1. Organic Pedagogical Electronic Network Stereoselectivity in Wittig Reactions Created by Jonathan Greenhalgh Edited by Margaret Hilton Honors Organic Chemistry Chem 2321 (Sigman), 2013

2. Stereoselectivity of Wittig Reactions Wiki Page: http://en.wikipedia.org/wiki/Wittig_reactionhttp://en.wikipedia.org/wiki/Wittig_reaction http://en.wikipedia.org/wiki/HWE_reaction Overview: The reaction of phosphonium ylides and carbonyls to form alkenes was discovered by Georg Wittig in 1954. He received a Nobel Prize in Chemistry for his discovery in 1979. Wittig reactions are widely used in organic synthesis because of their ability to selectively create E (trans) or Z (cis) alkenes. Early Examples General Mechanism Georg Wittig 1954 The carbon in the ylide acts as the nucleophile, attacking the carbonyl. This first step forms a C-C bond. The bonds rotate so that the oxygen nucleophile can attack the phosphorus. Then, the P-C bond and C-O bonds break, forming C=C and P=O bonds Horner-Wadsworth-Emmons Reaction 1958 Stephen Martin and Christian Harcken 2001 Other References: Martin, et. al. Org Lett., 2001, 3 (22), 3591Martin, et. al. Org Lett., 2001, 3 (22), 3591 Hodgson, et. al. Org. Lett., 2010, 12 (18), 4204

3. Destabilized Ylides and Z-Alkenes Wiki Page:http://en.wikipedia.org/wiki/Wittig_reactionhttp://en.wikipedia.org/wiki/Wittig_reaction Destabilized ylides react with carbonyls to form Z (cis) alkenes Destabilized ylides have no electron withdrawing groups (EWG) attached to the carbon chain The Z in Z-alkene stands for the German word “Zusammen” which means “together” The Z (cis) product is the kinetic product so these reactions are under kinetic control

4. Stabilized Ylides and E-Alkenes Wiki Page:http://en.wikipedia.org/wiki/HWE_reactionhttp://en.wikipedia.org/wiki/HWE_reaction Stabilized ylides react with carbonyls to form E (trans) alkenes E stands for the German word “Entigen” which means “opposite” Equilibration to the most stable intermediate occurs due to the electron withdrawing group on the carbon chain The equilibrium favors the thermodynamic product, which is the E (trans) alkene Steric hindrance and other factors can alter the E:Z ratio of a reaction

5. Examples Hong, et. al. Org. Lett. 2009, 11 (22), 5246-5249 In 2009, experiments using Wittig and Michael reactions were used to successfully obtain high selectivity of all-cis molecules, as shown above. This is possible in part due to the stereo-specificity of the Wittig reactions used. The above reaction, another variation of the Wittig Reaction, gave 99% enantiomeric excess and a 90% yield.

6. Problems Reference s : 1aMartin, et. al. Org Lett., 2001, 3 (22), 3592Martin, et. al. Org Lett., 2001, 3 (22), 3592 1b Martin, et. al. Org Lett., 2001, 3 (22), 3592Martin, et. al. Org Lett., 2001, 3 (22), 3592 1c Hodgson, et. al. Org. Lett., 2010, 12 (18), 4205Hodgson, et. al. Org. Lett., 2010, 12 (18), 4205 1. Provide mechanisms for the following reactions: a. b. c. 2. Predict the product of the reaction: 3. Predict the structure of intermediate A, the product of the Wittig Reaction of 1 with 2, prior to the Michael reaction. Indicate stereochemistry of the product(s). 1 2 2Hodgson, et. al. Org. Lett., 2010, 12 (18), 4205Hodgson, et. al. Org. Lett., 2010, 12 (18), 4205 3Hong, et. al. Org. Lett. 2009, 11 (22), 5246-5249Hong, et. al. Org. Lett. 2009, 11 (22), 5246-5249