structural assignment and synthesis of palau’amine
DESCRIPTION
Structural Assignment and Synthesis of Palau’amine. Toni Rizk. Beauchemin Research Group Department of Chemistry University of Ottawa. 11. 3. 1. 5. 1. Discovered in 1993 by Scheuer et al. - PowerPoint PPT PresentationTRANSCRIPT
1
Structural Assignment and Synthesis of
Palau’amine
Toni Rizk
Beauchemin Research GroupDepartment of Chemistry
University of Ottawa
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
2
Pyrrole-Imidazole Alkaloids
HN
ONH
NHN
NH
O
NHN
HN
Br
Br
Br
Br NH2
NH2
O
mauritiamine
N NH
NHN
OMe
H
H
HH
O
Br
agelastatin
HN
O
NH
O
HNN
NH
NNH2
H2N
NH
HN
Br
Br
ageliferin
NNH
N
NH
Br
Br
H2N
O
cyclooroidin
NHN
N
NHBr
Br
H2N
O
(-)-dibromoisophakellin
N
H
H
Cl
N
O
NHN
H2N
NNH
H2N
HO
H2N
palau'amine
dibromoagelaspongin
N
H
H
Cl O
NHNHN
H2N
NNH
H2N
HO
H2N
styloguanidine
N
Br
Br
NHN
N
HO
H2N O
3
Pyrrole-Imidazole Alkaloids
NNHH
N
O
NH2
NH
Br
Br
Found exclusively in marine sponges, typically:
Agelasidae
Axinellidae
Halichondridae
Involve high nitrogen content:Most have ~2:1 carbon:nitrogen atom ratio N
HNN
NH
H2N
O
NNH
N
NH
H2N
O2.2:1
Complexity proportional to number of adjacent rings
Biologically, all is hypothesized to be mapped back to a common metabolite: oroidin
4
Precedent on Pyrrole-Imidazole Alkaloid Synthesis
Alkaloid IsolatedCompounds
Publ. on Total Synthesis
Hymenialdisine (1982)
Agelastatin (1993)
Phakellin (1969)
Mauritiamine (1996)
Isophakellin (1986)
Cyclooroidin (2000)
Ageliferin (1986)
Sceptrin (1981)
Axinellamine (1999)
Styloguanidine (1995)
Palau'amine (1993)
12
4
3
1
5
1
10
9
4
3
4
9
3
0
1
1
0
0
0
0
2
0
NNH
N
NH
Br
Br
H2N
O
HN
O
NH
O
HNN
NH
NNH2
H2N
NH
HN
Br
Br
HN
O
HN
O
NH
NH
NH
HN
NH
NHBr
Br
NH2
NH2
NHN
NHN
H2N
NH2
OHH
Cl
HN
O
HN OHO
NHNH
BrBrBr
Br
Hoffmann; Lindel Synthesis 2003, 1753
2003 Review on pyrrole-imidazole alkaloids
11
3
1
5
1
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
5
Outline
Isolation and challenges of palau'amine
Introduction
Biosynthetic hypothesis
Romo synthesis of the original palau'amine core
Overman analogous synthesis
Structural revision of palau'amine
Synthesis of the revised palau'amine core
Pyrrole-imidazole alkaloids
Conclusion
Current standings and challenges
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Original structure elucidation
Cis versus trans azabicycles
6
Isolation of Palau'amine
Kinnel; Gehrken, Scheuer J. Am. Chem. Soc. 1993, 115, 3376Kinnel; Gehrken; Swali; Skoropowski; Scheuer J. Org. Chem. 1998, 63, 3281
- Discovered in 1993 by Scheuer et al.
-Isolated from the marine sponge Stylotella aurantium found in the Yap sea, east of Asia off the coast of the Philippines
- Categorized in the bisguandine pyrrole-imidazole alkaloid family.
- Shows significant antifungal, antitumor, and � �immunosuppressive activities
7
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Structural Details and Challenges
Hexacyclic bis-guanidine structure
Low C:N ratio of 1.9:1 (C17H22ClN9O2)
Fully substituted cyclopentane core
8 stereocenters
Strained cis-azabiclyclo[3.3.0]octane fragment
Unknown absolute stereochemistry
A structural revision leads to a bigger challenge (more later)
"The palau’amines, styloguanidines and konbu’acidin are some of the most structurally intr icate members of this group of marine guanidine alkaloids."
Katz; Overman T etrahedron 2004, 60, 9559
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
8
T he Original Palau'amine Family
Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Palau'amine Styloguanidine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Br
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
BrBr
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Bromopalau'amine Dibromopalau'amine Bromostyloguanidine Dibromostyloguanidine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
Br
O HNBr
Br
Konbu'acidin A
Br BrBr
9
Ef forts T owards Palau'amine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
BnN
NBn
O
OTBS
O
HO
TIPSO Ts
N
BnN
NBn
O
OTBSO
OTIPSTs
Cl
O
CbzN
HNN N
NH
O O
NH HNBn Bn
CbzN
HNN
ONH
S
CO2Me
CbzN
OMe
O
O
MeO2C
NH
NH2
SH2N
[N] R1H
R2
R3H
R4H
Cl
H
Cl H
HH
R2
R3H
R1H
ClR1
HR2
R3 H
Lovely Romo
Gin Overman
Austin
Gleason
Baran
Harran
NN
NO O
Ph
O
TBSOOTBS
Bn
N
N
NO
O
Ph
Bn
OTBS
H
10
Outline
Isolation and challenges of palau'amine
Introduction
Biosynthetic hypothesis
Romo synthesis of the original palau'amine core
Overman analogous synthesis
Structural revision of palau'amine
Synthesis of the revised palau'amine core
Pyrrole-imidazole alkaloids
Conclusion
Current standings and challenges
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Original structure elucidation
Cis versus trans azabicycles
11
Original Biosynthetic Hypothesis
Kinnel; Gehrken; Swali; Skoropowski; Scheuer J. Org. Chem. 1998, 63, 3281
HN
OH
O
N
N N
HN
NH2
O
N
HN
H2N
NH2
N
NH
H2N
NH2
N
N N
HN
NH2
ONH
N
NH2
NH2Cl+
N
H
H
Cl
N
O
NH
N
NHN
NH2
NH2
N
NH
NH2
NHO
NH
oroidin
Palau'amine
N
Cl
N
O
N
HNNH2
NH2
N
N
NH2HHO
NH2
2-amino-1-(2-aminoimidazoly l)-prop-1-ene (AAPE)
1H-Pyrrole-2-carboxylic acid
[4+2]
H
H
dehydrophakellin
HO
H
12
Retrosynthetic Analysis -Diels-Alder/ Ring Contraction Approaches
RN
BnNN
O
OTIPS
R2
PhO
OH
R1
RN
BnN
N
OTIPSO
Ph
O
H
OH
RN O
TIPSO
BnN
N
Ph
OOH
Diels-AlderRing
Contraction
Biosynthetic hypothesis-driven synthetic efforts
Lovely; Du; He; Rasika Org. Lett. 2004, 6, 735Dilley; Romo Org. Lett. 2001, 3, 1535
NN
NO O
Ph
O
TBSOOTBS
Bn
N
N
NO
O
Ph
Bn
OTBS
H Diels-AlderRing
Contraction
PhN O
BnN
NOTBS
O
Romo et al.
Lovely et al.
13
Romo Forward SynthesisPreparation of the Diels-Alder Fragments
HN
NH
HO
O
O 1. NaH, BnBrDMF, 41%
2. DIBAL-H, CH2Cl2-78°C, 84%
BnN
NBn
HO O1. MnO2
CH2Cl2, 98%
2.POEt
EtOONaH,
BnN
NBnO
O
EtO
DIBAL-HCH2Cl2-78°C, 78%
BnN
NBnOHO
HN O
O
HO
5 stepsN O
TIPSO
Ts
dienedienophile
1 2 3
45 6
N
O
O
TsNBn
BnNO
HO
Si
Ph-H, 2,6-lutidine
95°C, 4 days
N
NN
O
TIPSO Ph
O
OH
Ts
Ph
N
NN
O
TIPSO
Ph
O
OH
Ts
Ph
7a, 64%7b, 15%
Dilley; Romo Org. Lett. 2001, 3, 1535
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
CO2Et
14
N
Ph
O
Diels-Alder Regioselectivity
N
O
O
TsBnN
NBnO
OH
Si
Ph-H, 2,6 lutidine
95°C, 4 days
N
NN
O
OTIPSPh
O
HO
Ts
Ph
N
NN
O
OTIPS
Ph
O
HO
Ts
Ph
7a, 64% 7b, 15%
N
O
O
Ts
Si
BnNNBn
O
HO
N Ts
O
N N
OPh
Ph
OH 7amajor
7bminor
TIPSO
NBnN
O
NTs
OSi
Ph
ONBnN
O
NTs
OTIPS
PhOH
OH
N
O
O
Ts
Si
BnNNBn
O
HO O
NTs
OTIPS
NBnBnN
O
OHO
NTs
OSi
NBnBnN
O
OH
disf avoured orbital interact ions f avour regioisomer 7a
N Ts
OTIPSO
NOPh
HO
Dilley; Romo Org. Lett. 2001, 3, 1535
15
Key Ring Contraction
N
NN
O
OTIPSPh
O
HO
Ts
Ph
7a
1. TBSCl, Et3NDMAP, CH2Cl2
2.DMDO, CH2Cl2,MgSO4, -45°C,
then Me2S, 84%
N
NN
O
OTIPSPh
O
TBSO
Ts
Ph
OH
NCS, C6H10
CH2Cl2-45 25°C, 8h
75%
N
O
OTIPS
TsBnN
NBn
OO
Cl
8 9
Method provides access to the fully substituted cyclopentane core
Installs the desired azabicyclic system, chlorine atom and the spirocycle
Epimeric at the chlorine-bearing carbon
Only introduces 3 of the 6 required rings
Currently only accounts for 33% of the nitrogen atoms required
Dilley; Romo Org. Lett. 2001, 3, 1535
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
TBSO
16
Outline
Isolation and challenges of palau'amine
Introduction
Biosynthetic hypothesis
Romo synthesis of the original palau'amine core
Overman analogous synthesis
Structural revision of palau'amine
Synthesis of the revised palau'amine core
Pyrrole-imidazole alkaloids
Conclusion
Current standings and challenges
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Original structure elucidation
Cis versus trans azabicycles
17
Overman Retrosynthetic Strategy
N
O OTBS
PGN N HNCO2Me
SMe
ONH
S
NHCBz
Katz, Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman T etrahedron 2004, 60, 9559
MeO2C R
NH2
OTBSOPG
HO
HN
N
O
O
MeO2CO
MeO2C
TBS
HN
N
OMeO2C
O
MeO2CO
TBSHN
OHO
HN
OTBSOPG
MeO2C R
MeO2C R
NH2
OTBSOPG
HO
RCM
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H OH
N
O
N NH
NH2
NHN
NH2
OHN
H
H OH
N
O
N NPG
NH2
NPGN
NH2
OHAcO
[3+2]
18
Overman Forward Synthesis
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman T etrahedron 2004, 60, 9559
HOOPMB
1. mCPBA, CH2Cl2 (94%)
2. vinylMgBr, CuBr-SMe2THF, Me2S, Et2O-50°C rt (69%)
HOOPMB
OH PG changes
3 steps77%
HOOPMB
OTBS
OOPMB
OTBSHOPMBOTBS
NH
MeO2C
MeO
4A MS, MeCN
then NaBH(OAc)3
MeO
MeO2C NH2
Dess-MartinCH2Cl2
75% (2 steps)
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
1 2 3
45
19
Overman Forward Synthesis
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman T etrahedron 2004, 60, 9559
BOPCl, i-Pr2NEtDMAP,CH2Cl2
SEMNHO2C
Br
Br
OPMBOTBS
NMeO2C
MeO
ONSEM
Br
Br
1. DDQpH 7 buffer
CH2Cl22. Dess-Martin
CH2Cl2
OOTBS
NMeO2C
MeO
ONSEM
Br
BrH
CO2MeP
OTBS
MeOMeO
O
NaOt-But-BuOH
THF83% (3 steps)
O
NMeO2C
ONSEM
Br
Br
CO2Me
OTBS TBS
OPMBOTBS
NH
MeO2C
MeO
SEMN
BrBr
O N
MeO2C
OTBSOTBS
CO2Me
MesN NMes
RuClCl
PCy3
Ph
CH2Cl240°C, 2 days
G2 10 mol%(51%)
G2
5 6 7
89
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
20
Insuf f icient Olef in Metathesis Selectivity
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman T etrahedron 2004, 60, 9559
O
NMeO2C
ONSEM
Br
Br
CO2Me
OTBS TBS
SEMN
BrBr
O N
MeO2C
OTBSOTBS
CO2Me
CH2Cl240°C, 2 days
G2 10 mol%
Horner -Emmons
Reaction gave an inconsequential 2:1 mixture of the enoxysilane stereoisomers
Problem: Product was enriched in one enoxysilane stereoisomer and diene starting material was enriched in the other geometric isomer
Hypothesis: Ring formation was likely occuring more rapidly with one of the two regioisomers of the starting material
Solution: Deprotection of the enoxysilane to remove the unwanted mixture from starting material.
Direct olefin methathesis gave a 51% yield of the desired product, and 28% recovered starting material
+ SM (8)
9 51% 28%8
21
Overman Forward Synthesis
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman T etrahedron 2004, 60, 9559
BOPCl, i-Pr2NEtDMAP,CH2Cl2
SEMNHO2C
Br
Br
OPMBOTBS
NMeO2C
MeO
ONSEM
Br
Br
1. DDQpH 7 buffer
CH2Cl22. Dess-Martin
CH2Cl2
OOTBS
NMeO2C
MeO
ONSEM
Br
BrH
CO2MeP
OTBS
MeOMeO
O
NaOt-But-BuOH
THF83% (3 steps)
O
NMeO2C
ONSEM
Br
Br
CO2Me
OTBS TBS
OPMBOTBS
NH
MeO2C
MeO
MesN NMes
RuClCl
PCy3
Ph
G2
5 6 7
8
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
O
NMeO2C
ONSEM
Br
Br
CO2Me
O
CsF, AcOHMeCN (87%)
TBS
10
CH2Cl240°C, 2 days
G2 5 mol%(80%)
SEMN
BrBr
O N
MeO2C
OTBSO
CO2Me
11
22
En Route to "Palau'amine"...
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman T etrahedron 2004, 60, 9559
SEMN
BrBr
O N
MeO2C
OTBSO
CO2Me
NH
S
NH2H2N
EtOH, 110°C48h, 71%
N
HNN NH CO2Me
OO
OTBS
S
SEMN
BrBr
SmI2, THF/MeOH
15 min, 79% N
HNNH NH2
CO2MeO
O
OTBS
S
SEMN
BrBr
1. MeI, i -Pr2EtNDMAP, CH2Cl2, 96%2. Teoc-Cl, i-Pr2EtN,
CH2Cl2, quant
N
TeocNN NH2
CO2MeO
O
OTBS
SMe
SEMN
BrBr
N
TeocNN
OO
OTBS
SMe
SEMN
BrBr
S=C=NCbz
CH2Cl2 92%
EDCI, CH2Cl2i-Pr2EtN, 40°C
NO2
NH3ClN
N
O
NHCbzO2N
OO SiTeoc =
OSiSEM =
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
11 12 13
1416 15
NO
OTBS
TeocN N HNCO2Me
SMe
O
SEMN
BrBr
S
NHCBz93%
23
Azomethine Imine Cycloaddition
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman Tetrahedron 2004, 60, 9559
SEMN
BrBr
O N
MeO2C
OTBSO
CO2Me
NH
S
NH2H2N
EtOH, 110°C48h, 71%
N
HNN NH CO2Me
OO
OTBS
S
SEMN
BrBr
SEMN
BrBr
O N
MeO2C
OO
CO2Me
NH
S
NH2H2NTBS SEMN
BrBr
O N
MeO2C
ON
CO2Me
TBS
NH
NH2S SEMN
BrBr
O N
MeO2C HNCO2MeN
NH2
S
N
H2N
N NH CO2MeO
O
OTBS
S
SEMN
BrBr
MeO
N
HNN NH CO2Me
OO
OTBS
S
SEMN
BrBr
OTBS
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Dipolar Cycloaddit ion
24
En Route to "Palau'amine"...
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman Tetrahedron 2004, 60, 9559
SEMN
BrBr
O N
MeO2C
OTBSO
CO2Me
NH
S
NH2H2N
EtOH, 110°C48h, 71%
N
HNN NH CO2Me
OO
OTBS
S
SEMN
BrBr
SmI2, THF/MeOH
15 min, 79% N
HNNH NH2
CO2MeO
O
OTBS
S
SEMN
BrBr
1. MeI, i -Pr2NEtDMAP, CH2Cl2, 96%2. Teoc-Cl, i-Pr2NEt,
CH2Cl2, quant
N
TeocNN NH2
CO2MeO
O
OTBS
SMe
SEMN
BrBr
N
TeocNN
OO
OTBS
SMe
SEMN
BrBr
S=C=NCbz
CH2Cl2 92%
EDCI, CH2Cl2i-Pr2NEt, 40°C
NO2
NH3ClN
N
O
NHCbzO2N
OO SiTeoc =
OSiSEM =
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
11 12 13
1416 15
NO
OTBS
TeocN N HNCO2Me
SMe
O
SEMN
BrBr
S
NHCbz93%
25
En Route to "Palau'amine"...
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman Tetrahedron 2004, 60, 9559
N
TeocNN
OO
OTBS
SMe
HN
BrBr
NN
O
NHCbzNO2
1. NaBH4MeOH/THF
2. Ac2O, pyridineDMAP, CH2Cl2
TBAF, THF, 23°C8 min, 95%
N
TeocNN
O
OTBS
SMe
HN
BrBr
NN
NHCbzNO2
R1
R2
R1= H, R2= OAc 51%R1= OAc, R2= H 29%
R2
R1
epimer ization
2 steps95%
1. mCPBA, CH2Cl22. NH3, CH2Cl2 79% (two steps)
CF3COO
R1= OH, R2= H 43%R1= H, R2= OH 22%
1. h, dioxane
2. H2, Pd/C, dioxane/H2O (0.1% TFA)
N
H
H H
N
O
N N
NHCbz
NHN
SMe
OH
OH
BrBr
NO2
N
H
H OH
N
O
N N
NHCbz
NHN
SMe
OH
H
BrBr
NO2
N
H
H OH
N
O
N N
NHCbz
NHN
NH3
OH
H
BrBr
NO2
2CF3COO
N
H
H OH
N
O
N NH
NH3
NHN
NH3
R1
H
R2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
17 18a18b
1920
21
22a22b
N
TeocNN
OO
OTBS
SMe
SEMN
BrBr
NN
O
NHCbzNO2
16
PG change
2 steps92%
OO SiTeoc =
26
Summary of Overman Synthesis
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896Katz; Overman Tetrahedron 2004, 60, 9559
N
H
H OH
N
O
N NH
NH2
NHN
NH2
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
30 linear steps2.2% overall yield
Incorporates all six ringsAccounts for 7 of the 8 stereocenters
Overman's Palau'amine PrecursorsOriginally Proposed Palau'amine
OHN
H
H OH
N
O
N NH
NH2
NHN
NH2
OH
C-20 -HJ11,12= 10.7 Hz
C-20 -HJ11,12= 12.0HzJ11,12= 14.1Hz
Observed that largest JAB value was 12.0Hz and still 2.1Hz smaller than that in the proposed structure of Palau'amine
11 12 1112 1112
27
Outline
Isolation and challenges of palau'amine
Introduction
Biosynthetic hypothesis
Romo synthesis of the original palau'amine core
Overman analogous synthesis
Structural revision of palau'amine
Synthesis of the revised palau'amine core
Pyrrole-imidazole alkaloids
Conclusion
Current standings and challenges
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
?
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Original structure elucidation
Cis versus trans azabicycles
28
Proposing the Original Palau'amine Structure
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
23
45
6
8
101112
13
1516
17
18
19
20
22
MS Data:
- HRFABMS: found 420.166 calc. for C17H22ClN9O2 [MH+]- Isotope indicates presence of one Cl atom
IR Data:
3350 cm-1 (O-H and N-H) 1658 cm-1 (amide) 1700 cm-1 (guanidine hydrochloride)
NMR Data:
- Strong NOE correlation for H11-H6 and H17-H12Indicates a syn relationship
- Weak NOE correlation for H17-H11- No mention of any NOE correlation between H11-H12
Should indicate an anti relationship
Kinnel; Gehrken; Scherer J. Am. Chem. Soc. 1993, 115, 3376
H
H
29
Elucidation of the Original Cis-Structure
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
23
45
6
8
101112
13
1516
1718
19
20
22
Kinnel; Gehrken; Scheuer J. Am. Chem. Soc. 1993, 115, 3376Lowry; Riggs T etrahedron Lett. 1964, 2911
Coupling constant between H11 and H12 of 14.1Hz used for assigning the cis relative
stereochemistry
Coupling of 14.1Hz seems large for cis assignment, how can this be explained?
H
H
>>
"This coupling constant seems large, but comparable values are observed in similar ly r igid, spiroannulated
f ive-membered r ings."
H
H
30
Elucidation of the Original Cis-Structure
Kinnel; Gehrken; Scheuer J. Am. Chem. Soc. 1993, 115, 3376Lowry; Riggs T etrahedron Lett. 1964, 2911
OO
OO
OAcAcO
AcO
OAc
O
O
OAc
OAc
OO
AcOH HHH
H
OAcLeucodrin
tetra-acetate
X-Ray shows => Lactone Ring B: JAB = 8.3Hz trans
A BB
A
Lactone Ring A, couplings of 7.8Hz and 12.4Hz were observed.Similarity in coupling magnitude between ring A and B leads
to the assumption that the 7.8Hz coupling is also trans
7.8Hz
8.3Hz
Conclusion: Protons with JAB = 12.4 Hz in lactone ring A must have cis relationship
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Palau'amine
This also means that the JAB = 14.1Hz observed in Palau'amine must indicate a cis relationship between the two bridgehead protons
Conclusion: cis-azabicyclo[3.3.0]octane fragment
12.4Hz
31
Cis- Versus T rans-Fused Azabicyclo Systems
Kinnel; Gehrken; Scheuer J. Am. Chem. Soc. 1993, 115, 3376Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586
N
H
H
Cl
NH2
1112 N
H
H
Cl
NH2
1112
cis-fused rings trans-fused rings
Thermodynamically cis-fused 5-5,bicycles are far more stable
cis-fused system of Palau'amine is ~27.3 KJ/mol (6.52 KCal/mol) more energetically favoured
Intuitively, the assignment of the cis system seems most probable and was accepted for over a decade
T wistedConformation
Envelope Conformation
32
Discovery of New Palau'amine Congeners
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH
BrBr
O HNBr
Br
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
BrBr
O HNBr
Br
Originally Accepted Palau'amine
1993
tetrabromostyloguanidine(carteramine A)
2007
tetrabromopalau'amine(konbu'acidin B)
2007
isolated from marine sponge styl issa car ibica
Characterization of the two new congeners showed inverted configurations at C12 and C17
Shows a trans-azabicyclo[3.3.0]octane system
Does this hold for all the Palau'amines ???
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Buchanan; Carroll; Addepalli; Avery; Hooper; Quinn J. Org. Chem. 2007, 72, 2309Grube; Köck Angew. Chem. Int. Ed. 2007, 46, 2320Kobayashi; Kitamura; Nagai; Nakao; Fusetani; van Soest; Matsunaga T etrahedron Lett. 2007, 48, 2127Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586 (Minireview)
33
Structural Assignment of New Palau'amine Congeners
Grube; Köck Angew. Chem. Int. Ed. 2007, 46, 2320Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586 (Minireview)
tetrabromostyloguanidine
Combining NMR and computational techniques allowed proper assignment of tetrabromostyologuanidine
O HNBr
BrR =
Computational Experiments
Rotated the dihedral angle in 5° increments from -180° to +180° and predicted the corresponding coupling constant
Plotted the coupling constant against the dihedral angle
The two maxima showed that at 180°, the coupling constant was highest (13.1Hz)
Indicates that a trans relationship (in this system) affords the largest coupling constant
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH
BrBr
R
HN
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH
BrBr
R
H
Köck and Grube:
Cou
plin
g co
nsta
nt (H
z)
Dihedral Angle (°)
34
Structural Assignment of New Palau'amine Congeners
Grube; Köck Angew. Chem. Int. Ed. 2007, 46, 2320
NOE Experiments
N
H
H
ClR
NH
1112
R
HN
H
H
ClR
NH
R
H
17
Köck and Grube:
cis- trans-
18
Inte
rpro
ton
dist
ance
(A)
H11/17 H11/H18 H12/H17
Black bars: Original (cis) configurationWhite bars: Revised (trans) configuration
Grey bars: Experimental values
35
Structural Assignment of New Palau'amine Congeners
Grube; Köck Angew. Chem. Int. Ed. 2007, 46, 2320
NOE Experiments
Largest interproton distance value observed between H11 and H17 in both systems (cis / trans)
Large interproton distance between H11 / H18 for cis system but small interproton distance for trans
Large interproton distance between H12 / H17 for cis systembut small interproton distance for trans
The two bridgehead protons (H11 and H12) have different interproton distances from H17, suggesting a trans relationship
N
H
H
ClR
NH
1112
R
HN
H
H
ClR
NH
R
H
17
Köck and Grube:
cis- trans-
18
Inte
rpro
ton
dist
ance
(A)
H11/17 H11/H18 H12/H17
Black bars: Original (cis) configurationWhite bars: Revised (trans) configuration
Grey bars: Experimental values
36
Structural Assignment of New Palau'amine Congeners
Buchanan; Carroll; Addepalli; Avery; Hooper; Quinn J. Org. Chem. 2007, 72, 2309
Konbu'acidin B2007
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
BrBr
Quinn et al.
O HNBr
Br
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
Br
O HNBr
Br
Konbu'acidin A1997
Nearly identical 1H and 13C NMRs were observed between these two palau'amine congeners
Differences: - Dibromo fused pyrrole ring versus monobrominated- Stereochemistry at C12 and C17 were inversed
NOE correlations allowed contradiction of the assignment for the original isolation of all the Palau'amine congeners
37
Overman's Experimental Evidence
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Katz; Overman J. Am. Chem. Soc. 2007, 129, 12896
N
H
H OH
N
O
N NH
NH2
NHN
NH2
H
OH
Palau'amines1993
C
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H OH
N
O
N NH
NH2
NHN
NH2
OH
H
Palau'amines2007
D
Overman PrecursorC-20 -H
A
Overman PrecursorC-20 -H
B
protons
11/1211/1311/1813/1813/18
2.23.4n.o3.1n.o.
2.33.3n.o.2.9n.o.
2.34.13.33.83.6
3.02.72.53.52.5
3.02.72.63.42.5
3.02.62.83.32.5
B1A1 C2 trans-B2trans-A2 D2
1 Experimental Data. 2 Computational Experiments
Interproton Distances (A)
Experimental 1,3 interproton distances for the precursors (C,D) do not match with thoseof Tetrabromostyloguanidine (Carteramine A)
Carteramine1
2.52.3
2.6
H
Very small interproton distances H11/H12 for precursors C and D suggest a strong NOE correlation not mentioned in original isolation
H
38
Structural Revision of Palau'amine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
H
The isolation and characterization of carteramine A and Konbu'acidin B allowed detailed study of Palau'amine congeners and provided an important structural revision
Conclusion: trans-azabicyclo[3.3.0]octane system and inversion of the chlorine-bearing carbon
Newly Revised Palau'amine
Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586Buchanan; Carroll; Addepalli; Avery; Hooper; Quinn J. Org. Chem. 2007, 72, 2309Grube; Köck Angew. Chem. Int. Ed. 2007, 46, 2320Kobayashi; Kitamura; Nagai; Nakao; Fusetani; van Soest; Matsunaga Tetrahedron Lett. 2007, 48, 2127
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
BrBr
O HNBr
Br
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH
BrBr
O HNBr
Br
N
H
H OH
N
O
N NH
NH2
NHN
NH2
H
OH N
H
H OH
N
O
N NH
NH2
NHN
NH2
OH
H
39
Outline
Isolation and challenges of palau'amine
Introduction
Biosynthetic hypothesis
Romo synthesis of the original palau'amine core
Overman analogous synthesis
Structural revision of palau'amine
Synthesis of the revised palau'amine core
Pyrrole-imidazole alkaloids
Conclusion
Current standings and challenges
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Original structure elucidation
Cis versus trans azabicycles
40
Structural Re-Assignment Repercussions
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
Bultman; Ma; Gin Angew. Chem. Int. Ed. 2008, 47 , 6821
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
With over 30 publications depicting attempts at fractional syntheses of Palau'amine, the structural revision is a very big drawback
O
O
HH
Cyclopentane core for originallyaccepted Palau'amine
Cyclopentane core for revised structureof Palau'amine
Gin et al. :
Syn relationship between amine and chlorine substitutions
Cis-proton orientation for the azabicyclic system
Anti relationship between amine and chlorine substitutions
T rans-proton orientation for the azabicyclic system
H
H
HHCl
O
O NBoc
O
OBnH
HCl
HNHBoc
O O
BnO
HO
41
Initial Progress T owards Palau'amine
Bultman; Ma; Gin Angew. Chem. Int. Ed. 2008, 47 , 6821
O
O
HH H2O2, Na2CO3
EtOH, 0°C95%
O
O
HH
O
NaOH, EtOH
23°C, 60%
HCO2Et
H
H
O
1 2 3
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
LiHMDS, THF-78°C, 60%
BOMCl, -78°C53%
CO2EtH
H
O
OBn28:78
CO2EtH
H
O
OBn
HH
HOBnO
EtO2C
55 4
42
T he Favorskii Rearrangement
Favorskii J. Prakt. Chem. 1895, 51, 533
OXH
OR
XO O ORO
OOR
OR
OR
OX O
OROR
H
O
OO
O
OOH
HCO2Et
H
H
O
EtO
OOHEtO
O
43
Initial Progress T owards Palau'amine
Bultman; Ma; Gin Angew. Chem. Int. Ed. 2008, 47 , 6821
O
O
HH H2O2, Na2CO3
EtOH, 0°C95%
O
O
HH
O
NaOH, EtOH
23°C, 60%
HCO2Et
H
H
O
1 2 3
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
LiHMDS, THF-78°C
BOMCl, -78°C53%
CO2EtH
H
O
OBn28:78
CO2EtH
H
O
OBn
HH
HOBnO
EtO2C
55 4
44
W oodward-Katz Skeletal Rearrangement
Woodward; Katz Tetrahedron 1959, 5, 70
HHH
OHH
H HHH
OHH
H HH
H
HOHH
HHH
OHH
H HH
H
HOHH
45
Initial Progress T owards Palau'amine
Bultman; Ma; Gin Angew. Chem. Int. Ed. 2008, 47 , 6821
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
CO2EtH
H
O
OBn
2) PBu3, CCl490°C, 82%
1) PhSeH, AcOHEtOH 0°C;
then NaBH4, 70% CO2EtH
HOBn
HPhSe
HCl
6
then Et3N 90°C, 92%
mCPBA, -20°C, CH2Cl2 CO2Et
H
HOBn
HCl
7
CO2EtH
HOBn
HClH
H
HOBn
EtO2CCl H
88
H
H
HCl
HBocHN
O
O
BnO OH10 steps
Access to the original Palau'amine core
4
46
T weaking the Conditions
Bultman; Ma; Gin Angew. Chem. Int. Ed. 2008, 47 , 6821
HH
HOBnO
EtO2C
5
CO2EtH
H
O
OBn
72:28
4
Original core Revised core
1) Al(OiPr)3, iPrOH reflux
2) SOCl2, CH2Cl245°C, 97%
HH
HOBn
EtO2CH Cl
HH
HOBn
EtO2CCl H
7 steps
epimers
H
H HHCl
O
O NBoc
O
OBnH
HClH
NHBoc
OO
OBnHO
10 steps
H
H
N
H
HCl
N NH
NH2
OH
NH2
R
Original Palau'amineCore
N
H
HCl
N NH
NH2
OH
NH2
R
Revised Palau'amineCore
47
SummaryThe Revised Palau'amine Family
Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Palau'amine Styloguanidine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Br
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
BrBr
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Bromopalau'amine Dibromopalau'amine Bromostyloguanidine Dibromostyloguanidine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
Br
O HNBr
Br
Konbu'acidin A
Br BrBr
48
SummaryThe Revised Palau'amine Family
Köck; Grube; Seiple; Baran Angew. Chem. Int. Ed. 2007, 46, 6586
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Palau'amine Styloguanidine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Br
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
BrBr
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH2
Bromopalau'amine Dibromopalau'amine Bromostyloguanidine Dibromostyloguanidine
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
Br
O HNBr
Br
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH
Br
O HNBr
Br
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH
Br
O HNBr
Br
BrBr
Konbu'acidin A Konbu'acidin B Carteramine A
Br BrBr
49
Conclusion
NH2
O
Y
Cl
NR2Cl
NRN
R2N
O
XNR2X
Gleason
OH
CO2MeCO2R
CO2Me
NHCbzHO
N3
OTBS
N3
Carreira
Structural diversity and complexity in pyrrole-imidazole marine alkaloids
Total syntheses for this family of alkaloids is on the rise but a publication on the completesynthesis of Palau'amine has yet to be reported
A structural revision of Palau'amine and its congeners proposes a strained trans-azabicyclic[3.3.0]octane moiety
Ongoing challenges involve assembly of the central cyclopentane ring
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
N
H
HCl
N
O
N NH
NH2
NHN
NH2
OH
NH2
50
Prof . André Beauchemin
Joseph MoranJoffré Bourgeois
Pamela CebrowskiIsabelle Dion
Hao PengJean-Grégoire Roveda
Francis LoiseauJennifer Pfeiffer
Ashley HuntPeter Ng
Éric BilodeauLei Zhang
Catherine SéguinChristian Clavette Jean-Philippe Wan
Acknowledgments
51
52
N
H
H
Cl
N
O
N NH
NH2
NHN
NH2
OH
NH2
BrBr
N
H
H
ClO
HN N NH
NH2
NHN
NH2
OH
NH
BrBr
O HNBr
Br