http://www.courses.fas.harvard.edu/~chem206/ O MeH Me OH MeHO BnO Me O OMe Me Me O MeH Me OH O BnO O O MeMe Me Me Me XHg O Me Me OR Me Me OR Me OH OHO A O OH OMe OR MeMe ORMe Me O Chem 206D. A. Evans Matthew D. Shair Wednesday, October 9, 2002 a73 Reading Assignment for week Olefin Addition Reactions: Part–3 Chemistry 206 Advanced Organic Chemistry Lecture Number 10 Olefin Addition Reactions–3 a73 Olefin Bromination a73 Olefin Oxymercuration a73 Halolactonization a73 Simmons-Smith Reaction Investigation of the early Steps in Electrophilic Bromination through the Study of the Reaction of Sterically Encumbered Olefins R. S. Brown, Accts. Chem. Res. 1997, 30, 131 (handout) A. Carey & Sundberg: Part B; Chapter 4"Electrophilic Additions to C–C Multilple Bonds" Hoveyda, Evans, & Fu (1993). Substrate-Directable Chemical Reactions. Chem. Rev. 93: 1307-70 (Handout) Hg(OAc)2, CH2Cl2 -78 oC to -20 oC 85%, dr = 93 : 7 a73 Predict stereochemical outcome 99% 1 16 99%, single diastereomer Hg(OAc)2, CH2Cl2 -78 oC to -20 oC Bromoniun Ions or -Bromocarbocations in Olefin Bromination. A Kinetic Approach to Product Selectivities M-F. Ruasse, Accts. Chem. Res. 1990, 23, 87 (handout) a70 a70 R.S. Brown . Acc. Chem. Res. 1996. 30. 131-137. C C Br R RBr R R Br Br3– C CRR RR Br Br– Br-1 Br-4 Br-2 Br-3 Br2 CC R R R R C C Br R RBr R RBr2 Ph H Me H Ph Me H Me Ph Me Me H R R R R Ph H H Me Me H H Me Me H Me H Chem 206D. A. Evans Olefin Bromination-1 Introduction a73 Reaction is first order in alkene At low concentrations of Br2, rxn is also first order in Br2 At higher concentrations of Br2 in nonpolar solvents rxn is second order in Br2. a73 Stereochemical outcome versus structure (Br2 in HOAc @ 25°) Alkene % anti addition 100% 100% 73% 83% 63% 68% Alkene % anti addition a73 Bromonium ion origin of the anti (trans) selectivity first suggested by Roberts, JACS 1937, 59, 947 a73 First X-ray Structure of a bromonuium ion: Brown, JACS 1985, 107, 4504 + krelAlkene 1 61 70 57 27 5470 2620 1700 130,000 1,800,000 CH2=CH2 CH3CH=CH2 n-PrCH=CH2 i-PrCH=CH2 t-BuCH=CH2 (CH3)2C=CH2 cis-CH3CH=CHCH3 trans-CH3CH=CHCH3 (CH3)2C=CHCH3 (CH3)2C=C(CH3)2 a73 Substituent Effects on Bromination Rates 2 eq Br2 -2 eq Br2 X-ray structure 2.116 ? 2.194 ? 1.497 ? C C H H H H Br C C Me Me Me Me Br R R R R R R R Br R C C H H Me Me Br Ad–C C–Ad Br Br3– C–AdAd–CC–AdAd–C Br Ad–C C–Ad Br3– C–AdAd–C X R R R R R R R Br R R R R R R R R Br R TScomplex complex Br2Br2 Br2 A B H Me3C R H Me3C H MeOH H Me3C Br H H H Me3C Br H H MeOH Br Br Br3– Br–.HOR H Me3C Br Br RH H Me3C Br OMe HH H Me3C OMe Br HH Chem 206D. A. Evans Olefin Bromination-2 a73 Calculated Geometries of Substituted Bromonium IonsRuasse, Chem Commun. 1990, 898 1.47 2.01 1.51 2.05 1.51 2.701.88 Note; the C–Br bond lengths in previous X-ray structure are 2.116 ?. a73 Bromonium Ions undergo fast exchange with olefinsBrown, Accts. Chem. Res. 1997, 30, 131 Unprecedented until 1991 (Bennet, JACS 1991, 113, 8532) X = Br: exchange rate: 2 x 106 M–1 s-1 X = I : exchange rate: 8 x 106 M–1 s-1 There is an intermediate in the halogen transfer (ab initio calcs): + + + Products (pi-complex) Overall Reaction Mechanism σ-complex σ-complex Second Order Kinetics Third Order Kinetics Products Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 Pyr–Br+ Br3– R = H, Me exclusive product Pyr–Br+ Br3– 47% 53% Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening (Lecture-3). It appears that bromine attack from both olefin faces occurs wilth near equal probability. H Me3C H MeOH MeOH H Me3C Me MeOH H Me3C Br H H H Me3C Br H H H Me3C OMe Br MeH H Me3C Br OMe HH H Me3C OMe Br HH Me H Me H H H RCO3H Me R R H HH BrBr H H H Me3C Br Me H H Me3C Br Me H H Me3C Br Me H HOMe H Me3C Br MeH OMe –H+ Me H Br2 H2O Me H O H H Br2 HOAc Me H O Me H Br OHH H Me H Br H2O Br Me R R H HHBr HH Me R R H HH H H Br Br Me H Br OH H H Me H Br H2O Chem 206D. A. Evans Olefin Bromination-2 Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 Pyr–Br+ Br3– 47% 53% Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening. (Lecture-2) Pyr–Br+ Br3– exclusive product syn-Unreactive Case A Case B From Case A, one assumes that both bromonium ions are formed; however, for the syn isomer to react, ring opeing must proceed against the polarization due to Methyl substituent. anti-Reactive Representative Examples of Diastereoselective Bromination syn-Unreactive not observed δ+δ+ δ+ Major Product(70%)Minor Product (7%) House 2nd Ed, pg 424 How to generate either epoxide from a conformatinaly biased olefin Epoxidation controlled by steric effects imposed by cis-fused ring How do we construct the other epoxide diastereomer?? base majorminor both bromohydrins afford same product R Hg–X NaBH4 H Me3C Hg–X Me H H–CO2– R Hg O H O –CO2 R Hg–H H Me3C Me H Me3C R THF, H2O R H Hg(OAc)2 H Me3C Hg–X Me H THF, H2O Hg(OAc)2 C CRH HH H Me3C OH HgOAc MeH H Me3C OH HgOAc RH ROH X–Hg–X H Me3C Br Me H C C RH HH XHg OR HOMe H Me3C HgOAc OH RH NaBH4 H Me3C Br Me H –H+ C C RH HH H OR H Me3C Me H Me3C Br MeH OMe H Me3C H MeOH MeOH H Me3C Br Me H MeOH H Me3C Br H H H Me3C OMe Br MeH H Me3C Br H H H Me3C Br OMe HH H Me3C OMe Br HH Chem 206D. A. Evans Olefin Oxymercuration-1 R = H 41% 48% R = Me 100% Oxy-Mercuration & bromination follow identical pathways (Pasto) Oxymercuration Pasto, JACS 1970, 92, 7480 exclusive product syn-Unreactive anti-Reactive Reduction of the Hg–C bond nonstereoselective radical chain process Formate is an excellent source of hydride ion for late transition and heavy main-group metals The basic process: Kinetics: Halpern, JACS 1967, 89, 6427 Reduction: Pasto, JACS 199, 91, 719Overview: B rown, JOC 1981, 46, 3810. δ+ δ+ Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 Pyr–Br+ Br3– 47% 53% Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening. (Lecture-2) Pyr–Br+ Br3– exclusive product syn-Unreactive Case A Case B From Case A, one assumes that both bromonium ions are formed; however, for the syn isomer to react, ring opeing must proceed against the polarization due to Methyl substituent. anti-Reactive syn-Unreactive not observed δ+δ+ δ+ HO HO RL RL C Hg X C H H H CH C H Me Hg X H H H OBn OC6H11H BnOBnO H OH Hg(OTFA)2 OH H AcNHR' H OBn CO2Me ORH O ORHO Me H OBn H N Me HBnO2C H H NaBH4 Ph3SiH Hg(OTFA)2 NaBH4 Hg(OAc)2 Hg(OAc)2 NaBH4 XHg–HgCH2 H NBnO 2C H Me H O H BnOBnO H H OC6H11 OBn O OR CO2Me OBn H R'AcNH H H OBn HMe HO O ORHO H N Me HBnO2C CH2–HgX H OAc Et n-Bu OH Me R OH OH RL HOH NaBH4 Hg(OAc)2 Me OBnO COOMe Hg(OAc)2 Hg(OAc)2 Hg(OAc)2 OH Et Me OAc OH R OR' HgOAc BnOH NaBH4 Hg(OAc)2 R OH MeEt OAc NaBH4 HOH HOH HOH MeOH COOMe BnO O Me OBn OR' R Me OH OH RL HgOAc Me OH HgOAc OR' RL OH With more electrophilic Hg(II) salt, more polar solvents, and longer rxn times, the rxn may be rendered reversible. Oxymercuration ExamplesD. A. Evans Chem 206 Diastereoselective ring closures via oxymercuration α:β = 96 : 4 Mukaiyama, Chem. Lett. 1981, 683 Sinay, Tet. Lett. 1984, 25, 3071 "one isomer" Isobe, Tet. Lett. 1985, 26, 5199 a73 Kinetic vs Thermodynamic control: Hg(OAc)2: short rxn times : 40 : 60 Hg(OTFA)2: longer rxn times : 2 : 98Harding, JOC 1984, 49, 2838 syn:anti = 80 :20Chamberlin, Tetrahedron 1984, 40, 2297 R'OH a73 Acyclic allylic alcohols: R'OH Ratio -Et 76 : 24 yield 65% 72%93 : 07-Et -Ph 88 : 12 66% 70%98 : 02-tBu Giese, Tet. Lett. 1985, 26, 1197 erythro 77 : 23 O-acetate participation will turn over the stereochemical course of the rxn diastereoselection = 83 : 17 (79%)Seebach, JACS 1983, 105, 7407 R OH O H R' HgClOAc 5% Yb(OYt)3 R OH O Me Me HgClOAc 5% Yb(OYt)3 R OH O Me Me HgClOAc Lewis acid addends were surveyed. the logic for this step was two-fold: (A) Lewis acid would promote the formation of the putative hemiketal imtermediate.(B) Lewis acid would promote reversability of the oxymercuration process Me3C OH O Me Me HgClOAc 5% Yb(OYt)3 O O H Me Me Me H Me O O H Me Me Me Me H MM-2 Me3C O O HgCl MeMe Me3C O O HgCl MeMe R O O HgCl MeMe R O O HgCl MeMe R O O HgCl R' HOAc, 5% Yb(OYt)3 O O H R Me Me H Yb(X2) O O H R Me Me H Yb(X2) O O H R Me Me H ClHg OH H R H HgClOAc HgClOAc O Me Me Yb(X2) HOAc, 5% Yb(OYt)3 O O H R Me Me H Yb(X2) HgX O O H R Me Me H Yb(X2) HgX 5% Yb(OYt)3 HgCl YbX3 O O H R Me Me H Hg H Cl YbX3 O O H R Me Me H Yb(X2) O O H R Me Me H H O O H R Me Me H HgCl –OAc Oxymercuration ExamplesD. A. Evans Chem 206 Oxymercuration via Hemiketals & Hemiacetals a73 Lewis acid catalyzes formation of hemiketal + J. L. Leighton et. al, Org. Lett. 2000, 2, 3197-3199 + a73 General Reaction: diastereoselection >10:1 a73 Mechanistic Observations: + a68 ~1:1-mixture of diastereomersProduct formed in low yield. much recovered starting material acetone, 2h rt + a68acetone, 2 min0 °C ~1:1-mixture of diastereomers 93% yield Proposed Mechanism a73 The Oxymercuration Step (Kinetic Phase) rate-determining step low diastereoselectivity Erel = 0 Erel = +5.2 kcal/mol Leighton presumes that mercurium ion formation is rate-determining under kinetic conditions. At higher temperatures and longer reaction times the products are shown to interconvert. Me OH OHMe Me O Me O O Me Me Me O O O Me OHMeHMeH Ca Me OH OH R Me O O Me OHMeHMeH O MeH Me OH Me HO BnO Me O OMe Me Me O MeH Me OH O BnO O O MeMe Me Me MeH XHg Me OH OH R Me HO O Me OHMeHMe RO CH C Me H Hg X H A A Me OR Me CO2R RLOH O OH OMe OR MeMe ORMe Me O B HgX2 O O O O OHMe Me Me OH Me Me O Me OH OHOH O O Et OH Me H MeOH Me MeH C Hg(OAc)2CH 2Cl2 RL D A H RL H H Hg–X Me CO2RH Me H OH H OR D Me Me OMe Me H Me OHEt O OO OR H OO Me Me O Me Me OR Me Me OR Me OH OHO F H O RLMe H RO 2R Me OR H H HgX F H O O Me Me R1 Me H HHO R2 Me H H H O O Me Me R1 Me H HHO R2 Me Hg H H X HgX+ Chem 206D. A. Evans Oxymercuration Examples: X-206 & Lonomycin Syntheses X-206 Synthesis (with S. Bender, JACS 1988, 110, 2506) 1 E E C17-C37 Subunit C1-C16 Subunit 16 7 + aldol Assemblage strategy for Ring A: 16 1 9 7 9 7 9 7 Predicted stereochemical outcome: 99% Ionomycin Synthesis (with Dow & Shih, JACS 1990, 112, 5290) Ionomycin Calcium Complex Hg(OAc)2, CH2Cl2 -78 oC to -20 oC 85%, dr = 93 : 7 + HO HO HO HO n-Bu CH C Me H I n-Bu n-Bu H CH C H Me Hg X C I C Me H H H H -O2C CH2 CMe C H Me I H + n-Bu OH Me Me OH n-Bu n-Bu OH Me Hg(OAc)2 HOAc HOAc OH n-Bu I Me OAc OAc Me I n-Bu OH OH n-Bu HgOAc Me OH Me OH Me RO O Me TIPSO Me OH Me TIPSO Me OH I OH O Me O Me TIPSO Me Me O HO OH Me R OH HO O Me Me O HO OH R HCO3– HCO3– HCO3– HCO3– A O Me OH Me MeO O HO C I CMeH Me CH2-O 2C Me I O HO RO O R HO O I Me Me O Me HO O I I O HO HO Me H B K2CO3 MeOH O MeO Me OH MeO I O HO MeO Me R = OMe R = H Related Olefin Addition Rxns: Halogen ElectrophilesD. A. Evans Chem 206 Other electrophilic olefin addition reactions afford the same stereochemical outcome ratio = 80 :20 Ratio = 98 : 2 (78%) Chamberlin, Tetrahedron 1984, 40, 2297 I2, HOAc I2, HOAc Ratio = 94 : 6 (85%) This is an exceptional approach to the creation of either syn or anti1,3-dioxygen relationships 67% overall n-Bu3SnH, toluene, 25 °C TsOH, (CH3)2C(OCH3)2, 25 °C I2, THF, 4 °C 0.25 M KH2PO4, diastereoselection 96 : 4 a73 Chamberlin methodology employed in cytovaricin synthesis (JACS 1990, 112, 7001) This methodology superior to oxymercurationalternative which was evaluated first a73 Chamberlin (JACS 1983, 105, 5819) Iodine-induced lactonization is also highly stereoselective I2, HOH/THF Ratio96 : 4 (85%) As we have seen before, gauche Bis more destabilizing than gauche A t-BuOOHVO(acac) 2 Lactonization Ratio = 96 : 4 Epoxidation Ratio = 3 : 97a73 Other cases: I2, HOH/THF Ratio >95 : 5 (49%) R = H: 77 : 23 (74%)I2, HOH/THF R = Me: 42 : 58 (81%) R = Me: 90 : 10 (94%) I2, HOH/THF R = H: 87 : 13 (41%) Me HO S Ph C C Et H H HO C C MeMe OHH Ar O O Me HEtH H Me CH2OHHO Me Me OO R R O O Me Me O Me H D O HO Me Me O Me O Me Me MeMe OO Me O Me Me OI n-Bu n-Bu CH C H Me Hg X C I C Me H H H H O EtAr Me OH Me Me H MeO H CH C H Me S Ph HMeO Me C D D D D D D H Et H Me OOAr H Br Me Me H Me O Me Me HOOH R + + + E E E E E Me OH n-Bu n-Bu OH Me Hg(OAc)2 HOAc OAc Me I n-Bu OH OH n-Bu HgOAc Me OH D A B O O O O O Me Me HO CH2OH Me HEtHMe HO Me HO O Me MeO Me C NBS D Me OMe Me OMe Me SPh Me Cl Me Et SPh Me MeO Et OMe Me Me MeMe SPh Me SPhMe PhS–Cl Me2ZnTiCl 4 Me2ZnTiCl 4 PhS–Cl PhS–Cl MeCN DMSO KI3 HCO3– Ag2CO3 H H-O O Me Me H El(+)-inducedheterocyclization Bartlett, Asymmetric Synthesis 1984, 3, Chap 6, 411-454 Cardillo, Tetrahedron 1990, 46, 3321-3408 Ratio = 95 : 5 (59%) Ratio = 99 : 1 (40%) The above stereochemistry is inferred from the following reaction: Reetz, Angew. Chem. Int. Ed. 1987, 26, 1028 + I2, HOAc Ratio = 98 : 2 (78%) ratio = 80 :20 Olefin Sulfenation follows the preceding stereochemical analogies Chem 206D. A. Evans Related Olefin Addition Rxns Halogen-induced heterocyclization in the synthesis of monensin Kishi, JACS 1979, 101, 259, 260, 262 Still, JACS 1980, 103, 2117-2121 E a73 The Kishi Ring D Construction: 57% only one diastereomer KO2_ 47% Stereocontrol through A(1,3)Strain a73 The Still Ring E Construction: 87% 50% I(+) Stereocontrol through A(1,3)Strain OH OH OR OO BnOH2C CH2OBn Me CH2 OR Me CH2OBnBnOH2C O O CH2 OH CH2 OH CH2 OH Zn-Cu CH2I2 CH2I2 Zn-Cu Zn-Cu CH2I2 CH2I2 Zn-Cu OH H OR R R HO R' R'' NHSO2Ar NHSO2Ar CH3Me3C HO CH2OHPhCH 2CH2 R CH3 OH ICH2ZnI CH2I2 CH2I2 Zn Et2Zn CH2I2 CH2I2 Zn-Cu CH2 ZnI I R R ICH2ZnI OH R'' R' PhCH2CH2 CH2OH Me3C R'' OH R CH3 OH R R ZnI2 R' OH R'' OH CH3R R' R" Ratio Ph nBu 1 : 1.4 Ph iPr > 200 : 1 Ph tBu > 200 : 1 tBu CH3 1 : 5.1 tBu iPr > 200 : 1 > 200 : 1 (99%) Isolated alkenes and homoallylic alcoholsare inert to these reaction conditions. G. A. Molander and J. B. Etter J. Org. Chem. 1987, 52, 3942 Sm or Sm/Hg a73 Low-valent Samarium Variants: Molander,JOC 1987, 52, 3942 These results suggest that the transition state might be binuclear. Construct a reasonable transition structure which accomdates the data 10 mol% 80% ee (82% yield) ? a73 Enantioselective Simmons-Smith Variants: Kobayashi, Tet. Let. 1992, 33, 2575 a73 The classical mechanism + + R Ratio CH3 57 : 43 Et 64 : 36 tBu 67 : 33 M. Pereyre and Co-workers J. Chem. Res. (S) 1979, 179 Absolute control of stereochemistry is possible through chiral ketal auxiliaries Yamamoto, Tetrahedron, 1986, 42, 6458 Mash, JACS, 1985, 107, 8256 Yamamoto, JACS, 1985, 107, 8254 diastereoselection 20:1 epoxidation also gives anti adduct 3 1 O–C1–C2–C3 dihedral = 165 ° S. Winstein, JACS, 1969, 91, 6892 9 : 1 >99 : 1 R = OAc: 4:1 R = OMe: >99:1 Sawada, JOC 1968, 33, 1767 CH2I2, Zn-Cu Dauben, JACS 1963, 85, 468 79 % >99:1 A large rate acceleration relative to simple olefins was observed. S. Winstein, JACS 1959, 81, 6523; 1961, 83, 3235; 1969, 91, 6892 The Simmons-Smith ReactionD. A. Evans Chem 206 For a recent general review of the Simmons-Smith reaction see: Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001) 165 o Me O Me EtMe Me O Me HO2C Me OHMe OH OH LnM O R O Me Me MeO Me Me OH[O] Me O Me Et Me Me O Me HO2C Me OHMe OH OH M OR O Me Me MeO Me Me OH O O O Me O Me EtMe Me O Me HO2C Me OHMe OH OH O LnM OOOOO Me MeO Me HO2C HO Me Me Me H H OHMe H Me H OHMe H OOOOO Me MeO Me HO2C HO Me Me Me H H OHMe H Et H OHMe H C. A. Morales Chem 206Olefin Addition Rxns in Polyether Synthesis-1 One plausible biosynthetic proposal for polyether natural products: Monensin B Cane, D. E. JACS, 1983, 105, 3394.Cane, D. E. JACS, 1982, 104, 7274. An alternate biosynthetic proposal: Townsend, C. A.; Basak, A. Tetrahedron, 1991, 47, 2591. from lecture 7 (Z,Z,Z)-premonensin triene [2+2] Monensin reductive elimination Me OH Me Me MeMe PCC HOAc Me OH Me Me Me Me PCC HOAc OO H Me Me Me O OO H Me Me Me O OHOO H Me H Me Me Me Me OHOO H Me H Me Me Me Me OHOO H Me H Me Me Me Me OHOO H Me H Me Me Me Me OR S RL H RZ RE OH O Cr H RZ RE RL RS H H O O OH i-Pr OHMe Me Me PCC HOAc O CrRL RS H H O O OH H RE RZ O CrRL RS H H O OH H R E RZ O O H i-Pr Me O Me C. A. Morales Chem 206Olefin Addition Rxns in Polyether Synthesis-2 A biomimetic model for syn-oxidative polycyclization: McDonald, F. E. JACS, 1994, 116, 7921. 9% combined, 11:1 (trans:cis) 38%, 9.9:1 19% combined, 3.7:1 (trans:cis) 24%, 17:1 High syn-stereospecificity for tertiary alcohols But for secondary alcohols... ...simple oxidation occurs more rapidly than oxidative cyclization. Conformational model for syn-oxidative cyclization: [2+2] reductive elimination trans-substitutedtetrahydrofuran Does this explain the lower degree of "trans-cross-ring" selectivity observed for (E)-olefins? Me EtMe Me O MeMe Me OEtHHO Me O Me EtMe Me O Me HO2C Me OHMe OH OH LnM O Me Et Me Me HO OH O MeMe Me OHEtHAcO (Cl2CHCO2)ReO3 (Cl2CHCO)2O O MeMe EtHAcO O Me OHH H C D OOOOO Me MeO Me HO2C HO Me Me Me H H OHMe H Et H OHMe H C D HO O O Me OEt HH OH H OH H OH n-C12H25 n-C12H25O H n-C12H25OH Et O HH OH H OH H OH n-C12H25HO O O Me n-C12H25OH (Cl2CHCO2)ReO3 (Cl2CHCO)2O NHSO2CF3 NHSO2CF3 Application of the model for syn-oxidative polycyclization using an all (Z)-polyolefin: McDonald, F. E. Pure App. Chem., 1998, 70, 355. (Z,Z,Z)-premonensin triene Monensin C. A. Morales Chem 206Olefin Addition Rxns in Polyether Synthesis-3 AD-mix β CrO3(py)2 1) Ac2O, Et3Ncat. DMAP 2) NaBH4, CeCl3 5 Goniocin 5 (E,E,E)-pregoniocin triene Et2Zn, Ti(O-i-Pr)4 * * One stereocenter ( ) controls the induction of six additional centers.* Application of the model for syn-oxidative polycyclization on an all (E)-polyolefin: