http://www.courses.fas.harvard.edu/~chem206/ Me2CH Me OH Me Ph NHCONHPh 9-BBN OH Me Me2CH OH O NHCONHPh Ph Me Chem 206D. A. Evans Matthew D. Shair Friday,October 4, 2002 a73 Reading Assignment for week A. Carey & Sundberg: Part B; Chapter 4"Electrophilic Additions to C–C Multilple Bonds" Olefin Addition Reactions: Part–1 Chemistry 206 Advanced Organic Chemistry Lecture Number 8 Olefin Addition Reactions–1 a73 Problems of the Day: (To be discussed) a73 Hydroboration a73 Epoxidation & Directed Epoxidation a73 Other Reading Material Smith, K. and A. Pelter (1991). Hydroboration of C=C and Alkynes. Comprehensive Organic Synthesis. B. M. Trost and I. Fleming. Oxford, Pergamon Press. 8: 703. Beletskaya, I. and A. Pelter (1997). “Hydroborations catalysed by transition metal complexes.” Tetrahedron 53(14): 4957-5026. Brown, H. C. and P. K. Jadhav (1983). Asymmetric Hydroboration. Asymmetric Synthesis. J. D. Morrison. New York, AP. 2: 1. Hoveyda, A. H., D. A. Evans, et al. Chem. Rev. 1993,93: 1307-70 “Substrate-directable chemical reactions” (handout) W. C. Still & J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487. diastereoselection 24:1H2O2 Rationalize the stereochemical outcome of this reaction Roush, J. Org. Chem. 1987, 52, 5127. m-CPBA CH2Cl2, 0 °C 75 % Diastereoselection = 95 : 5 Predict the stereochemical outcome of this reactionK. Houk, Tetrahedron. 1984, 40, 2257-2274Theoretical Studies of Stereoselective Hydroboration Reactions (Handout) C CHR HR C CHR HR M H H H C CHR HR –ROH C CHR HR –N2 C CHR HR –N2 OsO4 C CHR HR –N2 RO2H R2C=N2 R2C=C=O C C H R H R M H C C H R H R O OOs O O C C H R H R H H C C H R H R O C C H R H R OR R C C H R H R R2C C CHR HR C CHR HR C CHR HR C CHR HR H–X Hg(OR)2 R–S–X Br Br C C H R H RH X C C H R H RRO S–R C C H R H RBr Br C C H R H RRO Hg–OR C C H R H R X C C H R H R H C C R H H RH X D. A. Evans Chem 206Olefin Addition Reactions: Introduction Representative Cis-Addition Processes a73 Hydrometallation + M = B, Al, etc + a73 Hydrogenation M-catalyst + a73 Group Transfer (epoxidation) + a73 Group Transfer (dihydroxylation) + a73 Group Transfer (cyclopropanation) M-catalyst Attributes: Each process adds to the C=C via a stereospecific process Intermediates may be involved in some of the indicated reactions + a73 Cycloadditions (one of many!) Representative Trans-Addition Processes a73 Halogenation + a73 Oxy–metallation (M = Hg(II), Tl(III) + a73 Oxy–sulfenation (M = S(II), Se(II) + Attributes: Process may proceed via an bridged intermediate where H+ is the initiating electrophile Olefin substitution, reaction conditions as well as halide type may disrupt bridging a73 Addition of hydrogen halides + + Attributes: Each process may proceed via an bridged intermediate where X is the initiating electrophile Olefin substitution may disrupt bridging Me3C H CH2 A B H H H S C CRR RR RL OH RM Me B2H6 MCPBA RL RM H CH C MeCH 2OR HBH H H2O2 C RRCRR B S H H H RL RM MeRM OHRL OH H CH C MeCH 2OR HBH H C H C H2B R R R R Me OH OMe O Me Me OTrTrO Me OH Me O CH2OBn Me Me OH Me OH Me OH Me TrO OTr Me BnO OH Me Me Me B2H6 B2H6 B2H6 MeMe CH2OBnO OH OH TrO OTr Me OH Me OH MeMe O OMe Me OH OH OH MeMeMe OHBnO OH Me TrO OH Me OH Me OH Me OH OTr Still, W.C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487. Diastereoselection; 4: 1 ThexylBH2, then BH3 ThexylBH2, then BH3 Diastereoselection; 5 : 1 H2O2 Diastereoselection = 3:1 C. H. Heathcock et. al. Tetrahedron Lett 1984 25 243. H2O2 diastereoselection 12:1 Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 259. diastereoselection 8:1 H2O2 Hydroborations dominated by A(1,3) Strain Staggered transition states Steric effects; RL vs RM A(1,3) allylic straincontrol elements Houk, "Theoretical Studies of Stereoselective Hydroboration Reactions" Tetrahedron 1984, 40, 2257 (Handout) major diastereomer a73 Acyclic hydroboration can be controlled by A(1,3) interactions: BH3, H2O2 34:66 JOC, 1970, 35, 2654 JOC, 1967, 32, 136369:31 ReferenceRatio, A:EOxidant E a73 Response to steric effects: Here is a good calibration system: ? a73 The basic process Allylic Strain & Olefin HydroborationD. A. Evans Chem 206 δ+ δ– major minor H H HH H H H H H H RL RL HMe C MeC HCH C Me H Me HC H C Me Me CH C MeMe H B HH H C C H HMe B H H C MeCHH H RM H R B C H CHH Me R H CMe C H H BH R R OH Me R OH R Me OH 9-BBN R2BH RL H2O2 H Me H H CH2OHMe H Me CH 2 H H Me RM Me RL OH 9-BBNTS1 RM BH3A RL H2O2 OHRL Me RM TS2 BH3RMB H2O2 RM Me RL OHTS2 R2BH H2O2 OHRL Me RM R2BH RL Me RM H2O2 OHRL Me RM H2O2 RM Me RL OH TS1 RM R2BHR2BH R2BH structure is a potential variable Allylic Strain & Olefin HydroborationD. A. Evans Chem 206 What about the following substitution pattern? Houk's rules: Orient RL anti-periplanar to incoming reagents to avoid TS eclipsing: favored for BH3 from Lecture 4: a73 Case I: Borane +2.68kcal +1.39 kcal +0.06 kcal Φ = 180 Φ = 110 Φ = 50 Φ = 0 Φ = 180Φ = 0 The Torsional Energy Profile Midland finds that TS1 favored for R2BH reagents, but TS1 ~ TS2 for BH3 Others have found that TS1 favored over TS2 for BH3 favored for R2BH a73 Case II: Dialkylboranes Representative Examples 1 : 1 4 : 1 14 : 126 : 1 diastereoselection borane methylsulfidethexylborane 9-BBNdicyclohexylborane M. M. Midland & Co-workers,J. Am. Chem. Soc. 1983, 105, 3725.. H2O2 W. C. Still & J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487. R = CHMe2: diastereoselection 24:1 R = n-Bu: diastereoselection 11:1H 2O2 Model is consistent if you presume HO = RM: R = RL major minor major minor RM RO RO RM RM RM RO RO O Me Me OMe Me OMeMe O H OH Me O N O Bn A Lonomycin A RL CMe C H H BH R R R B C H CHH Me R B H RL H CHOHO2C O Me OMeMe Me OMe Me OHMe O O Me Me O O OMeMe Me OMe Me Me OH H H D F C B C H MeHH H H C B C H MeHH R R RL RL H H RL B H H H C C H HMe B H H C MeCHH H H RL H RL RL C H C B HMe H HH C H C B HMe H R R H H E 9 TS2 TS1 H2O2 R2BH H2O2 R2BH BH3?SMe2 9-BBN RM Me RL OH OHRL Me RM OXP Me Me OMe Me OMeMe O H OH Me OH OH OXP Me Me OMe Me OMeMe O H OH Me TS2 TS1 A B BH3 BH3 H2O2 H2O2 OHRL Me RM RM Me RL OH Allylic Strain & Olefin HydroborationD. A. Evans Chem 206 favored for BH3 favored for R2BH a73 Case I: Dialkylboranes a73 Case II: Borane TS1 favored TS2 disfavored 1 5 9 9 5 1 1 5 10 diastereoselection> 95 : 5 diastereoselection92 : 8 85% 60% TA1 disfavored TA2 favored Evans, Ratz, Huff, Sheppard, JACS 1995, 117, 3448-3467. C-9 → C10 10 10 9 major major minor minor CO2H CH2 Me Me Me CH2OH Me Me Me CH2 CO2H Me OH CH2 Me Me CH2OH Me Me OH CH2 Me O O MeEt OHHEt Me Et Et Et Et Me Et OH RO O O Me Me Me Me Me MeO O HO O OBn O O CH3 CH3 R H CH3 CH3 O O OBn OHO R H OHR R OH OH H B2H6 BH3.THF BH3.THF BH3.THF O OMe MeH H H Me Me O O Me OH MeH OH OH H Me OH Me Me OH MeH OH OH H Me OH Me Chem 206D. A. Evans Represetative Hydroboration Examples: Acyclic Control Y. Kishi & Co-workers, J. Am. Chem. Soc. 1978, 100, 2933. "one isomer" H2O2 diastereoselection 12:1Mori, K. Tetrahedron 1976, 32, 1979 R=H; Diastereoselection = 6.8:1R=OBn Diastereoselection = 6.6:1Oikawa et. al. Tetrahedron Lett. 1983, 19, 1987. R = CH3; Diastereoselction = 6.7:1 R = isopropyl "One Compound" Birtwistle et. al. Tetrahedron Lett. 1986, 25, 243. B2H6/[O] B2H6/[O] B2H6/[O] Schulte-Ette, K.H.; Ohloff, G.Helv. Chim. Acta 1967, 50, 153. Diastereoselection = 4.6:1 Diastereoselection = 10:1 Diastereoselection = 32:1 Diastereoselection = 19:1 B2H6/[O] 1. 9-BBN 2. H2O2, NaOH Diastereoselection = 10:1Wolinsky, J.; Nelson, D. Tetrahedron. 1968, 25, 3767. Wolinsky, J.; Eustace, E. J. J. Org. Chem. 1972, 37, 3376. Diastereoselection = 7:1 1. 9-BBN 2. H2O2, NaOH For each of the examples shown below, attempt to rationalize the stereochemical outcome of the reaction in terms of one of the models presented in the discussion. Me3C CH2 BH3.THF CH2 Me3C MeMe CH2 Me3C Me Me3C CH2 Me Me CH2 BH3.THF BH3.THF BH3.THF BH3.THF OH Me MeMe 3C OH MeMe3C Me3C OH OH MeMe3C OH Me Me OH BnOHO O H H O N–NHAr Me Me Me H HNO O O CH2 HH CH3 O CH2Me CO2Me H Me BH3.THF BH3.THF BH3.THF BH3.THF H Me Me Me N–NHAr OH O O HH HOBnO OH Me OH Me H CO2Me Me O OH H CH3 H H OO O HN OH Chem 206D. A. Evans Representative Hydroboration Examples: Cyclic Systems Diastereoselection = 2.1:1 Diastereoselection = 3.3:1 Diastereoselection = 2.4:1 Diastereoselection = 4.9:1(Compare with H.C. Brown's case, with 9-BBN; 1.5:1)Y. Senda et. al. Tetrahedron 1977, 33, 2933. Diastereoselection = 1.2:1 Minor diastereomer not detectedMcMurry, J. E.J. Am. Chem. Soc. 1968, 90, 6321. Ley, S. et.al. J. Chem. Soc. Chem. Commun. 1983 630. Major isomer; no ratio given.B. Fraser-Reid et. al. J. Am. Chem. Soc. 1984, 106, 731. 90% yield, no diastereoselection givenSallay, S. I. J. Am. Chem. Soc. 1967, 89, 6762. 55% yield with the diastereomeric alcohol produced in an unspecified amount. Recycling of the minor isomer furtherprovided 15% of the desired material X R A B A B X A B R B A X B A A B C C H HH A B C C H HH A B A B OH OH R R OH Et2Zn MCPBA Cl CO3H t-BuOOH Et2Zn CH2I2 OH Me CH2I2 R O CH2 R O Zn CH2I R OH O Me OH CH2 OH R R O CH2 OH R (Ir+) Stork JACS 105, 1072 (1983) (Rh+) Evans JACS 106, 3866 (1984) M(I) + H2 Mechanism-based: (HO & C=C must be allylic) Simmons-Smith Reaction Claisen Rearrangement ? [3,3] via Reagent Ligation Heteroatom-directed Reactions ratio 90 : 10 Winstein JACS 91, 6892, (1969) Henbest J. Chem. Soc. 1958, (1957) SharplessJACS 95, 6136, (1973) VO(acac)2 ratio 98 : 2 ratio 92 : 8 Hydroxyl-directed Reactions Directed C–C Bond Constructions Directed Reductions HydrogenationHydride reduction EpoxidationHydroboration Directed Oxidations Agenda Directed Reactions favored disfavoredfavored product a73 Associative Substrate-Reagent Interactions Noncovalent Interaction favors the syn diastereoface Review: Hoveyda, Evans, Fu Chem. Reviews 1993, 93, 1307 a73 Steric control: Stereochemical Control Elements for all reactions a73 Steric & Electronic Factors a73 Stereoelectronic Considerations a73 Associative Substrate-Reagent Interactions favored product favored disfavored Nonbonding Interactions disfavor the syn diastereoface Chem 206D. A. Evans Directed Reactions: An Introduction OHR O O O R R R R a71 O O H O R ???? a71 a71 a71 Me Me OH H H C OH H Me HC Me H RCO3H Me Me OH X CH Me C OH HMe H C H C H R R R R R R Me Me Me O R OO H C CR R H H OH Me Me OAc OH H MeMe Me Me O OHR Chem 206D. A. Evans Directed Reactions: An Introduction Orientation of the Directing Group ? ~ 120 ° ~ 50 ° > 99 : 1 95 : 5 71 : 29 CH2I2, Zn–Cu Φ EstimateSelectivityReagent reagent t-BuO2H, V +5 X = O, CH2 Reag Reag ?maj ?min ? ? TSmajor TSminor The transition state bite angles for the above reactions are either not known or have been only crudely estimated. The "best guesses" are provided. Orientation of directing group is not the same for all reactons Peracid Epoxidation note labeled oxygen is transferfedLUMO σ*O–O a73 General Reaction: + + HOMO piC–C a73 Reaction rates are governed by olefin nucleophilicity. The rates of epoxidation of the indicated olefin relative to cyclohexene are provided below: a73 The indicated olefin in each of the diolefinic substrates may be oxidized selectively. 1.0 0.6 0.05 0.4 a73 The transition state: View from below olefin O-O bond energy: ~35 kcal/mol A. Rao in Comprehensive Organic Synthesis, Trost, Ed., 1992, Vol 7, Chapter 3.1 O R OO H O C H CH 2 O C HR R O H O R O C CC H2 H R H OR CF3 OO H O CH CH 2 OR C H R O O H O CF3 CH 2 OR C H C RH ???? R OO HO O O H O HCR CR H CH 2 O C CR R H CH 2 O H O H O CF3 OH OTBS OH Me3C Me3C OTBS O H OO Me3C OH OTBS Me3C a71 a71 1 : 7 5 : 1 12 : 11 : 8 1 : 4 1 : 6100 : 1 24 : 1 100 : 1 5 : 1 50 : 124 : 1 Syn : Anti (CF3CO3H)Syn : Anti(m-CPBA) Syn : Anti(m-CPBA) Syn : Anti (CF3CO3H) Ganem Tet. Let. 1985, 26, 4895 require more acidic peracid both allylic alcohols and ethers OK require allylic or homoallylic alcohol a73 Transition State Hydrogen Bonding: Peracid as H-bond donor (Ganem) ? ? a73 Transition State Hydrogen Bonding: Substrate as H-bond donor (Henbest) The Directed Peracid Epoxidation Chem 206D. A. Evans Diastereoselective Peracid Epoxidation a73 Per-arachidonic acid Epoxidation: Corey, JACS 101, 1586 (1979) Stereoelectronic Implications of intramolecular Peracid Epoxidation a71 a71 a71 a71 Conditions: Perbenzoic acid, or meta-chloroperbenzoic acidin benzene or cyclopentane. O PhHN O HN Ph O HO HO HN Me O O HN HO HO Me O O R O O RO O Me R R Me O AcO RO AcO O RO OH OHO Me Et Me HO OH OH HO O Et Me Me HO Me OHO Me O Me HO O Me HO Me HO Me HO AcO HOH2C OAcO HOH2C (Table 14, p1318, from the Evans, Hoveyda, Fu review article) SelectivityMajor ProductSubstrate 9 : 1 "highlyselective" 16 : 1 1 : 1 5 : 1 21 : 1 Epoxidation of Cyclic Homoallylic Alcohols (Table 11, p1316, from the Evans, Hoveyda, Fu review article) Conditions: Perbenzoic acid, or meta-chlorobenzoic acid in benzene. "highlyselective" "highlyselective" Substrate Major Product Selectivity 10 : 1 3 : 1 5 : 1 a. R = NH2 b. R = NHBn c. R = NMe2 >20 : 1 >20 : 1 a. R = OCONHBn b. R = OCONMe2 6 : 1a. R = CONH2 b. R = CONHBn c. R = CONMe2 >10 : 1 2 : 1 Epoxidation of Cyclic Olefins with Amide &Urethane Directing Groups Diastereoselective Peracid EpoxidationD. A. Evans Chem 206 43 2 1 Relative Rates (Diastereoselectivities) for the Epoxidation of Cyclohexene Derivatives JACS 1973, 95, 6136 OH O O MeOH Me Me OHO Mo(CO)6 TBHP OH ROOH O V OR O O RO O O V OR O-OtBu OHO V O O OORO tBu OHO OHMe Me Me OH OAc OH OH OH O Mo(CO)6 Mo(CO)6 t-BuOH RDS HO O tBu V RO O OO O OR V RO O OR O O V RO O HO R –ROH HO O OVORO OR a,b The relative rate data apply only to a given column. Values in parenthesis refer to the ratio of syn:anti epoxide. krela,b (diastereoselectivityc ) 10.0 (98 : 2)11.0 (98 : 2) --0.07 (40 : 60) >200 (98 : 2)4.5 (98 : 2) 1.001.00 0.42 (60 : 40) 0.046 (37 : 63) 0.55 (92 : 8) 1.00 Substrate VO(acac) 2peracid 80 °C Stereoselection 98:2 (90 % yield)TBHP a73 Next step: Sharpless, Michaelson JACS 1973, 95, 6136 Regioselection 20:1 80 °C TBHP VO(acac)2 a73 The literature precedent: Sheng, Zajecek, J. Org. Chem. 1970, 35, 1839 4 : 1VO(acac)2 80 oC 1 : 1Catalyst t-BuOOH slowChem 3D Transition State Aldrichimica Acta, 12, 63 (1979) O–C2–C3–C4 = 41°The Sharpless estimate: ~50° The Sharpless Epoxidation + Sharpless Epoxidation (V+5)D. A. Evans Chem 206 a71 a71 a71 a71a71 a71 a71 a71 a71 OHMe MeMe Me Me OH C Me H CH Me C Me H OH C HO H MeH H O Me Me OH Me OHMe MeO CH Me C Me H C Me H OH C HO H Me OHMe MeOMe O Me Me OH H H Me Me OH R1 R2 SiMe3 OH OEt OH O O EtO Me Me Me Me O EtO O OH OEt OH Me HO t-BuOOH t-BuOOH t-BuOOH H OH MeMe O C5H11 OH SiMe3 R2R1 O O NHCONHPh Ph MeMe Ph NHCONHPh O OEt OH O O EtO Me Me Me Me O EtO O OH OEt O Bu Me HO Me OH O OMe Me OH OR1 R2SiMe 3 OH Ph NHCONHPh O Me Reagent + 64 : 36t-BuOOH / (t-BuO)3Al 29 : 71 64 : 36 t-BuOOH / VO(acac)2 m-CPBA RatioReagent t-BuOOH / Mo(CO)6 62 : 38 a73 Allylic Alcohols: Epoxidation of Acyclic AlcoholsD. A. Evans Chem 206 ~ 120 ° 40-50 ° Φ Estimate 71 : 29 95 : 5 t-BuOOH / VO(acac)2 m-CPBA RatioReagent t-BuOOH / Mo(CO)6 84 : 16 erythrothreo Reagent + a73 RCO3H Transition States: Φ ~ 120 ° TSminorTSmajor a73 V(+) Transition States: Φ ~ 45 ° TSminorTSmajor K. B. Sharpless & CoworkersTetrahedron Lett. 1979, 20, 4733. K. Oshima & CoworkersTetrahedron Lett. 1980, 21, 1657, 4843. 100 : 0t-BuOOH / (t-BuO)3Al 86 : 14 95 : 5 t-BuOOH / VO(acac)2 m-CPBA RatioReagent t-BuOOH / Mo(CO)6 95 : 5 +Reagent threo erythro 70 % 84 % YieldR1 99 : 1 99 : 1 RatioR2 +VO(acac) 2 Oshima, Tetrahedron Lett. 1982, 23, 3387. Depezay, Tetrahedron Lett. 1978, 19, 2869. only isomerVO(acac)260 % 60 % t BuOOH VO(acac)2 only isomer Boeckman, JACS 1977, 99, 2805. Diastereoselection = 7 : 1 60 % VO(acac)2 Roush, J. Org. Chem. 1987, 52, 5127. m-CPBA CH2Cl2, 0 °C 75 % + Diastereoselection = 95 : 5 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 H ROMe H H VO Me O L H H H VO L O O Et H H RMe V OR 2 R H O Me O L H HR1 H R1 H H VO L O O Me H H RR 2 L' L' L' L' OH Me Me t-BuOOH MeMe OH O O HO MeMe O OH Me Me Me R2 R1 OH OH R1 R2 Me t-BuOOH t-BuOOH OH Me Me Hex R OH OH Me Me C5H11 OH Et Me O OH Et Me OO Me Et OHOH Et Me Me OH t-BuOOH t-BuOOH R1 Me Me R1 Me C6H13 C6H13 Me OH R1 R2 O O R2 R1 OH Me O Me Me OH C5H11 Me Me OH O OH Me O OH RHex O Me Me i-Pr Me C5H11 Me O R2 R1 OH OH R1 R2 O Me OH Me Me O C5H11 Epoxidation of Homoallylic Alcohols with TBHP, VO(acac)2 1.4 : 1 R = (CH2)7CO2Me 4.6 : 1 Substrate Product Selectivity 2 : 1 Syn diastereomer Anti diastereomer Syn diastereomerAnti diastereomer Anti should be more diastereoselective than syn Homoallylic Alcohols (Mihelich, JACS 1981, 103, 7690) Prediction Control Elements Directed Rxn Diastereoselection 12 : 1 VO(acac)2 + Directed Rxn A(1,3) Strain Control Elements +VO(acac) 290 % Diastereoselection > 400 : 1 R2 Ratio 104 : 1 > 400 : 1 Yield 92 % 97 % VO(acac)2 + +VO(acac) 2 70 % 73 % Yield 85 : 1 70 : 1 RatioR2 81 % 16 :1 VO(acac)2 + Diastereoselection = 211 : 1E. D. Mihelich & CoworkersJ. Am. Chem. Soc. 1981, 103, 7690. Epoxidation of Acyclic Homoallylic AlcoholsD. A. Evans Chem 206 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 HO O CO2H Me Me Me OH O Et O Me Et Me Et H H OH A Epoxidation & Cyclization of Bishomoallylic Alcohols A H Et Me Et Me OH OAr B Me CHMe2 Et OH OH Et CHMe2Me Me Me Me CHMe2 Et OH Me MeH O V H R Et O O R H MeH O V H R Et O O R O R V O Et O RMe H Me H OH Et CHMe2Me O O MeR Et OH Me O Me CHMe2 Et OH Me Me OH Et CHMe2Me O Me OH Et R Me O OH Et R Me O iPr R Et MeOH A EtAr Me OH Et Me N Et O OBn OH MeO Me Ph O B TBHP AcOH O O O O OHMe Me Me OH Me Me O Me OH OHOH O O Et OH Me H MeOH Me MeH O OH Me EtR iPr C TBHP D AcOH HOAc OXN Et O OBn OHMe Me OH OBn O EtXN O D F Et OH MeOiPr R Bishomoallylic Alcohols (Kishi, Tet. Lett. 1978, 19, 2741) Epoxidation of Acyclic Homoallylic AlcoholsD. A. Evans Chem 206 C6H6, RT t-BuOOH, VO(acac)2 diastereoselection ~ 9 : 1 C6H6, RT t-BuOOH, VO(acac)2 diastereoselection ~ 20 : 1 C6H6, RT t-BuOOH, VO(acac)2 diastereoselection ~ 6 : 1 2nd stereocenter is reinforcing Diastereoselection 8:1 VO(acac)2 Ar = p-MeOPh VO(acac)2 The Kishi Lasalocid Synthesis (JACS 1978, 100, 2933) E Evans X-206 Synthesis JACS 1988, 110, 2506. C6H6, RT diastereoselection 20 : 1(89 %) VO(acac)2 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71 a71