D.A. Evans Olefin Addition Reactions: Part-3 Chem 206 Bromoniun lons or B-Bromocarbocations in Olefin Bromination. A Kinetic Approach to Product Selectivities httplwww.courses.fasharvardedu/-chem206/ M-F. Ruasse, Accts. Chem. Res. 1990, 23, 87(handout Investigation of the early Steps in Electrophilic Bromination through the emistry 206 Study of the Reaction of Sterically Encumbered Olefins R.S. Brown, Accts. Chem. Res. 1997, 30, 131(handout Advanced Organic Chemistry Predict stereochemical outcome Lecture number 10 Olefin Addition Reactions-3 ■ Olefin Oxymercura Hg(oAc)2, CH2Cl2 Halolactonization 78°cto-20° Simmons -Smith Reaction a Reading Assignment for week 99%, single A. Carey Sundberg: Part B; Chapter 4 Electrophilic Additions to C-C Multilple Bonds 0 Hg(OAc)2, CH2Cl2 Hoveyda, Evans, Fu(1993). Substrate-Directable Chemical 78°to-20° Reactions. Chem. Rev. 93: 1307-70( Handout) XHg S Brown. acc. chem. Res. 1996.30. 131-13 Wednesday Matthew d shair October 9. 2002
http://www.courses.fas.harvard.edu/~chem206/ O Me H Me OH Me HO BnO Me O O Me Me Me O Me H Me OH O BnO O O Me Me Me Me Me XHg O Me Me OR Me Me OR Me OH O OH A O OH O Me OR Me Me OR Me Me O D. A. Evans Chem 206 Matthew D. Shair Wednesday, October 9, 2002 ■ Reading Assignment for week Olefin Addition Reactions: Part–3 Chemistry 206 Advanced Organic Chemistry Lecture Number 10 Olefin Addition Reactions–3 ■ Olefin Bromination ■ Olefin Oxymercuration ■ Halolactonization ■ 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 ■ 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) ❋ ❋ R.S. Brown . Acc. Chem. Res. 1996. 30. 131-137
A. Evans Olefin Bromination -1 Chem 206 a Bromonium ion origin of the anti(trans )selectivity first suggested by Roberts, JACS 1937. 59. 947 Introduction Reaction is first order in alkene At low concentrations of Br. rxn is also first order in At higher concentrations of Br2 in nonpolar solvents rxn is second order in Br2 I First X-ray Structure of a bromonium ion: Brown, JACS 1985, 107, 4504 Substituent Effects on Bromination Rates Alkene eq -2 eq Br2 n-PrCH=CH2 t-BuCH=O (CH3)2C=CH CiS-CH3 CHECHCH 2620 trans-CH3 CH=CHCH Br-2 1,800,000 Br-4 X-ray structure a Stereochemical outcome versus structure( Br2 in HOAC 25) Alkene anti addition Alkene anti addition 2.116A A 100% 100% 73%
C C Br R R Br R R Br Br3 – C C R R R R Br Br– Br-1 Br-4 Br-2 Br-3 Br2 C C R R R R C C Br R R Br R Br2 R 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 D. A. Evans Olefin Bromination-1 Chem 206 Introduction ■ 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 . ■ Stereochemical outcome versus structure (Br2 in HOAc @ 25°) Alkene % anti addition 100% 100% 73% 83% 63% 68% Alkene % anti addition ■ Bromonium ion origin of the anti (trans) selectivity first suggested by Roberts, JACS 1937, 59, 947 ■ First X-ray Structure of a bromonuium ion: Brown, JACS 1985, 107, 4504 + Alkene krel 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 ■ Substituent Effects on Bromination Rates 2 eq Br2 -2 eq Br2 X-ray structure 2.116 Å 2.194 Å 1.497 Å
A. Evans Olefin Bromination -2 Chem 206 Calculated Geometries of substituted bromonium ions Overall Reaction Mechanisn Ruasse. Chem commun. 1990. 898 Second order Kinetics Products Br Br -HOR 2.01 188 mH Her C… Me mer Me 147 1.51 Note;the C-Br bond lengths in previous X-ray structure are 2.116A (π complex) a Bromonium lons undergo fast exchange with olefins Products Brown. Accts. Chem. Res. 1997. 30. 131 ird Order Kinetics Unprecedented until 1991(Bennet, JACS 1991, 113, 8532 Ad-C=C-Ad Ad-C--C-Ad Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 Ad-C-C-Ad Ad-C=C-Ad Me3C e3C r exclusive ex x=Br: exchange rate 2 x 106M-1s'1 H R=H Me Ad-C-C-Ad X=I: exchange rate: 8 X 10MS Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening( Lecture-3) OMe There is an intermediate in the halogen transfer(ab initio calcs) Me3C MeoH Br47% 仓Br 53% complex omplex OMe It appears that bromine attack from both olefin faces occurs wilth near equal probability
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 – Ad–C C–Ad Ad–C C–Ad Br Ad–C C–Ad Br3 – Ad–C C–Ad X R R R R R R R Br R R R R R R R R Br R complex TS complex Br2 Br2 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 R H H Me3C Br OMe H H H Me3C OMe Br H H D. A. Evans Olefin Bromination-2 Chem 206 ■ Calculated Geometries of Substituted Bromonium Ions Ruasse, Chem Commun. 1990, 898 1.47 2.01 1.51 2.05 1.51 2.70 1.88 Note; the C–Br bond lengths in previous X-ray structure are 2.116 Å. ■ Bromonium Ions undergo fast exchange with olefins Brown, 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 (p-complex) Overall Reaction Mechanism s-complex s-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
D. A. Evans Olefin bromination-2 Chem 206 Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 Representative Examples of Diastereoselective Bromination Diaxial opening of bromonium ions may be viewed as an extension of the Furst-Plattner Rule for epoxide ring opening.(Lecture-2 OMe Case A MeoH me3C\ Me3C Pyr-Br Br3 B→AB47%Hoe2dedg44 Br MeOh Me3C H Me3C 53% Minor product Major Product (70%) Pyr-Br Br3 How to generate either epoxide from a conformatinaly biased olefin 3C Me exclusive product RCO3H Epoxidation controlled by steric effects imposed by cis-fused ring OBr 8+ How do we construct the other epoxide diastereomer?? Me3C H syn-Unreactive anti-Reactive H20OB5 仓 Me3C、 Me observed Me HOMe syn-Unreactive 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. OH both bromohydrin afford same product
H Me3C H MeOH MeOH H Me3C Me MeOH H Me3C Br H H H Me3C Br H H H Me3C OMe Br Me H H Me3C Br OMe H H H Me3C OMe Br H H Me H Me H H H RCO3H Me R R H H H Br Br H H H Me3C Br Me H H Me3C Br Me H H Me3C Br Me H HOMe H Me3C Br Me H OMe –H+ Me H Br2 H2O Me H O H H Br2 HOAc Me H O Me H Br OH H H Me H Br H2O Br Me R R H H H Br H H Me R R H H H H H Br Br Me H Br OH H H Me H Br H2O D. A. Evans Olefin Bromination-2 Chem 206 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 d+ d+ d+ 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 minor major both bromohydrins afford same product
D A. Evans Olefin Oxymercuration-1 Chem 206 Oxymercuration Pasto JACS 1970, 92, 7480 Bromination of Cyclohexene Derivatives Pasto, JACS 1970, 92, 7480 The basic process Diaxial opening of bromonium ions may be viewed as an extension of the =”- NaBH Furst-Plattner Rule for epoxide ring opening.(Lecture-2) Case a Kinetics: Halpem, JACS 1967, 89, 6427 Reduction: Pasto, JACS 199, 91, 719 Overview B rown JoC 1981. 46. 3810 Me3C、 Oxy-Mercuration bromination follow identical pathways( Pasto) Br Me3C Meoh Me3C、 THF, H2O 53% OMe R=H41%48% OMe R=Me100% Meo Me3C、 Me exclusive product THF, H2O 8+ 仓Hgx Br Reduction of the Hg-C bond NaBH R-Hg-X R-Hg-H R-H observed HOMe OMe syn-Unreactive R-Hg From Case A. one assumes that both bromonium ions are formed: however Formate is an excellent source of hydride ion for for the syn isomer to react, ring opeing must proceed against the polarization late transition and heavy main-group metals due to Methyl substituent
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 C R H H H H Me3C OH HgOAc Me H H Me3C OH HgOAc R H ROH X–Hg–X H Me3C Br Me H C C R H H XHg H OR HOMe H Me3C HgOAc OH R H NaBH4 H Me3C Br Me H –H+ C C R H H H H OR H Me3C Me H Me3C Br Me H OMe H Me3C H MeOH MeOH H Me3C Br Me H MeOH H Me3C Br H H H Me3C OMe Br Me H H Me3C Br H H H Me3C Br OMe H H H Me3C OMe Br H H D. A. Evans Olefin Oxymercuration-1 Chem 206 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, 719 Overview: B rown, JOC 1981, 46, 3810. d+ d+ 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 d+ d+ d+
D. A. Evans Oxymercuration EXamples Chem 206 Diastereoselective ring closures via oxymercuration I Acyclic ally lic alcohols R ROH Et HoH 65% Mukaiyama, Chem Lett. 1981, 683 ese. Tet lett. 1985. 26. 1197 t MeoH93:0772% HOH88:1266 AcHr OTFAh - tBu HoH98:0270% AcNH CO2 Me "one isomer" OBn Sinay, Tet. Lett. 1984, 25, 3071 X Hg(OAc)2 H Hg(OAc)2 RL Isobe. Tet. Lett. 1985. 26. 5199 syn. anti=80: 20 Kinetic vs Thermodynamic control Chamberlin, Tetrahedron 1984, 40, 2297 H H O-acetate participation will tum over the stereochemical course of the n NaBH Bnoc BnOc H BnOc erythro Harding, JOC 1984, 49, 2838 Hg(OAC)2: short rXn times: 40: 60 Hg(OTFA)2: longer rxn times: 2: 98 With more electrophilic Hg() salt, more polar solvents, and COOMe BnO COOMe longer xn times, the rxn may be rendered reversible Seebach JACS 1983. 105 7407
HO HO RL RL C Hg X C H H H C H C H Me Hg X H H H OBn H OC6H11 BnO BnO H OH Hg(OTFA)2 OH H AcNHR' H OBn CO2Me OR H O OR HO Me H OBn H N Me BnO2C H H H NaBH4 Ph3SiH Hg(OTFA)2 NaBH4 Hg(OAc)2 Hg(OAc)2 NaBH4 XHg–HgCH2 H N BnO2C H Me H O H BnOBnO H H OC6H11 OBn O OR CO2Me OBn H R' AcNH H H OBn Me H HO O OR HO H N Me BnO2C H CH2–HgX H OAc Et n-Bu OH Me R OH OH RL HOH NaBH4 Hg(OAc)2 Me BnO O 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 Me Et 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. D. A. Evans Oxymercuration Examples Chem 206 Diastereoselective ring closures via oxymercuration a:b = 96 : 4 Mukaiyama, Chem. Lett. 1981, 683 Sinay, Tet. Lett. 1984, 25, 3071 "one isomer" Isobe, Tet. Lett. 1985, 26, 5199 ■ Kinetic vs Thermodynamic control: Hg(OAc)2 : short rxn times : 40 : 60 Hg(OTFA)2: longer rxn times : 2 : 98 Harding, JOC 1984, 49, 2838 syn:anti = 80 :20 Chamberlin, Tetrahedron 1984, 40, 2297 R'OH ■ Acyclic allylic alcohols: R'OH Ratio -Et 76 : 24 yield 65% -Et 93 : 07 72% -Ph 88 : 12 66% -tBu 98 : 02 70% Giese, Tet. Lett. 1985, 26, 1197 erythro 77 : 23 O-acetate participation will turn over the stereochemical course of the rxn Seebach, JACS 1983, 105, 7407 diastereoselection = 83 : 17 (79%)
D. A. Evans Oxymercuration EXamples Chem 206 Oxymercuration via Hemiketals Hemiacetals Proposed Mechanism J. L Leighton et al, Org. Lett. 2000, 2, 3197-3199 I Lewis acid catalyzes formation of hemiketal General Reaction: diastereoselection >10: 1 R HgCIOAC Yb(×2 a The Oxymercuration Step(Kinetic Phase) HocIOAc Yb(X2) Mechanistic Observations. rate-determining H + HgCIOAC HgCIOAC Me acetone, 2h rt HgCl do 1: 1-mixture of diastereomers Yb(X2) much recovered starting material that mercurium ion formation is rate-determining under A)Lewis acid would promote the formation of the putative hemiketal imtermediate tures and longer reaction times the products are shown to B)Lewis acid would promote reversability of the oxymercuration prooes M OAc, 5% Yb(oYtl3 5%Yb(oYt)3 1. 1-mixture of diastereomers H Me MM-2 H x‖ 93% yield Erel=+5.2 kcal/mol
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 Me Me Me3C O O HgCl Me Me R O O HgCl Me Me R O O HgCl Me Me 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 ) Hg X O O H R Me Me H Yb(X2 ) Hg X 5% Yb(OYt)3 Hg Cl 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 D. A. Evans Oxymercuration Examples Chem 206 Oxymercuration via Hemiketals & Hemiacetals ■ Lewis acid catalyzes formation of hemiketal + J. L. Leighton et. al, Org. Lett. 2000, 2, 3197-3199 + ■ General Reaction: diastereoselection >10:1 ■ Mechanistic Observations: + ❉ ~1:1-mixture of diastereomers Product formed in low yield. much recovered starting material acetone, 2h rt + ❉ acetone, 2 min 0 °C ~1:1-mixture of diastereomers 93% yield Proposed Mechanism ■ 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
D A. Evans Oxymercuration Examples: X-206& Lonomycin Syntheses Chem 206 X-206 Synthesis(with S Bender, JACS 1988, 110, 2506) lonomycin Synthesis (with Dow& Shih, JACS 1990, 112, 5290) lonomycin Calci C1-C16 Subunit C17-C37 Subunit Assemblage strategy for Ring A: Hg(OAch, CH2Cl2 Predicted stereochemical outcome: o' 3 8ct-20° CO2R H 85%,d=93:7 Hg(oAc)2 CH2Cl2 ROR
Me OH OH Me Me O Me O O Me Me Me O O O Me OH H Me H Me Ca Me OH OH R Me O O Me OH H Me H Me O Me H Me OH Me HO BnO Me O O Me Me Me O Me H Me OH O BnO O O Me Me Me Me H Me XHg Me OH OH R Me HO O Me OH Me H Me RO C H C Me H Hg X H A A Me OR Me CO2R OH RL O OH O Me OR Me Me OR Me Me O B HgX2 O O O O OH Me Me Me OH Me Me O Me OH OH OH O O Et OH Me H OH Me Me H Me C Hg(OAc)2 CH2Cl2 RL D A H RL H H Hg–X Me CO2R H Me H OH H OR D Me Me OMe Me H Me OH Et O O O OR H O O Me Me O Me Me OR Me Me OR Me OH O OH F H O Me RL H RO2R Me OR H H HgX F H O O Me Me R1 Me H H HO R2 Me H H H O O Me Me R1 Me H H HO R2 Me Hg H H X HgX+ D. A. Evans Oxymercuration Examples: X-206 & Lonomycin Syntheses Chem 206 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 +
D. A. Evans Related Olefin Addition RXns: Halogen Electrophiles Chem 206 Other electrophilic olefin addition reactions afford the same stereochemical outcome lodine-induced lactonization is also highly stereoselective a Chamberlin(JACS 1983, 105, 5819) Hg(OAc)2 e L2, HOH/THF to=80 CH2 OAC 么 HOAr Hc AH HOAC As we have seen before, gauche B is more destabilizing than gauche A Rato=98:2(78%) R=OMe Ratio BUOOH HOAc HO, Me H 96:4(685% Rato=94:6(85%) Chamberlin. Tetrahedron 1984. 40. 2297 This is an exceptional approach to the creation of either syn or anti ■ Other cases actonization ratio= 96:4 a Chamberlin methodology employed in cytovaricin synthesis Acs1990,112,7001 Me Ratio TIPSo O TIPSO >95:5(49% Me,THF4℃ 0. 25 M KH PO4 l2, HOH/THF R=H77:23(74% TsOH,cHs2cOcH3225°c TIPSO R=Me:42:58(81%) Me This methodology superior to oxymercuration 67% overall itemative which was evaluated first h2, HOH/THI R=H:87:13141% diastereoselection 96.4 HO 0NR=Me:90:10(94%)
HO HO HO HO n-Bu C H C Me H I n-Bu n-Bu H C H C H Me Hg X C I C Me H H H H -O2C CH2 C Me 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 C Me H Me CH2 -O2C Me I O HO R O O R HO O I Me Me O Me HO O I I O HO H O Me H B K2CO3 MeOH O MeO Me OH Me O I O HO Me O Me R = OMe R = H D. A. Evans Related Olefin Addition Rxns: Halogen Electrophiles 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 anti 1,3-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 ■ Chamberlin methodology employed in cytovaricin synthesis (JACS 1990, 112, 7001) This methodology superior to oxymercuration alternative which was evaluated first ■ Chamberlin (JACS 1983, 105, 5819) Iodine-induced lactonization is also highly stereoselective I2 , HOH/THF Ratio 96 : 4 (85%) As we have seen before, gauche B is more destabilizing than gauche A t-BuOOH VO(acac)2 Lactonization Ratio = 96 : 4 Epoxidation Ratio = 3 : 97 ■ 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%)
D A. Evans Related olefin Addition rxns Chem 206 Olefin Sulfenation follows the preceding stereochemical analogies Halogen-induced heterocyclization in the synthesis of monensin Men A Hg(oAc)2 CH2OH Kishi,JAcs1979,101,259,260,262 I The Kishi Ring D Construction St,JAcS1980,103,21172121 l2, HOAc △Me Rao=98:2(78%) kGaX。一 only one diastereomer Ph H OMe CI Stereocontrol through A(1, 3) Phs-cl Ar Reetz, Angew. Chem. Int Ed. 1987, 26, 1028 DMSO The above stereochemistry is inferred from the following reaction I The Still Ring E Construction D Meo CH2OH Stereocontrol through A(1, 3) Ag2CO3% Me Phs-cI 87% Rato=95:5{59% Me Me Cardillo, Tetrahedron 1990. 46. 3321-3405 Bartlett, Asymmetric Synthesis 1984, 3, Chap 6, 411-454
Me HO S Ph C C Et H H HO C C Me Me OH H Ar O O Me H Et H H Me CH2OH HO Me Me O O R R O O Me Me O Me H D O HO Me Me O Me O Me Me Me Me O O Me O Me Me I O n-Bu n-Bu C H C H Me Hg X C I C Me H H H H O Et Ar Me OH Me Me H MeO H C H C H Me S Ph MeO H Me C D D D D D D H Et H Me O O Ar H Br Me Me H Me O Me Me HO OH 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 Me H Et H 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 Me Me SPh Me SPh Me PhS–Cl Me2Zn TiCl4 Me2Zn TiCl4 PhS–Cl PhS–Cl MeCN DMSO KI3 HCO3 – Ag2CO3 H H -O O Me Me H El(+)-induced heterocyclization 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 D. A. Evans Related Olefin Addition Rxns Chem 206 Halogen-induced heterocyclization in the synthesis of monensin Kishi, JACS 1979, 101, 259, 260, 262 Still, JACS 1980, 103, 2117-2121 E ■ The Kishi Ring D Construction: 57% only one diastereomer KO2 _ 47% Stereocontrol through A(1,3) Strain ■ The Still Ring E Construction: 87% 50% I(+) Stereocontrol through A(1,3) Strain
