http://www.courses.fas.harvard.edu/~chem206/ Me Me HOOC Me I2, NaHCO3 NMe O OH NMe HM–H LiAlH4 R2AlH O O Me Me Me I NMe H OH Chem 206D. A. Evans Matthew D. Shair Monday,October 7, 2002 a73 Reading Assignment for week A. Carey & Sundberg: Part B; Chapter 4"Electrophilic Additions to C–C Multilple Bonds" Olefin Addition Reactions: Part–2 Chemistry 206 Advanced Organic Chemistry Lecture Number 9 Olefin Addition Reactions–2 K. Houk, Science. 1986, 231, 1108-1117Theory & Modeling of Stereoselective Organic Reactions (Handout) a73 Epoxidation & Directed Epoxidation a73 Hydrogenation a73 Hydride Reduction K. Houk, Tetrahedron. 1984, 40, 2257-2274Theoretical Studies of Stereoselective Hydroboration Reactions (Handout) Hoveyda, Evans, & Fu (1993). Substrate-directable chemical reactions. Chem. Rev. 93: 1307-70 (Handout) a73 Problems of the Day: (To be discussed) a73 Other Reading Material Takaya, H., T. Ohta, et al. (1993). Asymmetric Hydrogenation. Catalytic Asymmetric Synthesis. I. Ojima. New York, VCH: 1-39. Bolm, C. (1993). “Enantioselective transition metal-catalyzed hydrogenation for the asymmetric synthesis of amines.” Angew. Chem., Int. Ed. Engl. 32: 232. diastereoselection: 20:1 Predict the stereochemical outcome of the indicated reaction. Bartlett, P. A.; Richardson, D.; Myerson, J. Tetrahedron 1984, 12, 2317 Kinetic Control: 3 eq. I2, MeCN, NaHCO3, 0°C R. NoyoriBull. Chem. Soc. Japan 47, 2617, (1974) 28 : 7297 : 3 Rationalize the stereochemical outcome of the indicated reaction. For a recent general review of the Simmons-Smith reaction see:Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001) X R A B A B X A B R B A X B A A B C C H HH C C H HH A B A B A B OH OH R R OH MCPBA Et2Zn Cl CO3H t-BuOOH Et2Zn CH2I2 OH Me CH2I2 R O CH2 R O Zn CH2I R H 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 a71 O O H O R O O H O R ???? ?? a71 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 O R OO H C CR H H OAc OH H MeMe Me Me C CR H H 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 Transition state: What about lone pairs. [Consider a71 to be Sp2 hybridized]. O-O bond energy: ~35 kcal/mol A. Rao in Comprehensive Organic Synthesis, Trost, Ed., 1992, Vol 7, Chapter 3.1 HOMO piC–C LUMO: σ?O–O HOMO: O lone pair LUMO:pi? C–C 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 OMe O O CO2Et CH2OH O O OMe LiAlH4 C CHR HR C C H R H R H H EtOH H2 Pd-C EtOH H2 Pd-C C C H R H R M C C H R H R M HH CO2Et O O OMe H H OMe O O CH2OH C CHR HR C CHR HR M M H H H H N O HO H H H OH CH3 CHMe2 CHMe2 O CH3 H2 H2 H H N OH HO H H H H HO N OH H H CHMe2 H OH CH3 O CH3 CHMe2 Historically, primary stereochemical control designed around analysis ofsteric environment in vicinity of C=C. However, the influence of polar effects was documented only isomerH2, Pd-C however trans:cis = 55:45H2, Pd-C J. E. McMurry & Co-workers, Tetrahedron Lett.. 3731 (1970) Chem 206D. A. Evans Diastereoselective Hydrogenation: Introduction The Hydrogenation Reaction Relevant Review articles: J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987). trans : cis5 : 95Thompson, J.Org. Chem. 36, 2577 (1971) trans : cis85 : 15 Y. Kishi & Co-workers, J. Am. Chem. Soc. 102, 7156 (1980) 10% Pd-C 5% Pd-Al2O3 sole product 12 : 1 Steric Control Directed ? Polar functional groups may play a role in controlling the diastereoselectivityof the hydrogenation process; however, the control elements were not well-defined. + a73 General Mechanism M(0) +M(0) Pd(0) Pd(II) Rh S S Ph2P PPh2RhS S Ph2P PPh2 RhH S Ph2P PPh2 H RhH S Ph2P PPh2H 2C H CH2OK MeO O O RCH3O (Ph3P)3RhCl R CH2OH CHO CNCOONa COOH COOMe COMeCONH 2 MeO CH2O–Rh(PPh3)3 MeO CH2OH H CH3O R O O H H2 RhPh 2P PPh2 Rh PPh 2Ph2P SS (+S) CH3–CH3 CH2=CH2 H2 H2 (–S) Ir Py PCy3 RhH H SS Ph2P PPh2 Oxidative Addition Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts. 18-e-16-e–(CH2)n – BF4 Schrock & Osborne, J. Am. Chem. Soc. 91, 2816 (1969) (CH2)n R. Crabtree J. Organomet. Chem. 168, 183 (1979) – PF6 – BF4 Cationic Hydrogenation CatalystsThe first rational attempt to identify those FGs which will direct the reaction H. Thompson & Co-workers, J. Am. Chem. Soc. 95, 838 (1973) 10 H2, 5% Pd-C cis : trans 95 : 593 : 7 75 : 2555 : 45 18 : 8215 : 85 14 : 8610 : 90 The first rational attempt to associate catalyst with substrate: cis : trans>98 : 2 Thompson & Coworkers, J. Am. Chem. Soc. 97, 6232 (1974) H2 100 psi Rxn Catalytic in Rh (4 mol%) 50 °C, C6H6 Diastereoselective Hydrogenation: Introduction-2D. A. Evans Chem 206 S = solvent S = solvent Reductive Elimination Rh(+I): d8 Rh PPh2Ph2P SS + – BF4 CH2OH CH3 H2 CH3 OH CH3 CH2OH H2 CH2Cl2 CH3 OH OH CH3 H2 OH CH3 RhH H SS Ph2P PPh2 R2 H H2 C H RhP P OH H C OH H H Rh P P HBHA CH3 CHH RhP P H2 2H2 RhHA HB PP OH C HH R2 R2 O Rh P P HB R2HA H H H MeMe Me H MeH CO2H H Me H Me OH Me Me MeMe OH Me Me OH Me Me MeMe OH Me H HA H2 CHH OH CH2 R2 R2 CH3 OH Rh Ph2P PPh2 THF is important to success of rxn to buffer the Lewis acidity of the catalyst which causes elimination of ROH under normal conditions Chem 206D. A. Evans Diastereoaselective Hydrogenation: Cationic Catalysts – BF4 16-e- 18-e- Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts. + + + Which hydrogen migrates ?? A potential stereoelectronic effect + That H atom lying parallel to the pi-system (HA) should migrate preferentially if the dihydride is an intermediate. Rh(DIPHOS-4)+ 200 : 1 (89%) 300 : 1 (95%) 50 : 1 (82%) 150 : 1 (85%) Catalyst H2 Pressure trans:cis (Yield) 15 psi H2 375 psi H2 15 psi H2 15 psi H2 Mol% Catalyst 17.5 3.5 20.0 2.5 Ir(pyr)PCy3 19 : 1 Rh + 65 : 1 } Rh(DIPHOS-4)+ H2 1000 psi CH2Cl2 D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984) Retigeranic Acid Excessive Steric Hindrance Rh + 75 : 1 (95%) Rh(DIPHOS-4)+ H2 800 psi THF Rh + +2 S O N Me CO2Me CH3 CO2Me H2C CO2Me CH3 CO2Me CH3 Me NO H CH3 O XCH 3 Me O X OCH3 CH3 N N MeH H O H OH NH O H O H HMe N CH2OMe N CH3 O CH3CH3 O N CH3 CH2OMe CH3 CONC4H8 CH3X O CH3 X O Me CH3 OCH3 CONC4H8 CH3 X X OMe NC4H8 OMe NC4H8 Chem 206D. A. Evans Diastereoaselective Hydrogenation: Cyclic Substrates Polar functional groups other than OH may also direct the process A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907. J.M. Brown and S.A. Hall, J. Organomet. Chem., 1985, 285, 333. Ir(pyr)Pcy3+ H2 diastereoselection 91 : 9 H2 Ir(pyr)Pcy3+ Rh(DIPHOS-4)+ H2 diastereoselection 89:11 diastereoselection >99:1 Ir(pyr)Pcy3+ H2 diastereoselection >99:1 H2 Ir(pyr)Pcy3+ Diastereoselection 55:45 99:1 Ir(pyr)Pcy3+ H2 99:1 >99:1 Diastereoselection H2 Ir(pyr)Pcy3+ diastereoselection >99:1 A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907. 15 psi H2 Ir(pyr)Pcy3+ R.H. Crabtree and M.W. Davis, J. Org. Chem., 1986, 51, 2655. 15 psi H2 Ir(pyr)Pcy3+ diastereoselection >99:1 diastereoselection >99:1 A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907. R1R2 CH2 OH Rh P P RhP P Rh P P OH CH3 R2 R1 RhP P C H R2 C H H CH H CR2 H Rh P P C OH R1 H Rh P P RhP P OH C HR1 P Rh P OH C H R1 C OH R1H CH3 CH2R2 CH3 CH2R2 H2 H2 H2 H2 R 1R2 CH3 OH R1R2 CH3 OH OH CH3 R2 R1 OH CH3 R2 R1 R1R2 CH2 OH OH CH3 R2 R1 T D T D O Ph CH3 N O O CH3 OH CH3 R R N CH2 OH CH3 O O CH3 Ph O Rh P P RhP P C H H CR2H C OH R1 H Rh P P RhP P OH C HR1 CH3 CH2R2 H2 H2 R COXn CH3 OH CH3 COXn CH3 CH3 OH R R1R2 CH3 OH OH CH3 R2 R1 640 psi H2 H2 Rh(DIPHOS-4)+ 25 : 75 (23%) 52 : 48 (35%) 71 : 29 (-) 13 : 87 (6%) 12 : 88 (8%) 21 : 79 (-) 93 : 7 94 : 6 93 : 7 9 : 91 8 : 92 6 : 94 Anti : Syn Ratio Hydroxy-Olefin R = CH3 R = (CH3)2CH R = Ph R = CH3 R = (CH3)2CH R = Ph 15 psi H2 + + low pressure syn anti H2 Rh(DIPHOS-4)+ + + anti > 93 : 7 syn > 91 : 9 D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984) syn anti Acyclic Allylic Alcohols + + + + favored + disfavored disfavored favored + + + syn anti Diastereoaselective Hydrogenation: Acyclic SubstratesD. A. Evans Chem 206 OH CH3 R CH3 RhP P Rh P P B A HO CH3 CH3 OTBS HO OTBS CH3CH3 CCH 3 R CR CH3 O H RhP P CH2 C HCH3 C CH2 CH3 O H Rh H P P H H H2 H2 CH3 CH3 OTBSHO HO OTBS CH3CH3 CH3 R CH3 OH OH CH3 R CH3 Me HO Me Me EtO2C OHCH3O2C CH3 CH3 CH3 CH3 H2 Me EtO2C Me HO Me CHO Me HO Me O OH Me O Me O Me Me Me Et MeOH HOOC O O Me OH OHOH CH3CH3CH3 CH3CH3 CH3 CH3 CH3 CH3HHO O H2 A A B CH3 CH3 CH3CH3 CH3O2C OH Evans, DiMare, JACS, 1986, 108, 2476) } a54 a54 a54 with Dow, Shih, Zahler, Takacs, JACS 1990, 112, 5290 Rh(DIPHOS-4)+ Diastereoselection: 94 : 6 (93%) The Ionomycin Synthesis The Premonensin Synthesis Rh + RatioCatalyst 98 : 2 (90%) 65 : 35 85 : 15 Rh(+)(BINAP) + Rh(–)(BINAP) + Rh(DIPHOS-4) + anti syn Catalyst (H2 Pressure) syn : anti Rh(DIPHOS-4)+ (1000 psi) Ir(pyr)PCy3+ (15 psi, 2.5 mol%) Rh(DIPHOS-4)+ (1000 psi) 95 : 5 73 : 27 9 : 91 Olefin A(1,3) destabilization + + + + Homoallylic Alcohols Evans, Morrissey Tetrahedron Lett. 26 6005 (1985) syn anti Diastereoaselective Hydrogenation: Acyclic SubstratesD. A. Evans Chem 206 favored disfavored