Chemistry 206 Advanced Organic Chemistry Handout–10A Diastereoselective Attack of Electrophiles on Chiral Olefins Matthew D. Shair Wednesday, October 9, 2002 Michael Dart Evans Group Seminar, January 18, 1994 Electron Rich Substituents have lone pairs (OR, NR 2 , SR, SO 2 R) Electron Poor Substituents: SiR 3 (electropositive) Based solely on electrostatic considerations Mick Dart Evans Group Seminar Tues. Jan. 18, 1994 1. Diels Alder reactions2. Halogenation and related electrophilic additions3. Reactions of allylsilanes4. Hydroborations5. Osmylations Diastereoselective Attack of Electrophiles on Chiral Olefins D. Jones, J. C. S. Chem. Comm. 1980 , 739. a73 Other dienophiles also give adducts derived from endo addition syn to the hydroxyl anti syn Dienophile X SynAnti Electron RichElectron Poor Hehre's Proposal: a73 Opposite diastereofacial selectivity is observed with acrolein. (73%) a73 Stereocontrol: A(1,3) strain Trost, J. Org. Chem, 1989 , 54 , 2271-2274. Diastereoselective Diels–Alder Reactions: Chiral Dienes Diastereoselection 91 : 9 Diastereoselection >95 : 5 Kahn & Hehre, J. Am. Chem. Soc. 1987 , 109 , 663-666. (99%) PhN OO O O Me H H O NPh Me OH H H OH O H H Me H O H R X H MeMe OH O OO O O O Me Me OH H H OH Me Mick Dart Diastereoselective Attack of Electrophiles on Chiral Olefins 10A-01-Diels-Alder 10/9/00 12:12 AM Also see A. Kozikowski, J. Am. Chem. Soc. 1987 , 109 , 5167-5175. Allylic Ether Allylsilane Favored diene conformers in reactions with acetylenic dienophiles Dienophile a73 Rationalization for diastereofacial selectivity: Fleming, JCS Perkin Trans I, 1989 , 2023-2030. Diastereoselective Diels–Alder Reactions: Chiral Dienes Diastereoselection 82 : 18Diastereoselection 12 : 88 R. Franck, J. Am. Chem. Soc. 1988 , 110 , 3257 Dienophile Dienophile Dienophile Dienophile PhH, rt PhH, 60 °C 10 days 2 days (96%) (90%) 2 days PhMe, 100 °C Dienophile Dienophile Dienophile R. Franck, J. Am. Chem. Soc. 1988 , 110 , 3257 Diastereoselection 27 : 73 Diastereoselection >99 : 1 Fleming, JCS Perkin Trans I, 1989 , 2023-2030. PhMe, 100 °C 2 days (72%)(62%) See Houk & Co-workers Science , 1986 , 221 , 1108-1117. anti outside inside Dienophile Me H SiMe 2 Ph Me PhN OO NPh O O H SiMe 2 Ph Me Me HH H NPh O O H OSiMe 3 Me Me HH H HH H Me Me OSiMe 3 H O O NPh SiMe 2 Ph Me H H H Me Me Me SiMe 2 Ph H O O NPh O O PhN Me OSiMe 3 H Me H Me H Me OSiMe 2 Me H Me 3 SiO Me Me Me H OSiMe 3 H Me PhMe 2 Si Me Me Me 3 SiO H Me Me OSiMe 3 H Me Me H OSiMe 3 Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me H SiMe 2 Ph Me Me Me H H Me SiMe 2 Ph CO 2 Me CO 2 Me CO 2 Me CO 2 Me Me H OSiMe 3 Me Me HH Me H Me Me OSiMe 3 H SiMe 2 Ph H Me Me SiMe 2 Ph H Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me H SiMe 2 Ph H Me SiMe 2 Ph H Me Me PhMe 2 Si Me 10A-02-Diels-Alder 10/8/00 8:11 PM A preference for " inside alkoxy " is observed in these cyclizations B A low yield due to δ -lactone formation Gauche A is now more destabilizing than gauche B + I 2 , HOH/THF HCO 3 – Ratio >95 : 5 (49%) + A B How can the above results be rationalized? Chamberlin, J. Am. Chem. Soc. 1983 , 105 , 5819-5825. K 2 CO 3 MeOH Epoxidation Ratio = 3 : 97 Lactonization Ratio = 96 : 4 t-BuOOHVO(acac) 2 Gauche B is more destabilizing than gauche A + Ratio 96 : 4 (85%) HCO 3 – I 2 , HOH/THF + R = H R = Me A(1,2) strain 95 : 5 49 a73 Kinetic conditions: 3 equiv I 2 , aq Na 2 CO 3 , Et 2 O, 0 °C a73 Protection of the hydroxyl group (TBS or Ac) does not affect selectivity a73 Iodolactonization of allylic alcohols 75 : 25 9 : 91 ( cis : trans ) NIS, CHCl 3 , 25 °C 3 equiv I 2 , MeCN, O °C Kinetic Thermodynamic Conditions Bartlett, J. Am. Chem. Soc. 1978 , 100 , 3950-3952. Iodolactonization Yield (%) Selectivity Major Product Substrate 85 7481 4194 66 R = HR = Me 95 : 5 87 : 1390 : 10 93 : 7 77 : 2342 : 58 R = HR = Me Chamberlin, J. Am. Chem. Soc. 1983 , 105 , 5819-5825. a73 Bartlett's "thermodynamic conditions" produced complex mixtures I HO O O O O HO I MeMe RR Me OH HO O -O 2 C CH 2 HO H O C H C H Me HO I Me O H HO O I I O HO H O C I H OH C Me H R R Me H HO CH 2 Me OH Me -O 2 C O RO OH Me HO O O HO OHOH HO O O I Me O Me I O Me HO O O O O Me OH Me RO O -O 2 C CH 2 HO Me Me HO H C Me C HMe I O Me HO O I I O HO Me O Me HO C I C Me H Me H CH 2 -O 2 C O MeO Me OH Me Me I H I HO O O O Me OH Me MeO O OO OH O I Me 10A-03-Iodolactonization 10/8/00 8:11 PM a73 Place the medium size group (–OH) outside and the small group (–H) inside a73 Other conditions: I 2 , THF/phosphate buffer; I 2 , THF, aq Na 2 CO 3 provide 1,3–diols in very high selectivity Model for Stereoinduction? minor major Gauche B is more energetically destabilizing than gauche A I 2 , AgOAc + + – OAc AcO – B A A B H 2 O + + I 2 , AgOAc Gauche A is now more destabilizing than gauche B OH 2 Ratio 80 : 20 perfect regioselectivity HCO 3 – I 2 , HOH/THF Poor regioselectivity affords a mixture of products Evans, Kaldor, Jones, J. Am. Chem. Soc. 1990 , 112 , 7001. Chamberlin, Tetrahedron 1984 , 40 , 2297-2302. Diastereoselection 96 : 4 I 2 , THF aq KH 2 PO 4 Cytovaricin Synthesis a73 High selectivities are also observed with allylic ethers (OMe, OBn, OTBS) a73 Prevost conditions: 2 equiv I 2 , 2 equiv AgOAc, THF, –78 → 0 °C 94 : 6 98 : 295 : 580 : 20 7890 85 Substrate Major Product Selectivity Yield (%) Iodo diol formation from allylic alcohols a73 Analysis: D. A. Evans, Chem. 115, Lecture 23, Dec. 16, 1993 HO H R C H H OAc I OH R' R OH C Me I R' HO H R C Me C HH I I Me OH Me OH Bu Bu Me R Me OH TIPSO Me Bu OH Me OH Me OAc R Bu R' OH I OH OH Bu I Me OAc CC I H OH Me OH Bu OAc OH Me R R HO OH R OH OH Me I OH R MeMe Bu Bu OH I I I I Me Me HO OAc TIPSO OH R' H H R HO CC I HO H HR' R H 10A-04-Iododiol formation 10/8/00 8:11 PM a73 "The presence or absence of an internal nucleophile acts to determine the stereochemical outcome of the reaction by modifying the nature (timing) oftransition state. a73 Onium ion formation is rate determing in the addition reactions a73 π –complex cyclizes if R contains a Nu and its formation is rate determining For a review of the halogenation reaction see: Andy Ratz, Evans Group Seminar , Synthetic and Mechanistic Review of Electrophilic Halogenation , May 7, 1992. For a review of elctrophilic induced olefin cyclization reactions see:G. Cardillo & M. Orena, Tetrahedron 1990 , 46 , 3321. a73 "Facial preferences in electrophilic addition reactions are not invariant with respect to the location of the transition state along the reaction coordinate." Chamberlin & Hehre, J. Am. Chem. Soc. 1987 , 109 , 672-677. - I 2I 2 OH 2 cis : trans 95 : 5 ratio 99 : 1 I 2 I 2 H 2 O a73 A complete turnover in olefin diastereofacial selectivity is observed when adding internal and external nucleophiles Chamberlin & Hehre's Rationalization For electrophiles that react via onium intermediates (I 2 , Br 2 , Hg(OAc) 2 , PhSeCl), the major diastereomer from electrophile-induced cyclization is opposite to thatobserved in the analogous intermolecular electrophilic addition. General Observation: a73 Analysis of the stereoselectivity of electrophilic addition to chiral olefins: 1. Relative abundances of conformational minima2. Relative reactivities of the available forms 3. Stereoselectivies of the individual conformers a73 Change in diastereoselectivity is a consequence of a change in the rate-limiting step a71 Addition reactions: Formation of an onium ion intermediate (subsequently trapped by a Nu from the medium) a71 Cyclization reactions: Intramolecular attack on a ππππ –complex (not an onium ion) + + Nu Nu Disfavored π –complex Favored π –complex Disfavored iodonium ion Favored iodonium ion Cyclization product Addition product Favored ground-state conformerMore reactive ground-state conformer Hehre's Analysis Houk: Argument for the "inside alkoxy effect" in π –complex formation O O HO OH Me Bu OH I Me I H I OH Bu Me OH H I Me HO O O Bu H HO OH Bu Me Me OH HO O O O Me OH H I 2 H O O H H R H OH Me Me OH H R H I HO Me Me I H OH Me Bu OH I Me H R HO H H H H H H HO R H Me Me H R HO H H H H OH R H Me I I 2 10A-05-Iodolact/Hehre 10/8/00 8:12 PM D. A. Evans, Chem. 115, Lecture 23, Dec. 16, 1993 Diastereoselective Functionalization of (E) Allylic Alcohols a73 Halogenation a73 Oxymercuration a73 Hydroboration a73 Sulfenylation At least 3 major products H 2 O 2 ThexylBH 2 Ratio = 99 : 1 (40%) PhS –Cl Me 2 Zn TiCl 4 + Ratio = 50 : 50 (77%) Me 2 Zn TiCl 4 PhS –Cl + Reetz, Angew. Chem. Int. Ed. 1987 , 26 , 1028-1029. minor major Gauche B is more energetically destabilizing than gauche A syn : anti = 80 :20 Chamberlin, Tetrahedron 1984 , 40 , 2297-2302. Hg(OAc) 2 I 2 , AgOAc + + – OAc AcO – B A Hg(OAc) 2 R'OH Oxymercuration of Acyclic allylic alcohols: NaBH 4 R R'OH Ratio -Et HOH 76 : 24 yield65% 72% 93 : 07 MeOH -Et-Ph HOH 88 : 12 66%70% 98 : 02 HOH -tBu Giese, Tet. Lett. 1985 , 26 , 1197 Hg(OAc) 2 NaBH 4 HOH Hg(OAc) 2 syn syn : anti = 77 : 23 O-acetate participation will turn over the stereochemical course of the rxn Iodohydroxylation of thesesubstrates is not regioselective + + + + Favored Disfavored a73 Hehre's model could be invoked to explain turnover in π –facial selectivity O H R L C H C n-Bu OH Me OAc I OH HH Hg X R' OR H C Hg X H H C H R L O R OH OH R R C Hg R L H H C H OR' HgOAc OR' R H Me OH X C Hg H X C H H OH OH H n-Bu R' HO R L OH R L HgOAc HgOAc Me OH OR' n-Bu R L HO OH OH OH R L OR' HgOAc O R OR Me Me R L OR Et OR R L Me OR HO OBz H OH Et Me OBz OBz Et C H C HMe Hg X R RR ' OH I OAc CC I H S Ph C H C Et H H MeO Me Me Me SPh Me TBSO Et OMe Me Me OTBS Me TBSO Me SPh Me Me MeO Me SPh Et Me Me OH R' H H R HO CC I HO H HR' R H n-Bu 10A-06-Oxymercuration 10/8/00 8:12 PM Scott J. Miller Evans Evening Seminar , "The Chemistry of Allylsilanes and the β Silicon Effect," Dec 11, 1990, p 45. Path A Path B Paddon-Row, Rondan, and Houk JACS 1982 104 , 7162. + + El + El + a73 If A = H, then Path B can compete a73 If A ≥ Me, then Path A dominates due to A(1,3) strain tereochemical Model For Electrophilic Attack on Allylsilanes Model assumes: 1. Electrophilic attack anti to the silyl moiety 2. The silyl group is the "large" substituent Electrophilic Attack on Allylsilanes mCPBA Mei Pr PH 61 : 39>95 : 05 89 : 11 R RatioRatio R 58 : 42>95 : 05 91 : 09 Mei Pr PH AlMe 3 OsO 4 Mei Pr PH 34 : 66 67 : 33 92 : 08 R Ratio CH 2 I 2 a73 Epoxidation a73 Cyclopropanation a73 Osmylation The products on the left correspond to attack by Path A a73 Larger R groups result in higher selectivity a73 The size of R is more important in locking the substrate into the conformation leading to Path A than in shieldieng the El + Fleming, JCS Perkin Trans I, 1992 , 3303-3308. El C R SiR 3 R' A H R PhMe 2 Si Me R SiR 3 C H H C El C R' HR SiR 3 C H A R' R El RR ' Me R A Me PhMe 2 Si CH PhMe 2 Si OO PhMe 2 Si PhMe 2 Si Me R Me R R R H R SiR 3 C H Me PhMe 2 Si PhMe 2 Si Me R C A RM e R M e PhMe 2 Si R' PhMe 2 Si OH OH OH OH A El A A RR ' SiR 3 R' 0A-07-Allylsilanes 10/8/00 8:13 PM K. N. Houk, M. N. Paddon-Row, & Co-workers, Tetrahedron 1984 , 40 , 2257-2274. Assume OH (OR') = R m and results are consistent with the model W. C. Still & J. C. Barrish, J. Am. Chem. Soc . 1983 , 105 , 2487. BH 3 ? THF 9–BBN H 2 O 2 OR'OHOHOTMSOAcOH nBuiPrnBunBunBu 92 : 08 96 : 04 91 : 09 88 : 12 42 : 58 Selectivity R R 2 BH M. M. Midland & Co-workers, J. Am. Chem. Soc . 1983 , 105 , 3725. H 2 O 2 R 2 BH Dave Evans, Chem 115, Lecture 22, Dec 14, 1993BH 3 H 2 O 2 H 2 O 2 a73 A turnover in diastereofacial selectivity is sometimes observed using BH 3 Favored product fordialkyl borane reagents H 2 O 2 H 2 O 2 R 2 BH Worse Bad a73 Hydroboration of allylic alcohols (ethers) Selectivity 50 : 50 80 : 20 93 : 07 96 : 04 BH 3 ? DMS ThexylBH 2 9–BBN(Chx) 2 BH Diastereoselective Hydroboration Examples A Model for Diastereoselective Hydroborations OH Me R M OH R L R OR' R L R M Me B H B H H H Me R M Me C H R L H C Me C Me OR' R L R R OH R M H OR' Me OH H H R L R M H C Me C C B BH H H Me H R M R L R M R L R M Me R R R R Me R M R L R L OH R M Me OH HH H C C H H Me H R L Me H H Me Me H H Me HH OH H Me H H Me OH 10A-08-Hydroboration Models 10/8/00 8:13 PM I. Paterson & J. ChannonTetrahedron Lett. , 1992 , 33 , 797-800. BH 3 ?THF unexpectedly provided the anti isomer in high selectivity 5 syn anti 74%89% yield 95 : 05>95 : 05 9-BBNBH 3 ?THF anti : syn anti : syn 9-BBNBH 3 ?THF 85 : 15 05 : 95 yield 70%84% anti syn 80%99% yield 82 : 1817 : 83 (Chx) 2 BH BH 3 ?DMS anti : syn syn anti The sense of asymmetric induction is completely turned over in Andy's reaction when using R 2 BH ? BH 3 a73 Erythronolide synthesis: Annette Kim Diastereoselection 93 : 7 THF, 0 °C → rt 12 h 3 ThexylBH 2 a73 Lonomycin synthesis: Andy Ratz Diastereoselective Hydroborations BH 3 ?DMS (85%) Diastereoselection > 95 : 5 (anti) 9-BBN(60%) Diastereoselection 92 : 8 (syn) Nakata, Tatsuta & Co-workers, Bull. Chem. Soc . Jpn ., 1992 , 65 , 2974. Diastereoselective Hydroborations BH 3 ?THF BH 3 ?THF Diastereoselection 92 : 8 (anti) R = H Diastereoselection 6.8 : 1 (anti) Diastereoselection 6.6 : 1 (anti) R = OBn K. MoriTetrahedron 1979 , 32 , 1979. Oikawa & Co-workersTetrahedron Lett. , 1983 , 19 , 1987. a73 Anti –selective hydroborations with borane A 2:1 mixture of the lactol:lactone was obtained. This mixture wasoxidized to the keto-lactone in 73% overall yield from the olefin. Me OH Me H O Me Me OMe Me OMe Me X P OO H OH OH OBn OH Me OBn OH Me O Me OH X P Me OMe Me OMe Me O H Me OH Me Me OH Me H O Me OMe Me OMe Me X P O O Et OH Me O Me TBSO Me Me TBSO Me Me Et OH O OO H Et Me O Me TBSO Me OH OH Me OBn OH Me OH OH Me OH OBn Me OBn OH OBn Me Me OH OBn Me OBn OBn OH Me OH OH OHOH OH OH Me OH OBn OBn Me OBn OH Me Me OBn OH OBn Me OBn OH Me OH Me O O O O Me Me Me Me O BnO R Me Me O O Me R BnO OH O Me Me O O OH 10A-09-Hydroboration-2 10/8/00 8:13 PM RhL n Rh cat CB Evans & Fu JOC 1990 , 55 , 2280 and Evans, Fu, Anderson JACS 1992 , 114 , 6679. a73 Olefin ? catalyst complexation is the stereochemistry-determining step a73 Olefin binding to metal is irreversible for 1,1-disubstituted allylic alcohol derivatives Stereochemical Model RhL n The Catalyzed Hydroboration a73 Complexation involves back-donation from a filled metal d orbital →π * C=C a73 The EWG (alkoxy substituent) is aligned perpendicular to the olefin ( π→σ * C—O ) a73 This stereoelectronic interaction lowers the energy of π * a73 The small group is placed "inside", the most sterically congested site CB Rh cat syn anti anti syn 9-BBN El + 9-BBN El + The uncatalyzed variant: Complementary diastereoselectivity for the catalyzed and uncatalyzed reactions is observed for a wide range of substrates. Anti Syn 9-BBN9-BBN9-BBN 757267 Si( t -Bu)Me 2 3 : 97 95 : 595 : 5 96 : 4 R Conditions Anti : Syn H 50 : 50 15 : 85 68 65 77 Yield (%) THF 20 °C The Catalyzed vs Uncatalyzed Hydroboration Reactions Rh(PPh 3 ) 3 Cl / CB Rh(PPh 3 ) 3 Cl / CB Rh(PPh 3 ) 3 Cl / CB Si( t -Bu)Ph 2 Evans, Fu, & Hoveyda JACS 1988 , 110 , 6917 and JACS 1992 , 114 , 6671. K. Burgess & Co-workers, J. Org. Chem. 1991 , 56 , 1020-1027 i -Pr Me OR OR Me i -Pr i -Pr R H R'O C Me C HH R Me OR' OR' Me R Me OR OH C H H C Me OH H R'O R R Me OR' OH OH OH OH OR' Me R R'O H R C Me C HH R Me OR' OR' Me R C H H C Me H R OR' 10A-10-Cat Hydroboration 10/8/00 8:14 PM E. Vedejs & C. McClure JACS , 1986 , 108 , 1094. syn anti syn anti Vedejs Model OsO 4 X = SR, SO 2 R, SiR 3 X = OTBS, OAC OsO 4 Kishi Model OsO 4 OsO 4 34 : 6622 : 7833 : 6761 : 3962 : 38 selectivity PhMe 2 Si PhSO 2 PhSTBSOAcO X (E) Olefins (z) Olefins (E) Olefins (z) Olefins a73 Vedejs argues that hyperconjugative effects are not important because both EDG and EWG provide the same sense of induction a73 Addition occurs anti to the allylic heteroatom functionality X PhMe 2 Si PhSO 2 PhSTBSOAcO selectivity 78 : 2280 : 2083 : 1762 : 3870 : 30 OsO 4 Diastereoselective Osmylations James Barrow, Evans Group Seminar , "Osmium Mediated Dihydroxylation: Mechanism and Application" April 21, 1993. Kishi & Co-workersTetrahedron Lett ., 1983 , 24 , 3943 and Tetrahedron , 1984 , 40 , 2247. Acetates give lower selectivity a73 Allylic oxygen protecting group: H, Bn, SiR 3 , acetonides → all work well Works for both ( Z ) and ( E ) allylic ethers (alchols) OsO 4 attacks anti to the allylic oxygen substituent Arrange olefin in the stable ground state conformer a73 Kishi's Empirical Model: OsO 4 OsO 4 OsO 4 X MeOBn selectivity 60 : 4081 : 19 50 : 5086 : 14 selectivity MeOBn X Diastereoselective Osmylations OsO 4 Me OH Me X OH X Me H C H C H BnO OH X R OH OH BnO BnO C Me H C OH R X OH H Me BnO OH X X H Me OH Me Me X OH OH OH Me OH Me C (Me)H (H)Me C H H CH 2 OB n OBn X Me Me Me OH Me H X X OH Me C H C Me H X OH Me C Me H C H Me X H Me 10A-11-Osmylations 10/8/00 8:14 PM Houk, JACS , 1986 , 108 , 2754. a73 Oxygen avoids "outside" position to avoid repulsive electrostatic interactions with the incoming OsO 4 anti syn OsO 4 OsO 4 "inside alkoxy" Houk Model: Staggered transition states Vedejs model breaks downor iPr, Ph > Me 2 PhSi syn anti syn OsO 4 Fleming, JCS Perkin Trans I, 1992 , 3303-3308. Ratio R 34 : 66 67 : 33 92 : 08 Mei Pr PH OsO 4 Diastereoselective Osmylations PhMe 2 Si Me R RM e R M e PhMe 2 Si PhMe 2 Si OH OH OH OH H PhMe 2 Si R C H C HMe C Me H C H H XO R R H XO C H C H Me OH OH OH OH XO XO Me R Me R 10A-12-Osmylation 10/8/00 8:15 PM