Summary Synthetic approaches in medicinal chemistry

Summa advanced
r
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