Myers Chem 115 Sharpless Asymmetric Epoxidation Reaction Substitution patterns: Reivews: Katsuki, T.; Martin, V S Org React 1996, 48, 1–300 OH OH Johnson, R A.; Sharpless, K B In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New OH York, 1993, pp 103–158 OH OH Johnson, R A.; Sharpless, K B In Comprehensive Organic Synthesis, Trost, B M.; Fleming, OH OH I., Eds., Pergamon Press: New York, 1991, Vol 7, pp 389–436 Pfenninger, A Synthesis 1986, 89–116 • Z-disubstituted olefins are least reactive and selective Asymmetric Epoxidation of Allylic Alcohols: R3 R2 OH Ti(Oi-Pr)4, (+)-DET R2 t-BuOOH, 3Å-MS CH2Cl2, –20 °C R1 O R3 product OH R1 O (+)-DET = EtO2C CO2Et Ph OH • 10–20 mol% excess tartrate vs Ti(OiPr)4 required • (+)- and (–)-DET are readily available and inexpensive O Soc 1987, 109, 5765–5780 L-(+)-DET "O" R2 yield (%) ee (%) (+)-DIPT (6.0) 65 90 (+)-DIPT (7.0) –20 89 >98 OH 4.7 (+)-DET (5.9) –12 11 88 95 OH 10 (+)-DET (14) –10 29 74 86 (+)-DIPT (7.5) –35 79 >98 100 (+)-DET (142) –20 14 80 80 (+)-DET (7.4) –20 0.75 95 91 120 (–)-DET (150) –20 90 94 OH Pr O R3 R1 BnO HO Katsuki, T.; Sharpless, K B J Am Chem Soc 1980, 102, 5974–5976 Application of Mnemonic: CH3 OH AE-(+)-DET Ph CH3 O OH 97%, 86% ee OH OH CH3 CH3 D-(–)-DET "O" CH3 O H3C 97%, 86% ee h C7H15 CH3 O Ph OH Mnemonic for selectivity: OH °C O O Gao, Y.; Hanson, R M.; Klunder, J M.; Ko, S Y.; Masamune, H.; Sharpless, K B J Am Chem O tartarate(%) OH • (+)- and (–)-DIPT, diisopropyl tartrate, are also available and sometimes lead to higher selectivity AE-(–)-DET Ti(%) OH • 5–10 mol% catalyst in the presence of 3- or 4Å-MS CH3 OH Examples of Sharpless Epoxidation: O CH3 OH Ph From: Gao, Y.; Hanson, R M.; Klunder, J M.; Ko, S Y.; Masamune, H.; Sharpless, K B J Am Chem Soc 1987, 109, 5765-5780 and Johnson, R A.; Sharpless, K B In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp 103–158 M Movassaghi Myers Chiral Substrate: H3C Chem 115 Sharpless Asymmetric Epoxidation Reaction Kinetic Resolution: CH3 H3C O O CH3 O OH CH3 H3C O O O OH OH O O • Products are diastereomeric • Using the Sharpless mnemonic, contact between the C1 substituent (R) and the catalyst predicts the slow-reacting isomer (+)-DET "O" (+)-DET "O" Ratio (syn : anti) Reagent m-CPBA VO(acac)2-TBHP Ti(OiPr)4-TBHP Ti(OiPr)4-(-)-DIPT-TBHP Ti(OiPr)4-(+)-DIPT-TBHP R2 : 1.4 : 1.8 : 2.3 : 90 22 : R3 R1 MATCHED MISMATCHED HO R2 R H R3 R1 HO H R fast slow krel = kfast/kslow • Products are diastereomeric • Sense of induction is dominated by the catalyst • The C4 center reinforces and erodes this in "MATCHED" and "MISMATCHED" cases, respectively, as shown • With the exception of Z-disubstituted allylic alcohols, krel > 25 • When krel = 25, the ee of unreacted alcohol is essentially 100% at 60% conversion • Allylic tertiary alcohols are not successfully expoxidized under Sharpless conditions • Factors may combine for high selectivity: Ko, S Y.; Lee, A W M.; Masamune, S.; Reed, L A., III; Sharpless, K B.; Walker, F J Tetrahedron 1990, 46, 245–264 OH Homoallylic, bishomoallylic and trishomoallylic: H3C • Rates of epoxidation are usually slower • Enantiofacial selectivity of the catalyst is reversed for all three • Enantiofacial selectivity is generally lower H3C OH Ti(Oi-Pr)4 (1.0 equiv) (+)-DET (1.2 equiv) H3C H3C 40% conversion • Disubstituted olefin is more reactive than monosubstituted olefin (krel ~ 100) • kfast/kslow for chiral E-propenylcarbinols is ~100 OH O Excercice: Apply the Sharpless mnemonic to predict the stereochemistry of this product Sharpless, K B.; Behrens, C H.; Katsuki, T.; Lee, A W M.; Martin, V S.; Takatani, M.; Viti, S M.; Walker, F J.; Woodard, S S Pure Appl Chem 1983, 55, 589–604 Rossiter, B E.; Sharpless, K B J Org Chem 1984, 49, 3707–3711 OH OH 70% yield >95% ee 50%, 41% ee • Allylic 1,2-diols not follow the Sharpless mnemonic: Ti(Oi-Pr)4 (1.0 equiv) (+)-DET (1.2 equiv) TBHP, °C 48 h O (±) TBHP, –20 °C 1–4 d CH3 (–)-DIPT H O OH H OH CH3 22%, 29% ee Hosokawa, T.; Kono, T.; Shinohara, T.; Murahashi, S.-I J Organometal Chem 1989, 370, C13–C16 For other examples see: Johnson, R A.; Sharpless, K B In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp 103-158.and Katsuki, T.; Martin, V S Org React 1996, 48, 1–300 OH (+)-DIPT OH OH 71% 90% ee O OH O + OH 10% 90% ee Excercice: What isomer would you have predicted using the Sharpless mnemonic? Takano, S.; Iwabuchi, Y.; Ogasawara, K J Am Chem Soc 1991, 113, 2786–2787 M Movassaghi Myers Chem 115 Sharpless Asymmetric Epoxidation Reaction C2-Symmetric Substrates: Venustatriol: • Any minor diastereomer that is produced is rapidly removed by bis-epoxidation Exercise: Why? H3C CH3 OH O O CH3 H3C H3C CH3 (+)-DIPT OH OH O O Ti(Oi-Pr)4, (–)-DET H3C OH TBHP, 3Å-MS –20 ºC H3C OH H3C CH3 CH3 OBn OBn O OBn meso 92% OBn 89% H3C Schreiber, S L.; Schreiber, T S.; Smith, D B J Am Chem Soc 1987, 109, 1525–1529 H3C Schreiber, S L.; Goulet, M T.; Schulte, G J Am Chem Soc 1987, 109, 4718–4720 L-Hexoses: O O HO H3C Applications in Synthesis: H3C CN H Ti(Oi-Pr)4, (+)-DIPT OH RO O OH TBHP, –20 ºC 2,2-dimethoxypropane cat, POCl3 OAc SPh O m-CPBA, –78 ºC Ac2O, NaOAc, ! O H3C CH3 Ti(Oi-Pr)4, (–)-DET H3C O HO CH3 H O H3C RO O H3C H3C H3C H3C O Br O CH3 syn H H3C HO CH3 CH3 92% H O O CH3 TBHP 3Å-MS –23 ºC H3C OH 91% RO H CH3 SPh DIBAL-H CH2Cl2 –78 ºC 100% CN H OH RO 93%, 3-steps K2CO3 CH3OH 25 ºC O 74% 92%, >95% ee 71% RO HO H3C TrOOH, 3Å-MS " 23 ºC, 15 h PhSH, NaOH H2O/t-BuOH, ! R = CHPh2 H3C Ti(Oi-Pr)4, (–)-DET H CH3 RO CH3 O OH O O anti Ko, S Y.; Lee, A W M.; Masamune, S; Reed, L A., III; Sharpless, K B.; Walker, F J Tetrahedron 1990, 46, 245–264 H + Li O H H O O CH3 CH3 H • HWE-olefination, reduction, and AE provides an iterative route to the synthesis of polyols CH3 CN H O H3C H3C H3C H3C O H H OH H C H H Br O O H O H OH CH3 CH3 OH H Venustatriol Corey, E J.; Ha, D.-C Tetrahedron Lett 1988, 29, 3171–3174 M Movassaghi Myers Ferensimycin B: (+)-Neocarzinostatin Chromophore: H3C H3C O H3CO Chem 115 Sharpless Asymmetric Epoxidation Reaction CH3 N O CH3 H N CH3 Et Et EtLi N CH3 Et O CH3 Et EtMgBr Et TBHP OH Et2O CH3 (+)-DET, Ti(Oi-Pr)4 Et H3C O Li O H3C N HO2C OH CH3 H CH3 CH3 Et HO N O H H3C Et O O CH3 OH O H3C N CH3 OH CH3 Et H3C H O O CH3 OH H H Et Et TBDPSO TDSCl, Et3N, DMAP CH2Cl2, ºC CH3 TBS (–)-DET, Ti(Oi-Pr)4 TBHP, –20 ºC, CH2Cl2 4Å-MS Et Evans, D A.; Polniaszek, R P.; DeVries, K M.; Guinn, D E.; Mathre, D J J Am Chem Soc 1991, 113, 7613–7630 HO CH3 H H O OH H (+)-DET, Ti(Oi-Pr)4 TBHP, –20 ºC CH2Cl2 TMS CH3 H H3C H H3C O H H O OH TMS Red-Al, THF – 15 ºC; H2O 79% (two steps) H3C H3C H H3C H HO TBS O O H O H H OCH3 O O TBS 70%, !95% de (–)-7-Deacetoxyalcyonin Acetate: H3C H H3C 94%, !95% de CH3 OH H3C H HO Ferensimycin B H3C O H HO (+)-DET, Ti(Oi-Pr)4 TBHP, –20 ºC CH2Cl2, 4Å-MS Br CH3 H3C OH O H3C CH3 Et2NLi (1.5 equiv) THF NaHSO4, H2O Et Mg 76% of TY, 90% ee O Et O OH H HO CH3 • A further example of anomalous stereochemistry in AE of an allylic diol (no reaction with (–)-DIPT) H H3C N H O O • O O H O HO CH3 OH (+)-Neocarzinostatin Chromophore Myers, A G.; Hammond, M.; Wu, Y.; Xiang, J.-N.; Harrington, P M.; Kuo, E Y J Am Chem Soc 1996, 118, 10006–10007 Myers, A G.; Liang, J.; Hammond, M.; Harrington, P M.; Yusheng, W.; Kuo, E Y J Am Chem Soc 1998, 120, 5319–5320 H3C CH3 H H O AcO H CH3 H H3C H H3C O H H HO OH TMS (–)-7-Deacetoxyalcyonin Acetate MacMillan, D W C.; Overman, L, E J Am Chem Soc 1995, 117, 10391–10392 M Movassaghi Myers Chem 115 Sharpless Asymmetric Epoxidation Reaction • In this example, a stoichiometric amount of titanium and DIPT was necessary for high conversion Examples of the Sharpless Asymmetric Epoxidation Reaction in Industry: OEt OH O (–)-DIPT, Ti(Oi-Pr)4, TBHP NaOH O H O OH N H3C OH NHAc Gleave, D M.; Brickner, S J J Org Chem 1996, 61, 6470–6474 OEt CO2H F O OH OH O OH N H F (+)-Tartrate, Ti(Oi-Pr)4 TBHP, 4Å-MS CH2Cl2, >95%, 88–92% ee F O OH F (The choice of tartrate was not specified) (187.3 g) 58% (2 steps), 98% ee (S,S)-Reboxetine succinate a norepinephrine uptake inhibitor O F Henegar, K E.; Cebula, M Org Proc Res Dev 2007, 11, 354–358 F • In the following example, the minor enantiomer was unreactive, leading to enantiomeric enrichment: OH (–)-DIPT, Ti(Oi-Pr)4 TBHP, 4Å-MS O OH CH3 N CH3 H N An antifungal agent Saksena, A K.; Girijavallabhan, V M.; Lovey, R G.; Pike, R E.; Desai, J A.; Ganguly, A K.; Hare, R S.; Loebenberg, D.; Cacciapuoti, A.; Parmegiani, R M Bioorg Med Chem Lett 1994, 4, 2023– 2028 N3 O N N N O • In this example, excess TBHP was quenched with triethylphosphite instead of FeII sulfate N3 O An antibacterial agent OEt • HO2C O NHCbz O CH2Cl2, 84%, >95% ee OH EtOAc, –15 oC 97% conversion (150 g) (–)-DIPT, Ti(Oi-Pr)4 TBHP, 4Å-MS NHCbz OH OH CH2Cl2, –15 ºC CH3 95%, 98% ee 90% ee H3C OH CH3 (–)-DET, Ti(Oi-Pr)4 TBHP, 4Å-MS CH3 CH2Cl2, –10 ! 20 ºC 99%, 91% ee O H3C OH CH3 Geraniol CO2CH3 H3CO2C O O N N H3C HO CO2H NBoc OH HIV-1 protease inhibitor Jadhav, P K.; Man, H W Tetrahedron Lett 1996, 37, 1153–1156 N-Boc-(2R,3R)-3-methyl-3-hydroxypipecolic acid Noe, M C.; Hawkins, J M.; Snow, S L.; Wolf-Gouveia, L J Org Chem 2008, 73, 3295–3298 Jesse Teske, Andy Flick, Daniel Schmitt ... 115 Sharpless Asymmetric Epoxidation Reaction • In this example, a stoichiometric amount of titanium and DIPT was necessary for high conversion Examples of the Sharpless Asymmetric Epoxidation Reaction. .. predicted using the Sharpless mnemonic? Takano, S.; Iwabuchi, Y.; Ogasawara, K J Am Chem Soc 1991, 113, 2786–2787 M Movassaghi Myers Chem 115 Sharpless Asymmetric Epoxidation Reaction C2-Symmetric... Substrate: H3C Chem 115 Sharpless Asymmetric Epoxidation Reaction Kinetic Resolution: CH3 H3C O O CH3 O OH CH3 H3C O O O OH OH O O • Products are diastereomeric • Using the Sharpless mnemonic, contact