total synthesis of isoschizogamine
DESCRIPTION
Total Synthesis of Isoschizogamine. Guo Rui 2012.11.23. Introduction. Contents. Total Synthesis of (±)Isoschizogamine. Retrosynthetic Analysis of (±) Isoschizogamine. Total Synthesis of (±)Isoschizogamine. Total Synthesis of (±)Isoschizogamine. Total Synthesis of (±)Isoschizogamine. - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesis of Isoschizogamine
Guo Rui2012.11.23
Introduction
N
N HO
MeO
OMe
MeO
MeO NN
O
MeO
MeO NN
O
H
isoschizogamine
H
Contents
3, Total Synthesis of (-)-Isoschizogamine
1, Total Synthesis of ( )-Isoschizogamine
Heathcock, C.; et. al. Org. Lett. 1999, 1, 1315.
2, Explorations on the Asymmetric Total Synthesis of Isoschizogamine
Zhou, J.; et. al. J. Org. Chem. 2007, 72, 3808.
Fukuyama, T.; et. al. J. Am. Chem. Soc. 2012, 134, 11995
Total Synthesis of (±)Isoschizogamine
MeO
MeO NN
O
MeO
MeO NH
N
R
R=COX, COOR', CH(OR'')2
MeO
MeO
HN
R
O
NO2
MeO
MeO
N
RNH2
X
MeO
MeO
O
+OH
N
R
OH
O
R
NH2
OHOR
+ O N3
X
NO2
Retrosynthetic Analysis of (±)Isoschizogamine
Total Synthesis of (±)Isoschizogamine
O
O
O
i. KHMDS(slowly added)ii. Lewis acid
O
O O
N3
R1R2 H2-Pd/C(On isomer 2)
2: R1=H, R2=OH3: R1=OH, R2=H
O O
N
OH
Lewis Acid Yield Ratio 2:3
LiBr 67% 62:38
Bu2BOTf 49% >95:5
i-Bu2AlCl 71% 77:23
MeO
MeO NO2
CHO Meldrum's acidPyridine, rt
(58%) MeO
MeO NO2
OO
O O
4
i. 4, -40 oCii. PhMe, reflux
74% from 4
MeO
MeO
N
O
NO2
OH
O O
MeO
MeO
N
O
NO2
OH
O O
MeO
MeO NO2
O
X
X = Cl, OCOR, OR
4+
conditions
O O
O OHRNH2 O
+ RNHCOCH2CO2H CO2 + RNHCOCH3
Chem. Soc. Rev . 1978, 7, 345(Meldrum's acid)
iii. OHCN3
71%
+
88:12
Total Synthesis of (±)Isoschizogamine
[Ph(CF3CO]2SPh2DCM, rt
(74%)
MeO
MeO
N
O
O ONO2
MeO
MeO
N
O
NO2
OH
O O
Dehydration with Martin's sulfurane (Dehydrates secondary and tertiary alcohols to give olefins, but forms ethers with primary alcohols)
OS
OO
CF3
CF3
CF3
F3C
Ph PhPh Ph
HOH
CF3
F3C
Ph +
OS O
CF3
F3C Ph
Ph Ph
S OCF3
F3C Ph
Ph
O
Ph
O
CF3
F3C
Ph
H S OHCF3
F3C Ph
Ph
O
Ph-
+
O CF3
F3C Ph
SPh
O
Ph
H
+ Ph2S=O OH
CF3
F3C
Ph
O
CF3
F3C
Ph
+
Mechanism of the Dehydration with Martin's sulfurane
Martin, J. C.; et. al. J. Am. Chem. Soc. 1971, 93, 4327.
Total Synthesis of (±)Isoschizogamine
MeO
MeO
N
O
O O
i. LiAlH4, THFii.
5: X = NO2
6: X = NH2
NaBH4, Cu(acac)2EtOH, THF
NH
N
H
O
O
MeO
MeO NH
N
H
HOAc, H2Ort, 1h
O
O
HOAc, H2O, reflux, 3h
MeO
MeO NN
H
HO
PDCDCM
27% from 5
MeO
MeO NN
H
Oisoschizogamine
1
X
MeO
MeO
N
O ONH2
MeO
MeO
N
O ONH2
Hworkup
3 : 7
H
H
work up by sequential addition of water, 15% NaOH, water
Reagents for Organic Synthesis, Vol1;1967; p 584.
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
Retrosynthetic Analysis of Isoschizogamine
MeO
MeO NN
O
SN2
H
MeO
MeO N
O
HOTs
aminal and amide formation
N
H OTBDPS
MeO
O
H2Nlactam ring opening;
oxidation NH
H2N
MeO
MeO
TBDPSO
H
H
NH
fomal hetero-Diels-AlderMeO
MeO
MeO
MeO NH2
+
NHO
OHC
N
OMe
O
OLiN
OTBDPS
OLi
aza-Claisenrearrangement or
N
COOMe
Ac
N
R
HWE olefination
PO(OEt)2
R
N
CHO
Tr
+
O
or
OTBDPS
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
PO(OEt)2
COOMe+ N
CHO
Tr
Ba(OH)2
wet THF, rtN
COOMe
Tr
TFA, Et3SiH
NH
COOMe
71%
Ac2O, Et3N
90%N
COOMe
Ac
LiHMDS, PhMe
-78 oC
N
OMe
O
OLi
PhMe, 80 oC
77%
NHO
MeOOC
97% ee
DIBALH
PhMe, -78 oC
59%
NHO
OHC
E/Z=11:186%Tr = C(Ph)3
LiBHEt3 or LiAlH4/swern oxidation
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
N
R
OTBDPS
R = Tr
R = H
all acidic conditions
failed
N
OMe
O
OLiN
OTBDPS
OLi
vs
less facile
N
OTBDPS
HH
OTBDPS
Nu
OTBDPS
O
HN
H2N
Oproduct observed
TFA, Et3SiH
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
MeO
MeO NH2
+
NHO
OHC TsOH (10 mol%)
PhMe, reflux
MeO
MeO NH
NH
O
MeO
MeO NH
NH
O
H
H
trans
(dr=10:1)
70% of 8 NH
H
H
NH
O
MeO
MeO
8 (majior)
NH
H
H
NH O
MeO
MeO
7
+
MeO
MeO NH
NH
O
H
HMeO
MeO NH
NH
OH
N
NH
OH
H
MeO
MeO
HHH
NH
NH
OMeO
MeO
+
+
prefered
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
NH
H
H
NH
MeO
MeO
9-BBN, THFNaOH, H2O2
55%NH
H
H
NH O
MeO
MeOO
HO i. TBDPSCl, Et3NDMAP
ii. Boc2O, Et3NDMAP
66% 2 steps
NH
H
H
NBoc
MeO
MeO
TBDPSO
MeONa, MeOH
55%NH
H
H
MeO
MeO
TBDPSO
MeOOC
NHBoc
N
HMeO
MeO
TBDPSO
MeOOC
NHBoc
oxidationsfailed
O
TPAP, NMO; Swern oxidation;
MnO2;Hg(OAc)2;
(NH4)2Ce(NO3)6; trichloroisocyanuric acid;
H2O2,Na2WO4
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
An Alternative Plan To Avoid Imine Formation
MeO
MeO NN
O
SN2 MeO
MeO N
HOTs
H2N
H
MeO
MeO N
HN
O
OTBDPS
H+MeO
MeO N
N
OR
MeO
MeO NH
O
HNO
R
MeO
O
HNO
R
+
MeO
MeO NH2
NH
R
O
O
MeO
R= OTBDPS
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
P
TBDPSOOMe
O
OEtO
OEt
4 steps
NH
R
O
O
MeO
i. NaHMDSp-NsCl80%
ii. MeONaMeOH/THF
80%
R
O
O
MeO
HNp-Ns
OMe
i. DBU, CH3CNreflux, 82%
ii. PhSH, K2CO3DMF, 92%
MeO
O
HNO
R
3,4-dimethoxyanilineAlMe3, DCM
96%
R= TBDPSO
MeO
MeO NH
O
HNO
R
I2. PPh3i-Pr2NEt, rt
MeO
MeO N
ON
R
MeO
MeO N
N
ORisomerization
conditions
9
9
9
Me3OBF4Cs2CO3
DCM
82%
MeO
MeO NH
O
NMeO
R
Me2AlClDCM, rt
68%
MeO
MeO N
N
OR
98% ee
NaH, DBU, LHMDS, or KHMDS
LiAlMe3SPhor piperidine
Explorations on the Asymmetric Total Synthesis of Isoschizogamine
NH
OO
CH3
HN
O
CONHR
NHR = CH2CH=CH2
I2. PPh3, i-Pr2NEt, rtN
O
N CONHR
NH
56%
N
O
N COOMe
NH
LiAlMe3SPh
N
N
Me3AlO
COOMe
NH
SPh
NOBn
90%
CH3
O
NOBn
Li
N
N
O
COOMe
NH
NOBn
J. Am. Chem. Soc. 2001, 123, 5892
MeO
MeO N
N
OR
TfOH, DCM, rt
MeO
MeO N
N
O OH
MeO
MeO NNH
O
OH
TfOH, PhMe, reflux
Formation of amidine from diamide
Total Synthesis of (−)-Isoschizogamine
N
N HO
MeO
OMe
NH
[N]
O
MeO
OMe
ORO
H
MeO
OMe
[N]
NHO
ORH
MeO
OMe
[N]
ORH
O O
ORH
O O
O
O
RO
O
OR
Wagner-Meerweinrearrangementmetathesis
coupling1,4-addition
ring-closing metathesiscondensation from
diaminoketone
Retrosynthesis:
Total Synthesis of (−)-Isoschizogamine
OHi. TPAP, NMO, MS4A, DCM,rt
ii. TrisNHNH2, conc HCl, MeCN,rt96% NNHTris
i. s-BuLi(2 equiv.), THF, -78 to 0 oC
ii. ethylene oxide, -78 to 0 oC
iii. TBDPSCl, rt OTBDPS79%
mCPBA, NaHCO3, DCM
93%OTBDPS
O
o-tolMgI, Et2O, reflux
68%
HO
TBDPSO
Cl
O
i-Pr2NEt, DCM
96%
O
O
TBDPSOTBDPSO
O O
H
Hi-PrO
Ru
NN o-tollot-o
1,6-heptadiene
benzene, 60 oC
73%
H
H
O O
H
H
HH
O
O
TBDPSO
HH
TBDPSO
Tris = 2,4,6-triisopropylbenzenesulfonyl
(+)-exo-norborneol
Total Synthesis of (−)-Isoschizogamine
NNH
Ts
H
2RLi NN
Ts
- 2H
-Ts NN
E+-N2E
Mechanism of the Shapiro Reaction
Shapiro, R.; et, al. Tetrahedron Lett. 1975, 1811.
O
R'
RMgXO
R'
MgR
X
R'
OMg
HX
R
R'
HO
R'
HO
a
b
Mechanism of the Wagner-Meerwein rearrangement
Kleinfelter, D. J.; et. al.J. Org. Chem. 1971, 36, 3255.
R
Ha
b
Total Synthesis of (−)-Isoschizogamine
allylamine, 2-pyridone,
THF, 50 oC
84%
OH
H
H
MeO
OMe
OTBDPS
NH
O
Dess-Martin periodinane,DCM, rt
99%
H
MeO
OMe
i. conc HCl, MeOH, 0 oC, 98%
ii. PPTS, toluene, reflux, 72%
O
H
MeO
OMe
OTBDPS
NH
O
N O
O the second-generation
Hoveyda-Grubbs catalyst,
toluene, 70 oC, 97%
H
MeO
OMe
N O
OCu(NO3)23H2O,
Ac2O, DCM,
0 oC, 97%
H
MeO
OMe
N O
O
NO2
TBDPSO
O O
H
H
MeO
OMe
3,4-(MeO)2C6H3B(OH)2, [RhCl(cod)]2,Et3N
aq dioxane, rt,
93%TBDPSO
O O
H
H
RCM
Product
Total Synthesis of (−)-Isoschizogamine
i. NaBH4, Cu(acac)2, EtOH, rtii. FmocCl, i-Pr2NEt, CH2Cl2
86%
H
MeO
OMe
N O
O
NHFmoc
i. TMSOTf, 2,6-lutidine,ii. TBAF, AcOH
MeO
OMe
N O
NHFmoc
HO
H
MeO
OMe
N O
O
NO2
i. Dess-Martin periodinane
ii. (TMSOCH2)2, TMSOTf,
CH2Cl2, -78 oC
96%
MeO
OMe
N O
NHFmoc
OO
piperidine, DMF, rt
MeO
OMe
N O
NH2
OO
LiAlH4, THF, reflux
MeO
OMe
N
NH2
OO
aq AcOH, reflux
N
NH2 H
MeO
OMe
H+
N
HN H
MeO
OMe
O
O
O
ON
N HHO
MeO
OMe
Total Synthesis of (−)-Isoschizogamine
N
N HO
MeO
OMe
PDC, CH2Cl2, rt
23% (4 steps)
N
N HHO
MeO
OMe
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