DISCONNECTION APPROCH: Retrosynthetic Principles and Synthetic Applications XV Summer School in Pharmaceutical and Medicinal Chemistry Rio de Janeiro, Brasil 09-13 February 2009 Pier Giovanni Baraldi Department of Pharmaceutical Siences Ferrara University, Italy Disconnection Approach Retrosynthetic Analysis: the logical process of analysing the structure of a target molecule to discern a possible synthesis step by step Retrosynthetic arrow is: A B (B is a precursor of A) ( Means “can be made from”) Functional group interconversion (FGI) Functional group addiction (FGA) Functional group removal (FGR) Disconnection: the formal reverse of a bond forming reaction (conceptual cleavage of a bond to break the molecule into possible starting materials) dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of the functional group joined to the nth carbon atom an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of the functional group joined to the nth carbon atom Reagent: A chemical compound used in practice for a synthon Disconnection Approach Synthons and Reagents dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of the functional group joined to the nth carbon atom. d1 CN d2 CH2CHO an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of the functional group joined to the nth carbon atom. a1 CH2OH a2 CH2CHO a3 CH2CH2CHO Reagent: A chemical compound used in practice for a synthon. Synthon Reagent CH3 CH3I or CH3oTs CH3 CH3MgBr CH2CH2CHO CHO Retrosyhthesis of Benzocaine Retrosynthetic Pathway: Benzocain from toluene O O O OEt C-O OH FGI OH H2N H2N O2N Benzocaine FGI •Toluene is a readily available starting material • Me is activating and ortho/para- directing Me Me + • We know reagents for the synthon NO2 C-N O2N Toluene Synthesis O O Me OH Me H SO HNO OH 2 4, 3 KMnO4 H2 Pd/C H2N O2N Oxidation O N Chemoselective 2 reduction EtOH/ H+ O OEt H2N Eletrophilic Aromatic Substitution How to identify the most suitable synthons and reagents? Which disconnection and which sense of polarity? O O MeO or O Synthons MeO MeO O Reagents + Cl Me MeO O O AlCl3 Synthesis + Me MeO Cl Me o/p directing and activating MeO Eletrophilic Aromatic Substitution How to identify the suitable synthons and reagents? Key reactions and Reagents for FGI in the contest of Aromatic Chemistry Synthon Reagent Reaction R+ RBr with Lewis acid Friedel Craft alkylation ROH/H+ + RCO RCOCl with Lewis Acid Friedel Craft acylation + NO2 HNO /H SO Nitration + 3 2 4 Cl Cl /FeCl Chlorination Br+ 2 3 Br2 and Lewis Acid Bromination SO3 H2SO4 Sulfonation Eletrophilic Aromatic Substitution How to identify the most suitable synthons and reagents? Key reactions and Reagents for FGI in the contest of Aromatic Chemistry Y X Reagent NO2 NH2 H2 COR CH(OH)R NaBH4 COR CH2R Zn/Hg CH3 COOH KMnO4 COR OCOR RCO3H CN COOH Hydrolysis Eletrophilic Aromatic Substitution Retrosynthesis of BHT OH Retrosynthesism of BHT = Buthylated Hydroxy Tolu BHT ia an antioxidant and is used as a food preserv OH Cl Cl OH OH Reagents OR Synthons OH Reagents Eletrophilic Aromatic Substitution Friedel-Craft alkylation or acylation C-C Cl NOT SUITABLE Problems: 1. Rearrangement of alkyl for more stable carbocation. 2. problem of polyalkylation Synthesis O O O FGI C-C Cl SUITABLE Nucleophilic Aromatic Substitution SN1 for nucleophilic aromatic substitution: Diazonium Chemistry X NH2 X Reagent + X OH H2O OR ROH CN CuCN Cl CuCl NH + Br CuBr 2 N2 X NaNO2/HCl -N2 I KI Ar ArH H H3PO2 Addition-Elimination F Cl Br I X Nu O2N O2N O2N O2N >> ∼ >> O2N O2N Nu- + X- More reactive Less reactive Aromatic Substitution Retrosynthesis of Trifluoralin B Herbicide N Cl Cl Cl Cl O2N NO2 O2N NO2 C-N FGI FGI C-Cl CF3 CF3 CF3 CCl3 CH3 CH3 Retrosynthesis of biphenyl derivative COOH CN NH2 NH2 NO2 Cl Cl Cl FGI C-C FGI C-N Aromatic Substitution The use of removable group to control selectivit Retrosynthesis of Propoxycaine Problem of Local anaesthetic Regiocontrol Synthetic Route to Propoxycaine Solution: ntroduction of a temporary group hat will be removed at a later stage of the synthesis Aromatic Substitution The importance of order of events- disconnection Retrosinthesis of Dinocap hex (Fungicide) hex OH O HO C-O + O O O2N NO2 O2N NO2 hex OH OH OH C-C 2x C-N Good disconnection- Correct order of events O N NO O2N NO2 2 2 hex hex OH OH OH 2x C-N C-C Poor disconnection- Wrong order of events O2N NO2 Para position not blocked to force alkylation ortho One Group and Two Groups Disconnection One Group C-X Disconnection For compounds consisting of two parts joined by a heteroatom (X), disconnet next to the heteroatom. This guideline works for esters, amides, ethers, sulfides etc. O Retrosynthesis of HN NH2 NO2 Propanil Weed killer C-N FGI Disconnection Cl Cl Cl Cl Cl Cl Cl Cl Synthons Reagents Cl S Cl SH + Cl Cl C-S + S Disconnection Retrosynthesis of Cl Cl Chlorbenside + S Cl Cl Cl One Group and Two Groups Disconnection Chemoselectivity Chemoselectivity arising from two groups of different reactivity. The preferential retrosynthetic route should avoid chemoselectivity problems. In pratice, this means that one should disconnect reactive groups first. To solve chemoselectivity problems, it is very often critical to choose carefully reaction condictions for the foreward synthetic step. O O NR2 O OH O OH Retrosynyhesis of I Cyclomethycaine C-O C-O (anaesthetic) Disconnection Disconnection + O O OH Chemoselectivity O OH O O O OH O O NR2 Synthesis of Cyclomethycaine excess base SOCl2 HOCH2CH2CH2NR2 OH O O O pKa phenol ~ 10 Both groups ionised pH> 10 pKa benzoic acid ~ One Group and Two Groups Disconnection Chemoselectivity Retrosynthesis of Paracetamol (Analgesic) O HN NH2 NO2 C-N C-N Disconnection FGI Disconnection OH OH OH OH O Synthesis of Paracetamol NH2 HN More Nucleophilic NH2 NH2 1.HNO3/ H2SO4 Ac2O 2. H2 Pd/C Under conditions that OH O- OH OH OH pKa phenol ~ 10 keep phenol unionised pKa aniline ~ 30More Nucleophilic Two Groups C- X Disconnection 1,1-Difunctionalised compounds Example 1 Cl 1,1 diX HO OH Cl + OO acidic conditions O Example 2 R FGI R 1,1 diX RCHO H N COOH NH3 HCN 2 H2N CN Strecker Synthesis Example 3 OH OH CN OH O NH2 FGI + 1,1 diX CN + KCN/H a1 d1 Two Groups C- X Disconnection 1,2-difunctionalised compounds ALCOHOLS 1,2 diX O NR2 HO HO NR2 a2 Important synthon Reagent is epoxide Example 1: Phenyramidol (muscle relaxant) 1,2 diX Ph O Ph + + N N HN N H2N N H OH Ph OH Example 2: Propranolol (beta-blocker reduces blood pressure) O N O OH H O OH O 1,2 diX Cl Epichlorhydrin Propranolol allows for two possible 1,2-diX readily available but it is best to disconnect the more reactive amine group first. Two Groups C-X Disconnection 1,2-difunctionalised compounds CARBONYLS O 1,2 diX O O Nu Nu Cl R R R a2 Important synthon Reagent N O O O N Cl 1,2 diX Reagent N HN k rel Note: α-chloro or bromo highly reactive electrophiles Me-Cl 200 and Control of mono-versus polyhalogenation. iPrCl 0.02 allylCl 80 920 MeOCH2Cl 10000 PhCOCH2Cl Two Groups C- X Disconnection 1,3-difunctionalised compounds CARBONYLS O 1,3 diX O O Nu R Nu R R a3 Important synthon Reagent Example 1: Atropine (Muscle relaxant) O O 1,3 diX Ph Ph N O Ph Reagent N H Two Groups C- X Disconnection 1,3-difunctionalised compounds NITRILES FGI O O CN NH2 1,3 diX OH + N Protecting Group Chemistry To avoid if you can…Each protection event adds two steps: protection-deprotection Synthesis requiring protecting group chemistry O Br C-Br HO FGI HO HO Salicylic acid HO HO HO O Synthesis: Br HO HO HO LiAlH4 Br2 O HO HO HO HO Revised Synthesis: Side-product Br2 ia also an oxydant O HO O HO acetone O LiAlH4 Br2 pTosOH HO O O HO + H /H2O Br HO HO Amines and One Group C-C Disconnections Synthesis of secondary amines O FGI N + NH2 O HN or FGI COCl HN + H2N Retrosynthesis of Fenfluramine (Drug CNS) NHEt NHCOMe NH2 FGI C,N-amide F3C F3C F3C FGI Reagent for reductive amination: Carbonyl dervative, amine and NaBH4 NaOAc/HOAc pH 6 O NOH F3C F3C Amines and One Group C-C Disconnections Synthesis of primary amines These targets are not conveniently prepared from unsubstituted imines [unstable] or primary amides. Alternative and better solutions are available and include: • the reduction of cyano group • the reduction of azido group • the reduction of oximes • alkylation and reduction of nitro compounds • the Ritter reaction followed by hydrolysis • the Gabriel synthesis Amines and One Group C-C Disconnections The synthesis of amines is slightly more complicated in comparison with the synthesis of e.g. ethers or sulfides because the product of an N-alkylation is at least as reactive as the starting material, therefore leading to complex reaction mixtures. X C-N + N R2 R NH Bad disconnection H 1 2 R2 The problem of polyalkylation X X X + R2 R2 R2 R1 NH2 R1 N R2 R1 N R2 R1 N R2 - H X R R Secondary amine 2 R2 2 More reactive than primary amine The solution: FGI prior to disconnection Suitable FGI involved amides, imines or oximas. H H N R LiAlH N R1 RNH2 R1COCl 1 4 R R O H LiAlH N R1 RNH R1COR2 4 2 N R1 R R or NaBH3CN R2 R2 Amines and One Group C-C Disconnections Example 1 AMINES NH2 FGI C C-C - N + CN Synthons Reagent for reduction of cyano into amine is LiAl H4 Br + NaCN or KCN Example 2 Reagents OH OH OH FGI 1,2 diX O NH2 NH2 R R R R Reagent for reduction of azide into amine: PPh3 + NaN3 Example 3 2x alkylation H2 cat R1CH2NO2 R1R2R3CNO2 R1R2R3CNH2 Amines and One Group C-C Disconnections AMINES Example 4 Ritter Reaction MeCN/ H+ Hydrolisis R1R2R3COH R1R2R3CNHCOCH3 R1R2R3CNH2 + Ritter Reaction: VIA CARBOCATION R1R2R3C Example 5 Gabriel