SINTESIS
• Prostaglandines (PGs)
• Taxol
• Palytoxin
Total Synthesis of
Prostaglandines (PGs)
Strategy and method
Department of Chemistry, Graduate School of
Science, Kobe University
Masahiko Hayashi
Primary Prostaglandins
O
O
O
CO2H
HO
CO2H
HO
OH
PGE1
HO
OH
PGE2
HO
CO2H
OH
PGF1
OH
PGE3
HO
HO
HO
CO2H
CO2H
HO
OH
PGF2
CO2H
HO
OH
PGF3
Total Synthesis of
Prostaglandins (PGs)
Corey’s method vs Noyori’s method
Corey: 1990 Nobel Prize: linear synthesis
Noyori: 2001 Nobel Prize: convergent synthesis
Significance of the synthesis of
Prostaglandins (PGs)
1. It is necessary to synthesize PGs, because
the quantity in nature (in animals
including human being) is too little for
actual medical treatment.
2. Artificial modification is possible by
synthesis. For example, the analogues of
Prostacyclins (PGI2). Natural PGI2 is very
unstable as a drug.
bioactive = drug
Structure of Prostaglandins
9
8
7
5
6
10
14
11 12 13
4
3
16
15
1
2
COOH  side-chain
18
17
20
 side-chain
19
prostanoic acid
side-chain
cyclopentane ring
O
O
A
B
O
HO
O
C
COOH
O
D
OH
1
HO
COOH
O
O
HO
E
OH
HO
F
G (OOH at C-15)
H
2
COOH
COOH
OH
3
O
COOH
O
O
HO
OH
PGI2
OH
TXA2
Primary Prostaglandins
O
O
O
CO2H
HO
CO2H
HO
OH
PGE1
HO
OH
PGE2
HO
CO2H
OH
PGF1
OH
PGE3
HO
HO
HO
CO2H
CO2H
HO
OH
PGF2
CO2H
HO
OH
PGF3
The Major Problems in PG Synthesis
1. Selective creation of the four and five stereogenic centers in PGE
and PGF series, respectively.
2. Stereoselective placement of C=C bonds in the side chains
.
3. Overcomingunstability of the -hydroxycyclopentanone structure of
the PGE series.
Corey's solution
1. Use of highly functionalized key interm ediate derived from
cyclopentadiene via stereo-defined bicyclic interm ediates.
2. Introduction ofcis and trans double bonds by Wittig-type reaction
.
Retrosynthetic analysis
O
O
CO2H
CO2H
RO
OR
RO
OR
linear
convergent
Corey’s method
Noyori’s method
A
B
C
A
90%
90%
90%
C
90%
90%
90%
D
90%
E
90%
F
G
B
90%
D
E
90%
90%
90%
H
G
0.93 x 100 = 73%
convergent synthesis
C
D
F
90%
G
H
収束型
B
E
90%
F
A
H
直線型
0.97 x 100 = 48%
linear synthesis
Corey Method (17 steps + optical resolution)
O
HO
O
MeO
CO2H
Cl
CN
n-Am
AcO
HO
O
Corey lactone
OH
PGF2
Just-Upjohn Method (16 steps + optical resolution)
O
O
Corey lactone
O
O
CHO
Noyori Method (Three Component Coupling)
O
R+
O
CO2Me
RO
R
RO
OR
PGs
PGs
Retrosynthetic Analysis of Corey’s Method
(C6H5)3P
O
O
CO2H
CHO
RO
OR
RO
Wittig
OR
O
O
O
O
Wittig
CHO
RO
RO
OR
CO2-M +
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 2)
O
O
O
O
1. K2CO 3, MeOH
14
2. DHP, TsOH,
CH2 Cl 2
15
H
AcO
13
H OH
8
THPO
6
5
CO2H
13
H OTHP
DIBAL-H
toluene,
-60°C
5
Ph3 P
O
CO2
6
DMSO
H OTHP
1. H2Cr 2O7 , PhH/H2O
2. AcOH, H2O, 37 °C
AcOH,
H2O, 37 °C
HO
15
OH
H
H
H
THPO
O
9
14
12
DHP =
HO
6
THPO
O
H
H
H OTHP
H
CO2H
CO2H
HO
H
H OH
(+)-PGF 2
HO
H
H OH
(+)-PGE 2
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Do not confuse relative
configuration and absolute
configuration!
So far, control of relative
configuration (racemic
compound) was done, so optical
resolution is necessary to obtain
chiral compound!
Optical Resolution of Hydroxy Acid
CO2H
CO2H (+)-ephedrine
H
Ph
H
+
OMe
OH 1. PhH, 
NHMe 2. recrystallization
OMe
Me
HO
HO
[]D23 +37.2° (c 1.0, MeOH)
O
O
KI3 , H2O, 0 °C
O
CO2H
I
OMe
HO
[]D26 -45.8° (c 1.0, MeOH)
OH
OH
PGE2
synthetic sample: []D -61° (c 1.0, THF)
natural product: []D -61° (c 1.0, THF)
Corey et. al, J. Am. Chem Soc., 1970, 92, 397
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
Corey's Prostaglandin Synthesis (part 1)
MeO
NaH, T HF
Cl
MeOCH2 Cl
T HF, -55 °C
Cu(BF4 )2
0 °C
12
MeO
10
MCPBA,
NaHCO3
11
O
CN
CN
> 90%
1. NaOH, H2 O,
0 °C
6
11 O
CH2 Cl2
O
HO
6
KI3 , NaHCO3
9
8
10
2. CO2
11
> 95%
O
HO
O
1. Ac2 O, py
90%
OMe
HO
2. (n-Bu)3 SnH
AIBN, PhH
12
AcO
80%
PO(OMe)2
O
O
1. BBr3 , CH2 Cl2 ,
0 °C
8
OMe
H2 O, 0 °C
OMe
12
O
O
10
11
Cl
O
8
80%
I
KOH,
H2 O/DMSO
12
MeO
8
9
MeO
2. CrO3 .2py,
CH2 Cl2 , 0 °C
O
H 13
AcO
Corey lactone
99%
O
O
O
O
14
Zn(BH4 )2 , DME
O
14
15
NaH, DME
AcO
H
O
70%
15
AcO
H
13
H OH
> 97% of a 1:1 mixture of C-15 epimers
OH
O
ring-chain
tautomeric
equilibrium
6
9
O
HO
6
9
15
15
THPO
H
H OTHP
lactol form
THPO
H
H OTHP
hydroxy aldehyde form
stable ylide = unreactive
unstable ylide = reactive
A
B
C
A
90%
90%
90%
C
90%
90%
90%
D
90%
E
90%
F
G
B
90%
D
E
90%
90%
90%
H
G
0.93 x 100 = 73%
conversent synthesis
C
D
F
90%
G
H
収束型
B
E
90%
F
A
H
直線型
0.97 x 100 = 48%
linear synthesis
Noyori’ s method
Three component coupling
Michael-
O
エノラート捕捉
CO2CH3
RO
O
CO2CH3
Michael addition
+ Enolate trap RO
OR
OR
PGE2
1) Li
O
RO
O
OR
CuI, P(n-C4H9)3
CO2CH3
2) (C6H5)3 SnCl, HMPA
3)
I
CO2CH3
RO
OR
Conjugate Addition of Organocopper Reagents
RLi + CuI + x P(n-C4H9)3
Li[RCuI(P(n-C4H9)3)y] + (x-y) P(n-C4H9)3
RCu(P(n-C4H9)3)x + (x-z) P(n-C4H9)3 + LiI
O
O
H2O
+
"RCu"
R
R = sp 2- or sp3-carbon moiety
Vicinal carba-condensation of -unsaturated ketones
O
R
R
O
R
R
1. (C6H5) 3SnCl
HMPA
2. RX
O
R
RLi + CuI +
(n-C4H9)3P
O
X
CH2=CHX
R
M
O
RCHO
R
OH
R
R
R
R
RCH(OR') 2
(CH3 )3SiOTf
RC(OR') 3
BF3
O
O RO' OR'
R
R
R
OR'
R
R
R
An Organometallic Way to Prostaglandins: The Three Component Couplong Synthesis
O
O
MO
RM
RO
R
RX
RO
R
R
RO
Organocuprate/organotin procedure (1):
O
O
1. R Li + CuI + ( n-C4H9) 3P
CO2CH3
2. (C6H5) 3SnCl, HMPA
R3SiO
3. RI
RLi = Li
R3SiO
RI = I
OSiR3
SiR 3 = Si(CH 3)2-t-C4H9
OSiR3
CO2CH3
An Organometallic Way to Prostaglandins: The Three Component Couplong Synthesis
Organolithium/organozinc procedure:
O
O
1. R Li + Zn(CH 3)2
CO2CH3
2. RI, HMPA
R3SiO
R3SiO
RLi = Li
RI = I
OSiR3
SiR 3 = Si(CH 3)2-t-C4H9
OSiR3
CO2CH3
Stork法
LiO
O
+
LiCu
2
HCHO
C5H11
C5H11
OR'
RO
O
RO
OR'
O
1) MsCl
pyridine
OH
C5H11
RO
O
OR'
OR"
C5H11
2) i-Pr2NEt
RO
OR'
RO
LiCu
2
OR'
３ 成分連結を 狙っ たが， α鎖で直接， エ ノ ラ ート が
OR" 捕捉でき なかっ た。 そこ で、 ま ず反応性の高求電子
剤である ホルムア ルデヒ ド でいっ たん捕捉し ， それ
を 延ばし ていく 作戦に妥協。 それを 解決し たのがエ
ノ ラ ート の金属交換（ 野依法） 。
Synthesis of Prostacyclin (PGI2)
O
HO
CO2CH3 L-selectride
R3SiO
CO2CH3
R3SiO
OSiR3
CO2CH3
PdCl
OSiR3
CO2CH3
HCOO -NH 4+
deprotection
O
O
PdCl2 (C6 H5C
N)2
PGI2
platelet
aggregation
inhibitor
R3SiO
OSiR3
SiR 3 = Si(CH 3)2-t-C4H9
R3SiO
OSiR3
Synthesis of Isocarbacyclin Methyl Ester
OR'
C6H5(CH2) 2Si
O
CO2CH3
CO2CH3
R3SiO
R3SiO
OSiR3
CO2CH3
SiR 3 = Si(CH 3)2-t-C4H9
CO2CH3
1. HClO 4
2. CF3CO 2H
C6H5(CH2) 2Si
R3SiO
OSiR3
OSiR3
HO
OH
isocarbacyclin methyl ester
radical
cyclization
One-pot General Synthesis of Prostaglandins : Three-Component Coupling Synthesis
HO
O
CO2H
O
HO
OH
PGD1
O
CO2H
 chain
 chain
RO
HO
CO2H
HO
OH
PGE1
OH
PGF1
O
HO
CO2Me
RO
CO2H
O
OR'
OH
PGD2
COOH
HO
O
CO2H
CO2H
O
HO
HO
OH
PGI2
OH
PGF2
HO
OH
PGE2
O
O
O
NH
O
O OH
B
O
A
OH
H
OH
O
Taxol
C
D O
O
Synthetic Strategy for Taxol
R. A. Holton (1994)
O
O
OH
TESO
TESO
OBOM
taxol
(-)-camphor
O
TBSO
OH
TBSO
H
K. C. Nicolaou (1994)
O
OBn
OTBS
O
OH OBn
HO
OBn
O
TBDPSO
+
NNHSO2 R
TBSO
O
S. J. Danishefsky (1995)
H
O
O
O
O
H
O
O
OTf
OTMS
H
O
O
OTBS
OTBS
O
H
OBn
O
+
I
taxol
O
H
O OBn
chiral
O
O
O
O
OH
-pinene
O
O
P. A. Wender (1997)
O
taxol
O
O
O
optical resolution
O
OMe
OTBS
MeO
NC
OTMS
H
O O O
AcO
O
TIPSO
TIPSO
OTBS
H
O O
OBn
O
H
O OTBS
HO
O OTroc
H
OBn
OBOM
taxol
D,H,W
N
AcO
O
H,W
Bz
N
OR
HO
Ph
H
D
BzO
OAc
O
18
OTES
R=H
10
O
O
13
A
1
BzHN
OH HO
O
Ph
OH
9
B
15
C
all
HO
O
11
B
A
AcO
2
H; Holton
N; Nicolaou
D; Danishefsky
W; Wender
C
4
H
BzO
H
Baccatin III (R = H)
7
3
D,N
W
8
Taxol
5
D
OAc
20
O
Retrosynthesis of Taxol by Mukaiyama (1997)
OAc
BzHN
B
O
OH
OH
OBn
O
R
TBSO
O
Ph
O
A
C
D O
H
HO
BzO
B
OAc
PMBO
OBn
Taxol
BnO
OBn
OBn
OTBS
OTBS
OHC
OPMB
O
O
TBS
OPMB
Ciguatoxin
H
Hirama (2001, 11)
H
HO
OH
OH
H
O
H
HO H O
H OH
H
H
O
H
HO
OH
H
OH
H
O H
HO
H
OH
H
O O
OH
OH
H
H
Ring-closing metathesis (RCM)
Grubbs (1992-)
RCM
PCy3
Cl
Ph
Ru
Cl
PCy3
Grubb's catalyst
Organic Synthesis in the 21 century
1. Truly effficient production of known
valuable compounds
2. Creation of new valuable compounds and
materials
Coupling Reactions of Kishi’s
Palytoxin Synthesis
C7-C8: NiCl2/CrCl2 (NHK) coupling
C22-C23: Wittig reaction & Hydrogenation
C37-C38 : Wittig reaction & Hydrogenation
C51-C52: Horner-Wadsworth-Emmons reaction
C75-C76: Suzuki coupling
C84-C85 : NiCl2/CrCl2 (NHK) coupling
C98-C99: Wittig reaction
Structure of Palytoxin (1981)
Uemura, D.; Ueda, K.; Hirata, Y.; Naoki, H.; Iwashita,
T. Tetrahedron Lett., 1981, 22, 2781.
Moore, R. E.; Bartolini, G. J. Am. Chem. Soc., 1981,
103, 2491.
Coupling Reactions of Kishi’s
Palytoxin Synthesis
C7-C8: NiCl2/CrCl2 (NHK) coupling
C22-C23: Wittig reaction & Hydrogenation
C37-C38 : Wittig reaction & Hydrogenation
C51-C52: Horner-Wadsworth-Emmons reaction
C75-C76: Suzuki coupling
C84-C85 : NiCl2/CrCl2 (NHK) coupling
C98-C99: Wittig reaction
Ｎｏｚａｋｉ-Ｈｉｙａｍａ-Ｋｉｓｈｉ Ｒｅａｃｔｉｏｎ
Ｓｗｅｒｎ Ｏｘｉｄａｔｉｏｎ
Ｓｕｚｕｋｉ Ｃｒｏｓｓ-Ｃｏｕｐｌｉｎｇ
（Ｓｕｚｕｋｉ-Ｍｉｙａｕｒａ Ｃｒｏｓｓ-Ｃｏｕｐｌｉｎｇ）
Total Synthesis of Palytoxin
by Kishi group
C51をアルデヒドに変換