Retrosintetik dan Strategi Sintesis
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Transcript of Retrosintetik dan Strategi Sintesis
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Retrosintetik dan Strategi Sintesis
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Pengertian•Analisis retrosintetik adalah proses
“menguraikan” molekul target sampai didapat bahan awal yang tersedia
•Caranya dengan melakukan pemutusan ikatan imajiner (diskoneksi) dan konversi satu gugus fungsi ke gugus fungsi yang lain melalui reaksi kimia yang efisien (interkonversi gugus fungsi/tukar gugus fungsi).
Let, 2/11-10-2010
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Sinton dan Ekivalen sintetik•Sinton adalah fragmen yang dihasilkan
dari proses diskoneksi ikatan pada molekul target. Ada sinton positif (+) dan sinton negatif (-).
Let, 2/11-10-2010
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Kepolaran latenThink about some of the reactions we've looked at for carbonyl compounds:
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Let, 2/11-10-2010
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Sinton Ekivalen Sintetik Sinton Ekivalen Sintetik
R+ R-Br, R-I, R-OMs, R-Ots R = alkil, bukan aril
RMgBr, RLi, R2CuLi
R R
OH
R R
O
R
OH
R
O
R
OH
Br
R
O
R
O
R
O
R
O
OEt R
O
Cl R
O
O R
O
R
R
O
R
O
R
O
CO2Et
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Sinton harus mempunyai kepolaran laten yang sama dengan ekivalen sintetik
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R H
OH
R H
O
≡
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Contoh analisis retrosintetik 18
OH
DISCONNECT
A B
SYNTHONS
REAGENTS
SYNTHONS
REAGENTS
OH OH
? ? PhMgBr
O
H
Br i) Mg/Et2O
ii) CHO
OH
Sintesis:
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Contoh analisis retrosintetik 29
OH
DISCONNECT
A B
SYNTHONS
Syntheticequivalents
SYNTHONS
Syntheticequivalents
Br
OH OH
?PhCHO BrMg
Br i) Mg/Et2O
ii) PhCHO
OH
PhSintesis:
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Contoh analisis retrosintetik 310
OH
Ph Ph
OH
Ph
O
BrMg
OH
PhPh
OBrMg
Sintesis:
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Contoh Analisis Retrosintetik 411
OH
Ph
O
Ph
FGI
DISCONNECT
O
Ph
O
Ph
Br
(as enolate)
O
Ph
Br
i) base
ii)
O
Ph
LiAlH4T.M.Sintesis:
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Contoh analisis retrosintetik 512
O
Ph
O
Ph
Ph
O
LiCu( )2
O
PhPh
O
t-Bu2CuLi NaBH4T.M.
Sintesis:
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Analisis retrosintetik 6
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OH
PhPh
OH "H2O"
Ph
OH
PhPh
i) Hg(OAc)2
ii) NaBH4
Sintesis:
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Strategi dan Perencanaan1. Pertimbangkan berbagai kemungkinan2. Jika memungkinkan, pilihlah rute sintesis
konvergen dari pada linier, karena akan memberikan rendemen yang lebih besar
3. Cobalah berbagai cara diskoneksi dan IGF4. Arahkan ke penyederhanaan terbaik
(diskoneksi di tengah atau di percabangan)5. Manfaatkan simetri yang ada pada molekul
target6. Masukkan gugus fungsi pada posisi yang
diperlukan untuk mempermudah pembentukan ikatan
7. Menggunakan gugus pelindung
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ABCDEF ABCDE + F
ABCD + EF
AB + CD , E + F
A + B , C + D
ABCD + E
ABC + D
AB + C
A + B
linear
Linear vs. convergent synthesis assume 80% yields (optimistic!)
eg.
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A AB ABC ABCD ABCDE ABCDEF A...K A......Pstep 1 2 3 4 5 ...10 ...15
approxoverall yield: 80% 64% 51% 40% 32% ...10% ...3.5%
A AB
E EF
C CDABCD
ABCDEF
80% 64%
G...KL...P
A...KA......P
51% 40% 32%
Linear:
Convergent:
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Ph
O O
Ph
O O
Ph
O
base
MVK Ph
O OO
methyl vinyl ketoneMVK
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Diskoneksi di tengah
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Di percabangan:
Ph
O
CO2EtPh
O
CO2Et
Ph
O
CO2Et
NaOEt
Br
Ph
O
CO2Et
Ph
O
CO2Et
?
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Perhatikan simetriO O
HO
O
HO
NaOEt
self -condensation
H2O
OO
O
O
HO
O
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OEt
O O
O
Sometimes it helps the retrosynthesis if you add a functional group to facilitate bond formation (Functional Group Addition, FGA). An example of this is acetoacetic ester synthesis:
Thus:
O O
CO2Et
Bu
FGACO2Et
O
CO2Et
Odiscon. discon.
SM, Ethylaceto acetate
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The synthesis therefore is
O
Bu
O
CO2Et
Bu
CO2Et
O
NaOEtBuBr
NaOEt
O
CO2H
Bu
H3O+
CO2
CO2Et
O
MeICO2Et
O
Acidic proton
TM
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Alternatively, potentially reactive groups can be protected or masked so they don't react, eg. reduction of an ester in the presence of a ketone
Ph
O
CO2MeHO
OH
cat. TsOH
OO
PhCO2Me
Ketal(stable to bases and
nucleophiles)
OO
Ph OH
LiAlH4
Et2O
H3O+
Ph
O
OH
Note that protection strategy requires two extra steps (must be efficient); better syntheses minimise the use of protecting groups.
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Menggunakan gugus pelindung