Master Course 2018-19 in Organic Chemistry methods and design in organic synthesis Pere Romea Rubik’s cube 4.2. Single & Double Bonds Non functional group R R disconnection Carbon-a Carbon-d R R ¿"? Alkyl%d Alkyl%a Li Potential precursors X Alkyl lithium Alkyl halide, X: Cl, Br, I MgBr RSO3 Alkyl magnesium halide Alkyl sulfonates M + Y M: Li, MgX M: halide, sulfonate The reaction is plagued by many side reactions due to high pKa of Alkyl-d (pKa 45–50) OH OMe O N O MeO H N O (–) Hennoxazole A ?antiviral Smith, T. E. JOC 2008, 73, 142 Polyfibrospongia OH OMe O N O MeO H N O ¿ FGA ? OPG OMe TBS O N O MeO H N O OPG OMe TBS O N O Li Br MeO H N O Oxazole alkylation studies O Ph N two potential reacting sites Oxazole alkylation studies Li Li O base O O –78 °C Ph N Ph N Ph N MeI MeI ratio 1:2 O Me Me O BuLi LDA LiNEt2 (14:86) (37:63) (99:1) Ph N Ph N 1 2 This reversal of regioselectivity is thought to arise from the ability of Et2NH to mediate the low-temperature equilibration of a kinetic mixture of otherwise noninterconverting lithiated intermediates However, such a situation was dramatically modified in a model close to the TGT structure TAKE-HOME MESSAGE: the model should be as similar as possible to the real system Oxazole alkylation studies single product Chelation could be the reason O Li O Li O MeO OMe MeO OMe MeO OMe N base N N H N N N –78 °C H H O O O three potential base: BuLi, LDA, LiNEt2 reacting sites These results suggest that deprotonation at the heterocycle is thermodynamically as well as kinetically favored SOLUTION: BLOCKING THAT POSITION? TBS TBS TBS O O Me O Me MeO OMe 1) base, –78 °C MeO OMe MeO OMe N N + N H N 2) 2 equiv MeI H N H N O O O ratio mono:di:SM Me BuLi LDA LiNEt2 (60:12:28) (43:8:48) (88:5:7) Alkylation of OTBS the real system OMe TBS N O O MeO H O N 1) LiNEt2, THF, –78 °C 2) Br 77% OTBS OMe TBS N O O MeO H O N TBAF, THF, rt 99% OH OMe TBS N O O MeO H (–) Hennoxazole A O N Alternative (I): Terminal Alkynes FGA Alkynyl&d Alkyl&a R H + n-BuLi R Li + n-BuH THF, –78 °C pKa ca 25 pKa 50 R H + EtMgBr R MgBr + EtH THF, 0 °C Larva of Mexican bean beetle O O NH Epilachnadiene defense agains ants Rao, B. V. TL 1995, 36, 147 ? O OH OH FGI O NH OH OH Br OH OH OPG Alkyl%a Br Alkyl%a Alkynyl%d OH O Alkynyl%d Alkyl%a Alkynyl%d Rao, B. V. TL 1995, 36, 147 Alternative (II): Organocuprates ORGANOCOPPER REAGENTS, easily prepared by transmetallation, are very selective RLi + CuX RCu + LiX Monoorganocopper 2 RLi + CuX R2CuLi + LiX Homocuprates or Gilman’s reagents RLi + CuCN RCu(CN)Li Heterocuprates I Me I Me2CuLi R Me R Et O, 0 °C to rt 90% 2 90% Br I 81% 75% Me Me Cecropia moth O A classical synthesis OMe O (±) Cecropia Juvenile Hormone Hormone involved in the development of larvae Corey, E. J. JACS 1968, 90, 5618 ? + I 1) TsCl, pyr 1) H3O OH OH 2) OTHP 2) LiAlH4, then i2 OTHP Li2CuEt2 TMS PBr3 Br OH TMS H 1) BuLi 2) CH2O Me 1) LiAlH4, I2 OH OH 2) Li2CuMe2 O O OMe OMe O Bacillus species O OH HO Iedomycin D Maulide, N. OL 2015, 17, 4486 ? Strained bicycle CO H 2 H O OH OH O HO O OH H 4π#Electrocyclic#transform CO H OTIPS Activated Zn 2 Then CuCN, LiCl OTIPS I H O 1) H2SO4, MeOH 2) LiOH, MeOH O 98% H CO H O OH 2 Δ OH HO 63% over three steps Alternative (III): Pd-Mediated Cross-Coupling Reactions cat Pd(0) R1 X + R2 M R1 R2 + M X GENERAL MECHANISM PdL2 R1 X R1: better no ß-H Pd(0) X: I, Br, (Cl), OTf Oxidative addition R1 R2 Reductive elimination R1 R1 Pd(II) L2 Pd L2 Pd Pd(II) R2 X M X R2 M R2: alkyl, alkenyl, alkynyl, aryl TRANSMETALATION Fürstner, A. ACIE 2005, 44, 674 Reactants Pd-Mediated Cross-Coupling Reactions TRANSMETALATION Transfer of an organic group from one metal center to another. The process involves no formal change in oxidation state for either metal. For palladium-mediated cross-coupling reactions R1 X + Pd R1 Pd X R1Li, R1MgY Kumada R1B(OR)2 SUZUKI R1CuLn SONOGASHIRA R1ZnY Negishi R1SnR3 STILLE Mignani, G. CR 2006, 106, 2651 Magano, J.; Dunetz, J. R. CR 2011, 111, 2177 Reactants Suzuki Cross-Coupling Reaction X 1 Csp2 X X: I > Br > OTf >> Cl R X + OH O O 2 2 2 2 Csp2 R B R B R B R : alkenyl, aryl OH O O R2 B 2 2 Csp3 R B R2 9-BBN R : alkyl Pd(0) Base Pd(0): Pd(PPh3)4 Ph Ph P PdCl Pd(II): Pd(OAc)2 / PR3 or AsR3 Fe 2 1 2 P R R Ph Ph for Csp3–Csp2 dppf Reactants Suzuki Cross-Coupling Reactions 0.2 mol% Pd(OAc)2 OH K2CO3 B + I NO2 NO2 OH Acetone / H2O, 65 °C 97% 2 mol% Pd(PPh ) OH I 3 4 B NaOEt + OH PhMe, 65 °C 98% O B O OTHP 85% OTHP 3 mol% Pd(PPh3)4, NaOEt Br PhMe, 85°C OTHP 73% O B O Reactants Suzuki Cross-Coupling Reactions H OMe B OMe OAc OMe OMe S Csp3–Csp2 Coupling OTBDPS OTBDPS N I THF, rt B OTBS OTBS PdCl2(dppf), AsPh3 71% Regioselective Hydroboration Cs2CO3 DMF, H2O OMe O OH O OAc OMe O S OTBDPS S OH N N OTBS O Epothilone A Danishefsky, S. ACIE 1996, 35, 2801 Csp2–Csp2 Coupling HO OMe B O HO O OMe OTBS EtO O I EtO O H H 5 mol % Pd(PPh3)4,Tl2CO3, THF/H2O, rt H H OTBS 91% O OMe (+) Herboxidiene O HO O GEX 1A H H OH Romea P.; Urpí, F. OL 2011, 13, 5350; OBC 2017, 15, 1842 Reactants Sonogashira Cross-Coupling Reaction X Csp2 X X: I > Br ≈ OTf >> Cl R1 X + pKa 25 pKa 12 CuX R3N 2 2 2 2 H R + CuX H R XCu R + R3NH XCu R The acidity of Csp–H is enhanced via π-complexation Pd(0) Pd(0): Pd(PPh3)4 Pd(II): PdCl 2(PPh3)2 R1 R2 Doucet, H.; Hierso, J.-C. ACIE 2007, 46, 834 Reactants Sonogashira Cross-Coupling Reactions TBSO OH I 5 mol% PdCl2(PPh3)2 TBSO OH CO2Me CO Me CuI, Et3N 2 + N N CH3CN, –20 °C to rt MeO O MeO O 85% Meyers, A. I. JOC 2001, 66, 6037 TBSO TBSO O I O TBSO O O TBSO O O O O N N 5 mol% PdCl2(PPh3)2 S CuI, Et3N S CO2Et CO2Et CH3CN, –20 °C to rt 74% Kirschning, A. ACIE 2008, 47, 9134 Reactants Stille Cross-Coupling Reaction X 1 Csp2 X X: I > Br > OTf >> Cl R X + 2 2 R : alkynyl > alkenyl > aryl > benzyl ≈ allyl > alkyl R SnR3 Pd(0): Pd(PPh3)4, Pd2(dba)3 / PR 3 or AsR3 Pd(0) Pd(II): Pd(OAc)2 / PR3 or AsR3 R1 R2 Reactants Stille Cross-Coupling Reactions O O O SnBu3 O H OH H OH OMe O OMe O N Bu3Sn N I H 20 mol% PdCl2(MeCN)2, i-Pr2NEt H I O O DMF / THF, rt O O H H OMe OMe O OH 27% O OH O OH O OH OMe OMe Nicolaou, K. C. JACS 1993, 115, 4419 Extraordinary Functional Group Tolerance O O Bu3Sn OTIPS OH O 20 mol% Pd2(dba)3, AsPh3 CuTC O I OTIPS OH NMP, 35 °C OH OH 50% O O Williams, D. R. JACS 2001, 123, 765 Reactants Stille Cross-Coupling Reactions A total synthesis of Chivosazole F shows the tremendous potential of the Stille coupling Chivosazole F MeO OH O N O OH OH O OH Paterson, I. ACIE 2017, 56, 645 Reactants Stille Cross-Coupling Reactions A total synthesis of Chivosazole F 2 Stille coupling shows the tremendous potential of the Stille coupling MeO Br Stille coupling O OTBS Me Sn N 3 O O O O Si MeO I O t-Bu t-Bu P OH O (OCH2CF3)2 N O OH OH O OH 3 SG olefination 1 Stille coupling Stille coupling Bu Sn OH Bu3Sn H Stille coupling Still-Gennari olefination 3 OTES O The Stille coupling were carried out using Pd(PPh3)4 and CuTC [copper thiophene-2-carboxylate] Paterson, I. ACIE 2017, 56, 645 See Fürstner, A. Chem Commun. 2008, 2873 Reactants Heck Reaction cat Pd(0) R1 R1 X + R2 2 + HB X Base R HX R1 X R1: no ß-H PdL2 L X: I, Br, (Cl), OTf Reductive elimination Oxidative addition R1 H Pd L L Pd L X X Pd(0): Pd(PPh3)4, R1 Pd(dba)2+PR3 2 E olefin R Pd(II): Pd(OAc)2, R2 L PdCl 2(PR3)2, PdCl2(CH3CN)2 R1 H R1 Pd L Pd L R2 X R2 X Base: R3N, R2NH AcO–, CO32– β-Hydride elimination Olefin insertion R1 H H H H R1 R2 Pd L R2 Pd L H X H X Reactants Heck Reaction The regioselectivity of the Heck reaction is not completely defined.