DHAD and Bu3P were effective for the deprotonation of activated methylene substrates with large pKa,Alternative Reagents- Azodicarbo
13、nyl Portion,DEAD and ADDPThe reactivity : DEAD=DIAD ADDP TMAD DHAD,Alternative Reagents- Trisubstituted Portion,Alternative Reagents- Trisubstituted Portion,DPPE: great polarty of the resulting bis-phosphine oxide byproduct.- insoluble, removed by filtration. Bu3PO : water soluble Ph2Py: water solub
14、le,Alternative Reagents- Trisubstituted Portion,Appendix of Abbreviations & Acronyms,PNBA - p-Nitrobenzoic Acid DPPA - diphenylphosphoryl azide DEAD - Diethyl Azodicarboxylate DIAD - Diisopropyl Azodicarboxylate DMAD - Dimethyl Azodicarboxylate ADDP - 1,1-(Azodicarbonyl)dipiperidine TMAD - N,N,N,N,-
15、Tetramethylazocarboxamide DHTD - 4,7-Dimethyl-3,5,7-henxahydro-1,2,4,7-tetrazocin-3,8-dione,DAP-DP - (p-Dimethylaminophenyl) diphenylphosphine DPPE - 1,2-Bis(diphenylamino)phosphine tris-DAP - tris(dimethylamino)phosphine CMMP - Cyanomethyltrimethylphosphorane CMBP - Cyanomethyltributylphosphorane,R
16、eferences,1. Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1967, 40, 935. 2. Mitsunobu, O.; Eguchi, M. Bull. Chem. Soc. Jpn. 1971, 44, 3427. 3. Mitsunobu, O. Synthesis 1981, 1. 4. Hughes, D. L. “The Mitsunobu Reaction,” OrganicReactions ; John Wiley Pergamon Press, 1991, Vol. 6, p 65.,
