WHAT IS SYNTHESIS?WHAT IS SYNTHESIS?
FORMATION OF CFORMATION OF C--CC&/OR&/OR
FUNCTIONAL GROUP INTERCONVERSION FUNCTIONAL GROUP INTERCONVERSION (FGI)(FGI)
A BRANCH OF “PURE AND APPLIED ORGANIC”
MolekulPerubatan
yang Menarik
Molekul Teori yang Menarik
MolekulBiologi
SainsBahan
Taktik dan KaedahSintesis
Strategi SintesisMangkinReagen
DesignedMolecules
BahanSemulajadi
Orientasi KaedahBerorientasikan Target
(Sintesis Total)
BidangSintesis Organik
RETROSYNTHETIC ANALYSIS
CH3CO2H
Cl
CH3
Cl
H3CCH3
O
H3CCH3
O
H3CCH3
OH
H3CCH3
OH
The arrow " " means make 2-butanone from 2-butanol
The arrow " " means change 2-butanol to 2-butanone
HOW DO YOU BEGIN A RETROSYNTHESIS?HOW DO YOU BEGIN A RETROSYNTHESIS?
LOOK FOR FUNCTIONAL GROUPS IN THE MOLECULE.LOOK FOR FUNCTIONAL GROUPS IN THE MOLECULE.
PLAN REACTIONS THAT CAN BE CARRIED OUT TO PLAN REACTIONS THAT CAN BE CARRIED OUT TO FORM CFORM C--C BOND OR DO FGI.C BOND OR DO FGI.
O
HOH
O
HO
O
O
O
OO
OO
HHOAr
OAr
O
ArH
O
X
ArO
X
ArX Y
O
ArH
?
TWO SITUATIONS:TWO SITUATIONS:
i.i. GIVEN A STARTING MATERIAL (SM)GIVEN A STARTING MATERIAL (SM)
ii.ii. SM IS NOT GIVENSM IS NOT GIVEN
BOTH SITUATIONS WILL REQUIRE A ANTITHETIC BOTH SITUATIONS WILL REQUIRE A ANTITHETIC ANALYSIS: ANALYSIS: RETROSYNTHESIS ANALYSISRETROSYNTHESIS ANALYSIS
OMe
CO2Me
NO2 NO2
H OHPh
CO2Me
Features to consider when planning a synthesisFeatures to consider when planning a synthesis•• Efficient synthetic reactionEfficient synthetic reaction•• BrevityBrevity•• Readily available or inexpensive starting materialReadily available or inexpensive starting material•• Practical and convenient reactionsPractical and convenient reactions•• Flexibility of materialsFlexibility of materials•• Adaptability of synthesis to members of structural Adaptability of synthesis to members of structural
familyfamily•• Novelty, elegance and artistryNovelty, elegance and artistry
Which method is best???Which method is best???
Recommendation in planning a synthesis:Recommendation in planning a synthesis:
1.1. Carry out a thorough examination of the target molecule.Carry out a thorough examination of the target molecule.
O
HH
H
Me
HO
What are the functional groups or C-C bond that can be formed to make the above molecule?
OH
O
OH
HO
TM
OH
O
OH
HO
aa
O
HO
OH
O
OH
HO
O
HO
OH
OH
HO
b
b
Some strategy recommended:Some strategy recommended:
1. Consider as many range of possibility as possible.1. Consider as many range of possibility as possible.
2. Aim for the greatest simplification.2. Aim for the greatest simplification.
MeCO2Et
O
Me
MeCO2Et
O
Me
aa
b
b
Me
O CO2Et
Me
3.3. Introduce the most reactive functional group last.Introduce the most reactive functional group last.
O
NMe2
mCPBA
DIBAL-H
NMe2
OH
NMe2
OHO
4. Use any inherent symmetry in the target molecule.4. Use any inherent symmetry in the target molecule.
OH
OHHO
HO
SiPh
Ph
Sometimes, the symmetry in the molecule is not obvious.Sometimes, the symmetry in the molecule is not obvious.
OH O O
HO
O
HO
O
O
+
O
HO
O
O
+
Convergent Convergent vsvs linear approachlinear approach
(i) Linear Synthesis(i) Linear Synthesis
A synthesis where reaction is A synthesis where reaction is performed one step at a time performed one step at a time from the SM to the TM. from the SM to the TM.
(ii) Convergent Synthesis(ii) Convergent Synthesis
One molecule is “broken” One molecule is “broken” into many part and each into many part and each part is part is synthesisedsynthesised individually individually and then put together.and then put together.
A + B CD E + F H
A + B C
H
D
FGE + F
Convergent synthesis is Convergent synthesis is favouredfavoured over linear synthesis.over linear synthesis.
WHY???WHY???
Linear Synthesis:Linear Synthesis:
Consider a 5 step synthesis with 70% yield for every step.Consider a 5 step synthesis with 70% yield for every step.
Overall yield = 16.8%Overall yield = 16.8%
A + B C G G-E G-H G-H-I
A B2 steps 2 steps, 80 % each step; overall yield = 64%2 steps, 80 % each step; overall yield = 64%
[(0.8)[(0.8)22 x 100]x 100]
C D3 steps
3 steps, 80 % each step; overall yield = 51.2%3 steps, 80 % each step; overall yield = 51.2%[(0.8)[(0.8)33 x 100]x 100]
E F4 steps 4 steps, 80 % each step; overall yield = 40%4 steps, 80 % each step; overall yield = 40%
Overall yield drops dramatically with each stepOverall yield drops dramatically with each step
For 5 steps reaction of 80 % yield per step; overall yield = 33 For 5 steps reaction of 80 % yield per step; overall yield = 33 %%
Convergent approachConvergent approach
For 5 steps reaction of 80 % yield per step; overall yield = 64 For 5 steps reaction of 80 % yield per step; overall yield = 64 %%
NOTE:NOTE:CONVERGENT SYNTHESIS IS ONLY BETTER THAN LINEAR CONVERGENT SYNTHESIS IS ONLY BETTER THAN LINEAR SYNTHESIS IF ALL THINGS ARE EQUAL.SYNTHESIS IF ALL THINGS ARE EQUAL.
MultistriatinMultistriatin
O
O O
O
O OHO
+OH
OH
O
An example of a convergent synthesis: An example of a convergent synthesis: RetrosynthesisRetrosynthesis ananlysisananlysis
Forward Synthesis: 6 stepsForward Synthesis: 6 steps
Ref: Silverstein et. Al., Ref: Silverstein et. Al., J. Org. Chem., 1975J. Org. Chem., 1975, , 4040, 1705, 1705
O
O
OH
O
H2, BaSO4, PdMeOH, quinoline
OH
1. 2.3.4.
CH2O, HNMe2, HClK2CO3MeIKOH O
Mannich Reactio
+
290 oC, PhMe
O
HO5 %
O
OHO
HO
O
X
HO
HO
O
HOHO
HO
OHOHHO
Linear Approach: Linear Approach: RetrosynthesisRetrosynthesis AnalysisAnalysis
Forward SynthesisForward Synthesis
An example where a linear synthesis is better than a forward synAn example where a linear synthesis is better than a forward synthesis.thesis.
O
O
HO
HO
H2Lindlaar cat.
OH
OH
Me2COH3O+
O
O
O
O
O
Me2CuLi
O
O
Me
OH
mCPBA
HCl
HO Me
O
O
I Me
O
O
1. TsCl2. NaI
OO
O
O
H3O+
85%
Need to protect one functional group so that it will not interfeNeed to protect one functional group so that it will not interfererewith reaction carried out on the second functional group.with reaction carried out on the second functional group.
For example:For example:O
O O O OH
O O OHO OH
protect
react
deprotect
O OH
CH3
OO
(+)-Epiasarinin: Total SynthesisSteel et. al. Organic Letters, 2002, 4(7), 1159
Furofuran skeleton belonging to the lignin family of natural product.Considerable variation in the series.
Large range of biological propertiessuch asantioxidant, antiviral,immunosupressant, etc.
O
O
OO
OO
HH
3,7-dioxabicyclo[3,3,0]-octane (furofuran) skeleton
Darzen Condensation Reaction
Br CO2Me
O
O
Ar =
OCO2Me
Ar
O
Ar CO2Me+
trans alkene only3:4 syn/anti epoxide
LDA, ArCHOTHF, 20 oC
O
O
Ar =
ArCHO
OCHO
ArXtBuOOH
NaOH
Electron donating effect of substituenton aryl group promoting ring-openingof epoxide.
ALTERNATIVE ROUTE
O
O
Ar =
OCO2Me
Ar
O
Ar CO2Me+
trans alkene only3:4 syn/anti epoxide
flash-vacuum pyrolisis500 oC, 0.04 mBar
O
Ar H CO2Me
O
H Ar CO2Me+
ConrotatoryRing-Opening
O
Ar H CO2Me
O
H Ar CO2Me+
O
O
Ar =
O Ar
CO2Me
O Ar
CO2Me8:1 cis/trans
Disrotatory Cyclization
Ratio of product is independent of the stereochemistry of the starting epoxide.
O Ar
CO2Me
O Ar
CO2Me8:1 cis/trans
O Ar
OH
Not isolated since product is unstable
O
O
H
MeO Ar
Ar
H
LiAlH4-40 oC, Et2O
> 99%
ArCH(OMe)2, TMSOTfDCM, -40 oC, then MeOH
55 %Endo product
(kinetic product)
O Ar
OH
Not isolated since product is unstable
O
O
H
MeO Ar
Ar
H
> 99%
ArCH(OMe)2, TMSOTfDCM, -40 oC, then MeOH
55 %
O Ar
O
Ar
O
O
H
Ar
Ar
H
..
O
O
HH
MeO Ar
Ar
O
O
HH
Ar
Ar
O
O
HH
Ar
Ar
O
O
O
ArH H
OBF3
+
Epiasirinin Asarinin
EpimerizesBF3OET2
Et3SiH, BF3.OEt2DCM, 40 oC
