CHNG 6: CHIN LC TNG HP HU C V K

THUT XC NH CU TRC CC HP CHT HU C

Mc tiu:
Hiu v phn tch cc con ng tng hp mt cht hu
c.
Chn la chn chin lc tng hp thch hp, kh thi v
hiu qu, t c mc ch mong mun.
Xy dng c mt chin lc tng hp mt cht hu c
c th t cc nguyn liu ban u.
Xc nh cu trc ca sn phm bng: IR, NMR, Mass
 NI DUNG
6.1. Cc chin lc da trn chuyn ha ha hc

6.2. Cc chin lc da trn cu trc v hnh hc topo

6.3. Cc chin lc da trn ha hc lp th

6.4. Cc chin lc da trn nhm chc v cc chin lc khc

6.5. Nhn danh cng thc phn t bng ph kh lng

6.6. Cc phng php xc nh nhanh cng thc cu to cng thc lp th

v cu dng: NMR, IR, MS, UV v UV vis

6.7. Nhng phng php khc cho s xc nh nhanh cng thc cu to,
cng thc lp th v cng thc cu dng
6.1. Cc chin lc da trn chuyn ha ha hc

6.1.1. Phn tch tng hp ngc (Retrosynthetic analysis)

The construction of a synthetic tree by working backward

from the target molecule (TM) is called retrosynthetic
analysis or antithesis.
The symbol signifies a reverse synthetic step and is
called a transform.
The main transforms are disconnections, or cleavage of C-C
bonds, and functional group interconversions (FGI).
Synthons are fragments resulting from disconnection of
carbon-carbon bonds of the TM.
The actual substrates used for the forward synthesis are the
synthetic equivalents (SE).
Donor and Acceptor Synthons
Donor and Acceptor Synthons
Retrosynthetic analysis A
Alternating Polarity disconnection
Nhm E: Groups conferring electrophilic character to the
attached carbon (+): -NH2, -OH, -OR, =O, =NR, -X
(Halogens)
Nhm G Groups conferring nucleophilic character to the
attached carbon (-): -Li, -MgX, -AlR2, -SiR3
Nhm A: Functional groups that exhibit ambivalent
character (+ or -):
One Functional Group
Two Functional Groups in a 1,3-Relationship
Two Functional Groups in a 1,4-Relationship
TM-21 O
O

CH2
(b) OH (a) H
OEt

O
O

H
OEt +
+

1. (b) Route
O
O

OEt CH2
OEt
+ 1.LaAlH4 OH

2. H2O, H
2. (a) Route O
O
CH2
OH
H H
1. NaBH4
+
2. H2O, H
TM-41 (a)
O
Br
(b)
H
H
+

O
Br

(b) Route is chosen because the aldehyde in (b) route can easy synthesized by
Diel- Alder reaction

1. PBr3

2. Base
Br
Br3P

o o

H Diel-alder H
+
3. Mechanis reaction:

PBr3
Base
Br H H
Br3P
Br3P O
Br
Br P O +
Br

Br3P O
 H
O O
TM-49 O O
Ph
+ 2Ph
H3C
Ph
O O
1. Synthon:
+ 2Ph

O O

2. Reagent equivalent: Et + MgBr

O

O O O OH
1. OH CH2 CH2 OH , H3O
3. Reaction formula: Et Ph
O H3C
2. Ph-MgBr ; H3O Ph
a. Protected group
H
O O O O
1. H3O 1. OH CH2 CH2 OH
Et Et
O O

O OH O H O OH O
O OH O
Et Et
Et
O O
O HO
+ O
H
H2O H

O O O H O O O
H
Et Et
O O
 MgBr
O O O
O O O O O O
2. Ph-MgBr 2. Ph-MgBr
Et Et
O O Ph
Ph
MgBr
O O OH OH OH O
O O H3O O O H3O O O
H H
Ph Ph Ph Ph
Ph Ph Ph Ph
H2O +
H2O + MgBrOH
O OH
H
H2 O + H3O
Ph + O CH2 CH2 OH HO OH
Ph H
(TM49)
TM-59 O

TM 59

O
O O
FGI FGI
+
H3C CH2

CH3
CH3
O

+ CH3
Synthon : H3C CH2

O O

+ Br CH2 C C H + CH3 I
Synthesis equivalent : OCH3

O O O
1. EtONa
Reaction formula:
OCH3
2. Br CH2 C C H
3. HO CH2 CH2 OH , H3O
4. NaNH2 , Me-I
5. H2 - Pd-C, BaSO4
 Mechanism
O O O O
1. EtO
+ EtOH
1. Activite group: OCH3 OCH3

2. Br CH2 C C H

O O

OCH3 + Br

H
3. Protected group
H
O O
HO CH2 CH2 OH
COOMe 3. H COOMe

H H

H H
H
O O
- H2O H O O OH HO O OH
COOMe COOMe COOMe

H H H

H
O O
-H O O
COOMe
COOMe

H
H
Hydrolysis and decarboxylation of ester (COOCH3) group

O O
O
H3C H3C
H3O H3C H2O O
O H
O
O H O H
C HO H C
C H3C
O OH2
O
H3C O
H3C
+ H2O
O
O O
H3C
H3C - CO2 H3C O
O - CH3OH, H H
O
O H
H O H C
H3C OH
O
O
H H
 O O CH3
O O 4. NaNH2 O O
CH3 I
C
C C C H3C
H3C H H3C

H3O
OH CH2 CH2 OH
-H
+ H2O
O OH CH3
HO H2C H2C OH2 O O
C H
H3C C
+ H3C

+ H2O
O CH3
O CH3
5. H2 - Pd -C, BaSO4
H3C H
H3C

H
 O
TM-71
FGI FGI
+
O
H

TM71

Reagent equivalent: O + MgBr

Reaction formula: 1. Mg, Et2O

Br

2. O

3. H3PO4
4. H2-Pd-C
O

Mechanism MgBr
O OH
3. H3PO4
1. Mg + 2.
Br MgBr

3. H3PO4

H
H
O
H2-Pd-C + H2 O - H2 O

+ H H

H3 O
 O
TM- 86 O O
O (b) Ph
+ + Ph
Ph O
Ph O
O
H O
Reagent equivalent: Ph
+ Ph

O O O
O
Reaction formula: Ph +
Ph
Ph
Mechanism O Ph OH

O O

+ Base + H Base

H
O
O
Ph H Base Ph O
Ph
Ph
O
O
+ Base

O
HO Ph
Ph

O
 O

TM-97 (TK) OEt

(TM 97)

OEt

O
O
H
OEt O

C COOEt + C
OEt OEt

O O

2. Reagent equivalent: CH2 COOEt +

EtO OEt

3. Reaction formula: 1. EtO , EtOH

CH2 COOEt (TM 97)
2. CO(OEt)2
4. Mechanism:
H OEt

OEt
+ EtO + EtOH
O

O
O
O
EtO OEt

OEt
EtO OEt
OEt
+
O

O
O OEt

OEt

+ EtO
O
 O O
O
O
TM-101
H
H +

O O

2. Reagent euqivalent:
H
+ Br

O O
O O
3. Reaction formula: H
base
H

H Br

O O O O

4. Mechanism:
H base H
+ acid
H

Br

O O

Br +
 O O
O O
TM-116 (TK)
OEt FGI
OEt

Ph Ph
Ph Ph
O
O O O O
H

1 1,5-Dicarbonyl
OEt OEt
group
5 +

Ph Ph Ph Ph
O O
H

O H
O O O
FGI
H Ph
+ Ph Ph Ph Ph
OH

O O O O
Ph CH2
+ +

2. Symthon: Ph CH2 H Ph OEt

O O O O
3. Reagent equivalent: + +

Ph H Ph OEt

O O O
4. Reaction formula:
O
1. , EtO , EtOH
H Ph OEt

Ph O O
2. Ph Ph
OEt
 O O O
EtO O O

2 EtOH
Ph Ph CH2 H Ph
+ Ph Ph

EtO EtOH
H
H H
O
O O
-H3O

Ph Ph
Ph Ph

+ H
H

2 EtO

O O O O
EtO + EtOH

OEt OEt
O O
O
O

OEt
Ph Ph
Ph Ph
O O
H
O O H
O O

OEt

OEt OEt
EtO
EtOH Ph

Ph Ph

Ph O

Ph O Ph O
EtO
 O O O O
O O

OEt OEt
2 EtOH
OEt

Ph Ph Ph
O Ph Ph
O
Ph O
H
H
+ EtOH
O O O O
H

OEt EtO OEt + EtOH

-H2O

Ph Ph Ph Ph
TM-120 O O O

FGI 1
5 a
b

O O
H 1,5- Dicarbonyl

O O
O
(Add control)
CH2
+ H3C

H
EtO O
O

CH2
H3C
O
FGI

O H H
+

H3C
O
EtO O

H O

+
C O
O H3C CH2
H
H
O
2.Reagent equivalent: + + C O +
I
H
EtO O
4. Mechanism:
O O

O O O O
2. I
1. EtO OEt

OEt OEt
H H
H (A)
H

O O O
C O
3. EtO , EtOH H
CH2
O

O H
O
2 EtOH H
O
- H3O

H (B)
H
 O O O O
O O

4. EtO
OEt OEt
OEt
H
Pr-i

(A) O
O O

O O
(B) (B)
O O
OEt
EtOH
Pr-i
EtO OEt
Pr-i
O

O O O O O
+ EtO

H2C OEt OEt 2 EtOH

Pr-i O Pr-i

O O
O O

H
H
OEt
OEt - H2O
Pr-i
O Pr-i
O O
H

OEt
Pr-i
 H
O O O O

+ H2O
OEt 5. H OEt
Pr-i Pr-i

H
O OH O O
O OH H
H
O
O
H OH
OEt
OEt Pr-i
Pr-i
Pr-i
H

O
+ EtOH
O O

-H OH
6. t0
Pr-i
- CO2
 Mt s v d v phn tch tng hp trong thc t

Cetaben ethyl ester-used to lower blood lipid levels

Thuc chng bo ph (Anti-obesity Drug)
Ocfentanil- Thuc gim au (painkiller)
Fenfluoramine-Thuc hot ha thn kinh (Neuroactive
drug)
Nafimidone-(Khng co git):Antiparasitic drug
Thuc iu tr ng c thuc tr su
Thuc iu tr huyt p thp (Propranolol-Beta-Blocker,
reduces blood pressure)
Arildone- Thuc ngn nga bi lit prevents polio
An anti-Malaria Drug
Topological Strategies: strategic analysis of correlated
bond disconnections

Utilizing Network Analysis: a topological

strategy

Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.
Guiding Principles of Network Analysis

in general: it is easier to synthesis fused rings that bridged

systems
identify the bonds that are made to the most bridged system
retrosynthetic removal of these bonds will lead to the most
simple keying element

Corey, E. J.; Ohno, M., Mitra, R. B.; Vatakancherry, P. A. J. Am. Chem. Soc. 1964,
86, 487
Guiding Principles of Network Analysis

in general: it is easier to synthesis fused rings that bridged

systems
identify the bonds that are made to the most bridged system
retrosynthetic removal of these bonds will lead to the most
simple keying element
Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.
Intramolecular Alkylation
Functional Group-Based

Key Features of a Functional Group-

based Approach:
functional group in the target directly
keys a disconnection
functional group in the target is
poised to assist in the installation of a
key stereocenter
often times installed and later
removed in order to enable a key
transform (overbred intermediate
may extend to modern photoredox
radical chemistry, traceless directing
groups, CH activation
Total Synthesis of Ouabagenin - a functional group-based approach

Clark, K. J.; Fray, G. I.; Jaeger, R. H.; Robinson, R. Tetrahedron, 1959, 6, 217

Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2011, 50, 9655
Total Synthesis of Ouabagenin - a functional group-based approach

LeBold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.; Sarpong, R. Nat. Chem.,
2012, 5, 126
Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of Ouabagenin - a functional group-based approach

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of Ouabagenin - a functional group-based approach
Total Synthesis of ()-Curvularin - A Transform-Based Approach

Key Features of a Transform-Based Approach:

in general: the late-stagekey-step

look-ahead to apply a highly
simplifying synthetic strategy
often cascades, rearrangements,
transformations which assemble
multiple CC bonds
Total Synthesis of ()-Curvularin - A Transform-Based Approach

Corey, E. J.; Ohno, M., Mitra, R. B.; Vatakancherry, P. A. J.

Am. Chem. Soc. 1964, 86, 487.
Total Synthesis of ()-Curvularin - A Transform-Based Approach

Werthermann, L.; Johnson, W. S.; Proc. Nat. Acad. Sci., 1970, 67, 1465.
Total Synthesis of ()-Curvularin - Retrosynthetic Analysis

Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612

Total Synthesis of ()-Curvularin - preparation
of the -ketolactone

Lin, W.; Zercher, C. K.; J. Org. Chem., 2007, 72, 4390

Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.
Total Synthesis of ()-Curvularin - Key Step
Total Synthesis of ()-Lycojapodine A - A Structure-Goal
Approach

Key Features of a Structure-Goal

Approach:
Implemented when a large number of
target structures are desired (collective
synthesis)
bulk of synthetic strategy relies on the
synthesis of a highly simplifying
intermediate
allows the implementation of multiple
retrosynthetic techniques
Total Synthesis of ()-Lycojapodine A - A Structure-Goal
Approach

Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature, 2011, 475, 183.
Total Synthesis of ()-Lycojapodine A -A Structure-Goal
Approach

Fieser, L. F.; Fieser, M. Steroids Reinhold Publishing, New York, 1959. pp 645659.
Total Synthesis of ()-Lycojapodine A -A Structure-Goal
Approach
Total Synthesis of ()-Lycojapodine A -A Structure-Goal
Approach
Total Synthesis of ()-Lycojapodine A -A Structure-Goal
Approach
Total Synthesis of ()-Lycojapodine A -A Structure-Goal Approach
Total Synthesis of ()-Lycojapodine A -A Structure-Goal Approach
Total Synthesis of ()-Lycojapodine A -A Structure-Goal Approach
Total Synthesis of ()-Lycojapodine A -A Structure-Goal Approach
Total Synthesis of ()-Lycojapodine : A retrosynthetic analysis
Total Synthesis of ()-Lycojapodine : A retrosynthetic analysis
Total Synthesis of ()-Lycojapodine A: preparing the common
intermediate
Total Synthesis of ()-Lycojapodine A: preparing the common
intermediate
Total Synthesis of ()-Lycojapodine A: synthesis of (+)-
alopecuridine
Total Synthesis of ()-Lycojapodine A : synthesis of (+)-
alopecuridine and ()-lycojapodine A

Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem., 2013, 78, 800.