Chemistry 206 Advanced Organic Chemistry Handout–19A Enantioselective Carbonyl Addition Handout Matthew D. Shair Friday, November 1, 2002 a73 Enantioselective addition of R2Zn to aldehydes a73 Enantioselective Reduction of Ketones & Imines 00 00 0000 0000 0000 Review: Noyori Angew. Chem. Int. Ed. 1991 , 30 , 49 the catalyst a73 Two zinc species per aldehyde are involved in the alkylation step. a73 Product is taken out of the picture by aggregation 4 a73 The method is catalytic in aminoalcohol. Enantioselective C=O Addition: Noyori Catalyst D. A. Evans Chem 115 Noyori & co-workers, J. Am. Chem. Soc . 1986 , 108, 6072. replace with chiral controller Catalytic Asymmetric Carbonyl Addition a73 Catalyst must be sterically hindered so that association is precluded 98% e.e. 91% e.e. 93% e.e. 93% e.e. 96% e.e. 90% e.e. 61% e.e. Et 2 Zn Me 2 Zn Et 2 Zn Et 2 Zn Et 2 Zn Et 2 Zn Et 2 Zn C 6 H 5 CHO " p-ClC 6 H 4 CHO p-MeOC 6 H 4 CHO Cinnamyl PhCH 2 CH 2 CHO n-C 6 H 13 CHO 0°C, toluene 59 - 97% Ar–CHO + R 2 ’Zn J. Am. Chem. Soc . 1989 , 111, 4028. the catalyst the catalyst Et 2 Zn 90-98% ee RDS The Catalytic Cycle (DAIB-Zn) Zn R Zn I I CO R R H Me Me N H Me Me MeZn O H Et Me Me N H Me Ar R’ OH Me MeZn O H Et O C H Zn Et Et Zn Et C Et O H O Zn Et H H N Me Me Me Me Me O C H Et H O Zn Et H H O N Me Me Me Me Me Me Me N H Me Me MeZn O H Et Zn– E t O C H O R' Zn O Zn Zn O Zn O R R R R'O Z nR R' Zn R R' R' R O R' O R' Zn R OZ n Zn O R R' R' R Zn Et H H O N Me Me Me Me Me 19A-01-Et2Zn-1 1/19/00 1:49 PM Other Catalysts for the R 2 Zn Addition Process Chem 115 D. A. Evans Enantioselective C=O Addition: Noyori Catalyst-2 a73 Non-linear effects observed with the Noyori Catalyst (DAIB-Zn) Product (%ee) 100 %ee of catalyst 100 25% ee Catalyst affords product in 95% ee. There is no correlation between catalyst and product ee. Et 2 Zn + PhCHO (S,S) dimer (R,R) dimer + (S) catalyst (R) catalyst (S) catalyst 90% e.e. (R) 90% e.e. (R) 90% e.e. (R) (Results are cited for the reaction of benzaldehyde and Et 2 Zn) 95% e.e. (S) 100% e.e. (R) 97% e.e. (S) Problem: Rationalize the stereochemical course of each of the catalysts Explanation for Nonlinearity of DAIB Catalyst (S,R) dimer Observations a73 (S,S) dimer dissociates upon addition of RCHO & effects catalysis a73 (S,R) dimer is overwhelmingly more stable than (S,S) homodimer a73 (S,R) dimer is ineffective as a catalyst Ph Me OH O Zn Me 2 N Me Zn Me Me 2 NO Zn Me Me 2 NO O Zn NMe 2 Me Zn O O Zn Me NMe 2 Me 2 N Me Zn O O Zn Me NMe 2 N Zn O Me Ph Ph Et Zn Et Ph H N O Me 3 C Me 2 N Me Li O N Me Me N Me H H Ph H Ph NO N Li N Me Me Me Me N Zn N Bu Me O Et LiLi Bu Ph 19A-02-Et2Zn-1 1/19/00 1:49 PM 93% ee 95% ee 78% ee 88% ee Improved Selectivity with Aliphatic Aldehydes Soai, J. Org. Chem. 1991 , 56 , 4264 (6%) RCHO + Et 2 Zn 0 ° C, hexane 70 - 100% 60% ee Et 2 Zn (S) catalyst Review: Noyori Angew. Chem. Int. Ed. 1991 , 30 , 49 (S) catalyst Et 2 Zn 90% ee (S) catalyst (n-Pen) 2 Zn 85% ee 96% ee Et 2 Zn (S) catalyst (S) catalyst Me 2 Zn 91% ee 98% ee Et 2 Zn (S) catalyst Scope of the DAIB Catalyst (S) catalyst Enantioselective C=O Addition: Dialkylzinc Addn Scope D. A. Evans Chem 115 Lepicidin Application: The reaction functions in complex systems 3 9 Et 2 Zn, 3 3 15 15 11 diastereoselection 10:1 (98%) 21 the catalyst 21 21 0 ° C, hexane Evans, Black, JACS 1993 , 115 , 44974513 H O OH Et Me OH O Zn Me 2 N Me Ph NO Bu Zn Et Me Bu RE t OH O O H n-Bu H OO H Me H O Me OR OR O O Me Et H H H H H MeO OTIPS OTES O O HH O OH H Bu 3 Sn Me H O Et OH MeO SnBu 3 OTIPS OTES O Me C 5 H 11 OH O H H OH O Bu 3 Sn H n-Bu SnBu 3 HH Zn H O OH H N Bu Me O Et Bu n-Bu Ph 19A-03-Et2Zn-Scope 1/19/00 1:49 PM MgX 2 – dioxane complex MgX 2 + dioxane R 2 – Zn + MgX 2 + MgCl 2 2 R – MgX + ZnCl 2 Chem 115 D. A. Evans Enantioselective C=O Addition: Dialkylzinc Addn Scope Ohno, Tet. Lett . 1989 , 30 , 7095 RCHO + Et 2 Zn Ti(O- i -Pr) 4 toluene-hexane 78 - 95% a73 Knochel has described preparation of functionalized R 2 Zn reagents Knochel, J. Org. Chem. 1992 , 57 , 1956 Other Catalysts for Aliphatic Aldehydes -20 ° C -50 ° C 0 ° C -20 ° C 0.04 equiv0.02 equiv0.01 equiv0.04 equiv 98% ee99% ee92% ee99% ee 1.2 equiv. 0.3 equiv0.6 equiv0.6 equiv PhCHO PhCH=CHCHO PhCH 2 CH 2 CHO n-C 5 H 11 CHO Ti(OR) 4 Temp ligand aldehyde ee R – I + Et 2 Zn 3-5 equiv Et – I + R – Zn – Et distill R 2 Zn – Et 2 Zn + Et – I 2 X = Cl, OAc 2 Ohno catalystPhCHO 92% ee (90% yield) Reagent 2 is a more effective catalyst for the addition of Et 2 Zn to aldehydes MeMgI n-BuMgBr CH 2 =CH(CH 2 ) 2 MgBr MeMgBr n-BuMgBr MeMgI n-PrMgBr PhCHOPhCHOPhCHO i-PrCHO C 6 H 11 CHO CH 2 =CH(CH 2 ) 3 CHO Ph(CH 2 ) 2 CHO 55%82%83%40%35%69%60% 94%96%90% ≥ 90%90%95% ≥ 90% R 1 -CH 2 MgX (2 equiv.) 1) ZnCl 2 , Et 2 O, 23 ° C 2) dioxane; filter3) 0.15 eq. 1 , -78 ° C 4) 1.2 eq. Ti(OiPr) 4 5) R 2 CHO to -30 ° C (R,R)- 2 (R,R,R,R)- 1 Utilization of Grignard and Alkenyllithium Reagents Seebach, Angew. Chem. Int. Ed. 1991 , 30 , 1008, and 1321 Grignard RCHO % Yield % ee X Zn O t-BuO Zn t-BuO O Ph OH O Ti O OO O Me O Ph Me Ph Ph Ph OO Me Ph Me Ph Ph Ph OH Et R NHSO 2 CF 3 NHSO 2 CF 3 O Ti O OO O – CHMe 2 Me Ph Me Ph Ph Ph O – CHMe 2 R 2 OH R 1 19A-04-Et2Zn-Scope-2 1/19/00 1:49 PM Pb: S. Torii, Chem. Lett . 1986 , 1461-1462. Mo: J. Faller, Tetrahedron Lett . 1991 , 32 , 1271-1274. Cr: Y. Kishi, Tetrahedron Lett . 1982 , 23 , 2343-2346. P. Knochel, J. Org. Chem . 1992 , 57 , 6384-6386. Sb: Y. Butsugan, Tetrahedron Lett . 1987 , 28 , 3707-3708. Mn: T. Hiyama, Organometallics , 1982 , 1 , 1249-1251. Zn: T. Shono, Chem. Lett . 1990 , 449-452. Ba: H. Yamamoto, J. Am. Chem. Soc . 1991 , 113 , 8955-8956. a73 Many Other Metals Have Been Employed in the Allylation Reaction ... Allyl and Crotyl Metal Species-4: Catalytic Systems D. A. Evans, D. M. Barnes Chem 115 a73 Three Catalytic Asymmetric Allylations of Aldehydes are Known + BH 3 -THF BL n * E/Z = 61/39 + PhCHO 20 mol % BL n * H. Yamamoto, Synlett 1991 , 561-562. n-C 7 H 15 CHO + 81% yield97.4% ee 63% yield 90% ee E. Tagliavini, A. Umani-Ronchi J. Am. Chem. Soc . 1993 , 115 , 7001-7002. G. Keck J. Am. Chem. Soc . 1993 , 115 , 8467-8468. 20 mol % Ti(OiPr) 4 , 4 ? sieves Ti(OiPr) 4 , 4 ? sieves CF 3 COOH or TfOH 1 2 1 or 2 (10 mol %), RCHO R Ph Chex Catalyst 121212 Yield (%) 889866954278 ee (%) 959294928977 COOH iPrO OiPr O OH COOH Me SiMe 3 Me Ph Me OH Me OO Ti ClCl SnBu 3 n-C 7 H 15 OH H O SnBu 3 R OH OHOH OO Ti OiPrOiPr OHOH OO Ti OO 19A-04a - Allyl/Crotyl 4 1/19/00 1:49 PM 00 00 000 000 Brown's Model Chem 115 D. A. Evans Enantioselective C=O Addition: Ketone Reduction (R)-Alpine Borane Li + (S)-BINAL-H Enantioselective Reducing Agents Darvon alcohol, LiAlH 4 [LiAl(lig) 2 H] N-Methylephedrine, LiAlH 4 , (3,5-xylenol) 2 [LiAl( lig) (OAr) 2 H] - Reviews: Midland, Asymmetric Synthesis , Vol 2 , p 45- Granbois, Asymmetric Synthesis , Vol 2 , p 71- Brown, Accts. Chem. Res. 1992 , 25, 16-24 Singh, Synthesis 1992 , 605-617 78% e.e. R=Me90% e.e. R=CO 2 Me 95 - 100% e.e.(71% ee, R=i-Pr)15 - 75% e.e. ---- 59 - 89% e.e.>95% e.e.25% e.e.78 - 98% e.e.(cyclic ketones) 72 - 92% e.e.84 - 96% e.e.(57% ee, R=i-Pr)34 - 90% e.e.75 - 90% e.e. Alpine-BoraneBINAL-HDarvon-LiAlH 4 N-Methylephedrine- LiAlH 4 Reagent Reductions of Representative Carbonyl Compounds THF 50 - 90% Less hindered aliphatic ketones are not reduced with useful levels of enantioselectivity 2 Brown, J. Org. Chem. 1985 , 50 , 5446 98%98%79%95%91% -25 ° C -25 ° C -25 ° C 25 ° C, 12 days 25 ° C, 2 days acetophenone butyrophenone 2,2-dimethylpropiophenone 3,3-dimethyl-2-butanone 2,2-dimethylcyclohexanone Ketone Reaction Conditions % ee Brown, J. Org. Chem. 1986 , 51 , 3394 Brown, J. Org. Chem. 1988 , 53 , 2916 Stoichiometric Chloroborane Reducing Agents Small ligand (R s ) Large ligand (R L ) Favored TS Me B OO Al HOEt B n Ph Ph Me Me 2 NO H NMe 2 OH Me O R R O R O Me BC l R L R S O OH R S R L X B Me Me Me H H O R L R S Y 19A-05-Asym Redn-1 1/19/00 1:48 PM LiBH 4 EtOH ( 1 : 3 : 1.3 ) -78 ° C, THF 73% 84% e.e . 83% e.e. (R) * 72% * t-BuOH replacing EtOH Soai, Chem. Commun . 1987 , 801; Chem. Commun . 1986 , 1018 Brown, J. Am. Chem. Soc. 1988 , 110 , 1539 Brown, J. Org. Chem. 1988 , 53 , 1231 Brown, J. Org. Chem. 1986 , 51 , 1934 Miscellaneous Chiral Borohydride Reagents 86 - 98% e.e. R = alkyl, aryl THF, -78 ° C 75 - 85% 97% e.e.87% e.e.92% e.e. R = t-Bu = i-Pr = Et THF, -78 ° C 90 - 95% K + - Brown, Tetrahedron Let. 1991 , 32 , 6691 Ketone Rxn time (THF, -25 ° C) % Conv. % ee Brown, J. Org. Chem. 1989 , 54 , 4504 % ee % Conv. Rxn time (THF, 23 ° C) Ketone acetophenone 3-methyl-2-butanone cyclohexyl methyl ketone 2,2-dimethylcyclopentanone trans-4-phenyl-3-buten-2-one 2-cyclohexenone 4-phenyl-3-butyn-2-one 24 h 2 d3 d 24 h 14d 7 d5 h 80%65%65%80%60%60%82% >99% 95%97% >99% 82%74%33% 2 Improved Enantioselectivity with Alphatic Ketones 72%88%86%76%72%79% 50% 100% 60%30%40%50% 7 days2 days4 days 14 days 4 days4 days acetophenone 3-methyl-2-butanone cyclohexyl methyl ketone cyclohexyl ethyl ketone cyclopentyl methyl ketone cyclohexenone Enantioselective C=O Addition: Ketone Reduction-2 D. A. Evans Chem 115 BC l B O Cl tBu Bzl B O H O O O OO S Ph R O R Ph OH OEt R O O O OH R OEt S PhCOHN NHCOPh CO 2 H CO 2 H H H N Me O OH Me N Cl O OH Cl 19A-06-Asym Redn-2 1/19/00 1:48 PM (Review) Martens, Tertrahedron Asymmetry 1992 , 3 , 1475 97 % ee 97 % ee91 % ee But how does it really work ? R = Ph, R = t-Bu, R = c-C 6 H 11 BH 3 – + BH 3 R = HR = Me a73 The Catalytic Process: Corey, 1987 Itsuno, J. Chem. Soc. Perkin Trans I . 1985 , 2615 Itsuno, J. Org. Chem. 1984 , 49, 555 Itsuno, Chem. Commun . 1983 , 469 a73 The Stoichiometric Process: Itsuno, 1983-1985 ( H – BX C ) 2 equiv BH 3 30 ° C, 10 hr Chiral Boron Hydride ( H – BX C ) R = Me, 94 % eeR = Et, 94 % eeR = n-Bu 100 % ee Chem 115 D. A. Evans Enantioselective C=O Addition: Corey-Itsuno Catalyst Discovery of a Catalytic Process (0.1 equiv) B B BH 3 – + + – + – The Catalytic Cycle + – + Corey, JOC 1988 , 53 , 2861 Corey, JACS 1987 , 109 , 5551 Corey, JACS 1987 , 109 , 7925 Improved version Catalyst X-ray, Corey, Tet. Let 1992 , 33 , 3429 Mathre, JOC 1993 , 58 , 2880 catalyst prep: Mathre, JOC 1993 , 58 , 799 Mathre, JOC 1991 , 56 , 751 O H 2 B C RL H RS OBH 2 O H 2 B H N CRL RS N B X Y X O B N O B O Y C RS X RL H 2 N Ph Ph OH Me 2 HC R O Ph Ph OH H R H H N NO Ph Ph BR BR O Ph Ph H 3 B Me O R H R OH Me O Y X O B N Y C RS RL H BH 3 N B O Ph B O Me Ph H H H X Ph B Me O N Ph Ph H Recent Review: Corey, E. J. and C. J. Helal (1998). “ Reduction of carbonyl compounds with chiral oxazaborolidine catalysts: A new paradigm for enantioselective catalysis and a powerful new synthetic method. ” Angew. Chem., Int. Ed. Engl. 37 (15): 1987-2012. 19A-07-Corey Cat 11/1/00 8:03 AM Chem 115 D. A. Evans Enantioselective C=O Addition: Catalyst Scope Representative Reductions 90 : 10 91 : 9 (R)-cat, as above (S) cat (0.1 equiv) BH 3 (0.6 equiv) THF 23 ° C, 2 min The catalyst Corey, JACS 1987 , 109 , 7925 (S) cat BH 3 86% ee 91% ee BH 3 (S) cat 91% ee BH 3 (S) cat (R) cat (0.2 equiv) 1.5 equiv 92% ee Tet. Let 1992 , 33 , 2319 Fluoxetine (Prozac?) Synthesis BH 3 94% ee (>99%) 0.1 equiv Na – I MeNH 2 NaH Prozac? An α -Amino Acid Synthesis Tet. Let 1989 , 30 , 5207 0.1 equiv R ee n-C 5 H 11 95%92% c-C 6 H 11 t-C 4 H 9 98% HO – N 3 – rm temp Corey, JACS 1992 , 114 , 1906 Tet. Let 1992 , 33 , 3435 Tet. Let 1992 , 33 , 3431 MeMe O Me Me Me Me Me Me Me Me Me N B O Ph Ph H Me O O n-C 5 H 11 O ArCOO ArCOO OH n-C 5 H 11 O O Me Me Me HO Me Me O BH O F F Cl O N O O n-C 5 H 11 OH ArCOO OO H Br OH O Br Me OH O Me B O Ph Ph H Me OH Cl NHMe OH O NHMe CF 3 CF 3 Cl CCl 3 R O OH R CCl 3 B n-Bu H Ph Ph N O O BH O CCl 3 R OH N 3 R COOH 19A-08-Corey Cat 1/19/00 1:48 PM with S. Kaldor, J. Am. Chem. Soc. , 1990 , 112 , 7001 98% 98.5 : 1.5 SmI 2 /i-PrOH 40% 60 : 40 Na/NH 3 0% 0 : 100 LiAlH 4 Yld Eq ROH Eq : Ax ROH Hydride Kagan, Nouv. J. Chim. 1986 , 10 , 229-232. 25 ° C, 30 min. SmI 2 0.1 equiv Me 2 CHOH A Kagan, Tet. Lett , 1991 , 32 , 2355 Kagan, J. Org. Chem , 1984 , 48 , 2045 10 % SmI 2 25 ° C Kagan 1984 10 % t -BuO-SmI 2 65 ° C Woodward: 1945 W. von E. Doering: 1950 The Oppenauer Oxidation Al(O-iPr) 3 80 ° C 80 ° C Al(O-iPr) 3 The Meerwein-Ponndorf-Verley Reduction Exercise: Work out a rational methanism which explains the stereochemical outcome. Assume that the resting state of the the catalyst is in the +1 oxidation state. 70% ee (94% yield) 27% ee (60% yield) 95% ee (91% yield) 93% (90% yield) -5 ° C, 5h 4 % AgBF 4 1.0 mol% BF 3 ? OEt 2 1.7 mol% 3.5 % 0 ° C, 14h 82% no rxn rm temp 1.7 % ee, % conditions catalyst none Additve H 3 O + additive 1 , Ph 2 SiH a73 Representative Reductions a73 The Reaction: The Catalyst ( 1 ) RhCl 3 The Ligand Nishiyama, J. Org. Chem , 1992 , 57 , 4306 Nishiyama, Organometallics , 1991 , 10 , 508 Nishiyama, Organometallics , 1989 , 8 , 846 Chem 115 D. A. Evans Enantioselective C=O Addition: Other Methods Enantioselective Hydrosilylation N O NN O Me 2 HC CHMe 2 CHMe 2 Me 2 HC O N N O NRhCl Cl Cl Me Ph O O SiR 3 Ph Me Me Ph OH Me OEt O OH O OH OEt Me OH Me Me Me R 1 R 2 OO H R 2 R 1 Me Me OH O Me Me R 1 R 2 OH O R 2 R 1 R 1 R 2 OH O R 2 R 1 OH H Me H Me DEIPSO PMBO H H O Et O H O O Et H H PMBO DEIPSO Me H Me H O 19A-09-Other Methods-1 1/19/00 1:48 PM 0 20 40 60 80 100 0.75 %ee 0.80 0.85 0.90 0.95 1.00 1.05 Sc Ionic Radius (?) for MI 3 MI 3 Source (<5% conv.) Lu La (40 %conv.) (57% conv.) Y Tb Sm Nd with Nelson, Muci, Gagne, JACS in Press a73 Yttrium (Y) a73 Terbium (Tb) a73 Neodymium (Nd) Other candidates Are other lanthanide reagents effective catalysts? a73 Representative Reductions 96 % ee R = H > 98 % ee 95 % ee 70 % ee 96 % ee R = Cl93 % ee R = OMe + 2 Bn-NH 2 a73 Catalyst Preparation: SmI 3 THF > 90 % ee 64 % ee 24 % ee 23 % ee 0 % ee 25 ° C 10 % SmI 3 ? a73 The Test Reaction: 10-20 equiv i-propanol a73 Tridentate Ligands: a73 Bidentate Ligands: An Enantioselective Meerwein-Ponndorf-Verley Variant Chem 115 D. A. Evans Enantioselective C=O Addition: Other Methods N O N O O Me N O R R R O N O N R Me R'N R Me R OLi O Li Cl Cl Me OH OOO OLiOLi MeMeMeMe OLiOLi OLi OLi Ph N Ph Bn BnN Ph Ph OO Sm Ph O I Me O R O Me O Me O Me 19A-10-Other Methods-2 1/19/00 1:48 PM Catalyst-Substrate Stereoinduction (Buchwald) Ti Ti Ti PhSiH 3 imine, H 2 (2000 psi) 81% 98% e.e. Buchwald, J. Am. Chem. Soc . 1992 , 114 , 7562 93% 76% e.e. 81-93% 77-85% e.e. 77% 98% e.e. Ti X 2 = 1,1'-binaphth-2,2'-diolate 2 n-BuLi, THF 2-10 mol % Asymmetric Hydrogenation of Imines The stereochemistry of reduction of oxime ethers depends on the geometry of the oxime C=N double bond BH 3 (2 equiv) THF, 23 ° C 64% 92% e.e. (S)92% e.e. (R) " 58%" 40% 86% e.e. (S)81% e.e. (R) " 46% Sakito, Tet. Lett . 1988 , 29 , 223; see also Didler, Tetrahedron 1991 , 47 , 4941 Itsuno, J. Chem. Soc. Perkin Trans I . 1985 , 2039 % ee BH 3 (equiv) 1 (equiv) 95%90%52% 411 1.0 0.250.10 1 , BH 3 , THF, 23 ° C (1) BH 3 Enantioselective C=N Addition: D. A. Evans Chem 115 H 2 N Ph OH Ph Ph Me Ph Me NH 2 OMe N N OMe Me Me NH 2 Ph Me OH NH 2 NH 2 Me OMe N Me Me Me N MeO Ph Ph NH 2 N Ph Me MeO NH 2 Ph Me X X R' R NHR" NN H Me NH – Bn Me N – Bn NH – Bn Me N – Bn Me NH n-C 5 H 11 n-C 5 H 11 N H H H N R N R 19A-11-Asym C=N Red-1 1/19/00 1:48 PM