哈佛大学：《高等有机化学》（英文版）Lecture 21 Enantioselective Carbonyl Addition

D.A. Evans Diastereoselective Enantioselective Carbonyl Addition Chem 206 ■ Problems http://www.courses.fasharvardedul-chem206/ Propose a mechanism for tihs highly diastereoselective transformation, Evans, Hoveyda JACS112,6447(1990) Chemistry 206 Advanced Organic Chemistry diastereoselection 15%Sm >100 Lecture number 21 Cume Question, 2000: Chiral amino alcohol 1 efficiently mediates the addition of Enantioselective Carbonyl Addition diethylzinc to aromatic aldehydes. While a number of other amino alcohols are also effective in controlling the absolute of the addition process, this amino alcohol has been the focus of a recent computational investigation that addresses the preferred Enantioselective addition of R2 Zn to aldehydes 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 Enantioselective Reduction of ketones imines modified under the reaction conditions to the competent catalytic agent. Provide a detailed mechanism for the overall transformation. Use 3-dimensional representations to illustrate Reading Assignment for this Week the absolute stereochemical aspects of the indicated transformation. Carey& Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Carey& Sundberg: Part B: Chapter 2 toluen Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey& Sundberg: Part B; Chapter 5 Cume Question, 2000. Corey's introduction of chiral ox Reduction of Carbonyl& Other Functional Groups borane-mediated enantioselective reduction of ketones re netric synthesis(Corey Helal, Angew. Chem. Int. m detailed mechanism for the overall transformation. Use 3-dimensional representations to Carbonyl Addn: Felkin Control: Evans, JACS 1996, 118, 4322(handout) illustrate the absolute stereochemical aspects of the indicated transformation. Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP(handout) Enantioselective Carbonyl Reduction: Corey Angew. Chem. Int Ed 1998,371986-2012 handout) Enantioselective Carbonyl Addition(R2Zn): Noyori Angew. Chem 0.1 equiv 1 Int Ed. 1991, 30, 49-69(handout) e 97%ee 1 equiv BH3THF 1,(R Wednesda Matthew d shair November 6. 2002

http://www.courses.fas.harvard.edu/~chem206/ R1 Me Me OH O R2CHO H O Ph OH N Ph Ph N B O Ph Ph R H Me O (R) Et2Zn, 0 °C toluene 1 equiv BH3•THF R1 Me Me R2 O OH O Me OH Et OH (R) (S) D. A. Evans Chem 206 Matthew D. Shair Wednesday, November 6, 2002 ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Diastereoselective & Enantioselective Carbonyl Addition Chemistry 206 Advanced Organic Chemistry Lecture Number 21 Enantioselective Carbonyl Addition ■ Enantioselective addition of R2Zn to aldehydes ■ Enantioselective Reduction of Ketones & Imines Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5 Reduction 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) ■ 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

D.A. Evans The Felkin-Anh Eisenstein model Chem 206 The flaw in the Felkin model: a problem with aldehydes ! Houk: Torsional effects in transition states are more important than in ground states R predicted to be destabilizing O Review Lecture-7 favored Ts H Transition state Hi, F*C-RL Nu: Wrong prediction GC№u Anh Eisenstein Noveau J. Chim. 1977. 1.61-70 Anh Topics in Current Chemistry. 1980, No 88, 146-162 RL a*C-RL Ground state Felkin M R M RL favored R Transition states H-radical and H-anion: antiperiplanar g*C-R orbital stabilized the ts anti-Felkin illustrated for Nu addition M R M RL C-RL C-RL New Additions to Felkin model: oC-Nu :c-nu Dunitz-Burgi C=o-Nu orientation applied to Felkin model The antiperiplanar effect Forming bond Hyperconjugative interactions between C-Rl which will lower T*C=O Forming bond ill stablize the transition state Houk, Science1981,231,1108-1117 Theoretical Support for Staggered Transition states Houk,JAcS1982,104,71626 Houk, Science1986,231,1108-17

H H C C H H H Nu C R H Nu C HO H Nu C Nu H OH R L R L R M R M H H C O R L R M R L O R M H H H H C O O C H R L R L R M R M H O C H R L R M C Nu C RL H H RL RL H H D. A. Evans The Felkin-Anh Eisenstein Model Chem 206 wrong prediction destabilizing interaction 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 ■ The antiperiplanar effect: Hyperconjugative interactions between C-RL which will lower p*C=O will stablize the transition state. ■ 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" sC-Nu s*C-RL Transition state sC-Nu s*C-RL Ground state Transition states H-radical and H-anion: antiperiplanar s*C–R orbital stabilized the TS illustrated for Nu addition Houk, Science 1981, 231, 1108-1117 "The Theory and Modeling of Stereoselective Organic Reactions" sC-Nu s*C-RL sC-Nu homo s*C-RL lumo Forming bond Forming bond

D.A. Evans The Felkin-Anh Eisenstein model: Verification Chem 206 Addition of enolate Enol Nucleophiles This trend carries over to organometallic reagents as well Ant-Felkin Isomer Felkin M R (Felkin) favored R Cram 5 R C. Djerassi& Co-workers, J.Org,chem.1979,44,3374 R-Ti(OiProp)3 Nu: disfavored M R+ Anti-Felkin Isomer Trend-1: For Li enolates, increased steric hindrance at enolate carbon results in enhanced selectivity M. Reetz Co-workers Angew Chemie Int. Ed.. 1982, 21, 135 R-Titanium >90:10 oH O (R-MgX gives Ca 3: 1 ratios) >90:10 Anti-Felkin Isomer Trend-2: Lewis acid catalyzed nxns are more diastereoselective OSiMe?tBr L. Flippin Co-workers Tetrahedron Lett. 1985. 26. 973 3:1 R=OtBu 4:1 R1 Anti-Felkin Isomer OH O OM。+ Anti-Felkin Isomer Ketone(R,) Enolate(R2 Ratio Lienolate R=Ph R=OM Co-workers R=Ph R=OtBu36:14:1 C Heathcock L Flippin J. Am. Chem. Soc. 1983, 105, 1667

Nu OH H Me H H Me Me H H Me H O H Cram R L H R M O H Me O R O Me H R OLi OLi OMe Me Me H H H C O O C H R L R L R M R M R OH O Me R Me OH O OMe Me Me OH R M Nu R L R L Nu R M OH H Me O R1 O Me H BF3 -Et2O R2 OSiMe2tBu R Me OH R2 OH O Me R1 ClMg C CEt Li (R–MgX gives Ca 3:1 ratios) >90 : 10 R–Ti (OiProp)3 R = n-Bu R-Titanium Ratio R = Me >90 : 10 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 R = Ph R = Me 10 : 1 Enolate (R2) R = t-Bu -78 °C R = Ph R = OMe 15 : 1 R = Ph R = Ot-Bu 36 : 1 R = c-C R = Ot-Bu 16 : 1 6H11 ■ This trend carries over to organometallic reagents as well Lewis acid catalyzed rxns are more diastereoselective Trend-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 L. Flippin & Co-workers, Ketone (R) Ratio Tetrahedron Lett.. 1985, 26, 973. R = c-C6H11 9 : 1 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

D.A. Evans The Felkin-Anh Model: Ketone reduction Chem 206 Addition of Hydride Nucleophiles H Hydride Anti-Felkin Isome Felkin R (Felkin) favored Cram M. M. Midland& Co-worke J. Am. chem. Soc. 1983 3725. Li'H-B(sec-Bu)3 54: 1 Felkin aBH4 5: 1 LiAlH4 3: 1 H-B(Sia)2 1:10 Anti-Felkin anti-Felkin R Note: Borane reducing agents do not follow the normal trend disfavored Nu: Transition States for c=o-Borane reductions H2C 人 Ant-Felkin Isomer 78h2C R2B-H Ketone(R) Reagent Felkin G. Tsuchihashi Co-workers Tetrahedon Lett. 1984. 25, 2479 Li'H-B(sec-Bu)3 96: 4 DIBAL 47:53 (Felkin) disavowed R=Me Li'H-B(sec-Bu3 >99: 1 DIBAL M-H R2B-H anti-Felkin favored Reagent Ratio M. M. Midland Co-workers Nonspherical nucleophiles are unreliable in the Felkin Analysis J. Am. chem.Soc.1983,1053725 Li'H-B(sec-Bu)3 22: 1 Felkin H-B(Sia)2 1:4 Anti-Felkin Exercise: Draw the analogous bis(R2BH)2 transition structures Review hydroboration discussion in Lecture-8

H Me H H Me HO H R L R C O H B R R R M Cram R L R R M O O Me Me H2C (CH2)2Ph O Me R M–H M–H H H R C O O C R R L R L R M R M Me Me OH R Me OH H2C (CH2)2Ph OH Me Me OH R M R R L R L R R M OH O R M R R L H O Me H H Me R2B–H R2B–H [H] H O C R B H R R R L R M LiAlH4 NaBH4 R L R R M OH OH R M R R 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 Li 22 : 1 +H–B– (sec-Bu)3 Reagent Ratio Reagent Ratio Li+H–B– (sec-Bu)3 96 : 4 Ketone (R) R = H - 78 °C R = H DIBAL 47 : 53 R = Me DIBAL 88 : 12 R = Me Li+H–B– (sec-Bu) >99 : 1 3 G. Tsuchihashi & Co-workers, Tetrahedron Lett. 1984, 25, 2479. TS ‡ H–B(Sia)2 1 : 10 Anti-Felkin Li 54 : 1 +H–B– (sec-Bu)3 Reagent Ratio 5 : 1 3 : 1 M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725. Hydride D. A. Evans The Felkin-Anh Model: Ketone Reduction Chem 206 disfavored (Felkin) favored Nu: ‡ ‡ Felkin Nu: Hydride anti-Felkin Addition of Hydride Nucleophiles + Anti-Felkin Isomer + Anti-Felkin Isomer Felkin Felkin Felkin Review hydroboration discussion in Lecture-8

D A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Chelate organization provides a powerful control element in carbonyl addition reactions Lets begin with a case where chelation is precluded:(Path A) Nu-M BuanF-PhiMe in the ahn-Eisenstein model iN >99:1 T Hiyama& Co-workers, J.Am.Chem.Soc.1984,106.4629 X=OAC X= OCOPh 96 Reviews Reetz, Accts. Chem. Res. 1993, 26, 462-468(pdf) Reetz, Angew. Chem. Int. Ed. 1984, 23, 556-569 PhMe2SH-H Lets begin with the hydride reductions of alkoxy ketones H-bonding Chelate Model path A Substituent (X) Ratio X= NHCO,Et <1: 99 J Am. chem.196.421×:0cph7:93 R RL LiAIH4 10°C H: Chelation model Ratio Model R=CH,OBn THF 30:70 Tet Lett. 1982, 23, 2355 R=CH2OBnE202:98Chelate path C R=SiPh2(t)Bu THF 95: 5 Cram: RL=OR 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: Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP(handout)

R R O O R M R O O R R M R L R OR O H: RO H C O M O R R R C O O O M R R R Nu O C R O M O R R R Nu OR R L R L H R L H H: H: H + H + Nu R OH O R R Nu R R O OH R OH OR R R L R L R OR OH OH OR R R L Me O Me OR Me Ph Me O X X O Me Ph Bu4N + F￾LiAlH4 PhMe2Si–H PhMe2Si–H (OR) THF THF Et2O X OH Me Ph OR OH Me R Ph Me OH X R Me OH OR Ph Me OH X X OH Me Ph 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 99 : 1 Nu–M Reviews Reetz, Angew. Chem. Int. Ed. 1984, 23, 556-569 Reetz, Accts. Chem. Res. 1993, 26, 462-468 (pdf) ‡ Nu–M Chelate organization provides a powerful control element in carbonyl addition reactions D. A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Chelation model Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP (handout)

D.A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Addition of Carbon Nucleopiles MgB TBs path A OCH2 OBn Chelate Model OCH2OBn OR diastereoselection 50: 1 Felkin: R=OR TBS Me-MgBr Chelate Model BSo path B W. C. Still Co-workers Tetrahedron Lett. 1980. 21. 1031 diastereoselection >100: 1 Chelation model RL IgEr path C M-O R Chelate only one isomer Y Kishi& Co-workers Chelate model Tetrahedron Lett. 1978. 19. 2745 SnB H Chelate Felkin: RL=OR nly one isomer Y Kishi Co-workers elate Mode (OR Tetrahedron lett 1978. 19. 2745 R=CH2OBn MgBr2 THF(O 20:80 R=CH20Bn MgBr2 CH2Cl2(-20)>99. R=CH2OBn TICl4 CH2Cl2(-78)>99: 1 MeMgBr R= SiMe2(tBu BF3-Et2O CH2Cl2(-78)5.95 G. Keck Co-workers. Tetrahedron Lett. 1984. 25. 265 Y Kishi Co-workers Chelate Model J.Am.Chem.Soc.1979,101,260

H O OR R L H OR O SnBu3 RO H BF3-Et2O TiCl4 MgBr2 MgBr2 (OR) O C O M H R H C O O C H OR R L R L H H R L OR OH C6H11 H5C3 H5C3 C6H11 OH OR R L Nu OR OH OH OR Nu R L OH OR Nu R L O H O Me Et OBn H OCH2OBn TBSO O Me Me O O Me Et OBn H O TBSO OCH2OBn Me O O O Et H H H OMe Me Me Me R CH2OH H O THF Me MgBr Me-MgBr Me MgBr Et2O EtMgBr MeMgBr Me OH TBSO OCH2OBn Me Me OCH2OBn TBSO OH Me H OBn Et Me OH O Me Me O OH Me Et OBn H Et OH H R Et O R' Me Addition of Carbon Nucleopiles Chelation model ‡ path C path B path A ‡ Nu: ‡ Nu: D. A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Nu: Chelate Felkin: RL=OR G. Keck & Co-workers, Tetrahedron Lett. 1984, 25, 265 CH2Cl2 (-78°) 5 : 95 R = CH2OBn CH2Cl2 (-78°) >99 : 1 CH2Cl2 R = CH (-20°) 2OBn >99 : 1 20 : 80 Acid Solv. Ratio 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 : 1 W. C. Still & Co-workers, Tetrahedron Lett. 1980, 21, 1031 Chelate Model Chelate Model

D.A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Kinetic Evidence for Chelate- Controlled C=o Additon Alpha-Versus Beta-Chelation Since o-m much more reactive than MgB Substrates which can participate in C=o chelation will be more reactive Chelate model since the effective ntration of chelated intermediate will be higher OCH2OBn R W. C. Still Co-workers Tetrahedron Lett. 1980. 21. 1031 Ketone + R-M R R-M OMg 78°C rel rate o Chelate Model -Bn 74 M. T Reetz Co-workers OMg) JAm.Chem.Soc.1983,105,4833 Me-MgCI THF 40: 60 -SiMe3 Other nu reported Me-TICI eference rxn -Si-H-P 1 rxn run inThE at-78° Eliel, Frye, JACS 1992, 114, 1778-84(read SiMe3 Me However, these trends are not transmitted strongly to B-chelation t isomer Bno Acid-78° Chelate Model M. T Reetz Co-workers 2.5 Tetrahedron Lett. 1984. 25. 729 95:5 OS(Pn)3 k? BF3-OEt2 R Note that beta chelation can be developed as a control element by R、M varying solvent&Nu Hence, organization a Note BF3 gives"apparent" chelate control

O Bu Me Me OR O Me2Mg O R M R Me2Mg R–M Me Me Bu OMgX OMgX OR Me 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 Me Me OMgX OR O Me OBn OSi(i Me Pr)3 O R O O R R M R R O O R M Me2Mg Me2Mg CH2Cl2 Me-MgCl Me-TiCl3 R-M BnO OH Me R BnO OH Me SnCl4 TiCl4 BF3-OEt2 Me OH TBSO OCH2OBn Me THF CH2Cl2 Hence, organization better than through However, these trends are not transmitted strongly to b-chelation = 2.5 k2 k1 k2 k1 rxn run inTHF at - 78°C Eliel, Frye, JACS 1992, 114, 1778-84 (read) 1 7 9 –Bn 174 –Me 213 k1 k2 reference rxn rel rate product + Ketone + Substrates which can participate in C=O chelation will be more reactive since the effective concentration of chelated intermediate will be higher. Since much more reactive than Kinetic Evidence for Chelate-Controlled C=O Additon D. A. Evans Carbonyl Addition Reactions: Chelate Organization 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-workers J. Am. Chem. Soc.. 1983, 105, 4833. Solv. Ratio 40 : 60 90 : 10 Other nucleophiles reported Chelate Model 95 : 5 95 : 5 Acid Ratio Chelate Model M. T. Reetz & Co-workers Tetrahedron Lett. 1984, 25, 729. + isomer Acid -78 °C 85 : 15 ■ Note that beta chelation can be developed as a control element by varying solvent & Nu. ■ Note BF3 gives "apparent" chelate control

D.A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Beta Chelation with Organometals OTBS OTBSOH t isomer Me-M t isomer 78°C BnOCH20 O BnOCH20 Chelate Model R-M M=Mgc70:30 D. A. Evans&E. sjogi Tetrahedron Lett. 1986. 27. 4961 M=znC|97:3 Me2cuLi H Me2 CuLi O stereoselection 78°cEz20 95:5 TBSO R= BOM (CH2OBn) D. A Evans and S L. Bender Bn0c0278℃的 diastereoselection JAm.Chem. Soc.1988 BnOCH20 >95:5 In press M=[cucN1298:2 M=Li 33:67 Chelate Model stereocenters reinforcing OTMS diastereoselection BnoCH20 O -78C Et20 BnOCH20 OH TC4-78°C Chelate Model CH2Cl2 Bno stereocenters non-reinforcing Chelate model M. T. Reetz Co-workers diastereoselection >92 H Me2CuLi Me Me diastereoselection Tetrahedron Lett 1984, 25, 729 BnOCH20 0 -78oC Et20 BnOCH2O OH CO2R Or WC.S圳& Co-workers Me2Zn Me Tetrahedron Lett. 1980. 21. 1035 J. Org. Chem. 1987, 52 diastereoselection 96: 4 Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP(handout)

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 BnOCH2O OH Me Me Me OH O O Me BnOCH2O OH Me Me R-M MeMgBr Me2CuLi O H BnO Me Me CHO O OTBS O N O Me2CH Me TBSO H RO Me O Me Ph OTMS M Me Me O O Me Me M Me BnOCH2O H O Me BnOCH2O OH Me H O O CO2R Me H H Me2Zn TiCl4 CH2Cl2 Me2CuLi XV OH O OTBS Me BnO OH Me Ph Me O H H Me CO2R OH Me O OH Me R RO Me Me O O Me Me chelate model diastereoselection 96 : 4 S. W. Baldwin & Co-workers J. Org. Chem. 1987, 52, 320. diastereoselection >92 % Chelate Model M. T. Reetz & Co-workers Tetrahedron Lett. 1984, 25, 729. + isomer TiCl4 -78 °C D. A. Evans & E. Sjogren Tetrahedron Lett. 1986, 27, 4961. Metal Ratio M = MgCl 70 : 30 M = ZnCl 97 : 3 + isomer D. A. Evans and S.L. Bender J. Am. Chem. Soc.. 1988, in press. 33 : 67 98 : 2 M = Li M = [CuCN]1/2 Metal Ratio R = BOM (CH2OBn) 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 D. A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Beta Chelation with Organometals Carbonyl Additon: Chelate Control: Evans JACS 2001, ASAP (handout) stereocenters reinforcing stereocenters non-reinforcing

D. A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 Beta Chelate-Controlled Reduction Directed reductions of B-hydroxy ketones Evans, Chapman, Carreira, JACS 110, 3560(1988) diastereoselection 97: 3 T Oishi Co-workers 人→=n Me4NBH(OAc)3 LiAIH4 t Isomer E20,0 91-99% Chelate Model diastereoselection 88: 12 0-H G.R. Brown& Co-workers diastereoselection 96: 4 M-H Ratio 0:100 HoAc-20°C CH2MOM diastereoselection 98: 2 Me Me MOMCH2 M Yamaguchi& Co-workers HOAC. 20 Tetrahedon Lett. 1985. 26. 4643 Zn(BH4)2 Et20 Tetrahedon Lett. 1980. 21. 1641 Zn(BH4)2 on esters KBH3H THF 0: 100 diastereoselection 98: 2 Hoveyda JACS 112, 6447(1990) isomer 100°C diastereoselection Chem lett 1980. 1415 diastereoselection 96: 4 15%Sm3 >100:1

O Me NH2 Ph Ph Ph MeO Me O LiAlH4 Zn(BH4)2 OEt O C3H5 O N CH2MOM MOMCH2 Me Me O Me O Ph Ph OH O O O Ph Ph 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 OH OH Ph Ph OH OH C3H5 Me Me O Me OH XC OH O Me Me Me Me Me Me Me Me OH O Me OH O Me Me Me Me Me OH O R1 R2 R3 R1 Me Me OH O Me4NBH(OAc)3 R2CHO H R3 H C H O B OAc OAc R1 O R2 C H B R1 O R2 OAc OAc O H H R3 H H R1 Me Me R2 O OH O Me Me Me Me OH OH OH OH Me Me Me Me Me Me Me Me Me OH OH Me R1 R2 OH OH R3 R3 OH OH R1 R2 favored ‡ – Beta Chelate-Controlled Reduction D. A. Evans Carbonyl Addition Reactions: Chelate Organization Chem 206 + isomer Chelate Model Et2O, 0 °C M. Yamaguchi & Co-workers Tetrahedron Lett. 1985, 26, 4643. diastereoselection 97 : 3 91-99% T. Oishi & Co-workers Chem. Pharm Bull. 1984, 32, 1411. J. Barluenga & Co-workers J. 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-workers Chem. Commun. 1985, 455. 0 : 100 100 : 0 Ratio T. Oishi & Co-workers Tetrahedron Lett. 1980, 21, 1641 (Zn(BH4 )2 on esters. + isomer -100 °C diastereoselection 96 : 4 K. Narasaka & Co-workers Chem. Lett. 1980, 1415. NaBH(OAc)3 HOAc, -20 °C + isomer diastereoselection 96 : 4 diastereoselection 98 : 2 + isomer HOAc, -20 °C NaBH(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)

D A. Evans Enantioselective C=O Addition: Noyori Catalyst Chem 206 Catalytic Asymmetric Carbonyl Addition The Catalytic Cycle eplace with chiral controller N-Me N-Me loyori& co-workers, J. Am. Chem. Soc 111.4028 Review Noyori Angew. Chem. Int. Ed. 1991, 30, 49 Review: L Pu. Chem. Reviews 2001. 101. 757-824 Zn -Et 9098%ee HcHO Me RDS H the catalyst Ar-CHO R 2 Zn 0°c, toluene 59-97% C6H5CHO Et2zn 98%ee. I Catalyst must be sterically hindered so that association is precluded 91% Et2Zn 93%ee. Et2 p-MeOC6H4CHo Et2Zn 93%ee PhcH2 CH2CHO Et2Zn 90%ee. R n-C6H13CHO 61%ee. 4 R O--ZnR The method is catalytic in aminoalcohol. a Two zinc species per aldehyde are involved in the alkylation step R-0—2n-R a Product is taken out of the picture by aggregation

Et2Zn Me Me N H Me Me Me O Zn H Et O C H Zn Et Et C O H Zn Et H H O N Me Me Me Me Me RDS O C H O Et H Zn–Et R' O Zn O Zn Zn O O Zn R R R R' R' R' R Zn R' O R O R' Zn R O Zn Zn O R R' R' R Me Me N H Me Me Me O Zn H Et Zn Et C Et O H O Zn Et H H N Me Me Me Me Me R'O ZnR Ar R’ OH Me Me N H Me Me Me O Zn H Et PhCHO Me2Zn Et2Zn Me2Zn Et2Zn Et2Zn Et2Zn Et2Zn Et2Zn Zn R Zn I I C O R R H (DAIB-Zn) Review: Noyori Angew. Chem. Int. Ed. 1991, 30, 49 Review: L. Pu, Chem. Reviews 2001, 101, 757-824 ■ Two zinc species per aldehyde are involved in the alkylation step. ■ Product is taken out of the picture by aggregation 4 ■ The method is catalytic in aminoalcohol. D. A. Evans Enantioselective C=O Addition: Noyori Catalyst Noyori & co-workers, J. Am. Chem. Soc. 1986, 108, 6072. replace with chiral controller Catalytic Asymmetric Carbonyl Addition 98% e.e. ■ Catalyst must be sterically hindered so that association is precluded 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