I-L. Wittig Reaction(s)I. Basic PrinciplesFirst report: 1953, Wittig and Geissler, Liebigs Ann. 1953, 580, 44.(Nobel Prize in Chemistry in 1979)Ph3P CH3IPhLiPh3P CH2Ph3P CH2ylidePhCOPhO PPh3PhPhO PPh3PhPh84%Ph Ph80 kcal/mol130 kcal/mol-Ph3P=ODr. P. WipfPage 1 of 432/20/2008Industrial preparation of Vitamin A (BASF, 1956)PPh3BrOOAcNaOH, MeOH, 98%OHvitamin AReagent control of Z/E-selectivity:OPh3P CHCH3+96 : 4ZEP+18 : 82ZEVedejs, JOC 1993, 58, 6509Dr. P. WipfPage 2 of 432/20/20081. The Wittig ReactionNicolaou, K. C.; Härter, M. W.; Gunzner, J. L.; Nadin, A., "The Wittig and related reactions innatural product synthesis." Liebigs Ann./Recueil 1997, 1283-1301.Hoffman, R. W., "Wittig and his accomplishments: Still relevant beyond his 100th birthday."Angew. Chem. Int. Ed. 2001, 40, 1411-1416.Murphy, P. J.; Lee, S. E., "Recent syntheticapplications of the non-classical Wittig reaction." J. Chem. Soc., Perkin Trans. 1 1999, 3049-3066.Rein, T.; Pedersen, T. M., "Asymmetric Wittig type reactions." Synthesis 2002, 579-595.Over much of its history, the Wittig reaction has been described as a stepwise ionic process.The hypothetical betaine intermediates were never observed, but lithium halide adducts couldbe isolated in some of the early Wittig experiments. The newest hypothesis attributesstereoselectivity to a combination of steric effects and varying degrees of rehybridization atphosphorous in the formation of the covalent oxaphosphetane.Dr. P. WipfPage 3 of 432/20/2008Energy profilenon-stab. ylidestab. ylide Ph3PRHOHR'RPh3P+HO-HR'RPh3P+O-R'HHPh3P OR R'H HRHHR'RPh3P+O-HHR'antiPh3P OR HH R'Ref.: Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1-157.A. Stepwise, ionic process (betaine mechanism):RR'HHsyn+(E)Wittig Mechanismsanti(Z)Dr. P. WipfPage 4 of 432/20/2008Evidence against this mechanism started to accumulate in the late 1960's. First, thesolvent dependence of the Wittig reaction did not concur with a chargedintermediate, the betaine. Also, it was found that the oxaphosphetane was actuallymore stable than the putative betaine. Experimental and theoretical insights can besummarized as follows:1. Under salt-free, aprotic conditions, ylides Ph3P=CHR (R=alkyl, alkenyl, phenyl) react withaldehydes to produce the oxaphosphetane directly via four-centered transition states.2. The Z:E ratio of alkenes corresponds to the cis-trans ratio of oxaphosphetanes in typicalreactions (kinetic control). This is true of nonstabilized ylides as well as carbonyl-stabilizedylides, although there are exceptions.3. The oxaphosphetane decomposes by a syn-cycloreversion process to the alkene.4. There are no zwitterionic or diradical intermediates having significant lifetimes.5. Betaines are energetically uphill compared to reactants as well as to oxaphosphetanes.Accordingly, since the stereochemistry of the alkene product appears to be established in theTS leading to the oxaphosphetane, we need a new mechanism to explain the observed Z:Eratios that depend on the level of stabilization (charge delocalization) of the ylide. The Wittigreaction must involve a mechanism other than the betaine pathway. A synchronouscycloaddition process is consistent with the available evidence (Vedejs, J. Am. Chem. Soc.1990, 112, 3905).Dr. P. WipfPage 5 of 432/20/2008Ph3PRHOH R'Ph3P OR R'H HRHHR'Ph3P OR HH R'RR'HHPORHR'HPhPhPhPOHRR'HPhPhPhB. Four-center transition state analysis according to Vedejs:(E)+(Z)POPhPhPhHHRR'Ref.: Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1-157.APlanar transition states A, resembling oxaphosphetanes, are destabilized by the gaucheinteraction between the developing P-O bond with two phosphorus ligands and by a 1,3-interaction between the aldehyde substituent and the nearby phosphorus ligand. The 1,3-interactions can be reduced by puckering the four-membered ring. Here the cis- is favoredover the trans-TS because of smaller 1,2-interactions between the ylide R substituent with R'(gauche interactions) and the eclipsing strain between R and the adjacent phosphorus Phsubstituent.If the phosphine rings are constrained as in the non-stabilized ylide shown below, the role of1,3-interactions is reduced especially since the third phosphorus ligand (ethyl) is compact.There is little steric advantage for a puckered geometry, even though the TS is relativelyearly, and the TS geometry resembles a planar oxaphosphetane. The trans-selective pathwayis favored because 1,2-interactions are now dominant.Dr. P. WipfPage 6 of 432/20/2008PHOH R'R3P OHH R'R'HHPOHHR'+(E)In the stabilized ylide case, increased P-O bonding in the (later) TS favors a more nearlyplanar four-center transition state geometry. Since phosphorus is closer to a trigonalbipyramidal geometry, the 1,3-interactions are relieved and 1,2-interactions controlselectivity. The normal thermodynamic advantage for the trans-disubstituted oxaphosphetaneis felt in the product-like TS, and the (E)-alkene is the major product. Because the TS isrelatively rigid, the result is not much affected by changes in the phosphorus ligands, incontrast to the nonstabilized ylide reactions.Ph3P OEtO2C HH R'EtO2CR'HHPOHHCO2EtR'Ph3PCO2EtHOH R'(E)+Dr. P. WipfPage 7 of 432/20/2008Stereo plot files (Vedejs, E., J. Am. Chem. Soc. 1988, 110, 3948, use stereoviewer):a) The cis-selective TS has a puckered ring and the aldehyde substituent in apseudoequatorial orientation as far as possible from the phosphorus ligands. b) The trans-selective variation is less stable because α-CH3 and tertiary alkyl are nearly in thesame pseudoequatorial plane. If the transition state were late, this interaction would bereduced because of the phosphorous hybridization changes. This is why the final product isalways more stable as the trans-disubstituted oxaphosphetane. Dr. P. WipfPage 8 of 432/20/2008c) The trans-selective planar transition state reduces the gauche interaction butinvolves increased interactions with L”, the nearby phenyl substituent at thepartially rehybridized phosphorus. Again, in a later transition state whenphosphorus rehybridization from sp3 to dsp3 (trigonal bipyramidal) hasproceeded, these interactions will be reduced. The variation in Wittig reaction stereochemistry is attributed to dominant kinetic control innearly all cases. Formation of cis or trans oxaphosphetanes is the decisive step, and thisoccurs by an
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