Disconnection Approach Retrosynthetic Analysis
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 Reaction
O O O O RNH2
NH3 KOH/ EtOH NH O NH NR then NH2NH2 NH RBr O O O O Amines and One Group C-C Disconnections One Group C-C Disconnection
SYNTHONS REAGENTS
R1 R1 OH OH 1,1 CC - R RMgBr + R1COR2 R2 R2 R3
OH OH O 1,2 CC RMgBr + R- R R1 R1 R1
O O 1,2 CC + R RBr + R1COMe
R R1 R1
OH 1,3 CC OH - R RMgBr/ CuX + CH2=CHCOR1 R R1 R1 Amines and One Group C-C Disconnections One Group C-C Disconnection- Alcohols
1,2CC Disconnections leading to alcohols
O 1,2 CC + PhMgBr Ph Ph OH OH Reagents
Example
1,2 CC O FGI
OH OH Br OH
1,1 CC
MgBr +
O
Reagents: PBr3 or the Apple Reaction [PPh3 /CBr4] Amines and One Group C-C Disconnections One Group C-C Disconnection- Alcohols 1,1CC Disconnection leading to alcohols
OH 1,1 CC OEt + 2eq MeMgBr
O
Retrosynthesis of Pirindol- Muscle Relaxant
NH 1,1 CC 1,3CX N OEt N OH OEt
Ph Ph O O 1,1CC Disconnection leading to carboxylic acid Synthons Reagents OH 1,1 CC MgBr + CO2 COOH CO2 O COOH NaCN Amines and One Group C-C Disconnections One Group C-C Disconnection- Carbonyl Compound as Target
1,1 CC 1) The use of ester and Grignard as double O O 1,1CC addition will generate the alcohol
R 1 R2 R1 R2 2) The use of less reactive organocadmium Synthons like R1CdR2
Alternative routes are: ketones from nitriles,from acids and from Weinreb amides
1,2CC COOEt COOH 1,2CC Br COOH COOEt Example: Br O
O O EtO O Synthons Reagents Amines and One Group C-C Disconnections One Group C-C Disconnection- Carbonyl Compound as Target
1,3CC R 1 R R 1 R R + RMgX/CuI
O O O
OH O Example: O FGI 1,3 CC
a3 +
COOEt COOEt COOEt Synthons Keys aspects for the synthesis: • organocopper chemistry O O • stereoselectivity of Michael Hagemann’s Ester addition and reduction O
MgBr/CuI O O
COOEt COOEt COOEt Reagents Synthesis and Use of alkenes and Alkynes
OH FGI Ph Synthesis of R Ph Ph Alkenes R or Ph via elimination FGI Ph EtO R R + PhMgBr HO Ph 2 x 1,1 CC O
Synthesis of Alkenes via Wittig Olefination + PPh3 base phosphorus Ylide Wittig Reagent R1CH2Br R1CH2PPh3 R1CHPPh3 Phosphorus Ylide Br-
R CHPPh Wittig Reaction 1 3 + R2CHO R1CH=CHR2 + OPPh3
Decision making: PPh3 + O=CH2
O + Ph3P=CH2 Synthesis and Use of alkenes and Alkynes
Ph3P O this approach may not lead Elimination or to single geometrical isomer Wittig Olefination? Problem of elimination: product selectivity + OH OH or OH OH +
Stereochemistry of the Wittig E/Z geometry is a function of theReaction structural features of the phpsphorus ylid
STABILISED YLIDE E ALKENES
UNSTABILISED YLIDE Z ALKENES O PPh O O stabilised ylids R 3 Horner-Wadswoth- R PO(OEt) 2 Emmons variant
PPh unstabilised ylids R 3 Synthesis and Use of alkenes and Alkynes Stereochemistry of the Wittig Reaction E/Z geometry is a function of the structural features of the phosphorus ylid Z selective Wittig IRREVERSIBLE PPh3 Ph PO R PHPh O 3 3 + R'CHO R' R R' R R' R E selective Wittig REVERSIBLE
Ph3PO
EtOOC R' SLOW R' R O PPh EtO 3 + R'CHO
Ph3PO R FAST R' EtOOC R' oxaphosphetane formation is reversible Synthesis and Use of Alkenes and Alkynes Synthesis of E,E or E,Z Diene
Solution needs to take into account E,Z or E,E geometry of the diene
Wittig E-stabilised ylid + O PPh3
Wittig O Z-unstabilised ylid PPh3 +
Synthesis Alkenes upon reduction of Alkenes
For Z isomer Hydrogenation [Lindlar's catalyst]
For E isomer Na/NH3 reduction
Revision: Mechanism of Na-ammonia reduction SET - origin of E selectivity Synthesis and Use of Alkenes and Alkynes Problem for trisubstituted alkenes: Control over E/Z geometry
One solution to the problem: Synthesis involving a cyclic intermediate
OH OH O
OH Double O O FGI OEt FGI OEt
OEt OEt
Revise Birch reduction: the Mechanism and the issue of Product Selectivity Synthesis and Use of Alkenes and AlkynespKa and key transformations R H pKa 25
R Na R H R MgBr + RH
RX R R alkylation
OH O R R addition onto carbonyl derivatives O R R epoxide ring opening OH R Conversion of terminal Alkynes into Carbonyl Derivatives
2+ O R H Hg / H2SO4 R Me O O H Me d1 H2C d2 t-hexyl2BH R H H H2O2/ NaOH R O Synthesis and Use of Alkenes and Alkynes
Example 1
O + CH2=CHMgBr
OH or acrolein readily available O MgBr
FGI FGI OH Br OH OH
Example 2
O FGI HO FGI HO 1,1 C-C + H Synthesis and Use of Alkenes and Alkynes Multistriatin Retrosynthesis
Br O 1,1-diX HO 1,2-CC + HO O O O OH OH
Br HO FGI Me OH HO HO HO OH OH OH
Reagents Me OH 1,2-CC OH O MeMgBr HO OH HO OH HO OH
O FGI FGI HO HO OH HO OH OH Two Group Disconnections 1,3-, 1,5- and 1,2- Difunctionalised Compounds • 1,3-Dicarbonyl Compounds and their derivatives Synthons Reagents O O O O O O
R R R d2 a1 R EtO
O O O O O
2 EtO EtO d2 a1 EtO Note: Mechanism of Claisen condesation • Example 1: Synthesis of Pival [Rat Poison] O O
O O
+ O EtO tBu tBu
O O O
O O O tBu COOEt O tBu O tBu COOEt COOEt
O Two Group Disconnections 1,3-Difunctionalised Compounds O O O OEt O COOEt COOEt • Example 2 + EtO OEt B A • A and B are the two possible disconnections O O • Example 3 Ph OCOR • B corresponds to the C-C NH2 + Dickmann cyclisation Me N N unstable
Me FGA Add a group!
O
COOEt EtOOC COOEt COOEt
NH2 + Me N N
Me Me • Example 4 Route to symmetrical ketones O O O
COOEt COOEt Add a group! OEt FGA R R R R R R Two Group Disconnections 1,3-Difunctionalised: β –Hydroxycarbonyl and α,β -Unsatured carbonyls • Example 1
O OH O
N OH OH O • Example 2 Oxanamide (tranquilliser)
O O FGI FGI C-N CHO
CONH2 COOH CHO
• Example 3 Doxpicomine (analgesic) O OH COOEt COOEt
N O N OH N N COOEt COOEt C. O acetal FGI H N N N N H3C CH3 H3C CH3 H3C CH3 H3C CH3
COOEt N COOEt O Two Group Disconnections 1,3-Difunctionalised Compounds – Amino alcohols • Reduction of nitriles O R R' HO R' R' HO reduction R CN CN C-C formation R' NH2 R' R' R Example Venlafaxine (Antidepressant) MeO MeO MeO MeO
Me CN CN MeO N NH2 HO HO HO O Me Br
• Mannich Reaction
R' R' R' O FGI
HO NR2 O NR2 O NHR2 R R R Example Clobutinol (Cough Medicine)
O MgBr H N OH N O N O Two Group Disconnections 1,3-Difunctionalised Compounds – Summary
O OH O O O ALDOL and Variants FGI R R' R R' R R'
O O O O CLAISEN and Variants R OEt R OEt OEt
R' R' R' O FGI MANNICH and Variants HO NH2 O NH2 O RNH2 R R R
R' R' R' CN FGI CN HO NH2 HO O R NITRILE and Variants R R Two Group Disconnections 1,5-Difunctionalised Compounds • 1,5-Dicarbonyl Derivatives
O O O O O 1,5diCO
d2 a3 Example O O O O
O Add a group! O OEt + COOEt OH OEt
COOEt Example Rogletimide (Sedative)
N N O O N O O N O O N O H OEt OEt NH2 OEt NH2 Two Group Disconnections 1,5-Difunctionalised Compounds • Robinson Annulation O O O O
1,5 diCO
O O O O O O OH • Synthesis of Coccinelline COOMe O
N FGI N O O CH(OMe)2 CHO
CH(OMe)2 CHO COOEt
COOEt O • Synthesis involving an intermediate featuring a 1,5-Difunctionality
FGI H N H N O 2 2 H2N MeNO NH NO + 2 2 FGA 2 pKa = 10
1,5 diCO O O
N N Two Group Disconnections 1,2-Difunctionalised Compounds • 1,2-Diols via alkenes OH O R'
R' FGI R' FGI R R R PPh3 OH • 1,2-Diols via cyanhydrins Cl Cl Cl Cl O FGI CN OH OEt OH OH OH O • α-Hydroxyketones via benzoin condensation O O Ph Ph Ph Ph Also Revise: acyloin condensation d1 OH a1 OH • α-Functionalisation of carbonyl compounds OH O Ph PhOC Ph Ph
N N Diphepanol PhOC PhOC spasmolytic Br Two Group Disconnection 1,4-Difunctionalised Compounds: Strategy 1 O O
R2 or R2 R1 R1 O OH
O O O X a2 R2 R2 R2 R1 R1 R1 O d2 O O Example: Precursor of antibiotic methylenomycin
O O O O O Br O COOEt COOEt OH COOH COOEt COOEt O O O METHYLENOMYCIN O base cyclisation COOEt O O Synthesis: Br COOEt COOEt O Two Group Disconnection 1,4-Difunctionalised Compounds: Strategy 2
O O O a2 R2 R2 R2 R1 R1 R1 O OH d2 OH Example:
COOH O CH2(COOEt)2 OH 1,4-Difunctionalised Compounds: Strategy 3
Reagents O O O d1 R2 R2 R1 R1 R1 O a3 O With nitrile or nitro derivative Two Group Disconnection 1,4-Difunctionalised Compounds: Strategy 3 Nitrile Ph Ph Ph Ph CN
O O HOOC COOH N NC COOH COOH H
Synthesis: H+/H O Ph NaOEt Ph CN 2 PhCHO + NCCH2COOEt Then MeNH2 O Then KCN NC COOEt O N H 1,4-Difunctionalised Compounds: Strategy 3 Nitro base NO2 O R NO R2 R2 1 2 R2 R1 R1 O O O O O O NO2 FGI
OH O O Two Group Disconnection 1,4-Diols and derivatives: Strategy 4 Alkynes OH HO OH O O R2 R1 R R R1 R2 OH 1 2 O Example: FGI OH HO O COOH O R OH R
R
HO O
R R 1,4-Difunctionalised Compounds: Strategy 5 Allylation
O FGI Br
CO2Et CO2Et CO2Et Two Group Disconnection 1,6-Difunctionalised Compounds: Ozonolysis “Reconnection” is a reliable strategy for synthesising 1,6-difunctionalised compounds since the cyclohexenes required for the oxidative cleavage are easily accessible O OH HO “Reconnection” Example: O O O O 1 reconnect 6 O
1,6-Difunctionalised Compounds: Baeyer-Villiger
O O O OH reconnect OMe OMe O
O O “Revision”: mechanism of Baeyer-Villiger reaction and migratory aptitude Two Group Disconnection 1,6-Difunctionalised Compounds
“Reconnect” O or Br O O O EtO
O EtOOC Synthesis O EtO COOEt Br O O HCl O Then O O O Polyphosphoric EtOOC COOEt acid Two Group Disconnection 1,6-Difunctionalised Compounds O O O “Reconnect” EtO O
Retrosynthesis- Solution 1 O O O O EtO O CN Br COOEt O O
COOEt COOEt COOEt COOEt Retrosynthesis- Solution 2 O OH OH EtO O EtO O
E/Z O Dithianes are d1 Reagents Acyl anion equivalents Which dithiane?
BuLi BuLi SS SSbut S S S S S S Li Li Not stable Example
Br Br
O O O O O O
Revision: pKa and mechanism/reagents to transform dithianes into
aldehydes or ketones HgCl2, oxidation or alkylation Ring Synthesis Three-membered rings
• Three-membered rings
a OEt O Mechanisms O O Epoxidation b O O OEt : Ring closure OEt
OEt Synthesis a: H2O2, base O O O
Cl O OEt EtO- /acetone Synthesis b:
OEt Ring Synthesis Three-membered rings
• Three-membered rings
O O O O C-C FGI + O
R Br R HO R EtOOC R
• Three-membered rings
Br
Br O O O Br COOEt O : + O HO Br EtOOC HO Ring Synthesis Four-membered rings
O O R R R
BuLi R1 R2 S S S R1 R2 R R R
R 1 O R + O H R2 S
R R1 R1 R O 2 R2 Ring Synthesis Five-membered rings
• Five-membered rings: chemoselectivity ozonolysis, control over recyclisation step
O O Limonene Natural Product
O • Acyloin condesation as a key step for the synthesis of 5-membered rings O O O O O EtO EtO
OH OH OH O O
OEt OEt
Corylone NMe2 NMe2 Spicy coffee O
COOEt • Favorskii Ring Contraction Ring Synthesis Six-membered rings
• Six-membered rings via Diels-Alder Cycloaddition
+
O O • Six-membered rings via complete Reduction
O OH OH
• Six-membered rings via partial Reduction
O O MeO MeO
O O Synthesis of Nuciferal Bisbolane type sesquiterpene isolated from wood oil of Torreya Nucifera
BrMg
OH O A ? Nuciferal O STAGE 1 O CHO O
STAGE 2 ?
1. Suggest a synthesis for the starting material A 2. Suggest reagents for stages 1, 2 and 3 3. Draw out the retrosynthetic ? analysis with suitable labelling STAGE 3 for all retrosynthetic steps CHO 4. Which synthon does the Nuciferal starting material A represent? CHO Synthesis of Coccinelline
Ladybird compound COOMe O
N FGI N O O CH(OMe)2 CHO
CH(OMe)2 CHO COOEt
COOEt O
H O H OMe OMe O OMe OMe NaOMe MeOH/H+ MeOOC COOMe CH2=CHCHO MeO OMe then decarboxylation NaOMe COOMe
MeOOC MeOOC OMe O OMe OMe NH2 OMe
NaCl, DMSO NH4OAc Krapcho MeO OMe NaB(CN)H3 MeO OMe dealkoxy- decarboxylation H
O NH O H 2 N O pH 5, H2O H MeO2C CO2Me N O O H H H MeOOC COOMe
OH MeOOC COOMe N N O
COOEt MeOOC COOMe COOEt O O Retrosynthesis of Terfenadine
Ph NaBH Ph 4 Me H Me Ph C N(CH2)3 C C Me Ph C N(CH2)3 C C Me Me Me OH OH FGI OH O
K2CO3 DMF Antagonist H1 Δ
Ph Ph C OH O Me
Cl (CH2)3 C CMe Me N H
1) PhMgBr FGI, AlCl3 RETRO ACILAZIONE 2) NaOH, BuOH RETRO GRIGNARD CHCl3 FRIEDEL CRAFT Δ
CO2Et CO2Et ClCO2Et Cl Me TEA (CH2)3 CMe COCl Me
N FGI N H COOEt Retrosynthesis of Minaprine -Antidepressant
5 O 4 FGI FGI 6 N Ph N Ph O 3 Ph Cl H POCl NN RNH , Δ 3 NN 1 2 2 NN Δ H
FGI Br, AcOH, Δ
O FGI 1 Ph O Ph CO H 2 NH2NH2 NN 2 Δ H
FGI RETRO ACILAZ. 1 FRIEDEL - CRAFT
2 AlCl3 CH2Cl2 PhCO O O Ph O
HO CN OR Ph C H2CCCO2R O N CH3 O O
O Retrosynthesis of (+)-Norgestrel 19-Nor Steroid
OH O OH H H
RETRO 17 FGI ETINILAZIONE H H H H
H+, Δ 1) H H H H LiC CH H H 2) NH4Cl / H2O O MeO MeO
1) Li / NH2(l) FGI 2) Al (OiPr) , Δ RETRO 3 BIRCH
O H OAc OH RETRO KNOEVENAGEL FGI FGA, FGI *
* 1) H2,Pd / CaCO3 H 1) Ac2O, Py 2) KOH, MeOH O 2) TosOH, Δ MeO MeO MeO
RID. FGI ENZ.
O O RETRO TORGOR a d d a
O KOH, MeOH Δ OH O
MeO
MeO Retrosynthesis of Avenaciolide
C H O O 8 17 C8H17 O O C8H17 O O O C8H17 OH RETRO FGI METILENAZ. HH H H
a d O O O O H2C
O O O O
FGI CHO C8H17 O C6H13 O O RETRO WITTIG O Me FGA O Me O Me O O Me O Me Me RO2C RO2C RO2C
CON
Me O Me O D-GLUCOSIO
HO Me O Me O HO O O FGI HO RETRO O O FGI WITTIG OH O Me O Me FGA OH OH O Me H O O O Me Me OH O CO R Me 2 RO2C Retrosynthesis of Pentenomicina
d Me O O O O a CHO RETRO FGI FGI ALDOLIC
BuO AcO OO OO HO OH OH BuO OO (-)-Pentenomicina Me Me Me Me Me Me
FGI
Me O OMe TsO OMe O TsO O H C O 2 Me O O
O Me BuO OO O Me BuO OO BuO OH O Me BuO OH O Me Me Me Me Me
FGI
Me O Me Me O
RETRO RETRO Me O Me O Me O HENRY O NEF O O D-GLUCOSIO
d a OHC O Me O Me O Me O OH O Me O2N OH O Me O Me Retrosynthesis of 11-Deoxy-8-aza-PGE1
O O O (CH ) -CO R O (CH ) -CO R 2 6 2 (CH2)6-CO2R 2 6 2 (CH2)6-CO2R RETRO N N FGI N WITTIG FGI N
C H C5H11 5 11 CHO 1) K CO CO2R Zn(BH4)2 2 3 2) ClCO2Et, TEA 11-Deoxy-8-aza-PGE1 R = Me, H OH O NaBH4 . 3) CrO3 2Py
RX NaH
O NH2 O FGI Δ NH HO NH CO2H H CO H CH2N2 O FGI 2 H CO2R (R)-Acido Glutammico
Baraldi,P.G. et al. J.Org.Chem.,1979,10,1734 Retrosynthesis of ±4 –oxocyclopentane- 1,2-dicarboxylic acid
O FGA O FGI 1 1 RO2C CO2R CO R RETRO 2 DIECKMANN CO2R Δ, DMSO 160°C CO R 2 RO2C 2 CO2R
HO2C CO2H Δ RO2C CO2R
2
RETRO Δ MICHAEL
a CO2R CO R Br 3 2 3 CO2R CH2 CH2 d CO R CO R 2 2 EtONa CO R RO2C 2 RO2C etrosynthesis of cis-3-oxabicyclo[3.3.0]octan-7-o
RETRO 1 FGA DIECKMANN RO C O O 2 O O O 1 RO2C Δ EtONa, Δ cis-3-Ossabiciclo 3.3.0 -Ottan-7-one RO2C
1) CrO3 FGI, FGI 2) CH2N2
FGI RETRO OZONOLYSIS OTos OHC O O OH OHC TEA O3
TosCI TEA FGI O O RETRO FGI DIELS - ALDER OH O O OH LiAlH 4 Δ O O Baraldi,P.G. et al.,Tetrahedron,1984,40,761 Retrosynthesis of Diidroiasmone
O O
RETRO O ALDOLIC FGA
OH- Fe(CO)5 O - O OH / H2O
1) H2, PtO2 2) PhCOCl, Py 3) NaBH4 4) H+
O O O OO
NO2 NO2
PhNCO (CH2OH)2 TEA + 1-Esino H N O TMG
O
CH3NO2 Baraldi,P.G. et al..J.Org.Chem.,1979,44,105 Retrosynthesis of PGF2α
HO THPO
CO2H CO2R FGI
HO THPO PGF2α HO O
RETRO WITTIG
FGI
O O
O O O
CO2R FGI 1-Eptino a d
NO2 NO2 THPO C5H11 THPO THPO N O
RETRO MICHAEL
O O O O CO2R CO R 2 CO2R N CO2R CHO
FGI FGI FGR CO2Me THPO HO Br Synthetic scheme of PGE2α
O 1) CHO O O + CO R H H2O N 2 NBS CO2R CO R Δ CO2R BuOH, Δ 2 Diossano CCl4, Δ 2) H+ Δ Br
O
O O O O CH NO t DHP 3 2 LiAlH(O But)3 PhNCO CO2R CO R CO2R 2 TMG, 0°C pTsOH THF, Δ 1-Eptino
NO2 HO THPO THPO NO2 THPO
OH O THPO 1) Na, NH (l) DIBAH, -78°C O 1) Wittig 3 O 2) Si O CO2H 2 1-Eptino 3) NaBH4 2) DHP, pTsOH PGF2α 4) H+ C H C H 5 11 5 11 THPO NO THPO NO THPO NO Baraldi,P.G. et al. Tetrahedron,1987,43,4669 Retrosynthetic Route to Geiparvarin
O O 3 4 2 FGI 5 OOO OH OOO O 1 O AcOH, 0°C
Geiparvarin
AcOH,0°C FGI
N TMSO O FGI NH2 O
OOO TMSO O OO
Mo(CO)6 Δ
PhNCO RETRO TEA CICLOADDIZIONE 3+2 DIPOLARE
H
H OOO HO OO FGI NO 2 OH TMSO
DEAD FGI Ph3P
NO2 O CH3NO2 HO Baraldi,P.G. et al. Tet.Lett.1985, 43, 531 Retrosynthesis of Sarcomycin
O O
FGI FGA, FGI O O FGI O O O H+, RT, 5d O CH OH O CO2H + 2 H+, RT, 6 h. CrO3, H HC O 0°C 2 O O Sarcomicina O
1) O , -78° 3 FGI 2) NaBH4
O O
O O O RETRO DIELS-ALDER FGI Br
Δ, 3 d MED CO2R TosOH CO2R
CO2R
Baraldi,P.G. et al. J.Chem.Soc.Chem.Com.1984,1049 Retrosynthesis of Carbaprostacycline
CO2H
O
OO
FGI FGI
RETRO WITTIG C5H11 C5H11 C5H11
OTHP OTHP OH OH OTHP O Carbaprostacycline RETRO WITTIG
O OO OO
FGI FGI
CO2R CHO CO2R O O OTHP Retrosynthesis of a intermediate for Carbaprostacycline
O O O RETRO OH RETRO CLAISEN MICHAEL FGI
K2CO3 1) Im2CO Jones 2) CO2Et CO2R CO2R CH2 CO2H CO2H O O CO2H Mg(OEt)2
NaOH FGI
RETRO BAYER-WILLIGER O O NaOH, H O 2 2 O
Baraldi,P.G. et al. J.Org.Chem.,1980,45,4776 Synthesis and Retrosynthesis A2B Agonists O O R N H I NH2 HN N N N N N N H N N H N N N O H N N N O N O O O O O O NH2 OO Isopentylnitrite, O O OH OH 1) R NH CH2I2 2) TFA, H2O R = Ph hA1 Ki=8.5nM 1) SOCl hA2A Ki= >1000nM 2 2) EtNH2 hA2B EC50= 7.3nM hA3 Ki= 38.4nM
NH2 NH2 N N N N NH2 N N N N N N HO HO O O O N N HO O p-TsOH, O O KMnO4, O O 2,2-dimethoxypropane KOH OH OH
P. G. Baraldi et al., Bioorg. Med. Chem., 15, 2007, 2514-2527 Synthesis and Retrosynthesis A2B Antagonists O H hA K >1000nM N Cl 1 i N O hA2A Ki >1000nM N hA IC = 7nM O N N N 2B 50 N H hA3 Ki >1000nM
O NH N 2 1: , EDC O N NH2 O
OEt 2: NaOH
Cl O N N + O N N2-alkylated product N N KOH O H OH O HN
OEt Cl N EtONa, N p-Cl-acetanilide H
P. G. Baraldi et al., Bioorg. Med. Chem., 16, 2008, 2419-2430 Synthesis and Retrosynthesis of sulphur Duocarmycins X TEMPO
NBoc NBoc NBoc
S DBU S Zn powder S TEMPO, 14 (2 steps) O 10 (Me3Si)3SiH OR OBn R = Bn, X = OH, 11 PPH3, CCl4 Chiral column R = Bn, X = Cl, 12 Pd/C, H CO NH N R = H, X = Cl, 13 2 2 4 O I X
NBoc R COOEt
S S S NaH, allyl bromide LiOH 9 AcONa, Ac2O (2 steps) OBn OBn OR R = COOH, X = H, 6 R = Ac, 3 DPPA K2CO3 R = NHBoc, X = H, 7 R = H, 4 NIS BnBr R = NHBoc, X = I, 8 R = Bn, 5
COOEt CHO
S S 1 2 COOH t-BuOK, Baraldi P.G., Boger D.L., et al. diethyl succinate JACS., 2007, 129, 14092-14099