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Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
NH
NH
O
HN
O
BrBr
Discorhabdin C
NH
NH
O
HN
O
Br
Discorhabdin A
S
H NH
NH
O
HN
O
Br
S
H
Discorhabdin B
NH
NH
O
HN
O
Br
Discorhabdin E
NH
NH
O
N
O
Discorhabdin D
H
NH
NH
O
HN
O
Br
Discorhabdin G
NH
N
O
HN
O
Br
Discorhabdin P
Br
NH
NH
O
HN
O
Br
S
H
Discorhabdin Q
Me
NH
NH
O
HN
O
S
H
Discorhabdin R
O
NH
NH
O
HN
O
Br
S
NH
NH
O
NH
O
Br
S
Discorhabdin W
NH
NH
O
HN
O
BrBr
14-bromo-Discorhabdin C
Br
NH
NH
O
HN
OH
BrBr
Br
14-bromo-3-dihydro-7,8-dehydro-Discorhabdin C
NH
NH
O
N
O
Br
1-amino-Discorhabdin D
H
H2N
NH
NH
O
N
O
Br
1-methoxy-Discorhabdin D
H
MeO
NH
NH
O
HN
O
Discorhabdin I
S
H NH
NH
O
N
O
Discorhabdin L
S
H
HO
NH
N
O
HN
O
Br
MeS
Discorhabdin S
NH
N
O
HN
O
Br
MeS
Discorhabdin T
Representative Structures of the Discorhabdin Alkaloid Family:
S
H
For a comprehensive review see: Y. Harayama, Y. Kita. Curr. Org. Chem. 2005, 9, 1567-1588.
Paul KrawczukBaran Group Meeting The Discorhabdin Alkaloids
NH
NH
O
HN
O
BrBr
Discorhabdin C
NH
NH
O
HN
O
Br
S
H
Discorhabdin B
NH
NH
O
HN
O
Br
S
NH
NH
O
NH
O
Br
S
Discorhabdin W
Proposed Biosynthesis of the Discorhabdin core:M. Munro, J. Nat. Prod. 1995, 58, 306-311.
NH
COOH
NH
NH2
NH2
[O]NH
NH2
OH
NH
NH2
O
[O]
OOH
NH
HN
O [O]
OHH3N
NH
HN
O
ONH
HN
O
HO
NH
Makaluvamine D
Sulfur Insertion
NH
HN
O
HO
NH
S
Makaluvamine F
cyclization
cyclization
light
tyramine
tryptamine
OCOCF3
Ph
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
First Sythetic Approach to the Discorhabdin Alkaloids: Y. Kita et al Tet. Lett. 1989, 30, 1119-1120.
OH
NH2
O
O
MeO
EtOH
O
O
OH
HN
MeO
TMSO
O
O
OTMS
HN
DCM
PhI(OCOCF3)2O
O
O
NH
O
O
OMe
HN
PhI(OCOCF3)2O
O
OMe
NH
CF3CH2OH
CF3CH2OH
100%
PhI(OCOCF3)2 (PIFA)
CF3CH2OH
O
O
O
NH
32%
86%
O
O
OR
NH
R=H
R=TMS
O
O
O
NH
O
O
OTMS
NH
PIFA
PIFA
I
IPh
OCOCF3
O
O PhI(OCOCF3)2O
O
O
NH
CF3CH2OH
86%NEt
NEt
AcO AcO
O
O
OTMS
HN
PhI(OCOCF3)2O
O
O
NH
CF3CH2OH
42%
Br BrBr Br
53%
O
O
OTMS
HN
NEt
AcO
OTMS
NH
PhI(OCOCF3)2O
O
O
NH
CF3CH2OH
71%
EtN
AcO
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
First Total Synthesis of Discorhabdin C: Y. Kita et al J. Am. Chem. Soc. 1992, 114, 2175-2180.
NH
NH
O
HN
O
BrBr
Discorhabdin C
Route A
Route B
NH
NH
O
O
O
BrBr
NH
NH
O
HN
OH
BrBr
NH
NH
O
O
OH
BrBr
NH
NH
O
O
OH
BrBr
NH2
NH
O
OOH
BrBr
MeO
OH
CHO
MeO
OBn
MeO NH
CO2H
1) BnBr, K2CO3, EtOH, Reflux
2) N3CH2CO2Et, NaOEt, EtOH
1) Xylene Reflux
2) KOH, EtOH, Reflux
OBn
MeO
CO2Et
N3
Copper Chromite, quinoline, 215°C
OBn
MeO NH
N I-1)
2) MeI, 0°C
3) NaCN, H2O, 80°C
OBn
MeO NH
CN
OBn
MeO NH
1) H2, Raney Ni/NH3/EtOH
2) CF3COSEt,NaOMe
NHCOCF3 1) H2, Pd/C, EtOH
2) Fremy's Salt
O
MeO NH
NHCOCF3
O
OH
BrBr
NH2•HBr
TEA, Reflux
O
NH
NH
NHCOCF3
O
O
BrBr
NHR
NHR
NHR
O
NH
NH
NHCOCF3
O
OH
BrBr
OMe
OTMS
DCM
O
NH
NH
NHCOCF3
O
OTMS
BrBr PIFA,CF3CH2OH, R.T.
XNH
NH
O
HN
O
BrBr
Discorhabdin C
Intermediate A
73%68%
36%
78%
59%
58%
58%
N
O
SO3NaNaO3S
Fremy's Salt Review: Chem. Rev. 1971, 71, 229-246.
NHR
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
[The First] Total Synthesis of Discorhabdin C: Y. Kita et al J. Am. Chem. Soc. 1992, 114, 2175-2180.
NH
NH
O
HN
O
BrBr
Discorhabdin C
Route A
Route B
NH
NH
O
O
O
BrBr
NH
NH
O
HN
OH
BrBr
NH
NH
O
O
OH
BrBr
NH
NH
O
O
OH
BrBr
NH2
NH
O
OOH
BrBr
MeO
NHR
NHR
NHR
O
MeO NH
NHTEOC
O
X
TEOC=CO2(CH2)2TMS
Intermediate A
TsCl, t-BuOK, THF
O
MeO NTs
NHTEOC
O
N
MeO NTs
O
92%
Anhydrous TsOHMeCN
OH
BrBr
NH2•HBr
NaHCO3, EtOH, Reflux N
NH
NTs
O
OH
BrBr
51%
N
NH
NTs
O
OH
BrBr
OMe
OTMS
DCM
N
NH
NTs
O
OTMS
BrBr
NH
NH
O
HN
O
BrBr
Discorhabdin C
PIFA,CF3CH2OH, R.T.
42%
NHR
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
The Preparation of the Aza-Spirobicyclic System of Discorhabdin C via an Intramolecular Phenolate Alyklation: G. Kubiak, P. Confalone, Tet. Lett. 1990, 31, 3845-3848.
Ba(OH)2, Me2SO4
OH
OH
Pd/C, H2, DMF
OMe
OMe
Br2, HOAc, Fe
OMe
OMe
BrMOMO B(OH)2
Pd(Ph3P)4, Na2CO3, PhMe
92%85%
83%
OMe
OMe
MOMO
CAN
MeCN
O
O
MOMO
94%
1) HCl, 92%
2) Py•Br2•HBr, 87%
3) MOMCl, Base, 67%
O
O
MOMO
Br
Br
Br
OHH2N
2) MsCl, Py, DCM
67%
1)O
O
MOMO
Br
Br
NH
MsO
6N HCl
90%
O
O
HO
Br
Br
NH
MsO
t-BuOK
DMF, 80°C
O
O
O
BrBr
NH
33%
The Use of Hetrocyclic Chemistry in the Synthesis of Natural and Unnatural Products: Discorhabdin C P. Confalone, J. Het. Chem. 1990, 27, 31-46.
OH
CHO
OMe
1) Br2, HOAc2) Me2SO4
OMe
CHO
OMe
Br
80%
1) N3CH2CO2Me, NaOMe, 75%
OMe
OMe
Br
NH
CO2Me
MOMO B(OH)2
Pd(Ph3P)4, Na2CO3, PhMe
78%
OMe
OMe
NH
CO2Me
MOMO1) NaOH2) Cu, Quinoline3) POCl3, DMF
70%
5) HCl
6) Py•Br2•HBr
4) CAN, MeCN
O
O
NH
HO
Br
Br
CHO
71%2) Xylene, 140°C
O
O
NH
HO
Br
Br
CHO 1) MOMCl, DCM2) HO(CH2)2NH2, DMF
3) MsCl, Py, DCM
O
O
N
MOMO
Br
Br
CHO
MOM
1) 6N HCl, THF, 96%
2) tBuOK, DMF, 34%
MsOHN
O
O
N
O
BrBr
CHO
MOM
NH
1) CH3NO2, NH4OAc
2) NaBH4
O
O
N
O
BrBr
MOM
NH85%
NO2
Discorhabdin CX
O
O
i-PrO
i-PrO
Li OBn OH
O
i-PrO
i-PrO
OBn TFAA
Oi-PrO
BnO
O
79%
NTs
Li
OHi-PrO
BnO
O
TsN
50%
heat
i-PrO
BnO
NTs
OH
OH
FeCl3
i-PrO
BnO
NTs
O
O
76%
48%
An alternative squaric acid approach:
100%91%
Br
Br
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
Transition Metal-Diene Complexes in Organic Sythesis: Iron Mediated Approach to the Discorhabdin and Prianosin Alkaloids: H. Knölker, K. Hartmann, Synlett 1991, 428-430.
OMe
Fe(CO)3
O
NO2NAc
OMe
H2N
OMe
BF4
NAc
OMe
OMe
NH
OMe
(CO)3Fe
MeCN-20°C
O
NAc
OMe
OMe
NH
MeO
(CO)3Fe
52%
34%
Synthetic Studies on Tetrahydropyrroloquinoine-containing Natural Products: Synthesis of Discorhabdin C, Batzelline C and Isobatzelline C: S. Yamamura et al. Tetrahedron 1994, 2017-2028.
CHO
OMe
MeO NO2
1) Fe, HCl
2) CbzCl, Na2CO3
CHO
OMe
MeO NHCbz67%
1) Jones [O]2) CDI
3) NaN3, then !4) TMS(CH2)2OH
81%
NHTeoc
OMe
MeO NHCbz
1) H2, Pd/C
2) PhCHO, NaBH3CN
NHTeoc
OMe
MeO NHBn81%
O O
OEtNHTeoc
OMe
MeO
Cl
NBn
O
OEt
85%
1) H2, Pd-Black, HClO4
2) KOH, then DCC
OMe
MeO NH
O
HN
22%
1) BH3•SMe2
2) CAN51%
O
MeO NH
N3,5-dibromotyramine
74%
O
NH
NH
N
OH
BrBr
LiClO4
constantcurrentelectrolysisat 3 mA
O
NH
NH
N
O
BrBr
O
NH
NH
N
OH
Br
Br
24% 6%Discorhabdin C
Synthetic of 7,8-Dimethoxy-2-oxo-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline: A key Intermediate en Route to Discorhabdin C: M. Makosza et al. Synthesis 1997, 1131-1133.
OH
NO2
NO2
MeO 1) PhOCH2CN, t-BuOK, DMF
2) Me2SO4, NaHCO3, acetone
66%
OMe
NO2
NO2
MeO
CN
O
OEtBr
K2CO3MeCN
69%
OMe
NO2
NO2
MeO
CN
OEt
O
H2/PdCl2/Fe, EtOH, AcOH
4 days, 48%HN
NH
OMe
MeO
O
HN
NH
OMe
MeO
O
Discorhabdin C
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
A Biomimetic Approach to the Discorhabdin Alkaloids: Total syntheses of Discorhabdins C and E and Dethiadiscorhabdin D: K. Aubart, C. Heathcock, J. Org. Chem. 1999, 64, 16-22.
NTs
O
O
tyramine, MeCNNTs
O
O
NH
HO
TsN
O
O
NH
HO2:1
91%
CuCl2•2H2O, TEA, O2, MeCN
93%
NTs
O
O
NH
O
KOH, MeOH
NaOMe, MeOH
NH
O
O
NH
O
NH
O
O
NH
HO83%X
NH
OMe
OMe
1) (COCl)2, HNBn2, Et2O
2) LiAlH4, Et2O3) NaH, TsCl, THF
53%NTs
OMe
OMe
NBn2
2) Boc2O, DCM3) CAN, MeCN, H2O
1) H2, Pd(OH)2, EtOH
NTs
O
O
NHBoc
1) tyramine, O2, MeCN
49%NTs
O
O
NH
HONHBoc
+ other regioisomer
(3:2)
95%
NTs
O
N
X
TFA
NTs
O
O
NH
HONH3
X
NTs
O
NH
HON
OH
MeO NO2
1) BnBr, K2CO3, DMF2) Fe, HCl, H2O3) ICl, Et2O, Na2CO3
4) BrCHCH=CHCN5) 5% Pd(OAc)2, P(Ar)3, TEA, DCM
OBn
MeO NH
CN
53%
1) LiAlH4, Et2O2) Boc2O, DCM3) Ts2O, NaH, DMF
4) H2, Pd/C, MeOH5) Fremy's Salt, Acetone/H2O
50% O
MeO NTs
NHBoc
O
1) TFA, DCM
O
MeO NTs
N
NH2
HOR1
R2
O
NTs
N
NH
HO
R1
R2
NaHCO3, EtOH
46-62%
O
NTs
N
NH
HO
R1
R2
3 equiv CuCl2, TEA, O2, MeCN
O
NTs
N
NH
O
R1R2
81-90%
R1=R2=HR1=R2=BrR1=H; R2=Br
NaOMe, MeOH
67-80%
O
NH
N
NH
O
R1R2
Discorhabdin EDiscorhabdin C
Paul KrawczukBaran Group Meeting The Discorhabdin Alkaloids
A Biomimetic Approach to the Discorhabdin Alkaloids: Total syntheses of Discorhabdins C and E and Dethiadiscorhabdin D: K. Aubart, C. Heathcock, J. Org. Chem. 1999, 64, 16-22.
O
NH
N
NH
O
H2, Pd/C, MeOH5 Min
O
NH
N
NH
O
PhNMe3Br369% CHCl3/TFA
O
NH
N
NH
OBr
Basic Alumina
O
NH
N
NH
O
Formal Total Synthesis of Damirones A and B, Batzelline C, Isobatzelline C, Discorhabdin C, and Makaluvamines A-D: J. Joule et al. J. Org. Chem. 1997, 62, 568-577.
N
MeMeO
MeO
fuming HNO3
N
MeMeO
MeO
NO2
N
CHOMeO
MeO
NO2I2, t-BuI, FeCl2 80°C
DMSO, TFAN
CH(OMe)2
MeO
MeO
NO2
MeOH, HCl, refluxBH3•THF, then REDALClCO2Me N
CH(OMe)2
MeO
MeO
NO2
CO2Me
H2, Pd/C, EtOH
N
CH(OMe)2
MeO
MeO
NH2
CO2Me
1) 1 N HCl, THF, 55°C
N
MeO
MeO
TsN
CO2Me
2) Bu4NHSO4, NaOH, TsCl
N
OMeMeO NTs
MeO2C
7% overall
NH
CH(OMe)2
MeO
MeO
NH2
Cl
1N HCl, THF, 40°C
N
O
MeO
HN
64%
Direct Synthesis of N,O-Acetal Compounds as Key Intermediates of Discorhabdin A: Y. Kita et al. Chem. Eur. J. 2006, 12, 4893-4899.
R3 R2
HO HNR1
C6F5I(OCOCF3)2 (2 equiv)MS 3Å
MeCN/MeOH10:1
R2
HNR1
MeOO R2
HO HNR1MeCN/MeOH
10:1
R2
HNR1
MeO
reflux refluxO
NH
N
NH
O
OH
Br
MeCN/MeOH10:1
NaHCO3, RTO
NH
N
NH
O
MeO
Br
Discorhabdin A
C6F5I(OCOCF3)2 (2 equiv)MS 3Å
C6F5I(OCOCF3)2 (2 equiv)MS 3Å
79%
Paul KrawczukBaran Group MeetingThe Discorhabdin Alkaloids
The First Total Synthesis of Discorhabdin A: Y. Kita et al. Angew. Chem. Int. Ed. 2002, 41, 348-350. and Y. Kita et al. J. Am. Chem. Soc. 2003, 125, 11235-11240.
NH
NH
O
HN
O
Br
Discorhabdin A
S
H
NH
NH
O
HNHO
Br S
NH
NH
O
HN
O
Br
RS NH
NH
O
HN
OH
Br
RS
NH
O
HN
MeO
OH
NH3
CO2Me
TrCl, TEA, DMF
100%
OH
NHTr
CO2Me
NBS, DMF
65%
OH
NHTr
CO2Me
Br
NTs
O
N
MeO
1) 0.1N HCl, MeOH
2)
OH
NH
Br
NTs
O
HN1) DIBAH, DCM, -78°C
2) TBSCl, DBU, DCM
OTBS
NHTr
Br
OTBS OTBS
TBAF, THF
100%
OH
NHTr
Br
OTBS
84%
54%
PIFA, MK10
CF3CH2OH, 30min45%
O
NH
Br
NTs
O
HN
OTBS
O
NH
NTs
O
HN
OTBS
Br
(3:2)desired
1) BF3•OEt22) HBr/AcOH
-78-4°C
O
NH
NTs
O
HN
O
~80%
exclusively
1) BF3•OEt22) HBr/AcOH
-78-4°C~80%
O
NH
NTs
O
HN
O
exclusively
Br Br
easily separable
1) BF3•OEt2
O
NH
MeO
Br
NTs
O
N2) Pb(OAc)4 DCM/MeOH
p-MeOBnSHBF3•OEt2
thenHBr/AcOH
O
NH
PMBS
Br
NTs
O
N
NH
NTs
O
HN
O
Br
S
H NH
NTs
O
HN
O
S
H
X
X=Br (trace)X=H (32%)
22%
NaOMe, MeOH 61%
NH
NH
O
HN
O
Br
(+) Discorhabdin A
S
H
![The Discorhabdin Alkaloids - Scripps Research...O3S SO3Na Fremy's Salt Review: Chem. Rev. 1971, 71, 229-246. NHR Baran Group Meeting The Discorhabdin Alkaloids Paul Krawczuk [The First]](https://img.dokumen.tips/doc/110x75/60b57445c197a047db016de1/the-discorhabdin-alkaloids-scripps-research-o3s-so3na-fremys-salt-review.jpg)
