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 + FLiAlH4 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 <1 : 99 Ratio H-bonding Chelate Model T. Hiyama & Co-workers, J. Am. Chem. Soc. 1984, 106, 4629. TFA, 0 °C Substituent (X) 7 : 93 X = 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 X = OAc 95 : 5 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, 556-569 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)