Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
5
6
4a
4
3
7
HO
MeO
isoquinoline
N
2
8a
8
1
-isoquinoline first isolated from coal tar in 1885, sweetish odour
-isoquinoline alkaloids, large familiy,until now over 400 members
-Biological activities:
antimalarial, anti-HIV, insect growth retarding
antitumor, antimicrobial, antileukmic
antibacterial, Parkinson's disease
MeN
OAc
H
Me
O
H
O
O
RO
O
NAc
Me
MeO
curicyleatjehine
O
NH2
SCAr3
OMe
COOH
HO
cryptaustoline
NHTroc
Jieping Zhu et al, J. Am. Chem. Soc., 128, 87-89, 2006
Ecteinascidin 743
HO
NH
roebramine
OH
OH
O
N
O
OMe
MeN
O
O
chaetoindicin A
labrandine
HO
O
N
OMe
R
OMe
HO
MeO
NMe
O
R2
N Me
HO
NH
H
N
R1
Cl
H2N
COOEt
OH
HO
NMe
Me
MeO
OH
MeO
R3O
OMe
Br
MeO
HO
NHBoc
HO
O
H
NH
O
R
N
S
O
OMe
Berberine
Morphine
OMe
OMOM
H
Me
OMe
CHO
Me
N
NMe
HO
OMe
Papaverine
N
O
O
OMe
O
O
N
MeO
HO
Jun Shi
O
Chaetoindicin B
neocaryachine
Guo-Lin Zhang et al. Org. Lett. 2006, 8, 3613-3615
OMe
For a comprehensive review see: K.W. Bentley, Natural Product Report, 8, 365-391, 1992
1
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
5
6
7
8
Zhen Yang et al, Org. Lett., 6, 3155-3158, 2004
4
4a
3
N
8a
Jun Shi
1
2
planar, 10 ! electron deficient aromatic symtem
electrophilic attack: C4 and C8
nucleophilic attack: C1 and C3
isoquinoline
5
NH2
R1NC
5
4
6
3
6
7
NH
7
8
tetrahydroisoquinoline
1
I
O
NH2
R1NC
2
3
6
7
8
N
8a
2
Novel:
1
C8a-C1: Bischler-Napieralski reaction
Pictet-Gams reaction
C1-N2: Pictet-Spengler reaction
C4-C4a: Pomeranz-Fritsch reation
O
Cr(CO)5
Bu
+
CHO
N
R2
F3 C
CF3
R1
NH2OH
Pd(0), base
OMe CN
N
N
R1 +
R2
I
tBu
Pd(0),
Na2CO3
Me
N
R2
R1
O
N
N
Me
O
R3
O
O
NH2
R
NH2NHR
Pd(0), base
O
H
H
H
N
O
I
O
Jungha Chae et al, J. Org. Chem., 10172-10174, 2005
HN
H
N
N
O
CN
NC
Pd(0)
O
Ronald Grigg et al, Angew Chem Int Ed, 44, 7570-7574, 2005
Bu
MeO
I
N
R3
R3
Formation of C3-C4 and N2-C3
Ring expansion of other ring system
James W. Herndon et al, Org. Lett., 5, 4261-4263, 2003
R1
R2
R2
MeOH
CO2H
CHO
dihydroisoquinoline
Classic:
HN
R1
3
R2
4
O
N
R3
HN
I
Synthesis of core
5
4a
O
N
R3
R3
R2
O
Pd(0)
I
N
1 2
8
4
CO2H
CHO
R2
R2
MeOH
O
CO2Me
Pd(0), base
Me
N
O
H
H
H
NR
N
O
Me
N
O
H
R
H
H
N
CO2Me
R1
CF3
J. A. Joule and K. Mills, Heterocyclic Chemistry, P121-P143
2
R1
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Biosynthesis of isoquinoline alkaloids
Biosynthesis pathway to berberine in Berberis cell cultures
HO
HO
NH2
HO
HO
H3CO
NH
H3CO
NH
HO
H
CHO
OH
Coclaurine
Norcoclaurine
HO
H3CO
H3CO
NMe
HO
HO
H
OH
OH
NMe
H
HO
OH
OH
N
H
OH
OMe
OMe
reticuline
from siparuna
scoulerine
reticuline
HO
coclaurine
from zizyphus
H
H3CO
OH
H3CO
NMe
HO
H
O
N
H
OMe
O
N
O
H
OMe
O
N
OMe
OMe
OMe
OMe
canadine
Berberine
Heinz G. Floss et al, J. Am. Chem. Soc, 117(5), 1995
Berberine from
Berberis
3
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Photochemical Synthesis of Isoquinoline alkaloids
1. G. R. Lenz et al, J. Am. Chem. Soc, 88, 5369, 1966
5. K. Fukumoto et al, Tetrahedron, 27, 5993, 1971
h!
N
NCO2Et
hv
HO
O
O
NCO2Et
MeO
MeO
NCO2Et
h!
Br
NCO2Et
MeO
MeO
hv
[o]
MeO
NCO2Et
MeO
OH
2. T. Mori et al, Tetrahedron Lett., 3643, 1963
OH
HO
HO
H
MeO
h!
NR
NR
O
H
NMe
h!
Br
NMe
MeO
N
HO
O
O
3. P. D. Gardner et al, Tetrahedron Lett., 2493, 1967
6. Patrick S. Mariano et al Tetrahedron Lett., 26, 5867-5870, 1985
R
N Me
R
h!
N
Br
O
+
R
R
CN
O
O
O
MeO
OH
+
NH
MeO
h!
N
TMS
N
CN
hv
ClO4
TMS
4. Gregorio Torres et al, Tetrahedron Lett., 36, 1315-1318, 1995
MeO
N
MgCl
N
ClO4
R
h!
NR
TMS
OH
TMS
for more see Jeremy's group meeting materials
4
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Aymmetric Synthesis of Isoquinoline Alkaloids
1. Esther Leter et al, J. Org. Chem. 70, 10368-10374, 2005
MeO
MeLi
Lewis acid
MeO
N
MeO
4. Ihara, M. Heterocycles, 59, 51, 2003
OR
N
MeO
OR
O
Me
N
O
Me
N
2
O
MeO
MeLi
protic acid
1
OR
N
MeO
3
NHCOMe
R
O
Me
H
N
N
MeO
O
OMe
2
5. Tomioka, K., Tetrahedron Lett. 41, 5533, 2000
O
N
H
R
1
OMe
NEt2
N
N
H
CHO
O
SAMP, MS 4 A
HCl
MeOH-H2O
2. Marine Boudou and Dieter Enders, J. Org. Chem, 70, 9486-9494, 2005
O
H
Ph
N
OMe
Me2N
O
R
LDA, AlMe3
R
55%, 96%ee
N
MeLi
OMe
3. Jiang, L et al, Tetrahedron Lett., 36, 715, 1995
H
N
1
OMe
Me
2
O
S
C6H4NO2 R
R
NH2
1. CH2O/NaBH3CN R
TFA
S
1
NMe
NH 2. Raney Ni
O
Me
3
R
NH
C6H4NO2
2
3
R
N
Me
For more about SAMP-Hydrazone Methodology see Review: Dieter Enders et al, Angew Chem Int Ed, 44, 1304-1325, 2005
Me
OMe
3
5
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Aymmetric Synthesis of Isoquinoline Alkaloids
10. Hoye, T. R. and Chen, M. Tetrahedron Lett. , 37, 3099, 1996
6. Michiko Miyazaki and coworkers, Org. Lett, 8, 1295-1297, 2006
HO
MeO
MeO
CuCl, (R)-tol-BINA, TBAT
N
MeO
NH
MeO
Si(OMe)3
NaBH4
or H2/Pd-C
HO
NH
OH
H
N
67%, 97%ee
OH
7. Mikiko Sodeoka et al, J. AM. CHEM. SOC, JA065646R, 2006
HO
LiAlH4,
AlMe3
NH
Chiral Pd cat.
N
OH
NBoc
CO2R
11. Ligong Liu, Synthesis, 11, 1705-1707, 2003
*
CO2R
CO2R 2
n-BuLi, PhMe
+
8. Joanna Szawkalo and Zbigniew Czarnocki, Monatashefte fur Chemie,
136, 1619-1627, 2005
MeO
Me
MeO
O
NH
MeO
R1
N
N
MeO
(-)-sparteine
R2
O
berine
12. Eric N. Jacobson et al, Angew. Chem. Int. Ed, 44, 6700-6704, 2005
Chiral Ru complex
R1
N
R1
NH
Et3N/HCOOH
R2
1. RCOCl
N
R2
9. Takashi Itoh et al, Synlett, 10, 1595-1597, 2006
R1
HCN, Jacobson catalyst
N
TFAA
N
2. OTBS
chiral thiourea
R
tBu S
i
2 BuN
O
OR'
O
R'O2C
N
H
N
H
Me
Ph
13. Karl Anker J!rgensen et al, Angew. Chem. Int. Ed, 44, 6058-6063, 2005
R1
N
CN
CF3
N
O
H
O
10% Catalyst
Et3N
CH2Cl2
OMe
N
MeO
N
H
H
O
6
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Total synthesis of isoquinoline alkaloids natural product
Toshio Honda and Hiroki Shigehisa, Org. Lett, 8, 657-659, 2006
MeO
CHO
Pd(OAc)2, PPh3,
Na2CO3
MeO
CHO
1. BnBr
MeO
MeO
2. CH3NO2, NH4Ac
MeO
NO2
MeO
MeO
1. LiAlH4
2. AcCl, NEt3,
MeO
Br
2
1
HCHO, NaBH3CN
MeCN
POCl3, ACN
MeO
MeO
MeO
OH
Bn
OH
HO
NMe
3
3.Pd(OH)2, H2
B(OH)2
MeO
NHAc
PIDA, Then NaBH4
NH
MeO
MeO
TFAA
NTFA
MeO
NH
MeO
Cl
OAc
I
OAc
OH
O
O
Pronuciferine
OH
5
Stepharinine
4
Toshio Honda and Hiroki Shigehisa, Tetrahedron Lett, 47, 7301-7306, 2006
OMe
OMe
MeO
OMe
PIDA, Then NaBH4 MeO
N
O
NaBH3CN, HFIP
O
N
O
O
Pd(PPh)2Cl2
Bu3SnH, AcOH
MeO
N
O
O
OMe
MeO
HO
N
O
3
1
OTBS
2
O
O
Annosqualine
O
7
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Total synthesis of isoquinoline alkaloids natural product
Albert Padwa and M. Diana Danca, Org. Lett., 715-717, 4, 2002
MeO
O
O
CHO
TBSO
1
MeO
NH2
MeO
2
SEt
N
O
MeO
then EtSCH2COCl
MeO
O
SEt
N
CO2Me NaIO4
CO2Me
3. LDA
HCO2Et
MeO
O
MeO
1. H+, MeOH
2. TBSCl, DMAP
O
MeO
SEt
N
CO2Me
TBSO
CO2Me
1. CBr4, PPh3
2. NaIO4,
HO
Br
4
3
O
5
CSA
MeO
MeO
H
H
N
MeO
MeO2C
MeO
S
MeO
N
O
MeO
H
NaIO4 MeO
Lawesson's reagent MeO2C
MeO2C
Meerwein's salt
NaBH4
Jamtine
H
N
MeO
MeO
N
MeO2C
H
NaH
O
MeO
N
O
MeO2C
SEt
SEt
Br
6
8
9
7
Miwako Mori et al, Org. Lett., 5, 2323-2325, 2003
CHO
O
NO2
O
LiAlH4, (Boc)2O
O
O
Br
1
2. CH3NO2
1. CO2, Ni(cod)2, DBU
O
1. TMSCCH,
PdCl2(PhCN)2
3
TMS
O
NH
O
O
2. CH2N2
TMS
2
NHBoc
TMS
O
NHBoc
O
TFA, MeOH,
COOMe TBAF
ZnCl
4
5
CO2Me
8
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Total synthesis of isoquinoline alkaloids natural product
1. LiAlH4
2. (COCl)2, DMSO, TEA O
Grignard
O
Allyl bromide
N
O
HCl, Grubbs' reagent 1
N
O
O
O
N
O
3. Ac2O, TEA, DMAP
K2CO3
AcO
CO2Me
N
O
HO
OAc
6
Erythrocarine
8
7
Michiko Miyazaki and coworkers, Org. Lett, 8, 1295-1297, 2006;
Tietze, L. F et al, Angew. Chem. Int. Ed., 42, 4254, 2003
MeO
MeO
MeO
NH
MeO
(Boc)2O
NBoc
MeO
H
H
1
Grubbs'1
O
NH
MeO
H
ethyl acrylate
TMSOTf
H
N
H
EtOOC
H
H
H
H
CO2Et
MeO
MeO
N
MeO
pyrrolidine
O
2
MeO
4
H
O
EtOOC
3
Ph3PCH3Br, LiPh
then MeOH
Me
O
MeO
MeO
MeO
MeO
MeO
MeO
N
H
H
H
NH
1. AlMe3
2. POCl3
N
MeO
H
3. Ru catalyst
HCO2H/Et3N
6
emetine
Pd/C
N
MeO
H
H
H
EtOOC
5
H
H
EtOOC
9
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Total synthesis of isoquinoline alkaloids natural product
Christopher J. Bungard and Jonathan C. Morris, J. Org. Chem., 7345-7363, 2006
Yamamoto, H. J, J. Am. Chem. Soc., 124, 5365-5375, 2002
MeO
O
CHO
1,2-ethanediol
MeO
I
MeO
O
BuLi, Bu3SnCl
I
OMe
O
MeO
O
Pb(OAc)4
Bu3Sn
OMe
1
O
Me
9
Me
O
MeO
OMe OMOM
Me
OMe
Me
8
Me
MeO
OMe OMOM
Me
MeO
OMe OH
Me
Me
OMe
CHO
POCl3
2,4,6-collidine
MeO
Me
N
I
I
OMe
OMe
Me
Me
OMe Me
Ancistrocladidine
MeO
MeO
Me
N
11
10
OH
6
NHAc
CH3COCl
TBHP
OMe
7
NH2
OMe
1. MOMCl, NaH
2. NaH, (EtO)2POCH2CO2Et
3. DIBAL-H
TI(OiPr)4, D-(-)-DIPT
1. phthalimide, DEAD, PPh3
2. MeNH2,
MeO
OMe OMOM
OMe
MeO
OMe OMOM
OH
TsCl
OMe
5
Me
OTs
LiAlH4
OH
Me
4
O
MeO
OMe OMOM
OMe OH
OMe
3
MeO
OMe OMOM
CHO
pyridine, H2SO4
(AcO)3Pb
OMe
2
MeO
OMe OH
O
Me
N
Bu3Sn
MeO
OMe Me
Me
NH
Bu3Sn
OMe Me
N
(OAc)3Pb
OMe Me
MeO
OMe Me
Me
MeO
Me
NH
(OAc)3Pb
OMe Me
10
Isoquinoline Alkaloids
Baran Group Meeting
10/18/2006
Jun Shi
Total synthesis of isoquinoline alkaloids natural product
Brian M. Stoltz et al, J. Am. Chem. Soc., 125, 15000-150001, 2003
N Bn
N-Me-morpholine
NaBH4
O
Br
HN
N
O
O
O
1
N Bn
I
N Bn 1. TIPOTf
HN
S
Pd(PPh3)
HN
2. ICl
O
O
O
2
2. NaBH4
3. HCl
HO
N
Cbz
HO
O
OH
EA, LDA
O
N
SO2Ph
2. (MeO)2CH2
9
10
O
OH
N
O
NH2
HO
3. DIBAL
4. MsOH, PhO2SN
allyl alcohol
8
OH
Cbz
O
EtOH
O
7
O
2.CH2O,
NaBH3CN
13
HN
TsO
6
OsO4, NaIO4, TFA
OH
O
O
OH
O
N
N
13
12
11
O
O
OH
OH
N
O
Cbz
NH
OH
1. H2, Pd /C
2. (COCl)2, TEA, then
HCl, CAN
OH
O
14
N
H
O
1.Red Al, PhCH3
TsO
O
N
O
O
OEt TMSOTf
N
SO2Ph
OTIPS
O
O
O 1. HCl
Pd/C, H2
O
O
O
O
5
1.CbzCl
2. KOTMS
HN
OH
8
TsO
O
OTIPS
Cbz 1. (Boc)2OO
N
HN
O
OH
NH2
N Bn
OTs
O
O
O
B
OTIPS
O
O
4
3
O
O
OTIPS
OH
N
O
N
O
N
OH
O
OH
O
H
OH
O
Lemonomycin
N
11