http://www.courses.fas.harvard.edu/~chem206/ R1Me Me OOH R2CHO H O Ph OH N Ph Ph N B O PhPh R H Me O (R) Et2Zn, 0 °Ctoluene 1 equiv BH3?THF R1Me Me OHOR2 O Me OH Et OH (R) (S) Chem 206D. A. Evans Matthew D. Shair Wednesday, November 6, 2002 a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8Reactions of Carbonyl Compounds Diastereoselective & Enantioselective Carbonyl Addition Chemistry 206 Advanced Organic Chemistry Lecture Number 21 Enantioselective Carbonyl Addition a73 Enantioselective addition of R2Zn to aldehydes a73 Enantioselective Reduction of Ketones & Imines Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5Reduction of Carbonyl & Other Functional Groups Carbonyl Addn: Felkin Control: Evans, JACS 1996, 118, 4322 (handout) Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP (handout) Enantioselective Carbonyl Reduction: Corey Angew. Chem. Int Ed. 1998, 37, 1986-2012 (handout) Enantioselective Carbonyl Addition (R2Zn): Noyori Angew. Chem. Int Ed. 1991, 30, 49-69 (handout) a73 Problems: 15% SmX3 catalyst diastereoselection > 100:1 Propose a mechanism for tihs highly diastereoselective transformation, Evans, Hoveyda JACS 112, 6447 (1990) Cume Question, 2000: Chiral amino alcohol 1 efficiently mediates the addition of diethylzinc to aromatic aldehydes. While a number of other amino alcohols are also effective in controlling the absolute course of the addition process, this amino alcohol has been the focus of a recent computational investigation that addresses the preferred transition state geometry for this addition process (Pericas, et al. J. Org. Chem. 2000, 65, 7303 and references cited therein). It should be noted that, while 1 is not the actual catalyst, it is modified under the reaction conditions to the competent catalytic agent. Provide a detailed mechanism for the overall transformation. Use 3-dimensional representations to illustrate the absolute stereochemical aspects of the indicated transformation. 1 0.06 equiv 1 97% ee 1, (R = H or Me) 0.1 equiv 1 Cume Question, 2000: Corey's introduction of chiral oxazaborolidine catalysts 1 in the borane-mediated enantioselective reduction of ketones represents an important advance in asymmetric synthesis (Corey & Helal, Angew. Chem. Int. Ed. 1998, 37, 1986-2012). Provide a detailed mechanism for the overall transformation. Use 3-dimensional representations to illustrate the absolute stereochemical aspects of the indicated transformation. 97% ee H H C HCHH Nu C HR Nu CHO H Nu C Nu OHH R L R L R M R M H C OH R L R M R L O R M H H H CH O C HO R L R L R M R M H C HO R L R M C Nu C RL H H RL RL H H Chem 206The Felkin-Anh Eisenstein ModelD. A. Evans wrong prediction destabilizinginteraction predicted to be favored TS Nu:Nu: The flaw in the Felkin model: A problem with aldehydes!! Anh & Eisenstein Noveau J. Chim. 1977, 1, 61-70 Anh Topics in Current Chemistry. 1980, No 88, 146-162 anti-Felkin Nu: Nu: Nu: Felkin ? ? Nu: favored disfavored a73 The antiperiplanar effect: Hyperconjugative interactions between C-RL which will lower pi*C=O will stablize the transition state. a73 Dunitz-Bürgi C=O–Nu orientation applied to Felkin model. New Additions to Felkin Model: Theoretical Support for Staggered Transition states Houk, JACS 1982, 104, 7162-6 Houk, Science 1986, 231, 1108-17 Review Lecture-7 Houk: "Torsional effects in transition states are more important than in ground states" σC-Nu σ?C-RLTransition state σC-Nu σ?C-RLGround state Transition states H-radical and H-anion: antiperiplanar σ?C–R orbital stabilized the TS illustrated for Nu addition Houk, Science 1981, 231, 1108-1117"The Theory and Modeling of Stereoselective Organic Reactions" σC-Nu σ?C-RL σC-Nu homo σ?C-RL lumo Forming bond Forming bond Nu OH H Me H H MeMe H H Me H O H Cram R L H R M O H Me OR O Me H R OLi OLi OMeMe Me H H CH O C HO R L R L R M R M R OOH Me R Me OH O OMe Me Me OH R M NuR L R L Nu R M OH H Me O R1 O Me H BF3-Et2O R2 OSiMe2tBu R Me OH R2 OOH Me R1 ClMg C CEt Li >90 : 10(R–MgX gives Ca 3:1 ratios) R–Ti (OiProp)3 R = n-Bu R-Titanium Ratio >90 : 10R = Me M. Reetz & Co-workers, Angew Chemie Int. Ed.. 1982, 21, 135. C. Djerassi & Co-workers, J. Org, Chem. 1979, 44, 3374. 1 : 1 Reagent Ratio 5 : 1 3 : 1 4 : 1 Ratio Li enolate R = Ph 24 : 1 C. Heathcock & L. Flippin J. Am. Chem. Soc. 1983, 105, 1667. Ketone (R1) Ratio 10 : 1R = Ph R = Me Enolate (R2) R = t-Bu -78 °C R = OMe 15 : 1R = Ph R = Ph 36 : 1R = Ot-Bu R = Ot-Bu 16 : 1R = c-C6H11 a73 This trend carries over to organometallic reagents as well Lewis acid catalyzed rxns are more diastereoselectiveTrend-2: Trend-1: For Li enolates, increased steric hindrance at enolate carbon results in enhanced selectivity L. Flippin & Co-workers, Tetrahedron Lett.. 1985, 26, 973. R = Ph + Anti-Felkin Isomer >200 : 1 RatioKetone (R)L. Flippin & Co-workers, Tetrahedron Lett.. 1985, 26, 973. 9 : 1R = c-C6H11 R = OtBu 4 : 1 Enolate (R) Ratio 3 : 1 + Anti-Felkin Isomer R = Me Addition of Enolate & Enol Nucleophiles anti-Felkin Nu: Nu: Nu: Felkin ? ? Nu: (Felkin) favored disfavored D. A. Evans The Felkin-Anh Eisenstein Model: Verification Chem 206 + Anti-Felkin Isomer + Anti-Felkin Isomer + Anti-Felkin Isomer HMe H H MeHO H R L C OR BH R R R M CramR L R R M O O Me Me H2C (CH2)2Ph O Me R M–H M–H H H CR O C RO R L R L R M R M Me Me OH R Me OH (CH2)2PhH2C OH Me Me OH R M RR L R L R R M OH O R M RR L H O Me H H Me R2B–H R2B–H [H] H CO R HB R R R L R M LiAlH4 NaBH4 R L R R M OH OH R M RR L Exercise: Draw the analogous bis(R2BH)2 transition structures Nonspherical nucleophiles are unreliable in the Felkin Analysis Transition States for C=O-Borane Reductions anti-Felkin Felkin ? ? (Felkin) disavored favored Note: Borane reducing agents do not follow the normal trend M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725. TS ? Anti-Felkin Felkin H–B(Sia)2 1 : 4 22 : 1Li+H–B–(sec-Bu)3 RatioReagent Reagent Ratio Li+H–B–(sec-Bu)3 96 : 4 Ketone (R) R = H - 78 °C R = H 47 : 53DIBAL DIBAL 88 : 12R = Me R = Me >99 : 1Li+H–B–(sec-Bu)3 G. Tsuchihashi & Co-workers, Tetrahedron Lett. 1984, 25, 2479. TS ? Anti-FelkinH–B(Sia)2 1 : 10 54 : 1Li+H–B–(sec-Bu)3 RatioReagent 5 : 1 3 : 1 M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725. Hydride Chem 206The Felkin-Anh Model: Ketone ReductionD. A. Evans disfavored (Felkin) favoredNu: ? ? Felkin Nu: Hydride anti-Felkin Addition of Hydride Nucleophiles + Anti-Felkin Isomer + Anti-Felkin Isomer Felkin Felkin Felkin Review hydroboration discussion in Lecture-8 R R O OR M R O O R R M R L R OR O H: RO H C O M RO R CR O O MOR R R Nu C RO OMOR RR Nu OR R L R L H R L H H: H: H+ H+ Nu R OH O R R Nu R R O OHR OH OR RR L R L R OR OH OH OR RR L Me O ORMe Me Ph Me O X X O MePh Bu4N+ F- LiAlH4 PhMe2Si–H PhMe2Si–H (OR) THF THF Et2O X OH MePh OR OH MeR Ph Me OH X R Me OH OR Ph Me OH X X OH MePh Degree of chelate organization may be regulated by choice of solvent and protecting group. Note that SiPh2(t)Bu group prevents chelation for most Lewis acids. There are dramatic exceptions However: 2 : 98 -10 °C Overman Tet Lett. 1982, 23, 2355 Chelate Ratio 30 : 70 Solv. R = CH2OBn R = CH2OBn R = SiPh2(t)Bu Model 95 : 5 Chelate Cram: RL=OR X = OCOPh <1 : 99 RatioH-bonding Chelate Model T. Hiyama & Co-workers, J. Am. Chem. Soc. 1984, 106, 4629. TFA, 0 °C Substituent (X) 7 : 93X = NHCO2Et Lets begin with a case where chelation is precluded: (Path A) ? path C path B path A ? Lets begin with the hydride reductions of alkoxy ketones X = OCOPh 96 : 4 95 : 5X = OAc X = NMe2 Substituent (X) T. Hiyama & Co-workers, J. Am. Chem. Soc. 1984, 106, 4629. Let RL = X in the Ahn-Eisenstein model Ratio >99 : 1 Nu–M Reviews Reetz, Angew. Chem. Int. Ed. 1984, 23, 556-569Reetz, Accts. Chem. Res. 1993, 26, 462-468 (pdf) ? Nu–M Chelate organization provides a powerful control element in carbonyl addition reactions Chem 206D. A. Evans Carbonyl Addition Reactions: Chelate Organization Chelation model Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP (handout) H O OR R L H OR O SnBu3 RO H BF3-Et2O TiCl4 MgBr2 MgBr2 (OR) CO O HM R CH O C HO OR R L R L H H R L OR OH C6H11H 5C3 H5C3 C6H11 OH OR R L Nu OR OH OH OR NuR L OH OR NuR L OH O Me Et OBnH OCH2OBn TBSO O Me Me O O Me Et OBnH OTBSO OCH2OBn Me OOO Et H H H OMe MeMeMe CH2OHR H O THF Me MgBr Me-MgBr Me MgBr Et2O EtMgBr MeMgBr Me OHTBSO OCH2OBn Me Me OCH2OBn TBSO OH Me H OBnEt Me OH O Me Me O OH Me Et OBnHEt OHH R EtO R' Me Addition of Carbon Nucleopiles Chelation model ? path C path B path A ? Nu: ? Nu: Chem 206D. A. Evans Carbonyl Addition Reactions: Chelate Organization Nu: Chelate Felkin: RL=OR G. Keck & Co-workers, Tetrahedron Lett. 1984, 25, 265 CH2Cl2 (-78°) 5 : 95 >99 : 1R = CH2OBn CH2Cl2 (-78°) CH2Cl2 (-20°)R = CH2OBn >99 : 120 : 80 Acid RatioSolv. R = CH2OBn R = SiMe2(t)Bu THF (0°) Lewis Acid Felkin: RL=OR Chelate "only one isomer" Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 260. Y. Kishi & Co-workers, Tetrahedron Lett. 1978, 19, 2745 Chelate Model"only one isomer" "only one isomer" Y. Kishi & Co-workers, Tetrahedron Lett. 1978, 19, 2745 Chelate Model Chelate Model diastereoselection 50 : 1 diastereoselection >100 : 1W. C. Still & Co-workers, Tetrahedron Lett. 1980, 21, 1031 Chelate Model Chelate Model O BuMe Me OR O Me2Mg O R M R Me2Mg R–M MeMe Bu OMgX OMgX ORMe Me R O M R R–M R –CMe3 –SiMe3 –Si-i-Pr3 R R O O H BnO Me OCH2OBn TBSO O Me O H BnO Me SiMe3 R-M Me MgBr MeMe OMgX OR O Me OBn OSi(iPr)3Me O R O O R R M R R O OR M Me2Mg Me2Mg CH2Cl2 Me-MgCl Me-TiCl3 R-M OHBnO Me R OHBnO Me SnCl4 TiCl4 BF3-OEt2 Me OHTBSO OCH2OBn Me THF CH2Cl2 better thanHence, organization through However, these trends are not transmitted strongly to β-chelation = 2.5k 2 k1 k2 k1 rxn run inTHF at - 78°CEliel, Frye, JACS 1992, 114, 1778-84 (read) 1 7 9 –Bn 174 213–Me k1 k2 reference rxn rel rate product + Ketone + Substrates which can participate in C=O chelation will be more reactivesince the effective concentration of chelated intermediate will be higher. much more reactive thanSince Kinetic Evidence for Chelate-Controlled C=O Additon Carbonyl Addition Reactions: Chelate OrganizationD. A. Evans Chem 206 Alpha–Versus Beta-Chelation Chelate Model W. C. Still & Co-workers, Tetrahedron Lett. 1980, 21, 1031 diastereoselection 50 : 1 -78 °C + isomer M. T. Reetz & Co-workersJ. Am. Chem. Soc.. 1983, 105, 4833. RatioSolv. 40 : 60 90 : 10Other nucleophiles reported Chelate Model 95 : 5 95 : 5 RatioAcid Chelate Model M. T. Reetz & Co-workersTetrahedron Lett. 1984, 25, 729. + isomer Acid -78 °C 85 : 15 a73 Note that beta chelation can be developed as a control element by varying solvent & Nu. a73 Note BF3 gives "apparent" chelate control O Me H BnOCH2O Me H BnOCH2O Me O Me BnOCH2O H Me O O O Me H O Me2CuLi Me2CuLi Me2CuLi Me-M OH Me BnOCH2O Me Me Me OHBnOCH2O Me Me Me OH O O Me BnOCH2O OH Me Me R-M MeMgBr Me2CuLi O H BnO Me Me CHOO OTBS O N O Me2CH Me TBSO H RO Me O Me Ph OTMS M MeMeO O Me Me M Me BnOCH2O H O Me BnOCH2O OH Me OH O CO2R MeHH Me2Zn TiCl4 CH2Cl2 Me2CuLi XV OH O OTBS Me OHBnO Me Ph Me O H H Me CO2R OH Me O OH Me ROR Me Me O O MeMe chelate model diastereoselection 96 : 4S. W. Baldwin & Co-workersJ. Org. Chem. 1987, 52, 320. diastereoselection >92 % Chelate Model M. T. Reetz & Co-workersTetrahedron Lett. 1984, 25, 729. + isomer TiCl4 -78 °C D. A. Evans & E. SjogrenTetrahedron Lett. 1986, 27, 4961. Metal Ratio M = MgCl 70 : 30 97 : 3M = ZnCl + isomer D. A. Evans and S.L. Bender J. Am. Chem. Soc.. 1988, in press. 33 : 6798 : 2M = LiM = [CuCN]1/2 RatioMetal R = BOM(CH 2OBn) W.C. Still & Co-workers, Tetrahedron Lett. 1980, 21, 1035. -78 °C Et2O + isomer diastereoselection 50 : 50 diastereoselection 70 : 30 Chelate Model -78 °C Et2O -78 °C Et2O Chelate Model diastereoselection > 95 : 5 diastereoselection > 95 : 5 Chelate Model -78 °C Et2O -78 °C Chelate Model 97 : 3 50 : 50 Ratio + isomer Chem 206D. A. Evans Carbonyl Addition Reactions: Chelate Organization Beta Chelation with Organometals Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP (handout) stereocenters reinforcing stereocenters non-reinforcing O Me NH2 PhPh Ph MeO Me O LiAlH4 Zn(BH4)2 OEt O C3H5 O N CH2MOM MOMCH2 Me Me O Me O Ph Ph OH O OO PhPh B Bu Bu M-H M-H Ph NH2 Me OH Ph OH Me MeO Ph C3H5 OH OH XC OH Me O Me Me NaBH4 M-H M-H LiAlH4 THF Zn(BH4)2 Et2O KBH3H THF Zn(BH4)2 Et2O OHOH PhPh OH OH C3H5 Me Me O Me OH XC OOH MeMe Me Me MeMe Me Me OH O Me OOH MeMe Me MeMe OOH R1 R2 R3 R1Me Me OOH Me4NBH(OAc)3 R2CHO H R3 H C H O B OAc OAc OR1 R2 C H BOR1 R2 OAc OAc OHH R3 H H R1Me Me OHOR2 O MeMe Me Me OH OH OHOH MeMe Me MeMe MeMe Me Me OH OH Me R2R1 OH OH R3 R3 OHOH R1 R2 favored ? – Beta Chelate-Controlled Reduction Carbonyl Addition Reactions: Chelate OrganizationD. A. Evans Chem 206 + isomer Chelate Model Et2O, 0 °C M. Yamaguchi & Co-workersTetrahedron Lett. 1985, 26, 4643. diastereoselection 97 : 391-99% T. Oishi & Co-workersChem. Pharm Bull. 1984, 32, 1411. J. Barluenga & Co-workersJ. Org. Chem. 1985, 50, 4052. 91-99% diastereoselection 88 : 12 Et2O, 0 °C Chelate Model + isomer Ratio 100 : 0 0 : 100 G. R. Brown & Co-workersChem. Commun. 1985, 455. 0 : 100 100 : 0 Ratio T. Oishi & Co-workers Tetrahedron Lett. 1980, 21, 1641 (Zn(BH 4)2 on esters. + isomer -100 °C diastereoselection 96 : 4K. Narasaka & Co-workersChem. Lett. 1980, 1415. NaBH(OAc)3 HOAc, -20 °C + isomer diastereoselection 96 : 4 diastereoselection 98 : 2 + isomerHOAc, -20 °CNaBH(OAc)3 NaBH(OAc)3 HOAc, -20 °C + isomer diastereoselection 98 : 2 – + ? Directed reductions of -hydroxyketones Evans, Chapman, Carreira, JACS 110, 3560 (1988) 15% SmX3 catalyst diastereoselection > 100:1 Propose a mechanism for tihs highly diastereoselective transformation, Evans, Hoveyda JACS 112, 6447 (1990) Et2Zn Me Me N H Me Me Me ZnO H Et O C HZn Et Et C HO Zn Et H H O N Me Me Me Me Me RDS O C H O Et H Zn–Et OR' Zn O Zn Zn O ZnO R R R R' R' R' RZn ROR' O R'ZnR O Zn Zn OR R' R' R Me Me N H Me Me Me ZnO H Et Zn Et C Et O HO Zn Et H H N Me Me Me Me Me R'O ZnR Ar R’ OH Me Me N H MeMe Me ZnO H Et PhCHO Me2Zn Et2ZnMe 2ZnEt 2ZnEt 2ZnEt 2ZnEt 2ZnEt 2Zn Zn R Zn I I C O R R H (DAIB-Zn) Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49Review: L. Pu, Chem. Reviews 2001, 101, 757-824 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 CatalystD. A. Evans 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 precluded98% e.e. 91% e.e. 93% e.e. 93% e.e. 96% e.e. 90% e.e. 61% e.e. C6H5CHO " p-ClC6H4CHO p-MeOC6H4CHO Cinnamyl PhCH2CH2CHO n-C6H13CHO 0°C, toluene 59 - 97% Ar–CHO + R2’Zn J. Am. Chem. Soc. 1989, 111, 4028. the catalyst the catalyst 90-98% ee The Catalytic Cycle Chem 206 N B O PhB OMe Ph H H H X Ph B B + – + H2N Ph Ph OH Me2HC R O Ph Ph OH H R H N O Ph Ph B R Me O R BH3 BH3 H R OH Me H N B R O Ph Ph H3B B Me ON Ph Ph H RL H RS OBH2 O N B Y O H2B O BN Y C RS RL H X X BH 3 O BN Y BH3 H2B H N C RL RSO B OY X X C RSRL O (Review) Martens, Tertrahedron Asymmetry 1992, 3, 1475 97 % ee97 % ee 91 % ee But how does it really work ? R = Ph, R = t-Bu, R = c-C6H11 – + 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–BXC ) 2 equiv BH3 30 °C, 10 hr Chiral Boron Hydride ( H–BXC ) R = Me, 94 % eeR = Et, 94 % ee R = n-Bu 100 % ee Chem 206D. A. Evans Enantioselective C=O Addition: Corey-Itsuno Catalyst Discovery of a Catalytic Process (0.1 equiv) – + + –+ – TheCatalytic 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 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. O O n-C5H11 OArCOO N B O Ph PhH Me O OH Br OH O Me O Br Me OH ArCOO OH n-C5H11 O O O O n-C5H11 OHArCOO CCl3R O CCl3R OH Cl O O NHMe CF3 Me Me O Me Me Me Me Me Me F O BH O HO– O BH O N B O Ph PhH Me BH3 NaH CF3 Cl B n-Bu H PhPh N O N3 R COOH OH R CCl3 OH Cl NHMe OH Na–IMeNH 2 R t-C4H9 n-C5H11 Me Me Me Me MeMe HO Me Me F c-C6H11 D. A. Evans Enantioselective C=O Addition: Catalyst Scope Representative Reductions 90 : 10 91 : 9 (R)-cat, as above (S) cat (0.1 equiv) BH3 (0.6 equiv) THF 23°C, 2 min The catalyst Corey, JACS 1987, 109, 7925 (S) cat BH3 86% ee 91% eeBH 3 (S) cat 91% eeBH 3 (S) cat (R) cat (0.2 equiv) 1.5 equiv 92% ee Tet. Let 1992, 33, 2319 Fluoxetine (Prozac?) Synthesis 94% ee (>99%) 0.1 equiv Prozac? An -Amino Acid Synthesis Tet. Let 1989, 30, 5207 0.1 equiv ee 95% 92% 98% N3– rm temp Corey, JACS 1992, 114, 1906 Tet. Let 1992, 33, 3435 Tet. Let 1992, 33, 3431 Chem 206