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Total Synthesis of ( - )-Quinocarcin. 李楠 2009.04.20. Stoltz. J. Am. Chem. Soc. , 2008 , 130 (51), 17270-17271 Myers. J. Am. Chem. Soc. , 2005 , 127 (48), 16796-16797 Zhu. J. Am. Chem. Soc. , 2008 , 130 (22), 7148-7152. inhibition of lung cancer activity against lymphocytic leukemia etc. - PowerPoint PPT Presentation
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Total Synthesis of (-)-Quinocarcin
Stoltz. J. Am. Chem. Soc., 2008, 130 (51), 17270-17271Myers. J. Am. Chem. Soc., 2005, 127 (48), 16796-16797Zhu. J. Am. Chem. Soc., 2008, 130 (22), 7148-7152
李楠
2009.04.20
N
O
NMe
OMe
H
CO2H
A B C
D
E
(-)-Quinocarcin
inhibition of lung canceractivity against lymphocytic leukemia etc.
N
O
NMe
OMe
H
CO2H
1
NNMe
OMe
H
CO2H
OOH
N
OMe
H
OOBn
NCbz
OTIPS
Br
N
OH
O
NHCbz
OTIPSOBn
Br
OMe
HNH
CO2Me
OBnOMe
Br
HO2C
NHCbz
OTBS
CHO
OH
CHO
OBn
NCO2tBuPh
Ph
10
12
11
8
9
46
7
Zhu's total synthesis of (-)-Quinocarcin
J. Am. Chem. Soc., 2008, 130 (22), 7148-7152
intramolecularnucleophilic attack
intermolecular condensation
Pictet-Spenglerreaction
alkylation
install the labile oxazolidine ring
Br Br
OTBS
Ph2C=NCH2CO2tBu (11)
15 ( 0.1 eq ), CsOHCH2Cl2, -78oC
TFA/AcOH/H2O ( 1:1:1 )
Br
CO2tBu
NH2
OTBS
TBAF
THF
Br
CO2tBu
NH2
OH
H
Br
CO2tBu
NH2
OH
H
OBn
CHO
17 12
17
4A MS, AcOH
CH2Cl2 NH
CO2tBu
H3
H1
Br
OHOBn
NOE correlation betweenH1/H3:1, 3-cis
20
16
effectively obviated the regioselectivity
(a). Boc2O, DIPEA, MeCN
(b). Me2SO4, acetone,Cs2CO3 NBoc
CO2tBu
H
H
Br
OMeOBn
SOCl2
MeOHNH
CO2MeH
H
Br
OMeOBn
21 8
N
H
H
Br
OMeOBn
O
NCbz
OH
SEt
N
H
H
Br
OMeOBn
O
NCbz
N
H
H
Br
OMeOBn
O
NCbz
O
EtSH
Hf(OTf)4
Hf(OTf)4
EtSH
Hf(OTf)4
PhSH
25
O
A
26
N NN
N
OHHOAt
N NN
N
ON(CH3)2
N(CH3)2
PF6
HATU
mixture of two diastereomers (ratio 3/2)
NH
CO2MeH
H
Br
OMeOBn
8
HOOC
NHCbz
OTBS
HATU, HOAt
DIPEA, DMF
9
N
H
H
Br
OMe
22
OBnO
CO2MeNHCbz
OTBS
N
H
H
Br
OMe
22
OBnO
NHCbz
OTBS
LiBH4, MeOHEt2O
OH
Swern oxidation
N
H
H
Br
OMeOBn
O
NCbz
OTBS
OH
24Strong nucleophile
weak nucleophile
N
H
H
Br
OMeOBn
O
NCbz
OH
SEt
25
(a) Swern oxidation
(b) TIPSOTf,Et3NN
H
H
Br
OMeOBn
O
NCbz
SEt
OTIPS
27
N
H
H
Br
OMeOBn
NCbz
O
CHO
AgBF4,THF
28
Jonesoxidation
N
H
H
Br
OMeOBn
N-Cbz
O
COOH
35
E/Z = 8/1
deprotection under one-pot condition
(a) Pd/C, H2, MeOH
(b) HCHO, HCOOH NaBH3CN
N
H
H
OMeOH
NMe
O
COOH
Li/NH3then 2N HCl
4
N
O
NMe
OMe
H
CO2H
A B C
D
E
(-)-Quinocarcin
NFmoc
H
O
OBnOH
H
O
N
CNH2N
TMS
O
N
CNNH
TMS
NH
OHOBn
HCN
Na2SO4
DBU; HCN
N
NH
OH
HH
CNH
OBn
ZnCl2, TMSCNTFE, 60oC, 15h
12
3
4
Myers's total synthesis of (-)-Quinocarcin
key step : allyl silane-imine addition
C DN
N
OH
H
CNOBn
TMS
O
O
Fmoc
N
N
OMe
HH
CNH
OBn
OH
Me
O
1. Cs2CO3, Me2SO480%
2. NaIO4, OsO4, 88%3. Jones Reagent, 91%
5
AgNO3
MeOH, H2O70% ( 2 steps) N
N
OMe
HH
H
OH
Me
O
O
A B C D
(-)-Quinocarcin
J. Am. Chem. Soc., 2005, 127 (48), 16796-16797BCl3: Lewis acid capable of selective cleavage of ether and acetal protecting groups
BCl3N
N
OMe
HH
CNH
OH
OH
Me
O
DX-52-1 ( 6 )
N
NH
OH
HH
CNH
OBn
4
C D
N
MeN
O
OAr
OH electrocyclicring-opening
N
NMeO
OAr
OH COOH
exo-si
1,3-dipolar cycloaddition
N
MeN
O
O
COOH
Ar
OH
N
MeN
COOH
O
MeO
Quinocarcin
Garner ' s strategy
J. Am. Chem. Soc. 1992, 114, 2767–2768J. Am. Chem. Soc. 1993, 115, 10742–10753
N
N
O
H
OOH
Me
OMe
N
N
OOMe
Bn
OMeO
OMeOBn
AryneAnnulation
OMe
O NH
N
OOMe
Bn
OOMe
Quinocarcin (1) 9
+
BnO
10 11
HN
N
OOMe
Bn
O
12
Stoltz's total synthesis of (-)-Quinocarcin
HN
N
O
Bn
BrN
SO
O
+
1. N-Me-morpholine MeCN, -20oC
2. NaOMe, MeOH, 23oC
( 74% yield, 2 steps )13 14
O
HN
NBn
OOMe
O
12 (11:1 separable cycloadducts)
BnO
O
Cl 15
DMAP, Et3N
CH2Cl223oC reflux
( 93% yield )
N
NBn
OOMe
OO
BnO
16
Y(OTf)3, MeOH
CH2Cl2, reflux
( 69% yield )
NH
NBn
OOMe
O
BnOO
OMe11
auxiliary-controlled dipolar cycloaddition
Screened Zn(OTf)2, Sc(OTf)3, and Sm(OTf)3, and none provided enamine 11 in greater than 40% yield.
NH
NBn
OOMe
O
BnOO
OMe11
OMe
TMS
OTf+
17
TBAT
THF, 40oC
( 60% yield )
N
NBn
OOMe
OOMeOBn
OMe
9
Pd/CH2 ( 1atm )
THF, 23oC
3.3 : 1 dr18a : 18b
NH
NBn
OOMe
OOMeOBn
OMe
NH
NBn
OOMe
OOMeOBn
OMe
18a
18b
5
5
NaBH3CNconcd HCl
MeOH, 0oC
aryen annulation reaction
Si
Ph
FPh
FPh N
Bu
Bu BuBu
TBAT
NH
NBn
OOMe
OOMeOMe
NH
NBn
OOMe
OOMeOBn
OMe
19a ( 55% yield from 9 )
H
H
11a
11a
19b ( 17% yield from 9 )
OBn
toluene
110oC
(99% yield from 19a)
N
NBn
OOMe
OOMeOBn
H
20
Selectivelycondensed
aq HCHOPd(OH)2/CH2(1atm)
MeOH, 23oC
( 80% yield )
N
NMe
OOMe
OOMe
H
OH21
LiOH H2O
THF/H2O 23oC
N
NMe
OOH
OOMe
H
OH 22
Li, NH3(l), THF
-78oC -30oC then 1N HCl
81% yield, 2 steps
N
NMe
OOH
OMe
H
O
(-)-Quinocarcin
10% overall yield11 steps (shortest synthesis to date)
N
HN O
R1RHal
NR
HN O
R1-H+
NR
N O
R1
1 2 3
NMe
N O OOMe
NMe
N O
OMe
O 54
NMe
N O
+H+, -H+
4a
NMe
HN O
OMe
O6
Arkivoc. 2007 (xvi) 51-57
1, 3 - Dipolar Cycloadditions to Oxidopyriziniums
Y
X X
-X-
slow
H+
fastH
XX=halogen, Y=H or halogen
SiMe3
OTf
F-
-FSiMe3 OTf
H+
slow
-OTf-
fast
H
OTf
TMS
OTMS
n-Buli TMS
OLi
Tf2O
1.2eq 2 eq
SiMe3
OTf
SiMe3
OTf
F- FuranO
Kobayashi, H. Chem. Lett. 1983, 12, 1211–1214.
J. AM. CHEM. SOC. 2005, 127, 5340-5341
TMS
OTfOEt
O O
CsF(2.5 eq)
MeCN(0.2M)
80oC, 1.5 h
+
OEt
O O
+
Cs
CO2Et
O CsO
Me
RO
OEt
Cs
H+
O
EtO O1 2
34
5a, R = Me5b, R = H
753% yield
OEt
O O
Ph
642% yield
H+
Benzyne C-C insertion reactions
TMS
OTf
R NH
O
COOCH3
+F-
N
RO
COOCH3
COOCH3
NO
R
NCOOCH3
OR
Indolines
N
R
COOCH3
Isoquinolines
J. Am. Chem. Soc., 2008, 130 (5), 1558-1559
formal [3+2]
[4+2]
Synthesis of Indolines and Isoquinolines via Aryne Annulation
NH2
CHO
CO2H
O
N
CO2H
NH2
O H
NH
OH
H
-H2O
N
H
N
H
O
CO2H
H
NH
OCO2HH
H+
NH
CO2HOH2H
-H2O
NH
CO2H
air oxidation
-2H N
CO2H
Doebner reaction
Liebigs. Ann. Chem. 1887, 242, 256.
NH
CO2HHHO
Pictet-Spengler Reaction :The most popular procedure used to close the tetrahydroisoquinoline ring system
R1O
R1ONH2
+O
HR2
HCl
NH
R
R1O
R1O
R1O
R1ONH2
O
HR2
HR1O
R1OHN
R2
OH
H+ R1O
R1OHN
R2
OH2
-H2OR1O
R1ON
R2
H
R1O
R1ONH
HR2
R1O
R1ONH
HR2
NH
R
R1O
R1O
Ber. Dtsch. Chem. Ges. 1910, 44, 2030
Pictet-Gams Reaction
HN
R
O
OH
P2O5N
R
HN
R
O
OHP O P
O
OO
OHN
R
O
OH
P
O
O NH
OH
HR OPO2
N
R
OH
P O PO
OO
O
N
R
OPO2
HB
N
R
Ber. Dtsch. Chem. Ges. 1910, 43, 2384
HN
R
OPOCl3
N
R
HN
R
OP
O
Cl Cl
Cl
-Cl-
HN
R
OPOCl2
NH
ROPOCl2
NH
R OPOCl2H
Cl
N
R O PO
ClCl
H
Cl
N
R
HCl O PO
Cl
Bischer-Napieralski Reaction
Ber. Dtsch. Chem. Ges. 1893, 26, 1903-1912
Baldwin规则:由于不同类型反应的分子轨道重叠不同,因此特定组合的闭环反应具有相应得禁阻和允许性质。但含正离子和第二周期元素的反应通常不符合该规则。环中的原子个数,一般为 3-8;以 exo和 endo表示闭环时断键的位置,环内对应 endo,环外对应 exo;以 tet,trig和 dig表示反应中亲电碳的杂化状态, tet对应 sp3杂化, trig对应sp2杂化, dig对应 sp杂化。例:
O
OMe
O
5-endo-trigO
OMe
O1
2
34
5
0% 100%
5-exo-trigO
O