Wittig Olefination, Background: • in the Formation of Z-Alkenes, an Early, Four-Centered Transition State Is Proposed

Home , Julia olefination, Methylenation, Peterson olefination, Phosphonate, Stereoselectivity, Takai olefination

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. Cyclohexanone, 2 2 23 °C, 15 min.

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 be rate-determining, depending on the identity of OR. corresponding phosphonium ylides. • 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: to occur; nonstabilized phosphonates (W = R or H) afford stable !-hydroxyphosphonates.

1. NaH, DME 1. NaH, DME O Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654-5656. O O O O (EtO) P (EtO)2P H C OEt 2 OEt 2. n-BuBr, 50 °C OEt 2. CH O 3 2 • The ratio of oleﬁn isomers is dependent upon the stereochemical outcome of the initial addition and CH2 60%, two steps 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. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1961, 83, 1733–1738. Kent Barbay, Fan Liu

5 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

Acidity of Stabilized Phosphonates in DMSO: Michaelis-Becker Reaction:

O Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.; O 1. Na, hexane O O (EtO)2P W Bordwell, F. G. Unpublished results. EtO P EtO P H 2. ClCH2CO2Et OEt W pKa (http://daeiris.harvard.edu/DavidEvans.html) EtO EtO 58% CN 16.4 • Phosphonium salts are considerably more acidic than the

CO2Et 18.6 corresponding phosphonates: + – Kosolapoff, G. M. J. Am. Chem. Soc. 1946, 68, 1103–1105. Cl 26.2 (Ph3P CH2CN)Cl : pKa = 6.9 + – Ph 27.6 (Ph3P CH2CO2Et)Cl : pKa = 8.5 Acylation of Alkylphosphonate Anions: SiMe3 28.8 Bordwell, F. G.; Zhang, X.-M. J. Am. Chem. Soc. 1994, 116, 968–972. • !-ketophosphonates are prepared by acylation of alkylphosphonate anions:

1. n-BuLi, THF, Preparation of phosphonates: O –60 °C O O (EtO) P CH (EtO) P CH Michaelis-Arbusov Reaction: 2 3 2. CuI 2 3 3. Review: Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430. O CH3 H C 86% 3 Cl

CH3 O O P(OEt) O O Br 3 (EtO) P – EtBr OEt 3 P Mathey, F.; Savignac, P. Tetrahedron, 1978, 34, 649–654. OEt EtO OEt reﬂux Br EtO CH3 CH3 CH3 Phosphonate Ester Interchange: 59%

O O O O O O O CH PCl5 F3CCH2OH 2 P P P (EtO) P MeO OMe Cl OMe F3CH2CO OMe Arbusov, A. E.; Durin, A. A. J. Russ. Phys. Chem. Soc. 1914, 46, 295. 2 0 75 °C DIPEA, PhH O CH3 MeO " Cl F3CH2CO 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 • The use of isopropyl phosphonates minimizes alkoxy exchange at phosphorus. O O P(OEt) O P(OEt) (EtO)3P O 3 – EtBr 2 Br CH3 (EtO) P Br CH3 100 °C 3 H C CH H C CH CH3 2 3 2 3 O O Br (–)-menthol O O (i-PrO)2P (i-PrO) P major product OMe cat. DMAP 2 O (yield not provided) toluene, reﬂux H C CH 94% 3 3

Machleidt, H.; Strehlke, G. U. Angew. Chem. Int. Ed. 1964, 3, 443–444. Hatakeyama, S.; Satoh, K.; Kuniya, S.; Seiichi, T. Tetrahedron Lett. 1987, 28, 2713–2716. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430. Kent Barbay

6 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

Stereoselectivity of HWE Oleﬁnation: O (RO) P CO Et Disubstituted Oleﬁns: TESO OTBS 2 2 TESO OTBS O 5 • Reaction of phosphonates with aldehydes favors formation of (E)-alkenes. CHO H3C H3C OEt LiTMP, THF, –30 °C 4 CH3 CH3 CH3 CH3 O O NaOEt, EtOH O R O 68% for R = i-Pr (EtO) P + Ratio of products 2 OEt RCHO R OEt OEt R (E : Z) E Z Me 1 : 1.2 Ratio of products Aldehyde (E : Z) Et 1.75 : 1 i-Pr E only PhCHO 98 : 2 CH(Et) E only n-PrCHO 95 : 5 2

i-PrCHO 84 : 16 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: • The size of the phosphonate and ester substituents plays a critical role in determining the (1) in DME relative to THF, stereochemical outcome in the synthesis of trisubstituted olefins – large substituents favor (E)- (2) at higher reaction temperatures, alkenes. (3) M+ = Li > Na > K, (4) with increasing !-substitution of the aldehyde. O O

(R1O)2P In general, conditions which increase the reversibility of the reaction (i.e., increase the rate of OR2 CHO CO2R + CH3 retroaddition relative to the rate of elimination) favor the formation of E-alkenes. CH3

CH3 CH3 CH3 CH3 CO2R t-BuOK, THF Thompson, S. K.; Heathcock, C. H. J. Org. Chem. 1990, 55, 3386–3388. –78 °C (E)-alkene (Z)-alkene

• Bulky phosphonate and ester substituents enhance (E)-selectivity in disubstituted olefin synthesis: Ratio of products R1 R2 (E : Z) CH3 Reagent CH3 CH3 CO2R BnO BnO Me Me 5 : 95 CHO t-BuOK, THF + BnO CO2R –78 °C Me Et 10 : 90 Et Et 40 : 60 Ratio of products i-Pr Et 90 : 10 Reagent (E : Z) i-Pr i-Pr 95 : 5 O O (i-PrO) P 95 : 5 2 OEt Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873–3888. O O 1 : 3 • (Z)-selective olefination with the trimethyl phosphonate (R1, R2 = CH3) is unsuccessful with aromatic (MeO)2P OMe 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. Kent Barbay

7 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

Olefination of Ketones: O H • (E)-selectivities are typically modest in condensations with ketones. In some cases, use of a bulky P(OEt)2 H3C CH3 O O ester increases the selectivity: CH H3C CH3 3 O O O O OTIPS K CO CH LiCl, Et3N 2 3 O 3 H C H C O 3 O O 3 O OTIPS MeOH H H H H O CH3CN O H C O H C O 3 O (MeO)2P 3 O 1 mM 76% O OR O O O H CH3 H CH3 86% O O single olefin isomer O H CH3 t-BuOK, DMF R2 H CH3 R1 H Ratio of products H3C CH3 R A: R1 = CO2R, R2 = H O (A : B) CH B: R1= H, R2 = CO2R 3 Me 2.7 : 1 MeO O OTIPS t-Bu 9 : 1 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.; • Tetrasubstitued oleﬁns can be prepared in some cases, but isomeric mixtures are obtained: Luger, P.; Hartl, H. J. Am. Chem. Soc. 1988, 110, 4640–4646. O Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987, 52, 1201–1210. CH O 3 CH 3 CH H3CO OCH3 O 3 CH3O EtO2C OCH3 + EtO C EtO2C P(OEt)2 2 CH O O 3 O O NaH, THF, 55 °C CH3 OCH3 CH (MeO) P CH3 3 MeO O 2 Ot-Bu MeO O CH 83% 3 CH3 O E E : Z = 28 : 72 Z O O O O NaH, LiBr, THF, 23 °C O 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 O (EtO) P 2 OEt OEt OEt O n-BuLi, THF, –78 °C; P(OEt)2 H3C CH3 O O O O O O DIBAL-H, –78 ! 23 °C CH (EtO)2P H3C CH3 3 O(CH2)5CO2H 81%, 91 : 9 E : Z O OTIPS O O CH3 DCC, DMAP, CH2Cl2 O OTIPS HO O 100% • Ester reduction in the presence of the phosphonate minimizes overreduction of the intermediate O aldehyde. (1:1 mixture of diastereomers) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27, 1257–1260. Kent Barbay

8 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

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: O O (CF CH O) P O O 3 2 2 OMe NHCbz NHCbz O CHO H3C (EtO)2P H C CHO CH 3 KHMDS, 18-crown-6, 3 CH CO2Me 3 THF, –78 °C 90%, 12 : 1 Z : E LiCl, DIPEA CH CH3 3 CH CN, 23 °C, 17 h 3 aldehyde product Z : E yield, % 90% CHO H C H3C 3 >50 : 1 87 • This aldehyde substrate epimerizes under standard HWE conditions (NaH as base). CO2Me CHO • Addition of LiCl enhances acidity of phosphonate, allows use of weak bases (DBU, i-Pr2NEt) and 4 : 1 74 CO Me ambient temperature. 2

CHO M M solvent pKa >50 : 1 >95 O O K DMSO 19.2 CO2Me CH O CH O (EtO2)P 3 3 OEt Li diglyme 12.2 CH CH CH3 CH3 3 3 22 : 1 81 CHO H C • Application of the Masamune-Roush conditions does not alter the inherent (E)-selectivity of the H3C 3 HWE reaction. CO2Me Trisubstituted oleﬁns: Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. O O Tetrahedron Lett. 1984, 25, 2183–2186. (CF CH O) P 3 2 2 OMe • Application of mild HWE conditions to (Z)-selective oleﬁn synthesis (see adjacent column): CH 3 CH3 CHO H3C H3C KHMDS, 18-crown-6, CO2Me O O THF, –78 °C 88%, 46 : 1 Z : E P(OCH CF ) MeO 2 3 2 O O aldehyde product Z : E yield, %

CH 3 >50 : 1 79 CHO O O O CHO H3C H3C CO2Me H MeO C O CH3 2 CH H3C H CHO 3 LiCl, DBU, CH3CN H CH >50 : 1 80 CH3 3 H3C H CO2Me CH 3 H C O 3 CHO CH3 80%, 3 : 1 Z : E 30 : 1 >95 CO2Me A H H • Application of the normal conditions for (Z)-selective HWE (KHMDS, 18- From: Still, W.C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408. H C CH crown-6) yielded only the internal aldol product A. 3 3 • The electrophilic phosphonate and the use of strongly dissociating conditions favor rapid breakdown of the oxaphosphetane, resulting in excellent (Z)-selectivity. Hammond, G.S.; Cox Blagg, M.; Weimer, D. F. J. Org. Chem. 1990, 55, 128. Kent Barbay

9 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination Chem 115 (Z)-Selective Olefination – (Diarylphosphono)acetates: Trisubstituted olefins: Disubstituted olefins: O O O O (ArO) P 2 OEt (PhO) P 2 OEt R' R' CHO RCHO R CH CH3 3 NaH, THF base, THF CO Et –78 ! –10 °C CO2Et 2 100%, Z : E = 90 : 10

aldehyde Ar R' product base Z : E yield, % aldehyde product base Z : E yield, %

CH3 CHO n-Pr o-MePh Me Me3NBuOH 89 : 11 97 CHO CH3 n-Pr 89 : 11 97 CO2Et CH3 Me3NBuOH CO2Et CHO CH3 CHO o-i-PrPh Me t-BuOK 97 : 3 100 CO Et NaH 91 : 9 98 2 CO2Et CHO n-Bu Ph n-Bu NaH 96 : 4 91 CHO CO2Et Me NBuOH 93 : 7 98 CO Et 3 2 n-Bu CHO n-Bu n-Bu Ph n-Bu NaH 95 : 5 85 CHO CO2Et CH3 CH3 CH3 CH3 NaH 94 : 6 100 CO2Et CH3 CH3 CH3 n-C H CHO Ph i-Pr NaH–LiBr 91 : 9 75 7 15 n-C7H15 CH3 CO2Et CH3 CHO CH3 NaH 97 : 3 78 CH3 TBSO TBSO CO Et CH3 CHO 2 CH Ph i-Pr 3 CH NaH 98 : 2 65 OCH Ph 3 2 PhCH O CO Et • (Z)-Selectivity was further enhanced using ortho-alkyl substituted (diarylphosphono)acetates: 2 2

Ando, K. J. Org. Chem. 1998, 63, 8411–8416. O O • 93 : 7 – 99 : 1 (Z)-selectivity, 92–100% yield. • Masamune and Roush's mild conditions have been adapted for (Z)-selective oleﬁn synthesis using (ArO)2P • Aryl, ",#-unsaturated, alkyl, branched alkyl, and OEt (diarylphosphono)acetates: "-oxygenated aldehydes are suitable substrates. Ar = o-MePh, o-EtPh, o-i-PrPh CH O O 1. NaI, DBU, THF, 0 °C 3 • In analogy to Still's (Z)-selective HWE reaction employing [bis(triﬂuoroethyl)phosphono]acetates, (Z)- (PhO) P CH 2 OEt 2. 3 selectivity is attributed to the electron-withdrawing nature of the aryloxy substituent, which CH3 ArSO N CO Et 2 H 2 accelerates elimination relative to equilibration of oxaphosphatane intermediates. CHO CH 3 89%, 87 : 13 Z : E NHSO Ar Ando, K. J. Org. Chem. 1997, 62, 1934–1939. 2 • no racemization –78 0 °C • For (diphenylphosphono)acetate esters, (Z)-selectivity increases with increasing steric bulk of the ! Ar = 2,4,6-trimethylphenyl ester moiety.

Ando, K. J. Org. Chem. 1999, 64, 8406–8408. Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745–4749. Kent Barbay

10 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

HWE Reaction in Macrolide Synthesis: Amphotericin B: (–)-Vermiculine: H3C OTHP O O O TBSO CH3 O CH3 (EtO)2P CH3 OEt O 2 O O O O O CH3 H C CHO 3 LDA, THF, –78 ! 0 °C O NaH S S O 60% P(OMe)2 O O THF, 23 °C S S S O O H3C OTHP 5.6 mM S CHO 49% O O O O TBSO O CH3 H3C H3C O OEt O H C (–)-Vermiculine 3 O • High-dilution or syringe-pump additions are frequently required to achieve high-yielding macrocyclizations. OTBS OCH3 H3C O OTBS Burri, K. F.; Cardone, R. A.; Chen, W. Y.; Rosen, P. J. Am. Chem. Soc. 1978, 100, 7069–7071. DBU, CH CN, 10 mM TBSO O O O O O O OMe 3 (–)-Asperdiol: CH3 H C CH H C CH LiCl, 25 °C, 4 h 3 3 3 3 O O O H C 70% EtO 3 O OEt O P(OMe)2 P(O)(OEt) H 2 H O LiCl, DBU CHO O O Me Me CH CH EEO 3 CH3CN, 23 °C EEO 3 OTBS OCH3 3 mM H3C O OTBS

CH3 61% CH3 TBSO O O O O O O OMe (E) only CH3 H3C CH3 H3C CH3 O

Tius, M.A.; Fauq, A. J. Am. Chem. Soc. 1986, 108, 6389–6391. H3C O • Intramolecular HWE oleﬁnations are usually selective for (E)-alkenes, but the selectivity can vary based on ring size and substitution. For example, compare to above: OH OH H3C O OH O EtO O OEt HO O HO OH HO OH O OH CH3 H O P(O)(OEt)2 LiCl, DBU H C H 3 CHO Me O O CH3 CH3 Me CH CN, 23 °C EEO OH CH 3 Amphotericin B NH EEO 3 4 mM HO 2

30 % CH3 Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am. Chem. Soc. 1988, 110, CH3 2 : 1 E : Z 4685–4696. Nicolaou, K.C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035–1039. 4696–4705. Kent Barbay

11 Myers Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

Asymmetric HWE: Asymmetric Oleﬁn Synthesis – Chiral Ester: Chiral Phosphonamidates:

O Li R Li CH H O H O O O 3 t-BuLi, THF Ph P H CH Ph CH3 P H3C O O O 3 (MeO)2P H3C O N R' O N –70 °C; Ph CH3 n-BuLi, THF; (MeO)2P i-Pr O O CH3 O R R' = i-Pr O CH3

H H H O H O O O OTf CPh H O OH 3 Attack by "-face of phosphonate on Ph COTf, 2,6-lutidine H O OH THF, –60 °C convex face of ketone H C O P 3 3 R P N H3C O CH CN, 60 °C N R i-Pr Ph 3 i-Pr Ph 94-98%, 88-100% de

CH CH O O 3 O 3 Ph (MeO) P Ph CH3 CH3 R yield, % ee, % 2 O O Ph LiO H syn-elimination t-Bu 65 >99 CH3 CH3 Me 72 86 H H H 93%, 90% de Ph 71 >99 O H O O O R CO2t-Bu 75 95

• Electrophilic attack occurs from the less hindered !-face of the phosphonamidate-stabilized carbanion. Bulky nucleophiles display high selectivity for equatorial attack on cyclohexanones.

Gais, H.-J.; Schmeidl, G.; Ball, W. A.; Bund, J.; Hellmann, G.; Erdelmeier, I. Tetrahedron Lett. • Stable -hydroxy phosphonamidates are isolated and transformed to alkenes by electrophilic " 1988, 29, 1773–1774. activation with trityl salts. This procedure results in stereospeciﬁc syn-cycloelimination. (Attempted base-catalyzed oleﬁn formation led to retroaddition.) 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 Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Oleﬁnation Chem 115

Kinetic Resolution: Discrimination of enantiotopic or diastereotopic carbonyls: O CH3 H O O O H3C Ph H P(OCH2CF3)2 TBSO CH O O O 3 H H CHO 3 eq O O CO2R Ph CH3 H3C (F3CCH2O)2P + O RO2C CH3 CH3 1 eq KHMDS, CO2R CH OTBS 1.1 eq 3 18-crown-6 83%, 96% de 81%, 98% de 14%, 92% de OHC CHO KHMDS, 18-crown-6 THF, –100 °C THF, –100 °C Crude Z : E = 85 : 15 OTBS CH3 CH3 • E and Z products are formed from different enantiomers of the starting aldehyde. OHC CO2R CH3 O O CH CH • Mechanistic hypothesis: Ph 3 3 H3C P(OMe) O 2 53%, 90% de

H H3C O • Diastereoselectivity is dependent on conversion, because the minor diastereomeric products are CO2R preferentially bis-oleﬁnated. O O major product CH2 H O See: Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525-1529. O H syn- elimination Exercise: Based on the previous example, rationalize the stereochemical outcome of these Nu H H oleﬁnations. (Note that the phosphonate used in this example is enantiomeric to that used in fast-reacting the previous example). enantiomer O K • 18-crown-6 H Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J. Org. Chem. 1998, 63, 8284-8294. O CO2R (CH ) I CH 1. 2 2 CH3 O O 3 P(O)(OR)2 CH O O Felkin-Anh addition 3 Ph CH3 O O H3C Ph (F3CCH2O)2P CH P(OMe)2 O O 3 O H O O (RL = OR) H C Ph O O CH3 O CO2R 3 P(OMe) H C t-BuOK, THF O 2 3 O P(O)(OR)2 NaH, DMF, 23 °C –50 °C, 30 min Attack from !-face of (Z)-enolate H3C 2. Acetone, CH O 3 H2C O syn- Amberlyst-15 H O O elimination O H (MeO) (O)P Nu H 2 CO R H LiO 2 slow-reacting H CH3 K enantiomer O CO2R O O • Incapable of syn-elimination, H3C Ph therefore reverts P(OMe)2 (Slow step may be addition or elimination) O O CH3 H C minor product 3 O (MeO) (O)P 2 CO R CO2R LiO 2 CH3 O • For consideration of the stereochemical outcome of addition to "-alkyloxy aldehydes, see: CH Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353–3361. O CH3 O 3 • Auxiliary shields "-face of (Z)-enolate 80%, 98% de Rein, T.; Kann, N.; Kreuder, R.; Benoit, G.; Reiser, O. Angew. Chem., Int. Ed. Engl. 1994, 33, 556–558. • Attack occurs at either diastereomeric carbonyl from the face opposite the methyl group. Rein, T.; Reiser, O. Acta. Chem. Scand. 1996, 50, 369–379. Mandai, T.; Kaihara, Y.; Tsuji, J. J. Org. Chem. 1994, 59, 5847–5849. Kent Barbay

13 Myers Stereoselective Oleﬁnation Reactions: Peterson Oleﬁnation Chem 115

Reviews Advantages over the Wittig Reaction

Kelly, S. E. Alkene Synthesis in Comprehensive Organic Synthesis; Trost, S. M.; Fleming, I., Ed.; • The Peterson reagents are more basic and nucleophilic and less sterically hindered. As a result, they Pergamon, Oxford, 1991, 1, 729–818. are more reactive than phosphorus ylides. Weber, W. P. Peterson Reaction in Silicon Reagents for Organic Synthesis. Springer-Verlag, Berlin, • The byproduct siloxanes tend to be easier to remove than phosphorus byproducts. 1983, 14, 58–78. Magnus, P. Aldrichimica Acta 1980, 13, 43. Synthesis of Peterson Reagents, Applications

Overview • via halogen-metal exchange O • The Peterson oleﬁnation reaction was ﬁrst reported in 1968. It is considered to be the silicon variant of the Wittig reaction. n-BuLi Ph H Ph3Si Ph3Si Ph3Si Br Li Ph Et2O 81% HO O (H3C)3Si MgCl OH KH, THF (H C) Si Brook, A. G.; Duff, J. M.; Anderson, D. G. Can. J. Chem. 1970, 48, 561–569. Ph Ph 3 3 THF Ph Ph 23 ºC, 86% Ph Ph • via Deprotonation Peterson, D. J. J. Org. Chem. 1968, 33, 780–784. 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 O OLi alkoxides readily form the product alkene. Cy2NLi (H C) Si 3 3 OEt (H3C)3Si Mechanism THF, –78 ºC OEt

R1 O

CH3 CH3 R3Si R2 R3 H3C H3C CH3 –78 " –25 ºC CH3 Nu 82% CO Et TBSO O Z:E = 93:7 TBSO 2 R3Si O R3Si R3 R3Si OH R2 R2 Base Acid R1 R 3 R1 OH2 Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron Lett. 2001, 42, 6125–6128. R3 R1 R2 sec-BuLi Li O O R H3CO Si(CH3)3 H C 3 R2 3 THF H CO Si(CH ) –78 " –25 ºC 3 3 3 O R R H 1 2 + R1 R3

H3C CH3 Nu TMS R3Si OH OCH H CO 3 3 O R R3Si O O OH R3Si 2 R H3C H3C R Acid R 2 Base 3 1 R3 KH, THF O R2 O R1 R H H R1 OH2 3 0 ºC, 85%

H3C CH3 Z:E = 3:1 H3C CH3 73% • The silicon-substituted carbanion adds irreversibly to the carbonyl substrate, producing a mixture of diastereomeric !-silylcarbinols. Each diastereomer undergoes stereospeciﬁc decomposition to inseparable mixture of diastereomers give either E or Z alkenes depending on the elimination conditions, as shown above. Analogous reactions with the corresponding phosphonium and phosphonate reagents were not as

• when R1 = EWG, the intermediate !-silyl alkoxide undergoes spontaneous fragmentation as it is successful. formed to give the oleﬁnic products. 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 Stereoselective Oleﬁnation Reactions: Peterson Oleﬁnation Chem 115

Methylenation using commercially available (trimethylsilyl)methyllithium or • via addition of organometallics to vinylsilanes • O (trimethylsilyl)methylmagnesium chloride:

Li Si(CH3)3 EtLi H3C H O Si(CH3)3 Et Et OH H CH3 1. (H3C)3Si Li H CH3 Si(CH ) THF, –78 ºC 3 3 91% pentane, THF, –78 ºC H SPh H SPh Et 2. HF•pyr, CH3CN Et H C CH3 23 ºC, 84% H C CH3 NaH, HMPA 3 3 Et 23 ºC Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am. Chem. Soc. 2001, 123, 4851–4852. Z:E = 28:72

Hudrlik, P. F. Peterson, D. Tetrahedron Lett. 1974, 15, 1133–1136. OTBS OTBS 1. (H3C)3Si MgCl PivO O (4.5 equiv) 90% PivO O • via reductive lithiation CbzHN N CbzHN N Cbz O 2. SOCl2, C5H5N Cbz N(CH3)2 Ot-Bu Ot-Bu H3C H3C 86% SPh Li Li • Reaction with Ph3P CH2 at room temperature was not successful and more forcing conditions Si(CH3)3 Si(CH3)3 resulted in decomposition.

THF, –78 ºC Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103–2112. H3C CH3 H3C CH3 Stereoselective Synthesis of !-silylcarbinols O • Because "-silylcarbanion additions to carbonyl compounds are irreversible, the diastereomeric ratio in – + – + OBn H3C O K H3C O K H the addition step deﬁnes the cis/trans-alkene product ratio unless diastereomeric adducts can be separated and processed individually. Ar Ar KOAc OBn + • Other approaches rely on the stereoselective generation of !-silylcarbinols. Si(CH3)3 Si(CH3)3 n-Pr KH, THF, 23 ºC anti H3C CH3 H3C CH3 syn 96%, Z:E = 5:95 n-Pr O OH slow elimination fast elimination (H C) Si DIBAL-H (H C) Si 3 3 n-Pr 3 3 n-Pr AcOH, 60 ºC –78 ºC n-Pr pentane, –120 ºC n-Pr BF3•OEt2 H3C 97% OBn n-Pr n-Pr CH2Cl2, 0 ºC

OBn 99%, Z:E = 94:6 Hudrlik, P. F. Peterson, D. Tetrahedron Lett. 1974, 15, 1133–1136. H3C CH3 68% E:Z = 77:1 Ph O LiO CH3 MeLi, Et O TFA C5H11 C5H11 2 C5H11 • The syn-hydroxysilane in the example above underwent facile (base-mediated) elimination at – Ph Ph –78 23 ºC –78 # 23 ºC H C 78 ºC while the anti-hydroxysilane did not react until acetic acid was added to give (after Si(CH3)3 # Si(CH3)3 3 heating) the E-alkene. 57% E:Z = 9:91 Tamao, K.; Kawachi, A. Organometallics 1995, 14, 3108–3111. Barrett, A. G. M.; Flygare, J. A. J. Org. Chem. 1991, 56, 638–642. Perales, J. B.; Makino, N. F.; Van Vranken, D. L. J. Org. Chem. 2002, 67, 6711–6717. Fan Liu

15 Myers Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations Chem 115

Reviews: Petasis Modification (1990): 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. Cl MeLi or CH3 "-elimination Brown-Wensley, K. A.; Buchwald, S. L.; Cannizzo, L.; Clawson, L.; Ho, S.; Meinhardt, D.; Ti Ti Ti CH2 Stille, J. R.; Straus, D.; Grubbs, R. H. Pure Appl. Chem. 1983, 55, 1733–1744. Cl MeMgBr CH3 #

Generalized Reaction: Petasis reagent titanocene methylidene • 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 • This is a milder version of the Tebbe reagent, which avoids generation of the Lewis acidic aluminum intermediate. generated from either the Tebbe reagent or the Petasis reagent. • This reagent is also effective for olefination of silyl esters and acylsilanes. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-6394. CH3 CH3 Ti Al Ti or Order of Reactivity: Cl CH3 CH O 3 O O O O > > > R1 R2 R1 R2 (Tebbe Reagent) (Petasis Reagent) R H R1 R2 R1 OR R1 NR2

Tebbe reagent (1978):

O Cp2TiCH2AlCl(CH3)2

!15 ºC, 65% R H R1 R2 R1 OR R1 NR2

Acid halides and anhydrides: • Acid halides provide ketones rather than olefins under Tebbe or Petasis conditions. Anhydrides give 2 Al(CH ) Cl 3 3 CH3 Lewis base ketones under Tebbe conditions and olefins under Petasis conditions. Ti Ti Al Ti CH2 Cl Cl CH3 Al(CH ) Cl, 3 2 Al(CH3)2Cl Cp2Ti Cp2TiCH2AlCl(CH3)2 H+ O CH4 Tebbe reagent titanocene methylidene O O O O or R Cl R O R R R CH3 Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611–3613. Cl– or AcO– Mechanism: • The Tebbe olefination reaction follows a mechanism similar to the Wittig olefination, but the Cp Ti(CH ) titanocene methylidene is generally more nucleophilic and less basic than Wittig reagents. O O 2 3 2 O LB R O R R O R O R1 2 Chou, T.-S.; Huang, S.-B. Tetrahedron Lett. 1983, 24, 2169 - 2170. CH R 3 R1 R2 O Ti Al Ti CH2 Ti CH2 Advantages: CH Cp Ti CH2 Cl 3 Reagents are relatively simple to prepare. Cp • • Relatively bulky carbonyl groups can be olefinated. Cp2TiO • An alternative to the Wittig reaction, and works well on hindered carbonyls. Disdvantages: • A full equivalent of the reagent is required. R1 R2 • Limited to methylenation: substituted olefinations are difficult. Alpay Dermenci

16 Myers Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations Chem 115

• Selective mono- or bis-methylenation of dicarbonyls can be achieved by varying the equivalents of Petasis reagent O reagent. R R R1 R2 toluene or THF 1 2 CH3 O Ti Substrate Product Temp. (oC) Yield (%) CH3 O O (n equiv) O O 60–65 43 O THF, 65 oC O H C H H3C H 3 70% 1.0 equiv 10 : 1 O 60–65 90 2.0 equiv 2 : 1 Ph Ph Ph Ph 4.0 equiv 0 : 1

O 60–65 60 CH3 Ti O CH3 O O O (n equiv) N CH N CH 60–65 60 3 3 N CH3 OCH3 OCH3 toluene, 75 oC O O 75% O 1.5 equiv 1 : 0 O O 60–65 41 4.0 equiv 1 : 20 • Hindered carbonyls: Ph Ph CH O 3 CH3 Tebbe reagent 70 70 HO HO Ph Ph OSi(CH3)2t-Bu (1.5 equiv) OSi(CH3)2t-Bu CH O 3 O CH3 CH3 o CH O O THF, –78 C 3 65 67 76% Ph OCH3 Ph OMe

O Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. J. Am. Chem. Soc. 1988, 110, 5768 - 5779. OEt OEt 65 65 Ph Ph • Site-Selective Olefination: O 70 54 Ph N(CH ) Ph N(CH3)2 H3CO O 3 2 H3CO O O Cp TiMe (2.5 equiv) O O 2 2 O O N o H C H C 65 C, 8 h O N H3C 3 SPh 75 70 3 H CH SPh THF 3 CH Ph CH3 3 Ph 52% 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. Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918 - 5924. Alpay Dermenci

17 Myers Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations Chem 115

• Acyl chlorides can be converted into the corresponding methyl ketones without epimerization. • A strained enecarbamate was prepared using Petasis' olefination conditions: O O O O BocO H BocO H CH OEt Cp2Ti(CH3)2 OEt 3 H C H C Ti 3 3 CH C H N, toluene 3 Cl HN 5 5 HN O o O O 70 C, 8 h, 77% (1.2 equiv) Cp2Ti NH Cl O 4 77% BnO Cl BnO CH3 toluene, 0 oC BnO 76% CH3 CH3 CH3 14 steps (90.4% ee) (90.4% ee)

O Tandem Olefination/Aldol: HO H O N Gelsemoxonine OMe H3C N H O CH3 H Ti CH 3 Cl Diethelm, S.; Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 8500–8503. O O OH (1.2 equiv) Cp2Ti PhCHO Industrial-Scale Petasis Reaction: Ph O Ph Cl Ph • Dimethyltitanocene was used to produce Aprepitant, a recently approved substance P antagonist toluene, 0 oC Ph 69% used to prevent chemotherapy-induced nausea and vomiting:

CF3 CF3 CF3

Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1983, 105, 1664–1665. O CF3 H3C CF3 CF3 Tandem Olefination/Metathesis: O O O O Cp Ti(CH ) O O 2 3 2 steps • Cyclic enol ethers can be prepared through an olefination, ring-closing metathesis cascade (2.9 equiv) N sequence: N N THF, 91% H Ph F Ph F N F H H H Tebbe reagent H H H HN O O CH O O CH N BnO 3 (4 equiv) BnO 3 (250 kg) (227 kg) Aprepitant O O (Emend!) BnO O THF, 25 oC (20 min) BnO O H H H H H H CH3 then reflux (5 h), 71% 65% Relative reactivity: CF3

O Tebbe reagent H H H Tebbe reagent O CH3 CF3 O O CH O O H3C CH3 (1.3 equiv) 3 (2.0 equiv) O BnO H C < < H3C < O o 3 O CH3 THF, 20 min 25 C THF, 3 h, reflux OCH3 H3C O R CH2 H C BnO O 3 CH3 H H H CH3 N R: alkyl, CH2Ph CH3 77% Ph F

Payack, J. F.; Huffman, M. A.; Cai, D.; Hughes, D. L.; Collins, P. C.; Johnson, B. K.; Cottrell, I. F.; Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118, 1565–1566. Tuma, L. D. Org. Proc. Res. Dev. 2004, 8, 256–259. Alpay Dermenci

18 Myers Stereoselective Olefination Reactions: The Takai Reaction Chem 115

Reviews: Haloforms

X Furstner, A. Chem. Rev. 1999, 99, 991–1045. O CHX3, CrCl2, THF H3C H C Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1–36. H 3

Reaction Overview: Xa Temp (ºC) time (h) yield (%) E/Z

Cl 65 2 76 95/5 I 0 2 82 83/17 R2 X b R2 CHI2 O CHX3, CrCl2 Br 50 1 76 95/5 R CrCl -DMF R H 1 2 1 THF R1 THF E-isomer E-isomer a (major) (major) Reaction conditions: aldehyde (1 equiv), CHX3 (2 equiv), CrCl2 (6 equiv), THF. b CrBr3 and LiAlH4 (1:0.5) was employed in lieu of CrCl2.

R2=alkyl, aryl, B(OR)2, SiR3, SnR3 • Aldehydes are more reactive than ketones:

Mechanism: O

O H3C I CHI3, CrCl2 III H 2 CrCl X CrIIIX O X2Cr O X H C CHO 75% (E/Z = 81:19) 2 2 3 o CHX3 + THF, 0 C I III R1 III Cr X2 H R1 H Cr X2

H3C I 5%

X + R1 R1 Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410. X (E)-alkenyl halide (Z)-alkenyl halide 1,1-Geminal Dihalides (major) (minor) CH3 O

H CH3CHI2, CrCl2 H C General Trends: H3C THF, 97% 3 • Reactivity is dependent on the haloform: I > Br > Cl. CH E:Z = 94:6 CH3 • E/Z ratios are greatest in the order Cl > Br > I. 3 • Aldehydes react faster than ketones. • The E-isomer is the predominant product for both haloforms and 1,1-geminal dihalides. t-Bu t-BuCHI2 O CrCl2-DMF H C Advantages Disadvantages H3C H THF, 90% 3 • Reagents are readily available. • Stoichiometric amounts of by-products are generated. E:Z = 94:6 • Reaction is selective for the E-isomer. • Excess reagent is typically required. • High functional group tolerance. Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 951–953. Alpay Dermenci

19 Myers Stereoselective Olefination Reactions: The Takai Reaction Chem 115

• Oleﬁnation of ketones:

H3C H3C CH3 CH3 O H OH O CrCl , CHI OH O CHI , CrCl I 2 3 3 2 NBoc I NBoc O THF-dioxane t-Bu THF t-Bu CH3 CH3 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

H N O 2 H

Takai Olefination in Natural Product Synthesis CH3 CH 3 CH3 H CO OH 3 H NHAc O

CH3 CH3 H3C O TBSO CH3 OH HO CH3 O Superstolide A 1. CrCl2, CHI3, THF O CH3 O 2. PPTS, EtOH Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2008, 73, 9657 - 9667. I O H 64% (2 steps)

Sch-642305 CH 3 CH3 SEMO SEMO Dermenci, A; Selig, P. S.; Domaoal, R. A.; SpasovK. A.; Anderson, K. A.; Miller, S. J. Chem. OH Sci. 2011, 2, 1568–1572. 1. DMP I

2. CrCl2, CHI3, THF OTHP OTHP 23 ºC, 77% Cl Cl CH E:Z = 19:1 CrCl2, CHCl3 OTES 3 CH3 OTES H C H3C 3 CH CH3 3 THF, 65 ºC CH CH3 CHO 3 CH3 69% Cl HO

OH CH H 3 O CH3 Br O CH3 Cl CH3 H3C H3C O

Cl Amphidinolide J aplysiapyranoid C

Jung, M. E.; Fahr, B. T.; D'Amico, D. C. J. Org. Chem. 1998, 63, 2982–2987. Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198–11199. Alpay Dermenci

20 Myers Stereoselective Olefination Reactions: The Julia Olefination Chem 115

Reviews • The reductive elimination step can follow two different pathways depending on the reducing agent, Dumeunier, R.; Marko, I. E. Modern Carbonyl Olefination 2004, 104–150. however each pathway shows a preference for forming the E-olefin isomer. 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 O SO Ar SO Ar with aldehydes or ketones to provide olefins. 2 MeO 2 Ar O NaOCH H S Na(Hg) H O R4 3 O R4 R R • Initial Report: R1 1 2 R1 H R2 O H R2 O 1 e" H

1. n-BuLi (2 equiv) O Ph Ph – + SO2Ar 2. MgI2 (2 equiv) Al/Hg Ar O Na S R1 PhO2S H –ArSO Na Na(Hg) Ph Ph 2 R2 Ph 3. O 90% R R2 R2 1 Ph Ph R1 1 e" H H Ph Ph H E Z (favored) (disfavored)

Pascali, V.; Umani-Ronchi, A. J. Chem. Soc., Chem. Comm. 1973, 351. H Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 49, 4833–4836. R MeOH R 2 R2 E-isomer 1 R1 H • The reaction predominantly forms (E)-olefins H

• Typically, strong bases and stoichiometric quantities of reagents are required. SmI2 Reduction: • Often Julia olefination requires trapping of the initially formed !-oxido sulfone, which is then reduced to give the E-alkene. O Ar OSmI2 SO2Ar S H O O SmI2 H O R4 O R O R SO Ar SO Ar SO2Ar 4 4 2 Base 2 R2 R3 X R R1 R1 R1 O 4 R 1 e" H 2 O H R2 O H R2 O R R R1 1 1 R2 R3

O R 4 R2 ArO2S Reductant R R2 SmI R2 2 O H H 2 H R1 H R3 H H R1 R R H 2 R1 R1 " 1 R3 OCOR4 1 e OCOR4 OCOR4 (E)-alkene

• A variety of different trapping and reducing agents can be used. H Trapping agents: Ac O, BzCl, MsCl, TsCl R2 E-isomer 2 R1 H Reducing agents: SmI2 (most common), RMgX, Bu3SnH, Li or Na in ammonia, Na2S2O4, Raney/Ni, Al(Hg) amalgam, LiAlH4, SmI2/HMPA Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204. Alpay Dermenci

21 Myers Stereoselective Olefination Reactions: The Julia Olefination Chem 115

• 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 • In general, the E/Z ratio is dependent on reaction conditions, with PT-sulfones giving higher E- rearrangement-like mechanism. selectivities.

Julia-Silvestre Julia-Kocienski

S Ph SO2Het 1. (Me3Si)2NM Ar: Ar: N N CH3 CH3 N 2. c-C6H11CHO N N benzothiazole 1-phenyl-1H-tetrazole "BT-sulfone" "PT-sulfone" BT-sulfone PT-sulfone Solvent M Yield (%) E/Z Yield (%) E/Z Mechanism:

Li 2 70 : 30 94 72 : 28 O O O O O O O DME Na 32 75 : 25 95 89 : 11 N S R1 Base N S R1 R1 H N S R1 K 4 76 : 24 81 99 : 1 S S S O R2

Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett. 1998, 26–28.

O O R1 R N S 1 R1 N O O • Origin of Selectivity: R S 2 S O S R2 O R2 closed transition state open transition state N N N O + SO Ph N N H H O 2 R SO PT H R1 SO2PT 1 2 PT S O K S H Li R O S 1 R R1 O R2 O 2 O R2 O O H H H H R2 Sulfone Preparation

N N Ph 1. DIAD, PPh3, THF N SO2PT OH Smiles R1 SO2PT Smiles N N 0 ! 23 ºC, 89% SO2 R2 R R2 N R1 R2 2 R1 SH Ph rearrangement R1 rearrangement N O N CH CH 2. m-CPBA, NaHCO3 O 3 3 CH CH Li commercially CH2Cl2, 23 ºC, 68% 3 3 available PT-sulfone

Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett. 1998, 26–28. Alpay Dermenci

22 Myers Stereoselective Olefination Reactions: The Julia Olefination Chem 115

Examples • Application to the synthesis of BMS-644950, a next-generation statin candidate:

OTBS OTBS CH3 F H O H C 3 O Ot-Bu H + PTO2S H3C TBDPSO O O i-Pr O O O CH3 CH3 CH3 CH3 N N 1. LHMDS, THF + O S 2. EtOH, H O Conditions N N O 2 CH3 (crystallization) N N Ph N N CH3 N N Conditions E : Z (27.5 kg) (38.4 kg) NaHMDS, THF, –78 oC 1:8 OTBS OTBS CH LiHMDS 3 >30:1 DMF, DMPU, –35 oC O H O

TBDPSO CH3 CH3 CH3 CH3 H C HO O 3 O Ot-Bu H3C HO O NH4 O O Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772 - 10773. F F •H O 2 1. HCl i-Pr i-Pr • 2. NH3 The Julia olefination reaction was applied to the synthesis of LAF389, an anti-cancer agent. The N N N N addition of TMSCl was found to be crucial: the authors propose that TMSCl stabilizes the anionic 90% intermediate and the sensitive aldehyde substrate by attenuating the basicity of the reaction. N N N N CH3 CH3 N N N N CH3 (27.6 kg) CH3 (33.6 kg)

O O BMS-644950 74%, E : Z = 91 : 1 O O O O O t-Bu S S OCH3 t-Bu OCH3 + H 1. n-BuLi, TMSCl N O O O O

THF, CH3CN H3C CH3 H3C CH3 2. MTBE (168.5 g) (120.0 g) (crystallization) (65.9 g) 45%, single isomer

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.; Xu, D. D.; Waykole, L.; Calienni, J. V.; Ciszewski, L.; Lee, G. T.; Liu, W.; Szewczyk, J.; Vargas, K.; Young, J.; Parsons, R. L. Org. Process Res. Dev. 2010, 14, 441–458. Prasad, K.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 856–865. Alpay Dermenci, Fan Liu