retrosynthesis
Post on 23-Feb-2017
97 Views
Preview:
TRANSCRIPT
Synthon approachDr. Taj Khan
Dept. of Pharmaceutical Chemistry, Oriental college of pharmacy
Sanpada, New Mumbai.
Ref: Stuart Warren , Iyer R P
Retrosynthesis is the process of “deconstructing” a target molecule into readily available starting materials by means of imaginary breaking of bonds (disconnections) and by the conversion of one functional group into another (functional group interconversions).Its useful for finding out new route for synthesis of new drugs or existing drugs and comparing them in logical & straightforward wayAn operation that involves breaking of a bond between 2 atoms to produce oppositely charged synthons.
Indicates disconnection
Functional group interconversion (FGI): process of converting 1 fun grp into another by substitution, addition, elimination, oxidn or redn. Reverse operation is used in analysis
AB A+ + B -
COOH CN Hydrolysis
NH2 NO2 Reduction
Cl OH Substitution
Terms for Synthesis Retro analysisStarting structure SM Target
Steps Rx Transformation/disconnection
Steps shown by
Stru features needed
Fun grp Retron
Prdt after the step intermediate Precursor/ Synthon
Ending stru Desired prdt Possible SM
Disconnection: An analytical operation, which breaks a bond and converts a molecule into a possible starting material. The reverse of a chemical reaction. Symbol
and a curved line drawn through the bond being broken.⇒
FGI: Functional Group Inter-conversion: The operation of writing one functional group for another so that disconnection becomes possible. The reverse of a chemical reaction. Symbol with FGI written over it. –COOH -CN, -NH⇒ ⇒ 2 NO⇒ 2 -H⇒Target Molecule: The molecule whose synthesis is being plannedFunctional grp addition: process in which functional grp is addedin the retro scheme in order to make stable fragment e.g. addition of COOEt grpFunctional grp removal: removal of fun grp in order to make stable fragment
Transform: reverse of synthetic rxRetrosynthetic analysis: Logical process of analysing stru of TM to transform the target to a sequence of progressively simpler stru along a pathway which finally give simple & comm viable SM.“process of breaking down TM into available SM by FGI & disconnection”
O
O OH
Alcohol+
Cl
O
Acyl chloride
Ester
Synthon: A generalized fragment, usually an ion (cation/anion/radical), produced by a disconnection. (some people also use synthon for a synthetic equivalent).
2 typesdn Synthon (d= donor n= distance bet FG & reactive centre) functionalized Nuan Synthon ( a= acceptor ) functionalized E+
OH
R 1
R
O
12
R
OH
12 H3C
O
12 3
a3 synthona1 synthon
d2 synthon
a3 synthon
O
Cl
O
Br
Me
O
Me
OH
Reagent: A compound which reacts to give an intermediate in the planned synthesis or to give the target molecule itself. The synthetic equivalent of a synthon. e.g. MeI is reagent for Me+
Synthetic equivalent (SE ) A reagent carrying out the function of a synthon which cannot itself be used, often because it is too unstable. Every synthon has its SE H2SO4 and HNO3 mixture is SE of NO2
+
Retron: Minimal stru in mole in TM which causes transformation e.g. in Deil’s Alder rx 6 memb ring with pie electrons B: SM and A TM
Arrow: it could be made from
A B Ph Ph
OO OO
Ph Ph
OO
Target Retron
Precursor
Synthetic tree: Set of all possible disconnections and synthons leading from TM to SM
Route 1
Route 2
C C RO2N CO2N C R+
Disconnection towards NO2
Disconnection towards R
C C RO2N CO2N C R+
Stabilizedcarbanion
unstabilizedcarbonium ion
unstabilizedcarbanion
Strategies for disconnection approach:1) Simple route: good for industrial purpose. Avoid radical and photochemistry.2) Disconnection shd be done such that it gives stable ion fragments. Break down molecule 1 bond at a time. For heterocyclic compd disconnection is done such that 2 fragments in which 1 is +ve and other is -ve fragments generated e.g disconnection of C-C bond
Strategies for disconnection approach: contdStability of ion generated governs the mode to be followedCarbanion (C-) fragment is stabilized by EWG like CN, NO2, COOEtCarbonuim ion (C+) fragment stabilized by EDG or e releasing grp like R or ORIn this case route 1 is preferred because it gives Stabilized ion fragment , whereas route 2 gives both unstabilized fragments3) No of fragments generated shd be small in number as possible i.e. few steps strategy is preferred.
H3C CH3
OO
TM
H3C CO
H3C OEt
O
+
CH3
O
MgBr
O
GR
FGI
OH
O
O +
O
O
1
2
3
4
5
Total fragments 5
Route 1
2 3
2-3 disconnection
H3C CH3
OO
TM
OMichael Rx O+
Total fragments 2so preffered route
Route 2
3
4
3-4disconnection
Examine 1) mole as whole 2) watch various fun grps and 3) positional relationship between fun grps
4) C-C db can be considered to result from dehydration, dehydrohalogenation or Elimination of NH3, NH2OH....etc.Addition of mole of water or NH3 to db can set up the target for further disconnection
5) A bond joining a C atom to hetero atom (O, N, S) is always broken with electron pair remaining on hetero atom i.e. hetero atom shd have –ve charge
In this case disconnection follows principle of electronegativity i.e O, N, S > C
C N C
C Cl
N
HN
C-N+
6) Sometimes disconnection does not generate stable fragments in such cases FGI concept can be used to generate stabilized ion fragmentse.g. synthesis of alkylamine
R NH2 R + NH3
ab a
R Clb
R
R Cl
+ H2C NH2
UnstableFGI/FGC
H2C NO2 H3C NO2
Ana
lysi
s
H3C NO2Base
R Cl
RCH2
O2NReduction
R NH2
7) Fun grp addition: Sometimes disconnection does not generate sufficiently stable fragments in such cases stability could be achieved by introducing additional EWG & removing after use.
Ana
lysi
sS
y nth
esis
R
O
R CH2
O+ Cl
Unstable
FGA/carboethoxy
REtO
O
O
R
O
OEt
OBase
Cl
REtO
O
O H
-CO2-EtOH
R
O
TM
TM
8) In some cases reconnection of acyclic fragments can help to generate cyclic fragments that could result in simpler starting material & Rxn sequences. Of course, strategy must be in place for conversion of acyclic to cyclic fragments during synthetic sequence.
Diel's Alder Rxn
OMe
COOHOH
FGI
OH & COOH on same sideso can be reconnected to form lactone
OMe
O
O
OMe
O
O
OMe
O
OMeOMe OH
+
1) DA2) Oxidn3)BV oxidn
O
12
3 4
12
3 45
5
12
5
67
834
O
+vely charged alkyl fragments:
RCH2RCH2Cl or RCH2OH or RCH2OEt
+vely charged acyl fragments: acid chloride, acid, acid ester
OR Cl R
OOr
R OH
OOr R OEt
O
-vely charged fragments Corresponding protonated species
NO2
R
NO2
RR N
H
HR N
H
R O RO
HR
OEtO
R
OEtO
Retro analysis followed by synthesis:
One grp disconnection (C-X disconnection)Disconnection of simple alcohols, alkyl halide, ethers
Alkyl halide:
C-X disconnection in aliphatic compds gives a Nu (XH) &E+ carbon species usually represented by alkyl halide, tosylate and mesylate
R XC-X
X + R RY
XH
cationic C synthon
Y=Br, OTs good leaving grps
Following types of compds can be made using alcohols
Base Hal-R'OH
NuR'SH/base
R-XROH
R-OR'
RHal
RNu
R-S-R'
Ether
Alkyl halide
Other deri
SulphidesX= halOTs (tosylate)OMs (mesylate)
ROHTSClPyr
PBr3/HBr
MSCl
TEAROTsROMs
RBr
Methyl & 1o alkyl deri : SN2 mech so powerful Nu and non polar solvent effective.3o SN1 Polar solvents and catalysise.g. 1)
R1R3
R2
OHR1
R3R2
R1
R2
R3
R1R3
R2
X
R1R3
R2
Br
X-
C-C+
Cl
FGI
OH
A(TM)
B C
Synthesis:C B
PhH
AlCl3FC rxn
A(TM)
Ethers: 2)
Ph OPh O +
X
A route could lead to Elimination to give alkeneperfumeBpreffered
X
Ph+ HO
Benzyl alcohol is reactive but still preffered SM
C-O
C-O
Ph OH
AAB
Ether Synthesis: SN2 so base catalyst helps
HOBase
OPh Cl
OPh
Ana
lysi
sS
ynth
esis
OPh Ph OHC-O
+ HO
HO OPhBase
PhCH2Br
TM
TM
Acids:
Syn
thes
is:COOH
Br
+ H2CCOOH
COOEt
COOEtDiethyl malonate
Ana
lysi
s
COOEt
COOEt
NaOEt/EtOH
Br
COOEt
COOEtTM
KOH/H2O
H+, Heat
TM
C-C
Carbonyl compd synthesis by Michael additionR' R2
O C-C-R1 + R2
OGR/RLi
O
RC-C
O
+ R-
ORLi
n-Bu3P/ CuI
TM
Branch ponit at Beta and gamma C
O
RTM
Rings (5 & 6 membered), fused heterocyclic rings –more common in drugs3 & 4 memb less common tranyl cypromine (3 C) Beta lactum ring (4C)Retrosynthesis: 1) Follow similar rules with additional possibilities.2) Rich in functional grps so handle only readily predictable fragments like NH3, NH2NH2, NH2OH, guanidine, thiourea, (NH2)2(CH2)2, HO(CH2)2NH2
3)Break C-Het 4) Addition of H2O to db ( NH3, NH2OH etc)
5) 3-component cyclization, DA rxn, 1,3 dipolar rxn
C+ + - Hetero atom
Sulfides:
SPh Ph SHS-O
+ HO
TM
R1 S R2 R1S- + R2YUndergoes easy SN2
SH have low pKa than alcoholR1S- softer anion than RO-
so more Nu towards SP3 C
Ana
lysi
sS
ynth
esis
S
Cl
ClS
Cl
Cl
Cl
+
TMChlorbenzide-Acaricide
C-S
SH
Cl
Cl
Cl
+S
Cl
Cl
NaOEt
EtOH
TM
One grp C-C dix Alcohol: Best mtd is GR addition to ald/ketone
R1
R2
R
OH
R1
R2
OH+ R-
R1 R2
ORMgBr
1)
C-C
One grp C-C dix Alcohol contd…
+
R-
RLi
2)
OR1
ROH
R1
Epoxide ring opening
Ana
lysi
sS
ynth
esis
OR1 RLi+
ROH
R1
Dix of heterocyclic rings: Any 1 eg1)Pyridine e.g. Nifedipine
C-N
OHOH
N
N
N
2H
N ONH2 ONH2
+
CHHC
CHHC CH
N
3 component cyclization
1,5 di-CO
Michael CHO
+ CHO
C-N Stork enamine Rxn
Michael rxn
a)
b)
c)
d) Stork enamine Rxn followed by cyclization rxn is aviable route for synthesis of pyridine
ONH2
+ ONH NH2N NO
-2H
Dix of Het. Pyridine Contd..
Pyrimidine: eg barb, anticancer (MTX, 5FU), Anti viral AZT
N
NH2N
H2N NH2
NH+
H
HO
OMalonaldehyde
N
NH2N
H2O N
NH2N
O HH O
NH
H2N
NHH2N NH2
NH
+
H OH O
OEtH
H O
OEtO
H O
OEtO
H
H
N
N
Pyrrole: less common eg. Zomepirac (anti inflammatory)
NH
R1
R2 R3
COOEt
O O
R1 COOEt
R2 R3
Michaelrxn
O
NH2R2
R1+
R3
COOEtb)
a)
NH
Imidazole: Metro (anti bacterial, cimetidine H2 blocker
N
NH
H3C
H3C CH3
NH
O O
H3C
H3CCH3
NH2H3C
H3C+
H2O
-NH3
H3C NH2
OCl
b)
NH3
O
O
H3C
H3C+ +
H
CH3
O
Glyoxal acetaldehyde
a)
N
NH
Indole: Indomethacin
NH
R
R
H2O
H2O+H2O
NH
R
ROH
NH
R
R
HO
NH2O
R RFriedel C
NHAc
+R
RCl
O
FGI R
NO2
+Cl R
O
NH
O R
R
NH2
+R
RCl
O
Cl
NO2
+ RO
R
Fischer indole synthesis: 1,5 diene cope rearrangement Addition of NH3 in place of H2O
NH
R
RNH2 NH2
NH
R R
NHNH
R RH
NH
NH
RR
Dix of Het. Indole Contd..
Quinoline: Anitimalarial(prima, chloro) ciprofloxacin
N
N
O
CH3H2O
CH3ONH2
O
NH2
+
OEt
CH3
O
O
NH2
+
OEt
CH3
O
O
Diphenyl ether
250 0 C N
O
CH3
Ana
lysi
sS
ynth
esis
Piperazine: meclizine, cyclizine Cinnarizine (Valodailator)
NH
HN
NH
HN
OH
NH22
NH2
NH2
Cl
Cl
+
NH2
NH2+ O
C-N
C-N
+NH3
O
H2N
OHN
OHMe
Me
O
H2N
O H2N
O
Me
Me+
OH
H2N
O OCl+
OH
Cl
O
OH
HO
O
FGI
+ NH3
SOCl2
NH3
Base
2-(4-hydroxyphenyl)acetic acid
Atenolol
Epicholrhydrin
Dix of drugs
Sulfadiazine
H2N SO2NHN
N
H2N SO2ClN
N
H2N
H2N+
Free NH2 can react with ClSO2OH so need to be protected by acetyl grp and deprotected by aqs HCl
Malonaldehyde (unstable)
OHCCHO
+
H2N NH2
NH.HCl
OMeMeO
MeO
OMeDiacetal of Malonaldehyde (stable)
Ana
lysi
s
Dix of drugs contd..
Synt
hesi
s
Diacetal of Malonaldehyde + Guanidine HClN
NH2N
Aniline + Acetyl chloride HN SO2ClC
OCl
ClSO2OH
I
II
I + II H2N SO2NHN
NH2N SO2NH
N
NAqs HCl
Strategies:Guiding principles for selection of transform so as to keep size of retero-synthetic tree in controlTypes of strategies in disconnection:1)Transform based strategies depend on application of powerfully simplifying transformation like DA, Robbinsons annulation, Birch rx
2)Structure based strategies depend on recognition of possible SM /key intermediate for synthesis
3) Functional grp based strategies identify functional grp as key structural subunitOH, C=O , = etc can be useful for identifying suitable pts for disconnection
4) Topological based strategies depends on identification of 1/more individual bond disconnectionOr correlated bond-pair disconnection.There are several types of strategic bonds e.g. bonds in polycyclic syst, poly fused ring syst, bond connecting chai to ring, chain to fun grp5) Stereochemical based strategies remove stereocenters stereorelationships under control. Stereocontrol can be achieved by mechanistic or by substrate. Reconnection that moves stereocenters from chain (where they r difficult to introduce) or into rings (where introduction is much easier)
Basic rules of disconnection:Rule 1: Bond shd be disconnected such that stable fragment(ion) obtd
Route A ok as carbcation stabilized by EDG like OR Carbanions are stabilized by EWG like NO2, Cl
O2N C C OR
A
B
CO2N C OR
CO2N C OR
+
+
Rule 2: Total no of fragments shd be as min as possible i.e. synthesis shd be short. Disconnectionshd be made in middle of mole/ at branch pt
Analysis
OH
C-CCHO
+
BrMg
Br
i) Mg, Et2O
ii) CH3CHO OH
Synthesis
TM
TM
Rule 3: compds with 2 parts joined with hetero atom, disconnection shd be next to hetero atom,e pair remain with het atom (het atom more negative than C & so accommodate -ve charge easily)
AnalysisPh O Ph
C-O+
PyridineSynthesis
TM
O
Ph O
Ph
O
Ph O Ph
TM
O
PhCOClPh OH
Rule 3: If disconnection doesn’t give stable fragment then FGI done/ simple grps introduced soas to give stable fragments
Analysis RC-C
+
Synthesis
TM
NH2
R
TM
NH2
R CH2
R CH2Cl
H2C NH2
Unstable as NH2 is e rich
FGI
H2C NO2
Stable as NO2 is EWG
CH3NO2 + ClCH2CH2R R NO2
Reduction
Rule 5: Use disconnections corresponding to known reliable rx with high yields. +ve & -ve fragments generated by disconnection r replaced by known available chemicals.
H2C C CH
A
B
PhC CHH2C+
PhCH2+ C CH
Route B ok as acetylene forms anion with sodamide in liq NH3
R1HN R2
FGIR1
HN R2
O
C-NR1 NH3 Cl R2
O
+
OR
R1HN R2
FGIR1 N R2
C=NR1 NH2 Cl R2
O
+
h
Amine r converted to less reactiveamide/imine before disconnection
Positive fragments: +ve charge fragments equvt to good leaving grp/EWG
R CH2
H2C XR Alkyl halide
H2C OHR Alcohol
H2C OEtR Ether
+ve charged alkyl
R C
C XR Acyl halide
C OHR Acid
C OEtR Ester+ve charged acyl
O
O
O
O
C OR
O
C
O
R Anhydride
Positive fragments: -ve charge fragments equvt to their protonated species
O2NHC R O2N
H2C R
RO ROH
RNH RNH2
ROCOCHR' ROCOCH2R'
Rule 6: Disconnection route that avoid chemoselectivity (Rx of 1 fun grp in presence of other) shd be selected. For this reactive grps r disconnected first & 2 grp disconnection is done.
OPh
OH
a b
a
b
HO
OH
Ph
OH
OH
Ph
+
+
Route a involve 2 OH selectivity problem so route b is better
Guidelines for disconnection:G1: Examine relation bet grps in TM. Disconnect grp which is proper directive at last
COCH3
CH3
COCH3
CH3
TM
a
b
Acetophenone
Toluene
CH3+
+COCH3
Route b is better since in route a COCH3 is meta director & rx is not possible
Guidelines for disconnection:G2: Most EWG grp is to be disconnect first (It is to be added in last in synthesis)
CH3
TM
CH3H3C
NO2O2N
C-N
CH3
CH3H3C
C-C
CH3
OCH3 OCH3 OCH3
+ t-BuCl
CH3
CH3H3C
OCH3
OH
OCH3
Me2SO4
Base
CH3
OCH3
t-BuCl
AlCl3
CH3
TM
CH3H3C
NO2O2N
OCH3
HNO3
CH3
CH3
CH3 CH3
Analysis:
Synthesis
Guidelines for disconnection:G3: If FGI I needed it shd be done at proper stage to get right orientation. Other subs added either before or after FGI
Analysis
Synthesis
Cl
Cl3C
TM
Cl
Cl3C
TM
Cl
H3C
FGI C-Cl
H3C
H3C
Cl2
FeCl3H3C
Cl
Cl2PCl5
CCl3 is meta director (it is introduced by FGI)CH3 is para director so FGI shd be done before C-Cl disconnection
Guidelines for disconnection:G4: Avoid sequences that lead to unwanted rx at other site of mole
Route b is preferred as nitration e.g. benzaldehyde may lead to oxidation CHO oxidise to COOH
O2N CHO
ab
CHOCH3
O2N COOH COOH CH3
a
b
FGI
FGIFGIC-N
C-N
Guidelines for disconnection:G5: when fun grp of unequal reactivity present in mole, more reactive grp to be considered for Rxe.g. In Phenyl ring containing both OH and COOH grps in basic soln (pH> 10) phenolate ion is more reactive than carboxylate ion.
O
OO NH2
O
COOH
OH
COOH
+
I
C-O C-O
TM
Guidelines for disconnection:G6: For adding 2 O/ a P directing grp M to each other, dummy NH2 grp is added, which could be removed by diazotization and reduction
EtOH/H
RRRRR
NO2 NH2 NH2
X X
Guidelines for disconnection:G7: Grps like OH OR difficult to introduce so not disconnected instead use SM containing them
NH2
COOH COOH
OH
O
O
OSalicylic acidAnthranilic acid Phthaleic anhydride
Guidelines for disconnection:G8: If 1 fun grp can react twice then SM & final prdt compete for same reagent. Rx will be successful only when first prdt is less reactive than SM. Both contain COCl
Above Rx works as half ester TM is less reactive than phosgene b’se of conjugation
Phosgene
Cl
O
ClPh O Cl
O
Ph OH +C-O
TM
Guidelines for disconnection:G9: If both O, P subst involved, avoid separation of isomers. P can be blocked
TM
HC
H3C CH3
OH
O2N NO2a a
b
HC
H3C CH3
OH
OHOH
O2N NO2
OHC-C
C-N
b
a
OH
HNO3
OH
O2N NO2
AlCl3
Cl
TM
HC
H3C CH3
OH
O2N NO2
Route b preffered as it blocks P position
Disconnection involving 1 functional grp: C-X Disconnection:1) C-X means C joining to hetero atom X. It gives cationic Carbon syst
R-X X + RC-X
The reagent for R+ is good leaving grp attached to R
R = RY where Y= Br, OTs
R C
O
X C-X
R Y
O
+ XH
Order of reactivity:Acid chloride > Anhydride > Ester > Amide
Cl
Cl
HN
O
C-N
Cl
O
+
Cl
Cl
NH2
Cl
Cl
NO2
FGI
C-N
Cl
Cl
2) In case of Carbonyl deri RCOX
3) In case of Amine, prdt usually more reactive than SM
R2HNR1
C-NR2NH2R1 X+
R2NH2R1 X+ R2
HNR1
R3X
R2NR1
R3
R2NR1
R3
R4X
R4
Secondary amine are more reactive than primary amine
4) In case of alcohol, ether & alkyl halide
RX XH + R
R = ROMs alkyl mesylate or ROTs (Alkyl Tosylate)
Analsis
Me
OMe
Me
O
+ Me
Me
OH(Me)2SO4
Me
OMe
NaOH
C-O
Synthesis
Disconnection involving 1 functional grp: C-C Disconnection:a) Disconnection should be of C-C bond adjacent to fun grp specially next to -OH, -C=O
CH3C
OH
H
H2C CHO
C-C CH3CHOH
CH3CHO
+ CH2CHO (Synthons)
CH3CHO (Synthetic eqt)
Disconnection involving 1 functional grp: (Contd)C-C Disconnection:b) If C=C is a part of conjugated system involving hetero atom then C=C may be converted to C(OH)-CH before disconnection
H2C CH
C
O
CH3
FGIH2C
H2C C
O
CH3
OH
c) If there is a branching branch pt shd be disconnected to get unbranched C synthon
H3CH2C
HC
H2C
H2C CH3
CH3
C-CH3C
H2C CH H2C
H2C CH3
CH3
+
Disconnection involving 1 functional grp: (Contd)C-C Disconnection:d) In a conjugated/ non conjugate system, of double bond the disconnection of C=C can be done without adding H2O to C=C part
e) It is better to cut TM in middle rather than making uneven parts
H3C
C
H3C
C
H
CH3
C OH H2C CH3+
H3C
H2C
CH2
H2C
CH2
CH3C-C
CH3CH2CH2 + CH2CH2CH3
CuLi
H2C
CH2
H3C
CH2H2C
H3C
BrCH2CH2CH3
Disconnection involving 1 functional grp: (Contd)C-C Disconnection:f) Branches must be disconnected from rings
g) Disconnect C-C bond bet 2 fung grp separated by NMT 3 other C atoms
C-CCH3
O
+ C
O
CH3
PhH2C OEt
Ph
OO
C-C
PhH2CC HC
COEt
Ph
OO
+
Disconnection involving 2 functional grps:1,1-dix: Synthons are obtd by 2 grp disconnection on single C atom. Acetal, cyanohydrin,α hydroxy acid, α Amino acid, halohydrin r prepared from ald & ketone these TM need 1,1,dix
PhC
H
O
OPh
CHO +
HO
HO
Benzaldehyde Ethylene glycol
Disconnection involving 2 functional grps: Contd1,2-dix: When 2 heteroatom r present on 2 adjacent C compound called 1,2 difunctionalised e.g.
HO OH H2N NH2
C C
HO OH
O O
COOH
OH
H3CCOOH
NH2
R
Ethylene glycol Ethylenediamine oxalic acid
Lactic Amino acid
OPh
OHC-O O C
OH
H2C PhH
+
OHO
Ph+
Disconnection involving 2 functional grps: ContdDisconnect C-C bond which has 1 hetero atom on each C
CH CH
Y
CH3H3C
XC-C X
CH
H3C
Y
HC
CH3
Both X & Y could be same or dif f t
If you want to introduce 2 fun grp at C=C, TM can be obtd from corresponding alkene
OH
OH
Disconnection involving 2 functional grps: Contd1,3-dix (1,3 difunctionalized compounds)In 3 carbon compound 2 het atom on 2 C at 1,3 position it is 1,3 difunctional compd
PhC
CH2
CCH3
O O
12
3
RO NH2
12
3
Such compounds synthesized by condensation Rx Aldol, claisen, Knovengel, Michael, Reformatsky
O NH2 OCN
FGI
O
NH2
OH
+
CN
TM
Disconnection involving 2 functional grps: Contd1,4-dix (1,4 difunctionalized compounds)In 4 carbon compound 2 het atom on 2 C at 1,4 position it is 1,4 difunctional compd
RC
CH2
H2C
CH2
O
32
1
Such compounds synthesized by Michael, Robinsons reaction
OEt
4O
O O1 4
Maleic anhydride
C C
COOH
H
H
HOOC
Fumaric acid
COOH
OHOH
1
2
3
4
O
+COOH
CH2
EtOOCCOOEt
C-C
Disconnection involving 2 functional grps: Contd1,5-dix (1,5 difunctionalized compounds)1,5 Dicarbonyl compound can be disconnected at either α, β bond in reverse Michael Rx to give Michael acceptor (a3 synthon)
R1 R2
O O
12
34
5
1,5 diketone
O
HOOC
TM
C-CHOOC +
O
O
12
3d2 synthon
a3 synthon
12
3
45
top related