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Organic Synthesis
2
‣ The preparation of more complex molecules from commercially available starting materials via a multistep sequence of transformations.
Starting Materials
Target Product
OHO
AcO OH
AcO
H
PhOCO
O
O
PhCOHN
OH
O
Ideal Organic Synthesis
3
‣ Highest chemical yields (and purity) - important over many steps.
‣ As concise as possible.
‣ Convergent is more efficient.
‣ Introduce as many bonds and as much complexity as possible in a single operation.
Affect of Yield on Overall Efficiency
4
Number of Steps OVERALL Yieldaverage yield per step 80%90%
5 32%53%10 10%31%
20 1.1%11%
30 10-3%4%
60%
8%0.6%
0.004%
10-7%
Affect of Convergency on Overall Efficiency
5
Linear sequence of reactions
A B C D E F75% 90% 80% 85% 70%
Overall Yield: 32%
A B C
F
75% 90%
80%
G D E85% 70%
Overall Yield from A: 54%Overall Yield from G: 48%
Convergent Approach
Retrosynthetic Analysis
6
‣ a problem solving technique
‣ Start with the target structure and think about immediate precursor - how to make functional groups or new C-C bonds.
‣ Continue backwards until you get to the starting material.
HO OH
OO?
KMnO4Cl2
KOH
light
Cl
Retrosynthetic Analysis
7
‣ Need understanding of reactions, knowledge of feasible mechanism, repertoire of reactions.
‣ Need to understand selectivity
‣ Chemoselectivity - reaction one functional group
‣ Regioselectivity - where reaction takes place
‣ Stereoselectivity - control 3 dimensions
Best Strategy
12
OHPBr3
D1)
2)
Mg
D2O
Br
HBr
HBrBr
Br
+
no Regioselectivity and no Stereoselectivity
Multistep Synthesis
15
OH
TosClpyridine
NaCNDMSO
PBr3
NaOCH2CH3HOCH2CH3 HCl
a) BH3b) H2O2, -OH
BrCl
OTs CN