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Summary Synthetic approaches in medicinal chemistry
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Handwritten summary of the course synthetic approaches in medicinal chemistry given in the master Drug Discovery and Safety.
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Summa advancedr
Organic Chemistry
'
-n
in
| 11
=\ N → N
0
I
Advanced Organic Chemistry .
part B :
chapters 1-8 and 10-12
F. A.
Sundberg R
Carey . , , .
] .
ij
, Lecture A- of and other Carbon nucleophiles
1 :
lkylation e.noiates
↳
Chapter 1
Enolate Formation
Deprotonation Next to EWG
pka
no
À =
-0 8.84
↓, ⊖
ÉÉN
" "
11.0
" ⊖
ÙÉ
0
c.
we = <'
16.0
, ⊖
'
j
/
= 20.0
H
0 0
/ / 25.6
0 ≈ 0
t'
IE = 25.0
N
o.IN
↑ =
≈ 45.0
H
R
H
R És
yR ←
R
]
R
NO
Sigma bonds
↳
mesomerism
are brokers
Tautomerism :
u
bonds braken / mode
R Sigma
R = R
R
H
Regio selectivity in enoiate Formation
Kinetic product
#
u
u . ,
=
" "
V. 2 Thermodynamica product
↓
Kinetic product
-
Lower Ea but ,
lower DGO
-
RSS stable but RSS Crow .
ding in TS
Favored
b
-
irreversibele base ( minimise )
Strang V i
-
-
,
base ( minimise Vz)
Bulky
-
Ea)
LOW T ( vz
requireshigher
-
IJ
ijij
, Short reaction time ( avoid establishment of
any equilibrium)
-
-
MiniMise back protonation -
-
Aprotic SONENES
-
Strict
stoichiometry : no excess ketone
-
populair bases :
ii ii
NY
N
7- , ,
s
-
LDA
Is; -
Li HMDS / NAHMDS
The product
rmodynamic
'
High er Ea but
higher DG
-
,
- more stable . but more Crow
ding is
Allow equilibrium V2 / U -2 to dominate
•
'
Favored
b
-
weaker . reversibele base (maximise U -
D
base ( maxi mi se V2)
NON
bulky
-
-
( over (Ome for V2)
Higher T Ea
-
reaction time
Longer
-
-
Allow back protonatiOM
-
-
píotic solvent
-
Excess of ketone
In
general more highly Substitute enolate is the preferred isomer
.
-
exceptich for branched any groups
balanced
Also usu
anymore ciosely
-
Special cases
Acidifying effect of adjacent pheny / group outweighs sterk effects of smal R groups
'
In
cycli ( ketones a 3- methyl
group has a significant effect on regio Chemistry of kin
.
.
,
etic deprotonation but iitte effect on the thermo dynamic product
.
very .
Ireland model
Rz
R'
p.IR h
R,
'
Rz
☒
→
00 ④
00 Li
①
Li
2- enoiate E- enolate
§ Îme]
R R,
0
R, ~ me t Linrz -
# _ :O
,
# me + HNRZ
Y,
Li -
µ
-
H E- enolate
R
R and me pseudo equatoria) bond them
are :
breaking ieaves
syn
-
-
,
-
For smalt Ri :
no Serious Clash between pseudo equatoria,
-
substituent5
ijij
ij
, E-Î÷
Rt
°
-
/ -
„ o # "
+ HNRZ
me
/ 2- enoiate
R
-
R ,
and have pseudo equatoria1 -
: bond
breaking ieaves them
syn
-
Unfavorable i. 3 -
interaction between axial substituent's
↳ -
Buiky base (
big R) + smal Rt : axial Clash dominates
↳ e- enoiatefavored
domina Clash of Di and
Langer Ri
Ting me
-
:
↳ 2- enoiatefavored
Enolate
sonation-E.NO/ateS Can form
-
ion pairs
Aggregaten
-
Both
.
reducereactivityofenaat.es
Solution :
complexation of cation
a
-
complexa -40N b solvent
moderate : Excellent : di paar , aprotic solvent 's
Én
# ÉÉN
-
o_O -
-
Ë [ §
THE ☐ me
-
v [ - ,
I DMSO
☐MPU NMP DMF
HMPA
-
Also Crown -
ethers
Enola te
aikylation
( 10
Selectivity 0
r Ï Rz -
r rz + (
°
or "
rÉ
O_0
r Rz - + ,
-0
'
solvent
HMPA complexe scation aikyiation High accessibility of
- -
0
-
-
BUOH H bonds 0 atom
-
Favors
t C-
aikylatiOM atom 0
- →
- - - -
0 - -
THF AIIOWS 0 M
paring AIKYIATIOD alkylation
-
-
-
→
c-
'
( ation ( Mt )
Lit hard oxophiliccation C-
aikylation
- - -
,
kt soft
aikylati
-
- - 0 -
Leaving group
.
hard LG
late
aikylation
0
-
Tos
- - -
soft LG
I
alkylation
-
-
-
C-
ij
?⃝
ijijij
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