19 stereoselective olefination reactions

Myers Chem 115 Stereoselective Olefination Reactions: The Wittig Reaction Reviews: Vedejs, E.; Peterson, M J In Topics in Stereochemistry; Eliel, E L and Wilen, S H Ed.; John Wiley & Sons: New York, 1994, Vol 21, pp 1–158 • Phosphonium ylides react with aldehydes to produce oxaphosphetane 1Z or 1E, which decomposes by a syn-cycloreversion process to the alkene Maryanoff, B E.; Reitz, A B Chem Rev 1989, 89, 863-927 Wittig Olefination, Background: • Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler: O Ph Ph3P CH3 Ph Br • The reaction of non-stabilized phosphonium ylides with aldehydes favors (Z)-alkene products CH2 PhLi Ph Et2O, 84% • In the formation of Z-alkenes, an early, four-centered transition state is proposed TSZ is believed to be kinetically favored over TSE because it minimizes 1,2 interactions between R1 and R2 in the forming C–C bond Ph Wittig, G.; Geissler G Liebigs Ann 1953, 580, 44-57 Non-stabilized Ylides: Ar3P • Terminology introduced by Professor E J Corey in Chem 115 to help students conduct retrosynthetic analysis of trisubstituted olefins: T-branch (trans) RT O C-branch (cis) O Ar Ar3P + Ar P H O H R2 H H H R2 R1 1Z R1 Ph3P CCl3 THF, –40 ºC 59% O O N CCl3 CCl3 R2 (Z)-alkene Karatholuvhu, M S.; Sinclair, A.; Newton, A F.; Alcaraz, M.-L.; Stockman, R A.; Fuchs, P L J Am Chem Soc 2006, 128, 12656–12657 Ar3P O O + Ar3P O R1 TSZ R1 NaHMDS Cl– N H Mechanism: Ar R = simple alkyl H L-branch (lone) RL Rc R H H R2 R1 R2 Ar Ar Ar P H O H TSE R1 R2 R2 Ar3P O H R1 1E H R2 R1 Vedejs, E.; Peterson, M J Top Stereochem 1994, 21, 1–157 Vedejs, E.; Peterson, M J Advances in Carbanion Chemistry 1996, 2, 1–85 (E)-alkene Fan Liu Myers Chem 115 Stereoselective Olefination Reactions: The Wittig Reaction • 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 Stabilized Ylides: Ar3P CHO H3C CH3 R • Phosphonium ylides are generally prepared by deprotonation of phosphonium salts, which come from the reaction of trialkyl or triarylphosphines with alkyl halides R = aryl, alkenyl, -CO2R, or any anion-stabilizing groups Ph3P CO2Et CH3 CH2Cl2 CO2Et H3C 23 ºC, 85% E:Z = 92:8 CH3 R pKa (DMSO) H 22.5 Ph 17.4 CN O CPh 6.9 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 CH3 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 • Lithium ions catalyze the reversible formation of betaine (depicted previous page), which contributes to erosion in stereoselectivity O O Br O NaI, NaHCO3 DMF, 100 ºC PPh3, K2CO3 CH3CN, 85 ºC O O Ph3P O I– NaHMDS THF; 88% O H O H + Ph3P O C6H6 Et 23 ºC, 88% Z : E = 96 : O OO Et OTBS O OTBS O H + Ph3P C6H6, LiI Et 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 Myers Chem 115 Stereoselective Olefination Reactions: The Wittig Reaction Examples • !,"-unsaturated carbonyl compounds can undergo phosphoniosilylation and Wittig olefination to give substituted enones • Industrial synthesis of vitamin A (>1000 tons of vitamin A are produced per year using this chemistry): CH3 H3C CH3 CH3 PPh3 Br CH3 O + OAc NaOCH3 CH3OH 23 ºC, 98% H O OTBS TBSOTf, PPh3 THF, 23 ºC CH3 H3C CH3 PPh3+OTf– CH3 n-BuLi, THF, –78 ºC OH CH3 O H3C vitamin A H CH3 Pommer, H Angew Chem 1960, 72, 811–819 Pommer, H.; Nürrenbach, A Pure Appl Chem 1975, 43, 527–551 Paust, J Pure Appl Chem 1991, 63, 45–58 O OTBS TBAF 86%, E:Z = 13:1 THF/Hexane H H H3C O N CH3 OTBDPS Ph3P N CH2Cl2, 40 ºC H H3C OH H3C CH3 O 71% H3C H 80% CH3 H3C CH3 OTBDPS H3C CH3 O H H3C OH Kozikowski, A P.; Jung, S H J Org Chem 1986, 51, 3400–3402 • 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 H3C O BocHN NH OH (2.00 kg) O SO3•pyr, DMSO i-Pr2NEt, CH2Cl2, 23 ºC Et3P CO2Et –5 # 23 ºC, 86% BocHN NH CO2Et CH3 H H H3C H H3C H TBSO O H O I OCH3 Ph3P THF, –30 ºC TfOH, i-PrOH CH2Cl2 77% H3C H3C H H3C H TBSO CH3 H H O I H O (2.17 kg) 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 Myers Schlosser's Modification: • The ylide intermediate can be trapped with formaldehyde, providing a stereospecific synthesis of Ztrisubstituted 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 H O PPh3+I– CH3 O n-BuLi, THF, ºC Et H3C O O Chem 115 Stereoselective Olefination Reactions: The Wittig Reaction PhLi, THF, ºC CH3 H CH2TMS CH2OTHP CH3 PhLi, Et2O, –78 ! ºC O Et H3C O OH –78 ºC PPh3+I– CH2OTHP sec-BuLi, –25 ºC (CH2O)n, ºC CH3 50%, single isomer Corey, E J.; Yamamoto, H J Am Chem Soc 1970, 92, 6636–6637 O • Haloalkenes can also be prepared: O CH3 CH3 O CH2TMS O PhLi•LiBr O 71% E:Z = 96:4 Ph3P Br CH3 THF, Et2O –75 ! 25 ºC H Ph THF, –75 ºC BrCF2CF2Br CH3 Ph –75 ! 25 ºC Br PhLi•LiBr 47%, E : Z = : 99 Schmidt, R.; Huesmann, P L.; Johnson, W S J Am Chem Soc 1980, 102, 5122–5123 • The presence of soluble lithium salts promotes the reversible formation of betaine Addition of the 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 triphenylphosphonium group and R2 R1 + Ar3P O PPh3+I– H PhLi R2 H R1 R2 + Ar3P OLi Ar3P OLi H H R2 R1 PhLi Li R1 H R2 OCH3 I–Ph3P+ PhLi•LiBr O H • Interestingly, bromination is very sensitive to the size of the alkylidene: increasing the size of the ylide led predominantly to E-alkenes: n-Hexyl THF, Et2O –78 ! 25 ºC H3CO H O , –78 ºC PhLi•LiBr, –78 ! 25 ºC BrCF2CF2Br, –78 ! 25 ºC LiI OCH3 H3CO Br Li R2 Li R1 (E)-alkene Br Ar3P R1 Corey, E J.; Ulrich, P.; Venkateswarlu, A Tetrahedron Lett 1977, 18, 3231–3234 O 82%, E : Z > 99 : n-Hexyl H R2 Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M Chem Eur J 2003, 9, 570–574 Hodgson, D M.; Arif, T J Am Chem Soc 2008, 130, 16500–16501 Fan Liu Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Myers Reviews: Chem 115 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.; Pergamon: Oxford, 1991, Vol 1, pp 729–817 H O M W Applications in Natural Product Synthesis: Nicolaou, K C.; Härter, M W.; Gunzner, J L.; Nadin, A Liebigs Ann./Recueil 1997, 1283–1301 R' H R' (RO)2(O)P R'' O P(OR)2 O M 2E 1E R'CHO R'' W R' R'' H W (E)-alkene + Asymmetric Wittig-Type Reactions: Rein, T.; Reiser, O Acta Chem Scand 1996, 50, 369–379 O (RO)2P M Development and General Aspects: • Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler W R'' R' H O M W R'' Wittig, G.; Geissler G Liebigs Ann 1953, 580, 44-57 P(O)(OR)2 1Z • In 1958, Horner disclosed a modified Wittig reaction employing phosphonate-stabilized R' H W R' R'' O P(OR)2 O M 2Z H W R'' (Z)-alkene carbanions; the scope of the reaction was further defined by Wadsworth and Emmons O (EtO)2P CO2Et NaH, DME, 23 °C O OEt W = CO2–, CO2R, CN, aryl, vinyl, SO2R, SR, OR, NR2 + Cyclohexanone, 23 °C, 15 (EtO)2PO2Na 70% • Phosphonate anion addition to the carbonyl or breakdown of the oxaphosphetane intermediate can • Phosphonate-stabilized carbanions are more nucleophilic (and more basic) than the corresponding phosphonium ylides be rate-determining, depending on the identity of OR • The by-product dialkylphosphate salt is readily removed by aqueous extraction • Carbanion-stabilizing group (W) at the phosphonate-substituted carbon is necessary for elimination • In contrast to phosphonium ylides, phosphonate-stabilized carbanions are readily alkylated: O (EtO)2P NaH, DME O OEt n-BuBr, 50 °C O (EtO)2P NaH, DME O OEt CH2O to occur; nonstabilized phosphonates (W = R or H) afford stable !-hydroxyphosphonates Corey, E J.; Kwiatkowski, G T J Am Chem Soc 1966, 88, 5654-5656 O H3C OEt CH2 60%, two steps • The ratio of olefin isomers is dependent upon the stereochemical outcome of the initial addition and upon the ability of the intermediates to equilibrate CH3 Horner, L.; Hoffmann, H M R.; Wippel, H G Chem Ber 1958, 91, 61–63 Horner, L.; Hoffmann, H M R.; Wippel, H G.; Klahre, G Chem Ber 1959, 92, 2499–2505 Wadsworth, W S.; Emmons, W D J Org Chem 1961, 83, 1733–1738 Maryanoff, B E.; Reitz, A B Chem Rev 1989, 89, 863–927 Kent Barbay, Fan Liu Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Myers Michaelis-Becker Reaction: Acidity of Stabilized Phosphonates in DMSO: O (EtO)2P W Chem 115 Bordwell, F G Acc Chem Res 1988, 21, 456-463.; O EtO P H EtO Bordwell, F G Unpublished results W pKa CN 16.4 CO2Et 18.6 corresponding phosphonates: Cl 26.2 (Ph3P+CH2CN)Cl–: pKa = 6.9 Ph 27.6 (Ph3P+CH2CO2Et)Cl–: pKa = 8.5 SiMe3 28.8 Bordwell, F G.; Zhang, X.-M J Am Chem Soc 1994, 116, 968–972 (http://daeiris.harvard.edu/DavidEvans.html) Na, hexane ClCH2CO2Et O EtO P EtO O OEt 58% • Phosphonium salts are considerably more acidic than the Kosolapoff, G M J Am Chem Soc 1946, 68, 1103–1105 Acylation of Alkylphosphonate Anions: • !-ketophosphonates are prepared by acylation of alkylphosphonate anions: Preparation of phosphonates: O (EtO)2P CH3 Michaelis-Arbusov Reaction: Review: Bhattacharya, A K.; Thyagarajan, G Chem Rev 1981, 81, 415–430 n-BuLi, THF, –60 °C CuI O (EtO)2P O CH3 CH3 O 86% H3C Cl CH3 O Br P(OEt)3 OEt CH3 O – EtBr (EtO)3P Br reflux OEt CH3 O EtO P EtO O Mathey, F.; Savignac, P Tetrahedron, 1978, 34, 649–654 OEt CH3 Phosphonate Ester Interchange: 59% O (EtO)2P Arbusov, A E.; Durin, A A J Russ Phys Chem Soc 1914, 46, 295 CH2 CH3 O O MeO P MeO O PCl5 OMe " 75 °C O O Cl P Cl F3CCH2OH OMe DIPEA, PhH O F3CH2CO P F3CH2CO O OMe 40%, two steps • The synthesis of !-ketophosphonates from #-haloketones by the Michaelis-Arbusov reaction can be impractical due to competing formation of dialkyl vinyl phosphates by the Perkow reaction: Still, W.C.; Gennari, C Tetrahedron Lett 1983, 24, 4405–4408 Bodnarchuk, N D.; Malovik, V V.; Derkach, G I Zh Obshch Khim 1970, 40, 1210 Ester Interchange: O Br CH3 100 °C O P(OEt)3 O (EtO)3P (EtO)3P Br CH3 H2C CH3 Br O O P(OEt)2 – EtBr H2C CH3 major product (yield not provided) • The use of isopropyl phosphonates minimizes alkoxy exchange at phosphorus CH3 O (i-PrO)2P O (–)-menthol OMe cat DMAP toluene, reflux 94% Machleidt, H.; Strehlke, G U Angew Chem Int Ed 1964, 3, 443–444 Bhattacharya, A K.; Thyagarajan, G Chem Rev 1981, 81, 415–430 O (i-PrO)2P O O H3C CH3 Hatakeyama, S.; Satoh, K.; Kuniya, S.; Seiichi, T Tetrahedron Lett 1987, 28, 2713–2716 Kent Barbay Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Stereoselectivity of HWE Olefination: Disubstituted Olefins: TESO • Reaction of phosphonates with aldehydes favors formation of (E)-alkenes H3C OTBS CHO O O NaOEt, EtOH OEt RCHO R R OEt Aldehyde PhCHO TESO OTBS OEt 68% for R = i-Pr Ratio of products (E : Z) R CH3 CH3 O OEt O H3C + E CO2Et LiTMP, THF, –30 °C CH3 CH3 O (EtO)2P O (RO)2P Z Me Ratio of products (E : Z) 98 : n-PrCHO 95 : i-PrCHO 84 : 16 : 1.2 Et 1.75 : i-Pr E only CH(Et)2 E only Boschelli, D.; Takemasa, T.; Nishitani, Y.; Masamune, S Tetrahedron Lett 1985, 26, 5239–5242 Trisubstituted Olefins: Larsen, R O.; Aksnes, G Phosphorus Sulfur, 1983, 16, 339–344 Reaction of !-Branched Phosphonates with Aldehydes: • In a systematic study of the synthesis of disubstituted olefins by HWE, E : Z ratio increases: (1) in DME relative to THF, (2) at higher reaction temperatures, (3) M+ = Li > Na > K, (4) with increasing !-substitution of the aldehyde In general, conditions which increase the reversibility of the reaction (i.e., increase the rate of retroaddition relative to the rate of elimination) favor the formation of E-alkenes • The size of the phosphonate and ester substituents plays a critical role in determining the stereochemical outcome in the synthesis of trisubstituted olefins – large substituents favor (E)alkenes O (R1O)2P CHO CH3 Thompson, S K.; Heathcock, C H J Org Chem 1990, 55, 3386–3388 O OR2 CO2R CH3 t-BuOK, THF –78 °C CH3 + CH3 CH3 CH3 CO2R (E)-alkene (Z)-alkene • Bulky phosphonate and ester substituents enhance (E)-selectivity in disubstituted olefin synthesis: CH3 BnO Reagent CHO t-BuOK, THF –78 °C O O (MeO)2P O CH3 CO2R CO2R + BnO Ratio of products (E : Z) Reagent O (i-PrO)2P CH3 BnO 95 : OEt 1:3 OMe R2 Ratio of products (E : Z) Me Me : 95 Me Et 10 : 90 Et Et 40 : 60 i-Pr Et 90 : 10 i-Pr i-Pr 95 : Nagaoka, H.; Kishi, Y Tetrahedron 1981, 37, 3873–3888 • (Z)-selective olefination with the trimethyl phosphonate (R1, R2 = CH3) is unsuccessful with aromatic aldehydes The Still modification of the HWE olefination (see below) can be applied for (Z)-selective olefination of aromatic aldehydes Nagaoka, H.; Kishi, Y Tetrahedron 1981, 37, 3873–3888 R1 Kent Barbay Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Olefination of Ketones: O • (E)-selectivities are typically modest in condensations with ketones In some cases, use of a bulky ester increases the selectivity: O H3C O H H O H O H O O O (MeO)2P O OR CH3 CH3 H3C O H3C O H R2 t-BuOK, DMF H3C CH3 Me H R1 O O O O O CH3 OTIPS t-Bu 9:1 76% H3C CH3 O MeO MeOH single olefin isomer CH3 2.7 : CH3 OTIPS K2CO3 O 86% A: R1 = CO2R, R2 = H B: R1= H, R2 = CO2R O O CH3CN mM O CH3 O LiCl, Et3N H Ratio of products (A : B) R H H O H3C CH3 O O H3C H P(OEt)2 O O CH3 OTIPS HO • The failure of this hindered ketone to react with Ph3P=CHCO2Et (benzene, reflux) provides an example of the increased reactivity of phosphonates in comparison to phosphonium ylides Evans, D A.; Carreira, E M Tetrahedron Lett 1990, 31, 4703–4706 Mulzer, J.; Steffin, U.; Zorn, L.; Schneider, C.; Weinhold, E.; Münch, W.; Rudert, R.; Luger, P.; Hartl, H J Am Chem Soc 1988, 110, 4640–4646 • Tetrasubstitued olefins can be prepared in some cases, but isomeric mixtures are obtained: O Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T J Org Chem 1987, 52, 1201–1210 O (MeO)2P O O MeO O O O EtO2C O O Ot-Bu CH3 CH3O O MeO NaH, LiBr, THF, 23 °C O O P(OEt)2 CH3 H3CO CH3 EtO2C OCH3 83% E OCH3 + EtO2C CH3 OCH3 NaH, THF, 55 °C CH3 O O CH3 CH3O CH3 CH3 Z E : Z = 28 : 72 Ot-Bu 77%, 7:1 E : Z Bestmann, H J.; Ermann, P.; Rüppel, H.; Sperling, W Liebigs Ann Chem 1986, 479–498 White, J D.; Theramongkol, P.; Kuroda, C.; Engelbrecht, J R J Org Chem 1988, 53, 5909–5921 Single-step two-carbon homologation of esters: • Control of double-bond geometry in tri-substituted olefin synthesis has been accomplished by the use of a tethered HWE reagent: O H3C CH3 O O CH3 OTIPS O (EtO)2P O (1:1 mixture of diastereomers) P(OEt)2 O O O(CH2)5CO2H DCC, DMAP, CH2Cl2 HO OEt 100% H3C CH3 O O O O O (EtO)2P O OEt n-BuLi, THF, –78 °C; DIBAL-H, –78 ! 23 °C OEt O 81%, 91 : E : Z CH3 OTIPS • Ester reduction in the presence of the phosphonate minimizes overreduction of the intermediate O aldehyde Takacs, J M.; Helle, M A.; Seely, F L Tetrahedron Lett 1986, 27, 1257–1260 Kent Barbay Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Olefination of Base-Sensitive Substrates (Masamune-Roush Conditions): (Z)-Selective Olefination – Still Modification of HWE Olefination: • Masamune and Roush reported mild conditions (LiCl, amine base, ambient temperature) for Disubstituted olefins: olefinations employing base-sensitive substrates or phosphonates: NHCbz CHO O (EtO)2P O (CF3CH2O)2P O NHCbz OMe CHO H3C CH3 H3C KHMDS, 18-crown-6, THF, –78 °C CH3 LiCl, DIPEA CH3CN, 23 °C, 17 h CH3 O O CO2Me 90%, 12 : Z : E CH3 aldehyde product Z:E yield, % 90% CHO H3C • This aldehyde substrate epimerizes under standard HWE conditions (NaH as base) H3C CO2Me ambient temperature O (EtO2)P O OEt M solvent pKa K DMSO 19.2 Li diglyme 12.2 87 4:1 74 >50 : >95 22 : 81 CHO • Addition of LiCl enhances acidity of phosphonate, allows use of weak bases (DBU, i-Pr2NEt) and M >50 : CO2Me CHO CH3O CH3O CH3 • Application of the Masamune-Roush conditions does not alter the inherent (E)-selectivity of the CO2Me CHO H3C CH3 CH3 CH3 H3C CO2Me HWE reaction Trisubstituted olefins: Blanchette, M A.; Choy, W.; Davis, J T.; Essenfeld, A P.; Masamune, S.; Roush, W R.; Sakai, T Tetrahedron Lett 1984, 25, 2183–2186 O (CF3CH2O)2P • Application of mild HWE conditions to (Z)-selective olefin synthesis (see adjacent column): O O CHO H H3C O H CH3 O aldehyde O O H3C MeO2C CH3 LiCl, DBU, CH3CN O H H3C H CHO H3C O CHO Hammond, G.S.; Cox Blagg, M.; Weimer, D F J Org Chem 1990, 55, 128 >50 : 79 CH3 >50 : 80 CH3 30 : >95 CO2Me A crown-6) yielded only the internal aldol product A CH3 H3C yield, % CO2Me 80%, : Z : E • Application of the normal conditions for (Z)-selective HWE (KHMDS, 18- Z:E CO2Me CO2Me CH3 CH3 88%, 46 : Z : E product CHO CH3 H3C KHMDS, 18-crown-6, THF, –78 °C O P(OCH2CF3)2 MeO OMe CH3 CHO H3C O H H H3C CH3 From: Still, W.C.; Gennari, C Tetrahedron Lett 1983, 24, 4405–4408 • The electrophilic phosphonate and the use of strongly dissociating conditions favor rapid breakdown of the oxaphosphetane, resulting in excellent (Z)-selectivity Kent Barbay Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Trisubstituted olefins: (Z)-Selective Olefination – (Diarylphosphono)acetates: Disubstituted olefins: O (PhO)2P O (ArO)2P O OEt OEt CHO CH3 O NaH, THF –78 ! –10 °C R' RCHO CH3 R base, THF CO2Et R' CO2Et 100%, Z : E = 90 : 10 aldehyde aldehyde product CHO CH3 base CH3 CO2Et Me3NBuOH Z:E Ar product R' 89 : 11 97 n-Pr CHO o-MePh Me CO2Et CO2Et 91 : Me Ph n-Bu Ph n-Bu CO2Et 98 CHO CHO CH3 CH3 CO2Et CH3 TBSO TBSO CO2Et NaH CHO 97 t-BuOK 97 : 100 NaH 96 : 91 NaH 95 : 85 NaH–LiBr 91 : 75 NaH 98 : 65 CO2Et 94 : 97 : n-Bu n-Bu CO2Et CH3 100 CH3 78 CH3 Ph i-Pr Ph i-Pr CH3 CO2Et n-C7H15 CH3 CHO OCH2Ph CH3 CH3 CO2Et PhCH2O • (Z)-Selectivity was further enhanced using ortho-alkyl substituted (diarylphosphono)acetates: O (ArO)2P 89 : 11 98 n-C7H15CHO CH3 CHO 93 : n-Bu NaH Me3NBuOH n-Bu CH3 CH3 CH3 Me3NBuOH yield, % CH3 o-i-PrPh CHO CO2Et Z:E CH3 n-Pr CHO CHO NaH base yield, % Ando, K J Org Chem 1998, 63, 8411–8416 O • 93 : – 99 : (Z)-selectivity, 92–100% yield OEt • Aryl, ",#-unsaturated, alkyl, branched alkyl, and "-oxygenated aldehydes are suitable substrates • Masamune and Roush's mild conditions have been adapted for (Z)-selective olefin synthesis using (diarylphosphono)acetates: Ar = o-MePh, o-EtPh, o-i-PrPh • In analogy to Still's (Z)-selective HWE reaction employing [bis(trifluoroethyl)phosphono]acetates, (Z)- selectivity is attributed to the electron-withdrawing nature of the aryloxy substituent, which accelerates elimination relative to equilibration of oxaphosphatane intermediates Ando, K J Org Chem 1997, 62, 1934–1939 • For (diphenylphosphono)acetate esters, (Z)-selectivity increases with increasing steric bulk of the ester moiety Ando, K J Org Chem 1999, 64, 8406–8408 O (PhO)2P NaI, DBU, THF, °C O OEt CH3 CH3 CHO NHSO2Ar –78 ! °C CH3 CH3 ArSO2N H CO2Et 89%, 87 : 13 Z : E • no racemization Ar = 2,4,6-trimethylphenyl Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T J Org Chem 2000, 65, 4745–4749 Kent Barbay 10 Myers HWE Reaction in Macrolide Synthesis: Amphotericin B: (–)-Vermiculine: H3C O O CH3 O NaH O P(OMe)2 THF, 23 °C O 5.6 mM 49% O S S CHO O O CH3 O Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination O S S S S TBSO CH3 O O O O O O H3C CHO OEt LDA, THF, –78 ! °C 60% O O O OTHP TBSO H3C O (–)-Vermiculine O O (EtO)2P CH3 H3C O H3C OTHP CH3 OEt H3C O • High-dilution or syringe-pump additions are frequently required to achieve high-yielding OTBS macrocyclizations Burri, K F.; Cardone, R A.; Chen, W Y.; Rosen, P J Am Chem Soc 1978, 100, 7069–7071 H3C TBSO (–)-Asperdiol: O P(O)(OEt)2 H O O O H3C CH3 O H3C CH3 Me EEO CH3 CH3 OMe DBU, CH3CN, 10 mM LiCl, 25 °C, h O O 70% OEt O O Me EEO CH3CN, 23 °C mM CH3 OTBS H3C CH3 (E) only 61% TBSO OCH3 O O CH3 O O H3C CH3 O O O OH O CHO OEt HO O O HO CH3 OH HO OH OH OH O OH O H H3C LiCl, DBU Me EEO CH3CN, 23 °C CH3 mM CH3 O O Amphotericin B HO CH3 OH NH2 CH3 30 % CH3 O O H3C Me EEO OMe H3C based on ring size and substitution For example, compare to above: P(O)(OEt)2 OTBS O H3C CH3 • Intramolecular HWE olefinations are usually selective for (E)-alkenes, but the selectivity can vary H P(OMe)2 O Tius, M.A.; Fauq, A J Am Chem Soc 1986, 108, 6389–6391 EtO O H LiCl, DBU CHO O O CH3 OTBS H3C O EtO OCH3 O 2:1E:Z Tius, M A.; Fauq, A H J Am Chem Soc 1986, 108, 1035–1039 Nicolaou, K C.; Daines, R A.; Chakraborty, T K.; Ogawa, Y J Am Chem Soc 1988, 110, 4685–4696 Nicolaou, K.C.; Daines, R A.; Ogawa, Y.; Chakraborty, T K J Am Chem Soc 1988, 110, 4696–4705 Kent Barbay 11 Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Asymmetric HWE: Asymmetric Olefin Synthesis – Chiral Ester: Chiral Phosphonamidates: O Li H H3C H O Ph O P N i-Pr t-BuLi, THF H3C –70 °C; Li H O (MeO)2P R' = i-Pr R O R O O PR' N O (MeO)2P CH3 O Ph O Ph O n-BuLi, THF; CH3 CH3 CH3 O O CH3 CH3 O H H H H O O H H3C O O P N OTf OH R Ph3COTf, 2,6-lutidine CH3CN, 60 °C i-Pr Ph H H3C O O P N R R yield, % CPh3 OH O THF, –60 °C Attack by "-face of phosphonate on convex face of ketone R i-Pr Ph 94-98%, 88-100% de Ph O ee, % t-Bu 65 >99 Me 72 86 Ph 71 >99 CO2t-Bu 75 95 O (MeO)2P O LiO H CH3 Ph O CH3 H Ph O syn-elimination O CH3 CH3 H H 93%, 90% de H O CH3 O CH3 O O • Electrophilic attack occurs from the less hindered !-face of the phosphonamidate-stabilized carbanion Bulky nucleophiles display high selectivity for equatorial attack on cyclohexanones • Stable "-hydroxy phosphonamidates are isolated and transformed to alkenes by electrophilic activation with trityl salts This procedure results in stereospecific syn-cycloelimination (Attempted base-catalyzed olefin formation led to retroaddition.) Gais, H.-J.; Schmeidl, G.; Ball, W A.; Bund, J.; Hellmann, G.; Erdelmeier, I Tetrahedron Lett 1988, 29, 1773–1774 8-phenylmenthol: Corey, E J.; Ensley, H E J Am Chem Soc 1975, 97, 6908–6909 Denmark, S E.; Chen, C.-T J Am Chem Soc 1992, 114, 10674–10676 Denmark, S E.; Chen, C.-T J Org Chem 1994, 59, 2922–2924 Kent Barbay 12 Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Discrimination of enantiotopic or diastereotopic carbonyls: Kinetic Resolution: H O O (F3CCH2O)2P Ph O eq CH3 CH3 1.1 eq Ph O H3C H CH3 O CH3 O O H + O H CO2R 81%, 98% de 14%, 92% de OHC OTBS CHO OTBS H3C O O (F3CCH2O)2P major product synelimination O H Ph O CO2R (RL = OR) CH3 O H O Nu H Tullis, J S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T J Org Chem 1998, 63, 8284-8294 CH3 CO2R P(O)(OR)2 O 53%, 90% de preferentially bis-olefinated O Attack from !-face of (Z)-enolate H2C O CH3 CH3 • Diastereoselectivity is dependent on conversion, because the minor diastereomeric products are P(O)(OR)2 Felkin-Anh addition CH3 O P(OMe)2 Exercise: Based on the previous example, rationalize the stereochemical outcome of these olefinations (Note that the phosphonate used in this example is enantiomeric to that used in the previous example) O CH3 O O See: Schreiber, S L.; Schreiber, T S.; Smith, D B J Am Chem Soc 1987, 109, 1525-1529 H Nu H H fast-reacting enantiomer K • 18-crown-6 Ph O H3C H CO2R O CO2R OHC CH3 O CH3 CH3 83%, 96% de CH3 CH3 • Mechanistic hypothesis: O CHO KHMDS, 18-crown-6 THF, –100 °C • E and Z products are formed from different enantiomers of the starting aldehyde H TBSO RO2C Crude Z : E = 85 : 15 O CH2 O P(OCH2CF3)2 H3C CO2R eq KHMDS, 18-crown-6 THF, –100 °C O O H H H slow-reacting enantiomer H3C Ph O O O P(OMe)2 H CO2R (Slow step may be addition or elimination) minor product H3C Ph O O K O P(OMe)2 O Ph O H3C O O P(OMe)2 t-BuOK, THF O –50 °C, 30 CH3 O • Incapable of syn-elimination, therefore reverts O CH3 O CH3 • For consideration of the stereochemical outcome of addition to "-alkyloxy aldehydes, see: H3C (MeO)2(O)P CO2R LiO CH3 H3C O CH3 NaH, DMF, 23 °C Acetone, Amberlyst-15 H3C synelimination O (CH2)2I CH3 O O (MeO)2(O)P CO2R LiO CO2R O O CH3 Lodge, E P.; Heathcock, C H J Am Chem Soc 1987, 109, 3353–3361 O CH3 • Auxiliary shields "-face of (Z)-enolate Rein, T.; Kann, N.; Kreuder, R.; Benoit, G.; Reiser, O Angew Chem., Int Ed Engl 1994, 33, 556–558 Rein, T.; Reiser, O Acta Chem Scand 1996, 50, 369–379 80%, 98% de • Attack occurs at either diastereomeric carbonyl from the face opposite the methyl group Mandai, T.; Kaihara, Y.; Tsuji, J J Org Chem 1994, 59, 5847–5849 Kent Barbay 13 Myers Advantages over the Wittig Reaction Reviews Kelly, S E Alkene Synthesis in Comprehensive Organic Synthesis; Trost, S M.; Fleming, I., Ed.; Pergamon, Oxford, 1991, 1, 729–818 Weber, W P Peterson Reaction in Silicon Reagents for Organic Synthesis Springer-Verlag, Berlin, 1983, 14, 58–78 Magnus, P Aldrichimica Acta 1980, 13, 43 Overview • The Peterson reagents are more basic and nucleophilic and less sterically hindered As a result, they are more reactive than phosphorus ylides • The byproduct siloxanes tend to be easier to remove than phosphorus byproducts Synthesis of Peterson Reagents, Applications • via halogen-metal exchange • The Peterson olefination reaction was first reported in 1968 It is considered to be the silicon variant of the Wittig reaction O n-BuLi Ph3Si Br O Ph Chem 115 Stereoselective Olefination Reactions: Peterson Olefination (H3C)3Si Ph MgCl OH (H3C)3Si THF Ph Ph KH, THF Li Et2O Ph Ph • via Deprotonation O (H3C)3Si Mechanism R1 OLi Cy2NLi OEt (H3C)3Si THF, –78 ºC R2 H3C CH3 R3 CH3 Nu TBSO O R2 Base R3Si OH R1 R2 R3Si Acid R1 R3 R3 R2 OH2 R2 R2 O R1 + H3C CH3 –78 " –25 ºC 82% Z:E = 93:7 CH3 CO2Et TBSO Galano, J.-M.; Audran, G.; Monti, H Tetrahedron Lett 2001, 42, 6125–6128 sec-BuLi R3 R1 OEt O R3Si R3 Ph HO Substituted silanes can be metalated if an anion-stabilizing group is present • Magnesium and lithium alkoxides are not prone to elimination while sodium and potassium alkoxides readily form the product alkene R1 Ph3Si 81% Brook, A G.; Duff, J M.; Anderson, D G Can J Chem 1970, 48, 561–569 23 ºC, 86% Peterson, D J J Org Chem 1968, 33, 780–784 R3Si H Ph Ph3Si H3CO Si(CH3)3 THF –78 " –25 ºC R3 Li H3CO H3C O Si(CH3)3 O O H H3C CH3 Nu R3Si R3Si R1 R2 R3 OH2 Acid R1 OH R3 R2 R3Si O Base R1 R3 R2 • The silicon-substituted carbanion adds irreversibly to the carbonyl substrate, producing a mixture of diastereomeric !-silylcarbinols Each diastereomer undergoes stereospecific decomposition to give either E or Z alkenes depending on the elimination conditions, as shown above • when R1 = EWG, the intermediate !-silyl alkoxide undergoes spontaneous fragmentation as it is formed to give the olefinic products H3C H OCH3 O O H3CO H3C KH, THF TMS OH O H O ºC, 85% H3C CH3 Z:E = 3:1 H3C CH3 73% inseparable mixture of diastereomers Analogous reactions with the corresponding phosphonium and phosphonate reagents were not as successful Magnus, P.; Roy, G J Chem Soc., Chem Commun 1979, 822–823 Kende, A S Blacklock, T J Tetrahedron Lett 1980, 21, 3119–3122 Fan Liu 14 Myers • Methylenation using commercially available (trimethylsilyl)methyllithium or (trimethylsilyl)methylmagnesium chloride: • via addition of organometallics to vinylsilanes O Li EtLi Si(CH3)3 THF, –78 ºC Et H H3C Si(CH3)3 Et 91% Si(CH3)3 OH O Et SPh 23 ºC Hudrlik, P F Peterson, D Tetrahedron Lett 1974, 15, 1133–1136 OTBS H3C SPh H3C CH3 (4.5 equiv) OTBS MgCl O PivO CbzHN N Cbz Ot-Bu 90% SOCl2, C5H5N 86% Li Li Si(CH3)3 • Reaction with Ph3P CH2 at room temperature was not successful and more forcing conditions resulted in decomposition Si(CH3)3 THF, –78 ºC CH3 SPh H (H3C)3Si O PivO CbzHN N Cbz OOt-Bu • via reductive lithiation N(CH3)2 H CH3 Lebsack, A D.; Overman, L E.; Valentekovich, R J J Am Chem Soc 2001, 123, 4851–4852 Z:E = 28:72 H3C Li pentane, THF, –78 ºC HF•pyr, CH3CN 23 ºC, 84% H3C CH3 NaH, HMPA Et (H3C)3Si H CH3 H Et H3C Chem 115 Stereoselective Olefination Reactions: Peterson Olefination H3C Udodong, U E.; Fraser-Reid, B J Org Chem 1989, 54, 2103–2112 CH3 Stereoselective Synthesis of !-silylcarbinols O H3C O–K+ Ar Si(CH3)3 anti H3C H3C Ar Si(CH3)3 + CH3 O–K+ H3C CH3 H KOAc OBn OBn • Because "-silylcarbanion additions to carbonyl compounds are irreversible, the diastereomeric ratio in the addition step defines the cis/trans-alkene product ratio unless diastereomeric adducts can be separated and processed individually • Other approaches rely on the stereoselective generation of !-silylcarbinols 96%, Z:E = 5:95 fast elimination –78 ºC (H3C)3Si n-Pr DIBAL-H (H3C)3Si pentane, –120 ºC n-Pr n-Pr n-Pr BF3•OEt2 97% H3C OBn CH2Cl2, ºC CH3 n-Pr n-Pr 99%, Z:E = 94:6 OBn H3C n-Pr OH O slow elimination AcOH, 60 ºC n-Pr KH, THF, 23 ºC syn Hudrlik, P F Peterson, D Tetrahedron Lett 1974, 15, 1133–1136 68% E:Z = 77:1 • The syn-hydroxysilane in the example above underwent facile (base-mediated) elimination at – 78 ºC while the anti-hydroxysilane did not react until acetic acid was added to give (after heating) the E-alkene Tamao, K.; Kawachi, A Organometallics 1995, 14, 3108–3111 Perales, J B.; Makino, N F.; Van Vranken, D L J Org Chem 2002, 67, 6711–6717 O C5H11 Ph Si(CH3)3 MeLi, Et2O –78 # 23 ºC Ph LiO CH3 C5H11 Ph Si(CH3)3 C5H11 TFA –78 # 23 ºC H3C 57% E:Z = 9:91 Barrett, A G M.; Flygare, J A J Org Chem 1991, 56, 638–642 Fan Liu 15 Myers Chem 115 Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations Petasis Modification (1990): Reviews: Oleg G Kulinkovich, O G.; de Meijere, A Chem Rev 2000, 100, 2789–2834 Petasis, N A.;Hu, Y.-H Curr Org Chem 1997, 1, 249–286 Brown-Wensley, K A.; Buchwald, S L.; Cannizzo, L.; Clawson, L.; Ho, S.; Meinhardt, D.; Stille, J R.; Straus, D.; Grubbs, R H Pure Appl Chem 1983, 55, 1733–1744 Ti Cl MeLi or Cl MeMgBr Generalized Reaction: • The Tebbe and Petasis olefinations are useful methods for the methenylation of a wide variety of carbonyl compounds The active complex is a titanocene methylidene complex, which can be generated from either the Tebbe reagent or the Petasis reagent CH3 Ti "-elimination CH3 Ti CH2 # titanocene methylidene Petasis reagent • This is a milder version of the Tebbe reagent, which avoids generation of the Lewis acidic aluminum intermediate • This reagent is also effective for olefination of silyl esters and acylsilanes Ti O R1 R2 CH3 Al CH3 Cl Ti or (Tebbe Reagent) Petasis, N A.; Bzowej, E I J Am Chem Soc 1990, 112, 6392-6394 CH3 Order of Reactivity: CH3 O R1 (Petasis Reagent) R2 O > O > O > R H R1 R2 R1 OR R1 NR2 R H R1 R2 R1 OR R1 NR2 Tebbe reagent (1978): O Cp2TiCH2AlCl(CH3)2 !15 ºC, 65% Acid halides and anhydrides: Ti Cl Al(CH3)3 Cl Al(CH3)2Cl, CH4 Ti Al Cl CH3 Lewis base Ti CH2 CH3 Al(CH3)2Cl • Acid halides provide ketones rather than olefins under Tebbe or Petasis conditions Anhydrides give ketones under Tebbe conditions and olefins under Petasis conditions O titanocene methylidene Tebbe reagent R O or Cl R Cp2TiCH2AlCl(CH3)2 O Cp2Ti R O H+ O O R R Tebbe, F N.; Parshall, G W.; Reddy, G S J Am Chem Soc 1978, 100, 3611–3613 CH3 Cl– or AcO– Mechanism: • The Tebbe olefination reaction follows a mechanism similar to the Wittig olefination, but the titanocene methylidene is generally more nucleophilic and less basic than Wittig reagents O LB R O Ti Al Cl CH3 CH3 Ti CH2 Ti CH2 R1 R1 O R2 R2 Cp Ti CH2 Cp Cp2TiO Cp2Ti(CH3)2 O O R O R O R Chou, T.-S.; Huang, S.-B Tetrahedron Lett 1983, 24, 2169 - 2170 Advantages: • Reagents are relatively simple to prepare • Relatively bulky carbonyl groups can be olefinated • An alternative to the Wittig reaction, and works well on hindered carbonyls Disdvantages: R1 R2 • A full equivalent of the reagent is required • Limited to methylenation: substituted olefinations are difficult Alpay Dermenci 16 Myers Chem 115 Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations R1 • Selective mono- or bis-methylenation of dicarbonyls can be achieved by varying the equivalents of reagent Petasis reagent O R2 R1 toluene or THF R2 Ti O Substrate Temp (oC) Product Yield (%) O O H H3C H H3C O Ph Ph Ph 60–65 60–65 Ph CH3 O (n equiv) O 43 CH3 O O THF, 65 oC 70% 1.0 equiv 10 : 2.0 equiv : 4.0 equiv : 90 O 60–65 60 Ti O O O O OCH3 OCH3 60–65 O O 60–65 CH3 OSi(CH3)2t-Bu Ph OSi(CH3)2t-Bu 70 70 Ph OCH3 OMe 65 67 65 65 O OEt OEt Ph Ph N(CH3)2 Ph N(CH3)2 70 54 O H3C SPh CH3 1.5 equiv : 4.0 equiv : 20 CH3 O CH3 HO CH3 O CH3 THF, –78 oC CH3 76% Ireland, R E.; Thaisrivongs, S.; Dussault, P H J Am Chem Soc 1988, 110, 5768 - 5779 • Site-Selective Olefination: O Ph O Tebbe reagent (1.5 equiv) HO O O Ph N CH3 • Hindered carbonyls: O Ph 41 Ph Ph N CH3 toluene, 75 oC 75% O O CH3 (n equiv) N CH3 60 CH3 H3C SPh CH3 Petasis, N A.; Bzowej, E I J Am Chem Soc 1990, 112, 6392-6394 Petasis, N A.; Lu, S.-P Tetrahedron Lett 1995, 36, 2393 - 2396 75 70 H3CO O O N O H3C H Ph O Cp2TiMe2 (2.5 equiv) 65 oC, h THF O N 52% Colson, P.-J.; Hegedus, L S J Org Chem 1993, 58, 5918 - 5924 O H3CO O CH3 Ph Alpay Dermenci 17 Myers Chem 115 Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations • A strained enecarbamate was prepared using Petasis' olefination conditions: • Acyl chlorides can be converted into the corresponding methyl ketones without epimerization CH3 CH3 Cl Cp2Ti (1.2 equiv) Cl BnO toluene, CH3 O OEt H3C Ti O OH BocO oC HN NH4Cl O HN 77% CH3 CH3 (90.4% ee) 14 steps (90.4% ee) Tandem Olefination/Aldol: Gelsemoxonine OH HO O N OMe H3C O Ph CH3 Cl Diethelm, S.; Carreira, E M J Am Chem Soc 2013, 135, 8500–8503 Cl Cp2Ti (1.2 equiv) O PhCHO O Ph toluene, oC OH Ph Ph 69% Industrial-Scale Petasis Reaction: • Dimethyltitanocene was used to produce Aprepitant, a recently approved substance P antagonist used to prevent chemotherapy-induced nausea and vomiting: CF3 O Stille, J R.; Grubbs, R H J Am Chem Soc 1983, 105, 1664–1665 Tandem Olefination/Metathesis: O • Cyclic enol ethers can be prepared through an olefination, ring-closing metathesis cascade sequence: N H BnO BnO H O H H H O O O H CH3 H BnO BnO THF, 25 oC (20 min) then reflux (5 h), 71% H O H H H O O H BnO BnO H O H H H O O CH3 CH2 H CF3 H3C CF3 O Cp2Ti(CH3)2 (2.9 equiv) THF, 91% F CF3 O O steps N (250 kg) N H N F Ph HN (227 kg) CF3 O F N Aprepitant (Emend!) O H 65% Tebbe reagent (1.3 equiv) THF, 20 25 oC CH3 CF3 O Ph Tebbe reagent (4 equiv) CH3 H O N H CH3 Ti OEt CH3 BnO 76% BnO O H3C C5H5N, toluene 70 oC, h, 77% O O OH BocO Cp2Ti(CH3)2 Tebbe reagent (2.0 equiv) THF, h, reflux CH3 77% Nicolaou, K C.; Postema, M H D.; Claiborne, C F J Am Chem Soc 1996, 118, 1565–1566 CF3 Relative reactivity: O H3C H3C OCH3 CH3 < O H3C CH3 H3C O R R: alkyl, CH2Ph O < H3C O CH3 O CH3 O < CH3 CF3 O N Ph F Payack, J F.; Huffman, M A.; Cai, D.; Hughes, D L.; Collins, P C.; Johnson, B K.; Cottrell, I F.; Tuma, L D Org Proc Res Dev 2004, 8, 256–259 Alpay Dermenci 18 Myers Stereoselective Olefination Reactions: The Takai Reaction Chem 115 Haloforms Reviews: O Furstner, A Chem Rev 1999, 99, 991–1045 H3C Wessjohann, L A.; Scheid, G Synthesis 1999, 1–36 H Reaction Overview: R2 Xa CrCl2-DMF THF R1 E-isomer (major) H R1 THF Temp (ºC) time (h) 65 50 Cl I Brb X CHX3, CrCl2 O R2 CHI2 CHX3, CrCl2, THF X H3C yield (%) 2 76 82 76 R1 E-isomer (major) R2=alkyl, aryl, B(OR)2, SiR3, SnR3 aReaction bCrBr conditions: aldehyde (1 equiv), CHX3 (2 equiv), CrCl2 (6 equiv), THF LiAlH4 (1:0.5) was employed in lieu of CrCl2 and • Aldehydes are more reactive than ketones: Mechanism: O O CHX3 E/Z 95/5 83/17 95/5 CrCl2 X CrIIIX2 CrIIIX2 X2CrIIIO O + H R1 R1 H H X CHI3, CrCl2 CHO H3 C I H3C 75% (E/Z = 81:19) THF, oC I CrIIIX2 I H3C 5% X R1 (E)-alkenyl halide (major) + R1 X (Z)-alkenyl halide (minor) Takai, K.; Nitta, K.; Utimoto, K J Am Chem Soc 1986, 108, 7408–7410 1,1-Geminal Dihalides CH3 O H General Trends: • Reactivity is dependent on the haloform: I > Br > Cl • E/Z ratios are greatest in the order Cl > Br > I • Aldehydes react faster than ketones • The E-isomer is the predominant product for both haloforms and 1,1-geminal dihalides H3C THF, 97% E:Z = 94:6 CH3 Disadvantages • Stoichiometric amounts of by-products are generated • Excess reagent is typically required H3C H3C CH3 t-Bu t-BuCHI2 CrCl2-DMF O Advantages • Reagents are readily available • Reaction is selective for the E-isomer • High functional group tolerance CH3CHI2, CrCl2 H THF, 90% E:Z = 94:6 H3C Okazoe, T.; Takai, K.; Utimoto, K J Am Chem Soc 1987, 109, 951–953 Alpay Dermenci 19 Myers Chem 115 Stereoselective Olefination Reactions: The Takai Reaction • Olefination of ketones: H3C O I CHI3, CrCl2 OH CH3 O NBoc O t-Bu THF t-Bu H CH3 CH3 CH3 H3C OH CrCl2, CHI3 O NBoc I THF-dioxane CH3 CH3 CH3 CH3 96% Lin, Y.-Y.; Wang, Y.-J.; Lin, C.-H.; Cheng, J.-H.; Lee, C.-F J Org Chem 2012, 77, 6100–6106 O H2N O Takai Olefination in Natural Product Synthesis H CH3 CH3 H3CO CH3 OH H NHAc O TBSO CH3 HO PPTS, EtOH H 64% (2 steps) O I O CH3 CH3 Superstolide A O CrCl2, CHI3, THF O H3C OH CH3 CH3 Tortosa, M.; Yakelis, N A.; Roush, W R J Org Chem 2008, 73, 9657 - 9667 O Sch-642305 CH3 CH3 SEMO Dermenci, A; Selig, P S.; Domaoal, R A.; SpasovK A.; Anderson, K A.; Miller, S J Chem Sci 2011, 2, 1568–1572 SEMO OH OTHP Cl H3C CH3 OTES CH3 CHO CrCl2, CHCl3 THF, 65 ºC Cl H3C OTES CH3 CH3 DMP I CrCl2, CHI3, THF CH3 69% Cl OTHP 23 ºC, 77% E:Z = 19:1 CH3 CH3 HO OH CH3 H O Br CH3 Cl H3C Cl aplysiapyranoid C Jung, M E.; Fahr, B T.; D'Amico, D C J Org Chem 1998, 63, 2982–2987 CH3 O H3C O CH3 Amphidinolide J Williams, D R.; Kissel, W S J Am Chem Soc 1998, 120, 11198–11199 Alpay Dermenci 20 Myers Chem 115 Stereoselective Olefination Reactions: The Julia Olefination Reviews • The reductive elimination step can follow two different pathways depending on the reducing agent, however each pathway shows a preference for forming the E-olefin isomer Dumeunier, R.; Marko, I E Modern Carbonyl Olefination 2004, 104–150 Julia, M Pure Appl Chem 1985, 57, 763–768 Na(Hg)/MeOH Reduction: Reaction • The Julia olefination and modified Julia olefination reactions involve the coupling of aryl sulfones with aldehydes or ketones to provide olefins • Initial Report: SO2Ar Ph n-BuLi (2 equiv) MgI2 (2 equiv) Ph PhO2S O Al/Hg Ph 90% Ph H Ph O Ar S Ph NaOCH3 MeO SO2Ar H R4 O R1 H R2 O R2 –ArSO2Na • Typically, strong bases and stoichiometric quantities of reagents are required SO2Ar R2 O R3 R1 R1 ArO2S R4 O R1 R3 O R2 H Reductant E-isomer H X R4 R3 R1 (E)-alkene Ar SO2Ar H R4 O R1 H R2 O R2 H R2 R1 SmI2 Reduction: O Base e" H Z (disfavored) MeOH • Often Julia olefination requires trapping of the initially formed !-oxido sulfone, which is then reduced to give the E-alkene SO2Ar O R1 R2 R3 e" Na(Hg) R2 H • The reaction predominantly forms (E)-olefins Na(Hg) R2 R1 E (favored) R1 S O H H R2 O R1 R2 R1 H Pascali, V.; Umani-Ronchi, A J Chem Soc., Chem Comm 1973, 351 Julia, M.; Paris, J.-M Tetrahedron Lett 1973, 49, 4833–4836 SO2Ar Ar O–Na+ R1 Ph Ph Ph SO2Ar H R4 O R1 H R2 O H R1 R2 SmI2 R1 e" H OCOR4 O OSmI2 S R4 O H H R2 O H R2 O SmI2 H e" R1 R2 H OCOR4 R4 O R1 R1 H R2 H OCOR4 • A variety of different trapping and reducing agents can be used H Trapping agents: Ac2O, BzCl, MsCl, TsCl Reducing agents: SmI2 (most common), RMgX, Bu3SnH, Li or Na in ammonia, Na2S2O4, Raney/Ni, Al(Hg) amalgam, LiAlH4, SmI2/HMPA R2 R1 E-isomer H Keck, G E.; Savin, K A.; Weglarz, M A J Org Chem 1995, 60, 3194–3204 Alpay Dermenci 21 Stereoselective Olefination Reactions: The Julia Olefination Myers • Second-generation Julia olefination reactions employ an one-pot procedure: use of specially designed heterocycles allows for in situ reductive elimination to occur, via a Smiles rearrangement-like mechanism Julia-Silvestre • In general, the E/Z ratio is dependent on reaction conditions, with PT-sulfones giving higher Eselectivities Julia-Kocienski Ph N N N N S Ar: Ar: N SO2Het 1-phenyl-1H-tetrazole "BT-sulfone" "PT-sulfone" Mechanism: N Base R1 O O S N S O R1 R1 H (Me3Si)2NM CH3 benzothiazole O O S Chem 115 O O S N S S O BT-sulfone Yield (%) E/Z PT-sulfone Yield (%) Li 70 : 30 94 72 : 28 Na 32 75 : 25 95 89 : 11 76 : 24 81 99 : Solvent M DME K R1 CH3 c-C6H11CHO E/Z R2 Blakemore, P R.; Cole, W J.; Kocienski, P J.; Morley, A Synlett 1998, 26–28 R1 R1 O N R2 S R2 S O N O O O S S O R1 • Origin of Selectivity: R2 closed transition state N + O S N N N N Ph O S HO R1 SO2 H R2 Sulfone Preparation Ph N N SH N N commercially available DIAD, PPh3, THF ! 23 ºC, 89% OH CH3 CH3 N N N N SO2 Ph m-CPBA, NaHCO3 CH2Cl2, 23 ºC, 68% Blakemore, P R.; Cole, W J.; Kocienski, P J.; Morley, A Synlett 1998, 26–28 CH3 R1 CH3 R1 Li H R2 O SO2PT R2 O Li open transition state SO2PT O H Smiles rearrangement O PT S H O K R1 R2 O H R1 R2 R1 SO2PT R2 O R1 H SO2PT R2 O H Smiles rearrangement R1 R2 PT-sulfone Alpay Dermenci 22 Stereoselective Olefination Reactions: The Julia Olefination Myers Examples • Application to the synthesis of BMS-644950, a next-generation statin candidate: OTBS OTBS TBDPSO CH3 + H O PTO2S H F CH3 CH3 CH3 CH3 N N N N E:Z NaHMDS, THF, –78 oC 1:8 LiHMDS DMF, DMPU, –35 oC O TBDPSO N N O + O CH3 CH3 H CH3 O NH4 HO •H2O N N N N O N + t-Bu OCH3 O H3C CH3 (168.5 g) (27.6 kg) N N N N CH3 CH3 (33.6 kg) 74%, E : Z = 91 : O H O N N BMS-644950 O O CH3 O i-Pr 90% CH3 Ot-Bu F HCl NH3 N N H3C O H3C O O i-Pr S EtOH, H2O (crystallization) CH3 • The Julia olefination reaction was applied to the synthesis of LAF389, an anti-cancer agent The addition of TMSCl was found to be crucial: the authors propose that TMSCl stabilizes the anionic intermediate and the sensitive aldehyde substrate by attenuating the basicity of the reaction S S O CH3 CH3 F t-Bu LHMDS, THF CH3 Liu, P.; Jacobsen, E N J Am Chem Soc 2001, 123, 10772 - 10773 O O (38.4 kg) HO O Ot-Bu N N Ph N N (27.5 kg) OTBS OTBS >30:1 H3C O H3C O i-Pr Conditions Conditions O O O O Chem 115 (120.0 g) n-BuLi, TMSCl THF, CH3CN MTBE (crystallization) OCH3 O O H3C CH3 (65.9 g) 45%, single isomer Xu, D D.; Waykole, L.; Calienni, J V.; Ciszewski, L.; Lee, G T.; Liu, W.; Szewczyk, J.; Vargas, K.; Prasad, K.; Repic, O.; Blacklock, T J Org Process Res Dev 2003, 7, 856–865 Hobson, L A.; Akiti, O.; Deshmukh, S S.; Harper, S.; Katipally, K.; Lai, C J.; Livingston, R C.; Lo, E.; Miller, M M.; Ramakrishnan, S.; Shen, L.; Spink, J.; Tummala, S.; Wei, C.; Yamamoto, K.; Young, J.; Parsons, R L Org Process Res Dev 2010, 14, 441–458 Alpay Dermenci, Fan Liu 23 ... Weglarz, M A J Org Chem 199 5, 60, 3194 –3204 Alpay Dermenci 21 Stereoselective Olefination Reactions: The Julia Olefination Myers • Second-generation Julia olefination reactions employ an one-pot... J Williams, D R.; Kissel, W S J Am Chem Soc 199 8, 120, 1 1198 –1 1199 Alpay Dermenci 20 Myers Chem 115 Stereoselective Olefination Reactions: The Julia Olefination Reviews • The reductive elimination... M A.; Seely, F L Tetrahedron Lett 198 6, 27, 1257–1260 Kent Barbay Myers Chem 115 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Olefination of Base-Sensitive Substrates