! Organic Synthesis II: Selectivity & Control Handout 2.1 ! Regioselectivity: a recap ! Reacting the less reactive: kinetic and thermodynamic approaches Trianions (and last in, first out) ! Protecting groups for oxygen: Silyl ethers Benzyl Ethers Acetal and Ketals Carbohydrates and protecting groups Selective cleavage of benzylidene acetals THP and butanediacetal protecting groups ! Case studies in protection: Synthesis of a segment of Epothilone, a complex natural product The synthesis of specifically functionalized carbohydrates ! Synthetic Planning: Reactivity and control provide synthetic ‘guidelines’ ! Books & other resources: Organic Synthesis: The Disconnection Approach (Warren & Wyatt, Wiley, 2nd Ed., 2008) Classics in total synthesis (Nicolaou & Sorensen, Wiley, 1996) Protecting groups (Kocienski, 3rd Ed., Thieme, 2003) ! Organic Synthesis II: Selectivity & Control Handout 2.2 ! Synthetic Planning: Reactivity and control provide synthetic ‘guidelines’ ! Two group disconnections: Two approaches to Mesembrine (i) intramolecular Mannich & MVK Michael addition (ii) Birch Reduction & Cope rearrangement route ! Pattern Recognition: The Diels Alder reaction Guanacastepene and a masked D-A disconnection The intramolecular Diels Alder reaction: Indanomycin Hetero-Diels Alder reactions: Carpanone ! Two directional synthesis Total synthesis through bi-directional synthesis ! Pharmaceuticals Commercial-scale synthesis of Crixivan ! Pericyclic cascades Colombiasin total synthesis Vinca alkaloid total synthesis ! Books & other resources: Organic Synthesis: The Disconnection Approach (Warren & Wyatt, Wiley, 2nd Ed., 2008) Classics in total synthesis (Nicolaou & Sorensen, Wiley, 1996) Protecting groups (Kocienski, 3rd Ed., Thieme, 2003) ! Hydrogenation: metallic catalyst+hydrogen ! Reductions of alkenes: usually Pd metal on carbon support (and H2 gas) H Pd/C Ph Ph H H2(g) E alkene H Pd/C Ph Ph Ph H2(g) H Ph Ph chiral (but racemic) Ph Z alkene meso-product Generally: overall stereospecific syn-addition of hydrogen across the alkene Pd, Pt, Ru, Rh can all be used in hydrogenation processes ! Mechanisms of ‘heterogeneous’ hydrogenation are complex H2 on catalyst surface Alkene on catalyst surface Ph H Ph H syn-reduced product Ph Ph H ‘half hydrogenated’ state Ph H H adsorption H Ph H addition H addition Ph Ph H2 (g) Substrate binds to catalyst surface from one face leading to overall syn-hydrogenation ! Hydrogenation: metallic catalyst+hydrogen ! More substituted alkenes are reduced more slowly slower than R3 R1 R4 slower than R3 R1 H R3 R3 tetra-substituted tri-substituted slower than R3 R1 H H H R1 H H di-substituted mono-substituted This can be attributed to steric hindrance to adsorption onto the catalyst surface ! We can also achieve selectivity in hydrogenation O H H Me O H2 (g) Pd/C Alkene is selectively reduced (C=C ! weaker than C=O !) Regioselectivity O H2 (g) O Pd/C H H Syn-addition of hydrogen Stereoselectivity a consequence of geometry (less hindered face) ! Birch-type reduction of ",# unsaturated ketones ! Birch-type reductions of ",# unsaturated ketones give enolates as intermediates Protonation on oxygen H OtBu Na NH3(l) O R1 R2 tBuOH (1eq.) Proton transfer (inter/intramolecular) O R1 Na NH3(l) OH R2 R1 H O OH R2 "e " R1 R1 R2 Radical anion R2 Enolate anion more stable than other anion ! These enolates can be used as reactive intermediates in ‘tandem’ reaction sequences O O O O O O Li, NH3 Li, NH3 MeI CN-CO2Me O H EtO2C Me CO2Et O O O EtO2C Reduction affords ester enolate that is alkylated with methyl iodide H Reduction affords ketone enolate that is acylated with methyl cyanoformate (see earlier!) ! Oxidation of enolates and enol ethers (electron rich alkenes) ! Birch reduction-enolate oxidation sequence H O Li, NH3 tBuOH Et3SiOTf Me OSiEt3 H Me Oxidation of silyl enol ethers: the Rubottom reaction Bu4N+F- H Protonation occurs to afford cisoid-ring system Silicon traps on oxygen (hard electrophile) HO m-CPBA H Me H H Oxidation from top face (opposite bicyclic ring system) Strong Si-F bond in desilylation ! Dioxiranes are alternative oxidizing agents for these materials Weak O-O bond OTBS O O Dimethyldioxirane ‘DMDO’ Weak O-O bond Electrophilic oxidising agent - v mild Biproduct is acetone O BnO OTBS OTBS O O PMBO sulfonic acid PMBO OTBS BnO OTBS OTBS Rubottom reaction via: (I) epoxidation (ii) epoxide cleavage via oxonium formation (iii) silyl migration ‘Protecting groups’:TBS = tert-butyl dimethylsilyl, Bn = benzyl PMB = para-methoxybenzyl (see later in the course) O ! Oxidation of enolates and enol ethers (electron rich alkenes) ! Oxaziridines can be used to perform similar transformations Generation of potassium enolate O N Me RO2S OTBS KHMDS, THF Oxaziridine (chiral but rac) Weak N-O bond Electrophilic oxidising agent - v mild O H Oxaziridine O Me HO O H OTMS OTBS O OTMS Oxidation of enolate with oxaziridine ! Stereochemical information can be transmitted with chiral dioxiranes O O chiral dioxirane catalyst (10 %) O O O Ph Ph O Ph Oxone, pH 10.5 Ph O O Oxone is the reoxidant (2:1:1 mixture of KHSO5, KHSO4, K2SO4) Dioxirane (non-racemic) Weak O-O bond Can be made catalytic with a reoxidant 97:3 ratio of enantiomers ! Selective oxidations of alkenes ! For alkenes there are essentially two modes of oxidation: O allylic oxidation C=C oxidation R1 H R1 H R1 O O ! C=C oxidations: Recap - OsO4 oxidation of alkenes [Os(VIII)] [Os(VIII)] R2 NMO O O O Os concerted O OsO4 R1 [Os(VI)] O R1 syn addition R1 O O Os O R2 R2 Re-oxidation Overall: syn-stereospecific dihydroxylation of an alkene O NMO = OH R1 R2 N O OH H2O O + HO Os OH [Os(VI)] Generally: dihydroxylation from the least hindered face O Compare with Woodward and Prevost methods for dihydroxylation (see Dr E Anderson Course HT 2011) ! Selective oxidations of alkenes ! The dihydroxylation reaction is accelerated by amines (catalysis) [Os(VIII)] L [Os(VIII)] O Os OsO4 R1 R2 O O O R1 NMO R3N (=L) [Os(VI)] concerted R1 syn addition R2 L O O Os O O O OH H2O + HO Os O + OH [Os(VI)] OH R1 R2 R2 L Re-oxidation ! We can transfer chirality from the amine to permit asymmetric dihydroxylation Os(VIII) Et N H H N N O Et O tBuOH-H O N H H MeO N reoxidant (DHQD)2-PHAL OMe HO OH Ratio of enantiomers: 99:1 Selective for most electron-rich alkene N L = Amine ligand ‘(DHQD)2-PHAL’ ! Recap: allylic alcohol alkene oxidations (see Dr Anderson course, HT 2011) ! Allylic epoxidation: m-CPBA-mediated OAc OAc OH Ar OH O m-CPBA m-CPBA O O H O H O O Major diastereoisomer Sterics: least hindered face is oxidized Major diastereoisomer Intramolecular H-bond stabilizes TS and directs oxidation H ! Allylic functionalization: Vanadium and Zinc mediated process OH OH VO(acac)2 tBuOOH OH tBu O O O OH Zn O V OR CH2I2 O Major diastereoisomer Alcohol-directed epoxidation H Major diastereoisomer Hydroxyl-directed cyclopropanation H H I Zn O H ! Allylic alcohol reactions: Sharpless asymmetric epoxidation ! Reactions directed by the allylic alcohol are faster & more selective tBuOOH (>1 eq.) Ti(OiPr)4 (10 mol%) M X CO2Et EtO2C H R1 O OH OH O 97:3 ratio of enantiomers OH (10 mol%) OH OH Chirality transferred from the diethyl tartrate to the product ! The complex formed by the reagents is, well… complex EtO2C tBuOOH, iPr O Ti(OiPr)4 OH iPr CO2Et EtO2C E iPr O iPr O O R Ti CO2Et Ti CO2Et O O HO O O iPr O O Ti CO2Et Ti O O O O O O O O OH O O L-(+)-diethyltartrate tBu tBu EtO EtO [L-(+)DET] R Alkene coordinates to complex and is epoxidized ! Allylic alcohol reactions: Sharpless asymmetric epoxidation ! Luckily there is a mnemonic to work out which enantiomer is produced D-(-)-DET delivers oxygen to top E iPr O iPr O O O O HO Ti CO2Et Ti O O O O O Arrange substrate with hydroxyl group to left O R R HO R tBu L-(+)-DET delivers oxygen to bottom EtO ! Examples: Me Me Me Me OH Ti(OiPr)4 (-)-DET tBuOOH Me Me O Chemoselective oxidation of allylic alkene OH Me Me Highly enantioselective oxidation of alkene ! Wacker Oxidation ! Mild method for oxidation of terminal alkenes O PdCl2, H2O R1 CuCl2, O2 Generally gives this regiochemistry of oxidation R1 ! Generalized mechanism: Pd(II) Cl Cl Cl Pd H2O L R1 Cl Pd R1 effective oxypalladation !-complex electrophilic Pd(II) Pd Cl R1 L L Cl OH Pd H L HO H R1 L "-hydride elimination !-complex Pd-H readdition L Cl Pd OH L H R1 O R1 Elimination Pd(0) Reoxidation with Cu(II) Attack of nucleophile (in this case H2O) is regioselective for the most substituted position Probably a consequence of charge stabilization in the TS (compare with attack of water on bromonium ions) but also a preference to put the bulky Pd in the least hindered position ! Oxidation of the allylic position ! The second of our two modes of reactivity: O allylic oxidation C=C oxidation R1 H R1 H R1 O O ! Oxidation in the allylic position is often a rearrangement process H O OCrO(OH) O Cr O Cr(VI) Ene reaction OH O Cr OH O 2,3-sigmatropic shift and/ or -Cr(IV) or Cr(II) Cr(IV) Disproportionation? O Allylic alcohol often oxidized in-situ ! Selenium dioxide can also be used: ‘Riley Oxidation’ H O O Se O Se Can be made catalytic in Se with tBuOOH reoxidant OH O and/ or Se O Se(IV) OH O Se(II) -Se(II) or Se(0) ! Chemoselectivity in Oxidation ! Epoxidation vs Baeyer-Villiger: a comparison Epoxidation Baeyer-Villiger (–) O O H H R O O H O O R O O (–) (+) O LUMO O-O "* HOMO C=C ! R O RCO3H O HOMO C-C ! O O (+) O O O (+) + RCO2H + RCO2H H O(–) LUMO O-O !* R O (–) Comparison: Though epoxidation is electrophilic attack on an alkene and Baeyer-Villiger rearrangement is nucleophilic attack on a C=O group, the slow steps both use the O-O !* as the LUMO CF3CO3H is the best peroxy acid for both reactions So difficult to achieve chemoselectivity by choice of reagent ! Oxidation: Epoxidation vs Baeyer-Villiger ! A delicate balance - take each case on its merits! O O RCO3H H O O RCO3H !max: 1715 cm-1 • Normal ketone H O • Alkene is trisubstituted so more nucleophilic O H H RCO3H MeO MeO !max: 1745 cm-1 • very strained ketone - strain relieved in slow step mCPBA O NaHCO3 CH2Cl2 H O • alkene is only disubstituted and only slightly strained O O • Nothing wrong with epoxidation! • strained ketone - strain relieved in slow step • alkene is disubstituted and only slightly strained Note regioselectivity in Baeyer-Villiger oxidation: more substituted carbon atom migrates with retention of configuration O O H !max: 1780 cm-1 ! Oxidation: Epoxidation vs Baeyer-Villiger of conjugated enones ! Chemo-selectivity and regioselectivity pKa H2O : 15.6 pKa H2O2: 11.8 O O O O H2O2 Ph H2O2 Ph NaOH O O HOAc O new, high H energy HOMO Ph True reagent: True reagent: O O !-effect: raises HOMO (kinetic) increases acidity (thermodynamic) O O O H O O normal peroxyacetic acid H normal B-V: alkene is better migrating group ! Mechanism: O OH O O O Ph better nucleophile than base high energy HOMO OH O O Ph Ph weak O–O bond means bad leaving group OK ! Regioselectivity: recapitulation of previous examples ! Generation of functionalized aromatic compounds Cl Cl NO2 SR PhSH Base Cl NO2 NO2 HNO3 H2SO4 Me Only the ortho-leaving group is substituted O2 N NO2 Me Combination of directing effects lead to specific nitration ! Elimination processes E1 elimination OH H2SO4 E2 elimination Me NaOH Me Br This geometry is the major product: consequence of lower TS energy (consider steric effects in intermediate cation & relate to TS energy) This geometry is the major product: H and Br must be antiperiplanar This reaction is stereospecific ! Complex materials are polyfunctional: selectivity? ! Functional groups may have the same type of reactivity: OH O NaBH4 O O OMe O OMe use selective reagent ketone - more electrophilic OH protect more reactive group ester - less electrophilic ! How we access a kinetically less reactive functional group? HO O O OH O H+ OMe LiBH4 O O OMe Ketone more electrophilic than ester: exploit in temporary blocking group formation H+, O H2O OH Ester now only electrophilic group Can be reduced selectively, and then blocking group can be removed to regenerate ketone The use of ‘protecting groups’ can allow us to perform selective transformations but they add length and complexity to many synthetic routes (we have to put them on and then take them off too!) ! Reacting the less reactive group ! Functional group reactivity can be a thermodynamic or kinetic phenomenon Thermodynamic product in base Amino alcohol has two reactive functional groups Thermodynamic product in acid Treat with base HO PhCOCl Ph N Et3N O PhCOCl HO H+ HN Ph O HN O Treat with acid ! The most stable product predominates under the reaction conditions HO H+ O N Ph O Ph Amides are thermodynamically more stable than esters: predominates in base H+ OH H+ O N Ph HN O O Ph H2N O Basic nitrogen is protonated in acid: unable to function as nucleophile ! Protecting groups: Case study I ! A fragment of a complex natural product: Epothilone mix of diastereoisomers Ratio = 3:2 OBn OBn Selective removal of Si group (Bn not touched by fluoride) O BrMg 89% yield OBn OBn TBAF TsOH, O3, PPh3 OTBS TBSO OH O O O O 94% yield (2 steps) 98% yield (2 steps) Stereocentre 1,3- to aldehyde so difficult to control facial selectivity of addition O K2CO3 MeOH MeO OMe Selective protection of diol(s) Bn not touched by acid ! Protecting groups are not always spectators: final step epimerization O OBn O O O K2CO3 O R H O O K2CO3 O MeOH R H MeOH H Desired diastereoisomer Groups equatorial on ketal chair Thermodynamically most stable Predominates at equilibrium OBn H O O O O R O O O H Undesired diastereoisomer One group axial on ketal chair Thermodynamically less stable Enolate intermediate ! Protecting groups: Case study II ! Carbohydrate targets often require access to specific functional groups OBn O HO OH OH OH O HO OH OH HO Need access to C-2 and C-3 HO O N3 OH MeO OH O Need access to C-1 and C4 (with inversion) D-Glucose ! D-Glucose is a polyfunctional material HO OH x hemiacetal x 2˚ alcohol x 1˚ alcohol HO OH HO O OH Pyran (2 diastereomers) HO O OH CH2OH HO HO OH O OH Open-chain aldehyde OH OH Furan (2 diastereomers) Must consider the position of these equilibria in carbohydrate manipulations ! Protecting groups: Case study II ! Carbohydrate targets: examples of chronic protection! Thermodynamic ketal formation OH HO OH HO O OH Acetals hydrolyzed and made in acid O NaH BnBr OBn OBn O Acetone TsOH O Pyran with axial C-1 group: Anomeric effect MeOH HCl HO PhCHO ZnCl2 O MeO NaH PrBr OBn O OBn HO CF3CO2H OH O O Benzyl ether untouched in acid Ph O O O H2O OH O MeO Ph O O O Strong acid hydrolyses acetals & ketals; ethers left untouched This is an extreme example of the use of protecting groups: we should aim to minimize their use through the application of chemoselective transformations where possible ! Synthetic planning, reactivity and control ! How we approach the synthesis of complex materials? OMe MeO Strategy Tactics Control The plan, as defined by disconnection O Which reagents and methods we use N H Me ! The basics of synthetic planning: some ‘guidelines’ to consider OMe Use two-group disconnections MeO Disconnect at branch points Disconnect rings from chains Disconnect to recognisable starting materials Use symmetry elements if possible Analyse oxidation states and potential FGIs Chemoselectivity is key to efficiency O O Li N Me Three simple fragments: How we choose this approach? ! Look for two-group disconnections ! Case study I: Mesembrine; two obvious two-group disconnections OMe OMe MeO OMe MeO C-N C-C 1,3-di X 1,3-di X HN O MeO N H Me O Me N Me O ! Both disconnections are viable: examine C-C disconnection first MeO MeO MeO Disconnect: Branch point Rings from chains C-C C-C O Li N Me O Aryl lithium made by Halogen-metal exchange OMe OMe OMe N Me N Me O Methyl vinyl ketone Common 4-carbon building block ! Look for two-group disconnections ! Putting it together: OMe MeO MeO OMe eq tBuLi MeO MeO MeO MeO H+ THF, -78˚C HO O Br Li Need two eq BuLi (one for reaction, one to destroy tBu-Br formed) -H2O N Me N Me t high b.p solvent N Me OH OH heat OMe MeO O OMe MeO N H Me O E1 elimination OMe MeO N Me Intramolecular Mannich O methyl vinyl ketone MeO MeO N Me This enolate unproductive O N Me ! Look for two-group disconnections ! Mesembrine disconnection II (more complex!) Call this group ʻArʼ for clarity OMe OMe MeO OMe MeO C-N FGI reductive amination [ox] HN O MeO Pattern for [3,3]: Two alkenes three bonds apart O O O Me Cope [3,3] Ar Ar FGI [red] MeO MeO O CO2NR2 CO2NR2 Add EWG for selectivity over other arene ʻcontrol groupʼ Ar Easier to functionalize next to carbonyl Birch reductionalkylation? ! Look for two-group disconnections ! Mesembrine final steps: Enol ether hydrolysis Non-conjugated diene formed Ar Li, NH (l) tBuOH (1 eq ) MeO CONR2 Br Regioselectivity in Birch directed by EDG and EWG Less electron-rich arene reduced preferentially Ar HCl MeO CONR2 Ar Ar 140˚C O3, Me2S O O O CONR2 Stereospecific Cope rearrangement [alkene transposed onto same face] CONR2 Reductive amination [reduce intermediate imine, not aldehyde] MeNH2 NaBH3CN OMe OMe MeO MeO Ar steps O O N H Me O R2NOC To remove ʻcontrol groupʼ N H Me R2NOC HN Me Intramolecular 1,4-addition ! Pattern recognition: the Diels-Alder reaction ! Simplest pattern: 6-ring containing an alkene O OMe FGI Simplest D-A pattern OMe D-A FGI to reveal D-A pattern Remember: we generally need EDG on the diene and EWG on the dienophile to accelerate the reaction (this lowers the HOMO-LUMO gap, in the FMO treatment) ! and don’t forget models for the actual reaction: CH3 !4s H3C O O O !2s HOMO diene LUMO dienophile In FMO terms [4q+2]s =1; [4r]a = Total=1: Allowed (by Woodward-Hoffman) O O Endo-TS favoured (2˚ orbital overlap) Kinetic product H3C H H O H H H3C H H H Draw product in same orientation as the starting material …but no obvious disconnection O H OH AcO OH MeO2C MeO2C O O reconnect C-O CO2Me MeO2C MeO2C Baeyer Villiger OR CO2Me OR CO2Me HOMO diene LUMO dienophile In FMO speak Diels Alder MeO2C MeO2C 6-ring with alkene highlighted O FGI ketone enol ether MeO2C MeO2C O Rotate to flat and transcribe stereochemistry ! Complex natural product example disconnection: Guanacastepene O O O ! Pattern recognition: the Diels-Alder reaction 6-ring looks promising for Diels-Alder… H ! Pattern recognition: the Diels-Alder reaction ! …and the actual synthesis: D-A: EDG on diene… Trap to form silyl enol ether O OSiMe3 LDA Me3SiO CO2Me TMSCl CO2Me CO2Me then H+ O OH O MeO2C O MeOH, H+ mCPBA MeO2C MeO2C …EWG on dieneophile MeO2C Kinetic enolate formation (not extended enolate) CO2Me MeO2C MeO2C Hydrolyze enol ether MeO2C Baeyer-Villiger: most substituted group migrates Note: the six membered ring that we start with is not the one that ends up in the product (as a consequence of the oxidative cleavage in the B-V reaction) ! Pattern recognition: the Diels-Alder reaction ! Intramolecular Diels-Alder Intramolecular D-A pattern Disconnects two rings Simplest D-A pattern ! Example: Indanomycin (an antibiotic ionophore) O H CO2H O N H H OEt PO PO O H EtO2C H H Electronics: best with EDG on diene and EWG on dienophile (or vice versa; an ʻinverse electron demandʼ Diels Alder Stereochemistry: alkene geometry is key (stereospecific) Endo vs exo: must consider length of ‘tether’ Intramolecular better than intermolecular (and so the ‘rules’ are less stringent for substituent effects) ! Pattern recognition: the Diels-Alder reaction ! Synthesis plan: consider functional groups; employ appropriate tactics allylic alcohol Wittig trans-alkene with EWG EtO2C Wittig (and FGI) PO Part of SM stereocentre to control absolute configuration trans-trans alkene ! Synthesis: OEt OEt P EtO2C TBSO TBSCl OH imidazole TBSO O O EtO2C NaH O Protects open chain 1˚alcohol Horner-Wadsworth-Emmons ʻextendedʼ phosphonate anion trans-alkene O OH ! Pattern recognition: the Diels-Alder reaction ! Final steps and intramolecular Diels Alder Only removes silyl group Reduces ester to 1˚ alcohol TBSO TBSO DIBALH Et3N EtO2C Bu4NF O MEMO Swern MEMO OMe O An acetal-type protecting group ʻMEMʼ Selective oxidation to aldehyde Cl Ph3P Major Isomer TS H H H H OMEM CO2Et Minor Isomer TS Clashing with alkene hydrogen disfavours O OEt H H H Major: endo-TS Least hindered MEMO toluene H H Stabilized ylide trans-alkene EtO2C 110˚C MEMO EtO2C CO2Et H OMEM CO2Et MEMO H ! Symmetry and the Diels-Alder reaction ! Extension of the simple D-A pattern: hetero Diels-Alder reactions O O O Simplest D-A pattern O Simple hetero D-A pattern: useful for O, N ! How symmetry can help (I): Carpanone Patterns to recognize in this case: H H O O H O H O O H O O O H O O O O O O O Carpanone rings, stereocentres O O O Unsaturated 6-membered ring Heteroatom in the ring Hetero-Diels Alder? Material is dimeric Two ʻmonomericʼ skeletons outlined ! Symmetry and the Diels-Alder reaction ! Disconnection: H O O Diels Alder O C-C O H O O O O O O [ox] O O O O O O OH O ! Synthesis: one step (!) Only this stereochemistry produced O O PdCl2 OH O O O H O O H O O O O O O O Palladium(II) probably generates this delocalized radical Radical dimerization is FAST (diffusion controlled) O O O Carpanone rings, stereocentres ! Symmetry as an aid to disconnection ! Symmetry & ‘two directional’ synthesis O H H C-C H EtO2C C-C H H N N H EtO2C CO2Et C-N H N Dieckmann H CO2Et P N P 1,4-addition H A hint of symmetry (but nothing obvious) Symmetrical intermediate ! Disconnection of starting material EtO2C CO2Et P N O O C-C P P N Symmetrical intermediate C-N P OH FGI [ox] Maintain symmetry Two-directional elaboration ! Symmetry as an aid to disconnection ! Total synthesis (I): requires a desymmetrization Mitsonobu reaction (N nucleophile) O Dihydroxylation and in situ diol cleavage NH O OH O N OsO4 O O N O NaIO4 PPh3, DEAD THF O HWE olefination gives transalkene Cleaves phthalimide group to liberate nucleophilic nitrogen O EtO EtO P NaH Imide reactivity is ketone-like (so is reduced with NaBH4 ) O CO2Et H H N EtO2C KOtBu benzene Li metal H Dieckmann (non-selective; afford mixture of regioisomers) Li removes EtOH from equilibrium CO2Et H H NaBH4; N H then AcOH 80˚C EtO2C Key step: facilitates double intramolecular 1,4-addition to give only this diastereoisomer CO2Et O O N O CO2Et ! Symmetry as an aid to disconnection ! Completion of the total synthesis: O O CO2Et H H N LiCl wet DMF H H CH3PPh3Br N 120˚C H H H2 (g) H N BuLi, THF H H Pd/C H Decarboxylation under neutral conditions Kraptcho reaction H H H N N H H Alkene reduction (not especially facially selective) Wittig reaction ! Review key diastereoselective step O EtO2C H H O CO2Et H H H2N H HN N H H H First cyclization: affords thermodynamically more stable cis-diequatorial piperidine Achiral (plane of symmetry) EtO2C CO2Et EtO OEt Second cyclization: directed by stereochemistry of the first ! Crixivan: HIV protease inhibitor (Merck) ! Patient requires ca kilo per year: very large scale, efficient synthesis required C-N Disconnect next to heteroatom N OH Ph tBuNH OH H N N N C-N Disconnect next to heteroatom C-C Disconnect next to carbonyl functional group (enolate?) O O C-N Disconnect amide bond (next to heteroatom OH H2N Cl TsO N Pyridine with benzylic leaving group Chiral epoxide: electrophilic at two positions HN Chiral indanol: to control other stereocentres O Ph NH Piperazine: two nucleophilic nitrogens (selectivity?) tBuNH O Cl O Acyl chloride: preactivated to generate amide bond ! Crixivan: Fragment Syntheses ! Epoxide ! Piperazine O Sharpless epoxidation HO O TsO Protected piperazine (one nucleophilic nitrogen) N O TsCl NH Made by asymmetric hydrogenation Epoxide fragment tBuNH O ! Indanol N O H2O2, H2SO4 Made racemically by the Ritter reaction OH MeCN NH2 Only cis stereochemistry through reversibility (and thermodynamic stability of fused tricyclic system) N N H2O OH Me H+ O Can be resolved to give access to a single enantiomer OH H+ Indanol fragment ! Crixivan: Fragment Assembly ! Diastereoselective alkylation is a key step N-acylation and N,O acetal formation OH H2N O Ph Z-enolate formation O Ph N LiO O TsO O N LDA H+ H H O Cl OMe E+ Alkylation from least hindered ʻtopʼ face: epoxide most electrophlic H N O Me R R Strongly Favoured O Ph Allylic strain controls enolate geometry H O H O H N Me R R Strongly Disfavoured O N Ph O N TsO O Epoxide reformation O ! Crixivan: Fragment Assembly ! Final steps… O O O Acid removes acetal and N-protecting group Ph N O N O N O heat Ph OH NH N N O O tBuNH tBuNH O O O Piperazine fragment HCl 80˚C pyridine fragment N OH H N N N tBuNH Cl Ph H OH N N Ph OH H N N O O tBuNH O O Crixivan Selectivity: N more nucleophilic than O ! Cascade processes and complexity generating reactions ! Cascade processes offer a rapid entry into complex structures Me O OH Me H Me Me Diels Alder OH OP [ox] Me H O Me O OP Me H O H OH Me Me tautomerize Me PO Me Me OH O Me OH OP 4! H H Me Me O Me OH OP 6! H H Me O Me Can we accomplish several of these steps in one operation? (a ‘cascade’ reaction) OH ! A Cascade process: synthesis of Colombiasin ! Electrocyclic cascades offer short sequences to complex materials Vinyllithium reagent traps onto squarate From Carvone (natural) iPr iPr Me NHNH2 O O tBuO Me tBuO Me Me Li iPr H O then BuLi H Me Me O OH H H Me Me Shapiro reaction (via hydrazone) 4! electrocyclic ring opening (conrotatory) O heat: 110˚C (microwave) Removes acid-labile protecting group Me Me O OH Me H heat 110˚C Me OH OtBu OtBu air BF3.OEt2 H H O H OH Me H OH OtBu O Me Me O Me Intramolecular Diels Alder Electron rich diene Electron poor dienophile O Me 6! electrocyclic ring closure (disrotatory) & tautomerization Hydroquinone-quinone oxidation is easy (happens in air ! Pericyclic cascades II ! Pericyclic cascades offer short sequences to complex materials N N N [4+2] O diene [4+2] O EWG EWG alkene -N2 O N alkene O EWG alkene alkene EWG product 1,3-dipole Three simple components Complex product ! Application in synthesis: vinca alkaloids N-O acetal Easily broken O N O N N reconnect cascade O N OAc HO CO2Me N O OP N MeO2C CO2Me Structure contains key bicycle alkene diene N N O Bn alkene ! Pericyclic cascades II ! Synthesis of vindorosine Cyclization and dehydration NH O N NH N O N Me N H MeO2C Me NH2 N N Me MeO2C CO2Me Simple and readily available SM N O NH O N O NH TsCl NH R N Amide coupling reagent O HO C N R O O N N N 60h steps O N N OAc HO CO Me Me CO2Me N O 230˚C OBn Me Bn O N N Me MeO2C Pericyclic cascade O Bn ! Pericyclic cascades II ! Synthesis of Vindorosine: examination of the pericyclic cascade Bridgehead stereochem unimportant (destroyed) ʻRʼ group = indole O 4! N N 60h N O N N Me MeO2C 230˚C O R MeO2C 2! N N Et O O N O N Et N OBn OBn Me N Me O N OBn Cascade product compare with outlined motif N 1,3-dipolar cycloaddition syn, concerted & pericyclic; endo TS N O N 2! OBn CO2Me N OBn CO2Me CO2Me O O O O N [Draw in same shape as TS before redrawing] 4! N N MeO2C N N H Intramolecular Diels Alder reaction O N O H Bn O R O Me OBn CO2Me In situ generation of 1,3-dipole N Me N O OBn CO2Me Loss of N2 (g) Irreversible, entropically & thermodynamically favourable ! Pericyclic cascades II ! Synthesis of Vindorosine: completion of the synthesis ʻLawessonʼs reagent Mech: similar to Wittig reaction (strong P=O bond) S Ar Enolate oxidation (weak O-O bond) O N N Me CO2Me S OTIPS N Ar S N Me Protection (bulky silyl group) S P O TIPSCl OBn S O LDA Me3SiO-OSiMe3 O P S S Ar O 100˚C OBn N CO2Me Me OBn CO2Me Raney Ni, H2(g) Cleaves C-S bond (similar to Mozingo) and also removes Bn protecting group N N OH OAc Me HO CO2Me Ac2O OTIPS N PtO2, H2 PPh3, DEAD N OTIPS N P N OAc Me HO CO2Me Elimination: related to Mitsonobu (but without a nucleophile) TBAF O N Me OAc CO2Me Reductive cleaveage of N-O acetal and silyl group removal (strong Si-F bond) ! Organic Synthesis II: ‘Questions’ ! Representative questions This a new course and hence there are no ‘current’ exam questions that relate specifically to this course (and the exclusion of any other) However, much of the material is what I would class as core material that will crop up across a range of examination questions As such, the attached questions (or in some cases parts of them) are representative of what you should expect: Sample paper, Q 2, 5, 2010: 1A, Q 4, 2009: 1A Q 6, 7, 2008: Q 2007: Q 6, [...]... alkene ! Pericyclic cascades II ! Synthesis of vindorosine Cyclization and dehydration NH O N NH N O N Me N H MeO2C Me NH2 N N Me MeO2C CO2Me Simple and readily available SM N O NH O N O NH TsCl NH R N Amide coupling reagent O HO C N R O O N N N 60h 5 steps O N N OAc HO CO Me Me 2 CO2Me N O 230˚C OBn Me Bn O N N Me MeO2C Pericyclic cascade O Bn ! Pericyclic cascades II ! Synthesis of Vindorosine: examination... O H O O O O O O [ox] O O O O O O OH O ! Synthesis: one step (!) Only this stereochemistry produced O O PdCl2 OH O O O H O O H O O O O O O O Palladium (II) probably generates this delocalized radical Radical dimerization is FAST (diffusion controlled) O O O Carpanone 6 rings, 5 stereocentres ! Symmetry as an aid to disconnection ! Symmetry & ‘two directional’ synthesis O H H C-C H EtO2C C-C H H N N H... DMF O R1 Pd/C Made by the classical Williamson ether synthesis OH Orthogonal to silyl ethers Removed by hydrogenation Pd common, but Ru, Rh, Pt also It is important to recognize that protecting groups are a (somewhat) necessary evil which can help or hinder efficiency in synthesis Their use must be considered in the overall strategic approach to a synthesis ! Protecting groups for oxygen: acetals and... O N O H Bn O R O Me OBn CO2Me In situ generation of 1,3-dipole N Me N O OBn CO2Me Loss of N2 (g) Irreversible, entropically & thermodynamically favourable ! Pericyclic cascades II ! Synthesis of Vindorosine: completion of the synthesis ʻLawessonʼs reagent Mech: similar to Wittig reaction (strong P=O bond) S Ar Enolate oxidation (weak O-O bond) O N N Me CO2Me S OTIPS N Ar S N Me Protection (bulky silyl... OTIPS N P N OAc Me HO CO2Me Elimination: related to Mitsonobu (but without a nucleophile) 2 TBAF O N Me OAc CO2Me Reductive cleaveage of N-O acetal and silyl group removal (strong Si-F bond) ! Organic Synthesis II: ‘Questions’ ! Representative questions This a new course and hence there are no ‘current’ exam questions that relate specifically to this course (and the exclusion of any other) However, much... tautomerization Hydroquinone-quinone oxidation is easy (happens in air ! Pericyclic cascades II ! Pericyclic cascades offer short sequences to complex materials N N N [4+2] O diene [4+2] O EWG EWG alkene -N2 O N alkene O EWG alkene alkene EWG product 1,3-dipole Three simple components Complex product ! Application in synthesis: vinca alkaloids N-O acetal Easily broken O N O N N reconnect cascade O N OAc... less stringent for substituent effects) ! Pattern recognition: the Diels-Alder reaction ! Synthesis plan: consider functional groups; employ appropriate tactics allylic alcohol Wittig trans-alkene with EWG EtO2C Wittig (and FGI) PO Part of SM stereocentre to control absolute configuration trans-trans alkene ! Synthesis: OEt OEt P EtO2C TBSO TBSCl OH imidazole TBSO O O EtO2C NaH O Protects open chain... of protecting groups: we should aim to minimize their use through the application of chemoselective transformations where possible ! Synthetic planning, reactivity and control ! How do we approach the synthesis of complex materials? OMe MeO Strategy Tactics Control The plan, as defined by disconnection O Which reagents and methods we use N H Me ! The basics of synthetic planning: some ‘guidelines’ to... O OMe MeO N H Me O E1 elimination OMe MeO N Me Intramolecular Mannich O methyl vinyl ketone MeO MeO N Me This enolate unproductive O N Me ! Look for two-group disconnections ! Mesembrine disconnection II (more complex!) Call this group ʻArʼ for clarity OMe OMe MeO OMe MeO C-N FGI reductive amination [ox] HN O MeO Pattern for [3,3]: Two alkenes three bonds apart O O O Me Cope [3,3] Ar Ar FGI [red] MeO... example disconnection: Guanacastepene O O O ! Pattern recognition: the Diels-Alder reaction 6-ring looks promising for Diels-Alder… H ! Pattern recognition: the Diels-Alder reaction ! …and the actual synthesis: D-A: EDG on diene… Trap to form silyl enol ether O OSiMe3 1 LDA Me3SiO CO2Me 2 TMSCl CO2Me CO2Me then H+ O OH O MeO2C O MeOH, H+ mCPBA MeO2C MeO2C …EWG on dieneophile MeO2C Kinetic enolate formation