Myers Stereoselective Olefination Reactions: The Wittig Reaction Chem 115 Reviews: Vedejs, E.; Peterson, M. J. In Topics in Stereochemistry; Eliel, E. L. and Wilen, S. H. Ed.; John • Phosphonium ylides react with aldehydes to produce oxaphosphetane 1Z or 1E, which Wiley & Sons: New York, 1994, Vol. 21, pp. 1–158. decomposes by a syn-cycloreversion process to the alkene. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927. Wittig Olefination, Background: • In the formation of Z-alkenes, an early, four-centered transition state is proposed. TSZ is believed to be kinetically favored over TS because it minimizes 1,2 interactions between R and R in the • Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler: E 1 2 forming C–C bond. • The reaction of non-stabilized phosphonium ylides with aldehydes favors (Z)-alkene products. O PhLi CH2 Ph3P CH3 Ph Ph Ph Ph Br Et2O, 84% Wittig, G.; Geissler G. Liebigs Ann. 1953, 580, 44-57. Non-stabilized Ylides: Ar3P R = simple alkyl R • Terminology introduced by Professor E. J. Corey in Chem 115 to help students conduct retrosynthetic analysis of trisubstituted olefins: T-branch RT L-branch H (trans) RL (lone) Rc O – NaHMDS C-branch N Cl N CCl3 (cis) O + O Ph P THF, –40 ºC 3 CCl 3 59% Mechanism: H O CCl3 Ar Ar P O Ar H 3 P H H Ar O R H 2 R1 R2 R1 R2 R1 1Z (Z)-alkene Ar3P TSZ R1 + Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M.-L.; Stockman, R. A.; Fuchs, P. L. J. Am. Ar3P O O Chem. Soc. 2006, 128, 12656–12657. H H H R2 R1 R2 2 Ar H Ar R P 2 Ar O R Ar3P O Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157. R1 2 R1 Vedejs, E.; Peterson, M. J. Advances in Carbanion Chemistry 1996, 2, 1–85. H H R2 R1 H (E)-alkene TSE 1E Fan Liu 1 Myers Stereoselective Olefination Reactions: The Wittig Reaction Chem 115 • Stabilized ylides are proposed to have a later and more product-like transition state with 1E thermodynamically favored over 1Z. Synthesis of Phosphonium Ylides Ph3PCH2R • The reaction of stabilized phosphonium ylides with aldehydes favors (E)-alkene products. These reactions generally proceed at higher temperatures than reactions of non-stabilized ylides. R pKa (DMSO) • Phosphonium ylides are generally prepared by deprotonation of H 22.5 phosphonium salts, which come from the reaction of trialkyl or Ph 17.4 triarylphosphines with alkyl halides. CN 6.9 Stabilized Ylides: Ar3P R = aryl, alkenyl, -CO2R, or any anion-stabilizing groups. R O CPh 6.1 • Alkyl/aryl phosphonium halides are only weakly acidic. A strong base is required for deprotonation. Precursors to stabilized ylides are more acidic than alkyl phosphonium salts and can be generated using weaker bases. CHO CO2Et CH Cl CO2Et H C 2 2 H C 3 Ph3P 3 CH3 CH3 23 ºC, 85% CH3 CH3 E:Z = 92:8 Bordwell, F. G.; Zhang, X.-M. J. Am. Chem. Soc. 1994, 116, 968–972. Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Org. Chem. 1996, 61, 1082–1100. 1. NaI, NaHCO3 O O • Lithium ions catalyze the reversible formation of betaine 2 (depicted previous page), which O DMF, 100 ºC O contributes to erosion in stereoselectivity. Br O Ph P O 2. PPh3, K2CO3 3 I– NaHMDS CH3CN, 85 ºC O 88% THF; H O C H 6 6 O O + Ph3P H O OTBS Et 23 ºC, 88% Et O Z : E = 96 : 4 O OTBS O C6H6, LiI Et H + Ph3P Et 23 ºC, 81% Z : E = 83 : 17 Keinan, E.; Sinha, S. C.; Singh, S. P. Tetrahedron 1991, 47, 4631–4638. Krüger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499–7504. Schlosser, M. ; Christmann, K. F. Liebigs Ann. Chem., 1976, 708, 1–35. Fan Liu 2 Myers Stereoselective Olefination Reactions: The Wittig Reaction Chem 115 Examples • Industrial synthesis of vitamin A (>1000 tons of vitamin A are produced per year using this • !,"-unsaturated carbonyl compounds can undergo phosphoniosilylation and Wittig olefination to give chemistry): substituted enones. CH3 H3C CH3 CH3 O PPh3 + OAc NaOCH Br H 3 CH3 CH3OH O OTBS 23 ºC, 98% TBSOTf, PPh3 THF, 23 ºC + – PPh3 OTf CH CH H3C CH3 3 3 1. n-BuLi, THF, –78 ºC OH 2. O H3C CH3 H vitamin A CH3 Pommer, H. Angew. Chem. 1960, 72, 811–819. O OTBS Pommer, H.; Nürrenbach, A. Pure Appl. Chem. 1975, 43, 527–551. TBAF Paust, J. Pure Appl. Chem. 1991, 63, 45–58. 86%, E:Z = 13:1 THF/Hexane 80% H3C CH3 H3C CH3 H CH3 OTBDPS H H H3C H3C OTBDPS Ph3P CH3 O O N N H3C CH3 O Kozikowski, A. P.; Jung, S. H. J. Org. Chem. 1986, 51, 3400–3402. H CH2Cl2, 40 ºC H H3C OH H3C OH 71% • Methoxymethylene ylides lead to vinyl ethers, which can be hydrolyzed to aldehydes. An example of this in synthesis: Overman, L. E.; Bell, K. L.; Ito, F. J. Am. Chem. Soc. 1984, 106, 4192–4201. H C H C 3 1. OCH3 3 CH3 Ph3P CH3 H3C H H THF, –30 ºC H3C H H H H H H O O H3C H3C NH 1. SO •pyr, DMSO NH O O 3 TBSO 2. TfOH, i-PrOH TBSO i-Pr NEt, CH Cl , 23 ºC H 2 2 2 I CH2Cl2 I OH 2. Et P O 77% BocHN 3 BocHN CO Et H O CO2Et 2 (2.00 kg) (2.17 kg) –5 # 23 ºC, 86% Chen, L.; Lee, S.; Renner, M.; Tian, Q.; Nayyar, N. Org. Process Res. Dev. 2006, 10, 163–164. MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391–10392. Fan Liu 3 Myers Stereoselective Olefination Reactions: The Wittig Reaction Chem 115 Schlosser's Modification: • The ylide intermediate can be trapped with formaldehyde, providing a stereospecific synthesis of Z- trisubstituted alcohols (note the hydroxymethyl group is in the C-branch). • Reaction of non-stabilized phosphonium ylides with aldehydes can be made to favor formation of (E)-alkenes using a modified procedure. 1. n-BuLi, THF, 0 ºC H 2. H C Et H3C Et O 3 O O O PPh +I– H CH2OTHP 3 1. PhLi, THF, 0 ºC 2. CH3 CH2TMS CH3 CH3 OH 3. PhLi, Et2O, + – –78 ºC O O PPh3 I –78 0 ºC CH2OTHP ! 3. sec-BuLi, –25 ºC CH3 4. (CH2O)n, 0 ºC 50%, single isomer Corey, E. J.; Yamamoto, H. J. Am. Chem. Soc. 1970, 92, 6636–6637 • Haloalkenes can also be prepared: O O CH3 CH2TMS CH3 O 1. PhLi•LiBr 2. Ph H 3. BrCF2CF2Br O O 71% CH3 Ph3P CH3 Ph THF, Et2O THF, –75 ºC E:Z = 96:4. –75 ! 25 ºC Br Br –75 ! 25 ºC 3. PhLi•LiBr 47%, E : Z = 1 : 99 Schmidt, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122–5123. • Interestingly, bromination is very sensitive to the size of the alkylidene: increasing the size of the ylide • The presence of soluble lithium salts promotes the reversible formation of betaine 2. Addition of the led predominantly to E-alkenes: second equivalent of PhLi deprotonates the "-position. The resulting #-oxido ylide is hypothesized to possess a cyclic geometry where steric interactions are minimized between the 2. OCH3 H triphenylphosphonium group and R2. – + I Ph3P 1. PhLi•LiBr H3CO O , –78 ºC R1 + – Ar3P O PPh3 I THF, Et O 3. PhLi LiBr, –78 25 ºC Ar3P OLi Ar3P OLi n-Hexyl 2 • ! + H H –78 25 ºC ! 4. BrCF CF Br, –78 ! 25 ºC R1 R2 H H Li H 2 2 O PhLi R R PhLi R R + 1 2 1 2 H R 2 2 LiI OCH3 Br H3CO Br Li R2 Li O n-Hexyl R1 82%, E : Z > 99 : 1 Ar3P H (E)-alkene R1 R2 Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Chem. Eur. J. 2003, 9, 570–574. Corey, E. J.; Ulrich, P.; Venkateswarlu, A. Tetrahedron Lett. 1977, 18, 3231–3234. Hodgson, D. M.; Arif, T. J. Am. Chem. Soc. 2008, 130, 16500–16501. Fan Liu 4 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Chem 115 Reviews: Mechanism: Wadsworth, W. S., Jr. Org. React. 1977, 25, 73–253. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I. Ed.; R' R'' H O M R' R'' Pergamon: Oxford, 1991, Vol. 1, pp. 729–817. H W W R' O P(OR)2 H W (RO)2(O)P R'' O M Applications in Natural Product Synthesis: Nicolaou, K. C.; Härter, M. W.; Gunzner, J. L.; Nadin, A. (E)-alkene 1 2 Liebigs Ann./Recueil 1997, 1283–1301. R'CHO E E + Asymmetric Wittig-Type Reactions: Rein, T.; Reiser, O. Acta. Chem. Scand. 1996, 50, 369–379. O (RO)2P W M R'' Development and General Aspects: R' W H O M R' W W H R'' • Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler. R' O P(OR)2 Wittig, G.; Geissler G. Liebigs Ann. 1953, 580, 44-57. R'' P(O)(OR)2 H R'' O M (Z)-alkene 1Z 2Z • In 1958, Horner disclosed a modified Wittig reaction employing phosphonate-stabilized carbanions; the scope of the reaction was further defined by Wadsworth and Emmons. CO2Et 1. NaH, DME, 23 °C – O O W = CO2 , CO2R, CN, aryl, vinyl, SO2R, SR, OR, NR2 (EtO)2P + (EtO) PO Na OEt 2.