1 diazonamide a: the long story of a misunderstood molecule seminar presented by elisia villemure...
DESCRIPTION
3 Why Is this Molecule So Interesting? Diazonamide A has a IC 50 of 2-5 nM against 4 human cancer cell lines (Diazonamide A is more potent than Diazonamide B) Molecule is trapped as a single atropisomer because of its rigidity Macrolactam unit Macrocyclic Heterocyclic core Quaternary center at the center of the molecule Over the years, many groups focused their efforts towards the synthesis of Diazonamide A. Only K. C. Nicolaou’s and P. G. Harran’s groups had been able to complete the total synthesis of the molecule. Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303 Initially proposed structureTRANSCRIPT
1
Diazonamide A: The Long Story of a Misunderstood Molecule
Seminar presented by Elisia VillemureFebruary 14, 2008
2
The Origin of Diazonamide
Isolated from the colonial ascidianDiazona angulata
Collected from the ceilings of cavesalong the northwest coast of SiquijorIsland in the Philippines
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
3
Why Is this Molecule So Interesting?
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
A B
C
D
EFG
12
10
11
25
27HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
A B
C
D
EFG
12
10
11
25
27
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
A B
C
D
EFG
12
10
11
25
27HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
A B
C
D
EFG
12
10
11
25
27
Diazonamide A has a IC50 of 2-5 nM against 4 human cancer cell lines (Diazonamide A is more potent than Diazonamide B)
Molecule is trapped as a single atropisomer because of its rigidity
Macrolactam unit
Macrocyclic Heterocyclic core
Quaternary center at the center of the molecule
Over the years, many groups focused their efforts towards the synthesis of Diazonamide A. Only K. C. Nicolaou’s and P. G. Harran’s groups had been able to
complete the total synthesis of the molecule.
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
Initially proposed structure
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
A B
C
D
EFG
12
10
11
25
27
4
Structure Determination of Diazonamide A and B
Structures determined by William Fenical (Scripps Institution of Oceanography)And Jon Clardy (Cornell University) in 1991
Diazonamide A Diazonamide B
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
H2NO
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOHBr
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
5
Strategy for Structure Elucidation
Purecompound
Molecularformula
Functionalgroups
Substructures
Very secure3D molecular
structure
MS, NMR
NMR, IR
UV
NMR
X-Ray
Insaturationnumber
Reasonable3D molecular
structure
New 2Dmolecularstructure
List ofworking 2Dstructure
Working 2Dstructures
Draw all isomers
NMR, MS, IR, UV
NMR
Molecularmodeling
Total synthesis
Jaspars, M Nat. Prod. Rep. 1999, 16, 241 Pretsch, E.; Toth, G.; Munk, M. E. ; Baddertscher, M. Computer-Aided Structure Elucidation, Wiley-VCH 2002, 279 p.
6
Evidence of the Presence of an Hemiacetal in Diazonamide A and B
HETCOR: Correlation between H at 6.46 ppm and C11 (106.6 ppm)
J= 3.5 HzD2O exchangeable proton
H 6.46 ppm
RNO
HN
Me MeH
O
N
ONH
ClO
N Cl
OOH H
H10
11
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
7
Evidence on the Structure of Diazonamide A and B
Diazonamide A Diazonamide B
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
H2NO
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOHBr
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
Similarity in the 2 structures
1H, 13C NMR, UV and IR indicate an identical polycyclic nucleus
UV shows evidence of their high degree of unsaturation
8
Evidences on the Structure of Diazonamide A and B
Diazonamide A Diazonamide B
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
H2NO
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOHBr
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
MS (M + H – H2O): C40H35N6O6Cl2 C35H24N5O5Cl2Br
+ 5 Carbons+ 11 Hydrogens+ 1 Nitrogen+ 1 Oxygen
+ 1 Bromine
An valine extra residue fits the differences in the molecular formula and coincides with NMR assignment
9
Crystal Structure of Diazonamide B
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
H2NO
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOHBr Br
O
Cl
HN
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OBr
O
Br
Amorphous solid Crystalline solidHemiacetal becomes
an acetal
Pyridine
Mass spectroscopy of Diazonamide A and B
gives M+ -H2O
10
First Synthesis by Harran’s GroupIn 2001, P. G. Harran published the first synthesis of ‘’Diazonamide A’’.
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
24 step synthesis
Spectroscopic data didn’t match the natural product
assignment!!!
Revision of the structure is proposed!
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4765
11
Structural Misassignment in Literature
NCN
O
O
AcO
OAc
OH
OAc
Me
HONN
O
O
AcO
OAc
OH
OAc
Me
HO
NH HN
O Me
NNH
O
Me
OMe
HO
OAc
Me
O
AcO
OH
MeMe
NH HN
O Me
NNH
O
Me
OMe
HO
OAc
Me
O
AcO
OH
MeMe
A search in the literature between January 1990 to April 2004 revealed 300 structural revisions of natural products
Kinamycin C:
(+)-tolyporphin A:
Nicolaou, K. C. Angew. Chem., Int. Ed. 2005, 44, 1012
Me H
HOO
O
Me
OH
Me
Wiedemannic Acid
Sauer, E., Barriault, L. Org. Lett. 2004, 19, 3329
12
Diazonamide Structure Revision In 2001, P. G. Haran’s group published the structure revision of Diazonamide
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
O
Dehydrated form
Mass spectroscopy and X-Ray appeared to coincide with the dehydrated form
Originally proposed structure
13
X-Ray Crystallography
X-Ray generator Crystal Diffraction pattern
Incident X-Ray
Scattered X-Ray
NucleusElectron cloud
Atom
Every atom scatters X-Ray differently depending on its sizeHydrogen atoms are almost invisible in X-Ray
Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.
14
X-Ray Crystallography
X-Ray Phasing Fitting
Crystal Diffractionpatterns
Electrondensity map
Atomicmodel
1- The crystal is mounted in the X-Ray beam and rotated
2- The crystal is irradiated by X-Ray (typical wavelength: 1 Å (0.1 nm))
3- Multiple diffraction patterns are obtained
Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.
4- Phasing :2D images are converted into a 3D model of the density of electrons by mathematic calculations
5- Fitting: Electron density map is converted into a atomic model
15
X-Ray Crystallography
X-Ray Phasing Fitting
Crystal Diffractionpatterns
Electrondensity map
Atomicmodel
Thermal ellipsoids atomic model: Represents the probability of finding the electrons around the atom as it vibrates.High probability = More precise atomic model = Smaller ellipsoids
OH>
O NH2 >OH
Thermal ellipsoids size:
Debye-Waller factor (B-factor): -Accountingfor the thermal motion of the atom- Numeric representation of the size of the ellipsoid
Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.
16
X-Ray Crystallography
Collected information Structure in the space
Stereochemistry Bond lengths Bond angles
Debye-Waller factor (B-factor)
Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.
17
Diazonamide Structure Revision
Typical C–O bond distances: 1.353-1.409 Å Typical C–N bond distances: 1.365-1.411 Å
C7–O2 bond length: 1.371 Å
C17–O3 bond length: 1.433 Å
Natural Diazonamide bicyclic core
C10(4.83) C12
(4.83)
C17(4.53)
O3(7.42)
C11(5.13)
O2(5.46)
C7(4.49)
C8(4.33)
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
O
C10
C11
O2O3C7
C17
18
Diazonamide Structure Revision
O3 has a large thermal motion compared with O2
X-Ray analysis of the synthetic Diazonamide BB(eq) : O2 = 6.00 Å2 O3 = 5.35 Å2
C10(4.83) C12
(4.83)
C17(4.53)
O3(7.42)
C11(5.13)
O2(5.46)
C7(4.49)
C8(4.33)
Natural Diazonamide bicyclic core
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
The bond length and the B-factor are consistent the hypothesis of O3 being a Nitrogen
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
O
C10
C11
O2O3C7
C17
19
Diazonamide Structure Revision
In X-Ray, the scattering power of an atom is proportionalto its atomic number. Neighboring atoms in the periodic
table differ slightly from one another, like O and N
C10(4.83) C12
(4.83)
C17(4.53)
O3(7.42)
C11(5.13)
O2(5.46)
C7(4.49)
C8(4.33)
Natural Diazonamide bicyclic core
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
O
C10
C11
O2O3C7
C17
20
Comparison of the Assignments
RNO
HN
Me MeH
O
N
ONH
ClO
N Cl
OOH H
H10
11
J= 3.5 HzD2O exchangeable proton
H 6.46 ppm
RNO
HN
Me MeH
O
N
NNH
ClO
N Cl
10
11
O H
H
J= 3.5 HzD2O exchangeable proton
H 6.46 ppm
HETCOR: Correlation between H at 6.46 ppm and C11 (106.6 ppm)
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
21
Diazonamide Structure Revision
To be consistent with the molecular formula, C40H35N6O6Cl2, one oxygen atom is missingand there is one extra nitrogen
HN
O
HN
Me MeH
O
N
NHNH
ClO
N Cl
O
OH2N
MeMe
5 oxygens
7 nitrogens
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
22
Diazonamide Structure Revision
Acid digests of diazonamide A do not produce valine, but indicatesthe presence of two isopropyl groups
HN
O
HN
Me MeH
O
N
NHNH
ClO
N Cl
O
OH2N
MeMe
7
37H
N7 protons are reported as a sharpone-proton doublet
C37 resonates at 76,9 ppm. Considerably downfield for a typical valine (~62 ppm)
These observations are consistent with C37 substituent being an alcohol rather than an amine
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
23
Diazonamide Structure Revision
HN
O
HN
Me MeH
O
N
ONH
ClO
N Cl
O
OHO
MeMe
37
C37-S: HN
OHO
MeMe
37
C37-R: HN
OHO
MeMe
37
Compound GI50 (nM)
Natural diazonamide A 8
C37-S 16
C37-R 191
Growth inhibition determined for human adenocacinoma OVCAR-3
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 470
Dehydrated form of the originally proposed structure
24
Find the differences!
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770
Later validated by total synthesis
Nicolaou, K. C. Angew. Chem., Int. Ed. 2002, 41, 3495Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12888
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N ClHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
OHOH
Original structure Revised structure
25
Diazonamide A Timeline Discovery
Fenical, W.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4765
Nicolaou, K. C. Angew. Chem., Int. Ed. 2002, 41, 3495
Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12888 Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
1991 Structure determinationby Fenical and Clardy
2001First synthesis of the originally proposed structure by Harran
2002 First total synthesis
of the revised structure by Nicolaou
2001Structure revision
by Harran
Confirmation of the revised strucutre
2003 Total synthesis
of the revised structure by Nicolaou
2003 Total synthesis of the
revised structure by Harran
26
Nicolaou’s Synthetic Strategy
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N ClHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N ClHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl Formation of theHeterocyclic core
Macrolactamization
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
27
Retrosynthetic Analysis of Diazonamide A
HO
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
O
FmocHN
Me
Me
FmocHN
OBn
NCbz
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Peptide coupling
Aminal formation
Macro-lactamization Me Me
O
N
NBnNMOM
O
N
OMe
Me
Robinson-GabrielCyclodehydration and [O]
NBnNMOM
O
N
OBn
O
NCbzMeMe
NOMe
O
Heteropinacol
coupling/
Oximecleavagecascade
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
O
FmocHN
OBn
NCbz
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Peptide coupling
Aminal formation
Macro-lactamization Me Me
O
N
NBnNMOM
O
N
OMe
Me
Robinson-GabrielCyclodehydration and [O]
HO
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
FmocHN
Me
Me
NBnNMOM
O
N
OBn
O
NCbzMeMe
NOMe
O
Heteropinacol
coupling/
Oximecleavagecascade
OBn
NCbz
FmocHNHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Peptide coupling
Aminal formation
Macro-lactamization Me Me
O
N
NBnNMOM
O
N
OMe
Me
Robinson-GabrielCyclodehydration and [O]
HO
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
O
FmocHN
Me
Me
NBnNMOM
O
N
OBn
O
NCbzMeMe
NOMe
O
Heteropinacol
coupling/
Oximecleavagecascade
28
Retrosynthetic Analysis of Diazonamide A
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
NBnNMOM
O
N
OBn
O
NCbzMeMe
NOMe
O
Suzuki coupling
NMOM
B OONO
OTBDPS
NBn Br
OTBS
BnO
NCbz
O Me
Me
+
29
Retrosynthetic Analysis of Diazonamide A
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
NMOM
B OONO
OTBDPS
NH
Br
8 steps
NBn Br
OTBS
BnO
NCbz
O Me
Me
OH
CO2Me
NH2
+NH
O
OBr
12 steps
30
NH
BrN
NO2 (1.1 equiv.)
TFA NH
Br NO2
LiAlH4 (6 equiv.)
THF, 25 65oC87% over 2 steps N
H
Br NH2
HO OTBDPSO
(1 equiv.)EDC (1 equiv.)HOBt (1 equiv.)DCM79%
NH
Br HNO
TBDPSO
1)DDQ (3 equiv.) THF/H2O (9:1), 0oC
2) IBX (3 equiv.) THF/DMSO (1:1)
90%NH
Br HNO
TBDPSO
O
IO
O
OHO
IBX:
CN N
N
EDC:
NN
N
OH
HOBt:
O
O
Cl
Cl
NC
NC
DDQ:
Synthesis of Indole-OxazoleBuilding Block
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 10162
31
Synthesis of Indole-OxazoleBuilding Block
NH
Br HNO
TBDPSO
O
NH
Br NO
TBDPSO
Cl3CCCl3 (2 equiv.), PPh3 (2 equiv.)
NEt3 (4 equiv.), 25oC, 15 min
Wipf's modification of the Robinson-Gabrielcyclodehydration
:PPh3
Cl
ClCl
Cl
Cl
ClPPh3Cl
Cl
R
HN
O
OOTBDPS
R= 4-bromoindole ON
R
OPh3P HH
:NEt3PPh3O
TBDPSO
ON
TBDPSO
R
Cl2C=CCl2 T.P.
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Li, J. J. Name Reactions in Heterocyclic Chemistry, Wiley-Interscience 2005, 557p.
32
Synthesis of Indole-OxazoleBuilding Block
NH
Br NO
TBDPSO
i) NaH (1.3 equiv.) THF, 0oC, 5 min
ii) MOMCl (1.2 equiv.) 0oC, 5 min
95%
N
Br NO
TBDPSO
OMe
N
B NO
OMe
OTBDPS
OOB B
O
O O
O
(2.5 equiv.)
Pd(dppf)Cl2 DCM (10 mol%)KOAc (3 equiv.)
1,4-dioxane, 95oC85%
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Miyaura, N. J. Org. Chem. 1995, 60, 7508
33
Synthesis of the Aryl Bromide Coupling Partner
OH
CO2Me
NH2
NH
O
OBr
Ph O
O
Cl(CbzCl)
Na2CO3 (aq) (excess)DCM94%
(1 equiv.)
OH
CO2Me
NHCbz
TiCl4, DCM58% N
HO
OH
HO
NHCbz
CO2Me
Br
1) SOCl2 90%2) NaCNBH3 (3 equiv.) MeCN 84%N
HO
Cl
NH
OHO
NHCbz
CO2Me
Br
1) LiBH4 (4 equiv.), THF97%
2) OMeMeO (10 equiv.)
p-TsOH (0.1 equiv.)acetone
98%NH
OHO
Br
NCbz
OMeMe
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
34
Synthesis of the Aryl Bromide Coupling Partner
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
Padwa, A. J. Am Chem. Soc. 1975, 97, 1837
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
NH
OHO
Br
NCbz
O MeMe
1) TMSCl (4 equiv.), Et3N (6 equiv.) DCM, 0oC
2) HCHO (37% in H2O, 10 equiv.) Yb(OTf)3 (0.25 equiv.)
NH
OHO
Br
NCbz
O MeMe
OH
NH
TMSOBr
H H
OYb(OTf)3
70%
Unseparable 1:1 mixtureof diastereomers. They were
carried forward together
35
NH
OHO
Br
NCbz
O MeMe
OHSi(tBu)Me2Cl (4 equiv.)
imidazole (8 equiv.)DCM84%
(TBSCl)
NH
OTBSO
Br
NCbz
O MeMe
OTBS1) LiOH (3 equiv.) DMF
2) BnBr (4 equiv.) KF alumina (5 equiv.) DME
85%NBn
OBnO
Br
NCbz
O MeMe
OTBS
9-BBN (5 equiv.)THF, 65oC
72%BH
9-BBN:
NBn
BnO
Br
NCbz
O MeMe
OTBS
Synthesis of the Aryl Bromide Coupling Partner
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
36
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
NMOM
B OONO
OTBDPS
NBn Br
OTBS
BnO
NCbz
O Me
Me
+
(1.05 equiv.)(1.0 equiv.)
Pd(dppf)Cl2 DCM (20 mol%)K2CO3 (5 equiv.)DME, 85oC, 12h78%
NBnNMOM
O
N
OBn
O
NCbzMeMe
TBDPSO
TBSO
37
Parikh-Doering oxidation
Synthesis of Diazonamide ANicolaou’s Group
NBnNMOM
O
N
OBn
O
NCbz
Me
Me
TBDPSO
TBSO
NBnNMOM
O
N
OBn
O
NCbz
Me
Me
HO
HO
TBAF (6 equiv.)
THF, 45oC94%
TBAF: (nBu)4N+F-
SO3 py (8.3 equiv.)DMSO/DCM (1:1), 0oC91%
NBnNMOM
O
N
OBn
O
NCbz
Me
Me
O
O
NBnNMOM
O
N
OBn
O
NCbz
Me
Me
N
O
OMe
MeONH2HCl (5 equiv.)
DMSO91%
Most accessible aldehyde
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
38
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
Mixture of 8 diastereomers
1) i) SmI2 (9 equiv.), DMA (36 equiv.), THF, 1h ii) NH4Cl(aq), 1h 2) FmocValOH (3 equiv.), EDC (3 equiv.) HOBt (3 equiv.), DMF, 10h
45-50%
HO
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
O
FmocHN
Me
Me
NBnNMOM
O
N
OBn
O
NCbzMeMe
NOMe
O
FmocValOH:FmocHN
OH
MeMe
O
Fmoc:O
O
39
Hetero Pinacol Sequence Proposed Mechanism
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
O N OMe
radical generation
SmI2, DMA O N OMeSmIII SmIII
Pinacolcyclization
O N OMeSmIII SmIII
SmI2, DMA
N-O Cleavage
O NSmIII SmIII
SmIII1) NH4Cl(aq)
HO NH
O
FmocHN
Me
Me
2) FmocValOHEDC, HOBt
40
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
HO
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
O
FmocHN
Me
Me
TPAP (1 equiv.)NMO (5 equiv.) 4 Å molecular sievesDCM65%
O
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
O
FmocHN
Me
Me
Ley oxidation
TPAP:Ru
O
O O
O
N(nPr)4
NMO:N
O
O
OxidantCo-oxidant
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
Mixture of 4 diastereomers
41
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
O
NH
NBnNMOM
O
N
OBn
O
NCbzMeMe
O
FmocHN
Me
Me
POCl3/pyridine (1:2)70oC35%
FmocHN
Me Me
O
N
NBnNMOM
O
N
OBn
O
NCbzMeMe
Robinson-Gabrielcyclodehydration
Mixture of 2 diastereomers
42
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
FmocHN
Me Me
O
N
NBnNMOM
O
N
OBn
O
NCbzMeMe
1) HF(aq) (3 equiv.), MeCN, 0oC 95%2) IBX (5 equiv.) DMSO3) NaClO2 (5 equiv.) NaH2PO4 (5 equiv.) resorcinol (5 equiv.) DMSO/H2O (10:1)
89% over 2 steps
H2N
Me Me
O
N
NBnNMOM
O
N
OBn
O
CbzHN
4) Et2NH/THF (1:5) 97%
OH
Acetonide deprotection
Alcohol oxidation
Fmoc deprotection
Mixture of 2 diastereomers
43
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
NNN
N
ON
N
PF6
HATU:
Only one diastereomer cyclizes: the desired one
H2N
Me Me
O
N
NBnNMOM
O
N
OBn
O
CbzHN
OH
CbzHNO
HN
Me Me
O
N
OBnNBn
NMOM
O
N
HATU (2 equiv.)2,4,6-collidine (6 equiv.)DMF/DCM (1:2, 0.1 mM)25oC, 7 days10-15%
Macrolactamization
44
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
!!!
CbzHNO
HN
Me Me
O
N
OBn
NBnNMOM
O
N
H2 (1 atm)Pd(OH)2/C (excess)EtOH
CbzHNO
HN
Me Me
O
N
OH
NHNMOM
O
N
O
Substrate specific:Doesn’t work with other model substrates
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
45
Proposed Mechanism for the Oxidation with Pearlman’s Catalyst
Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
NHOH
Pd(OH)2 2H2O
NO
[Pd]
HH
-hydrideelimination
NO
[Pd]
Migratory insertion
H
NO
[Pd]
-hydrideelimination
NO [Pd] H
H
-[Pd0]-H2
Attack by -OHor H2O
NHO
OH
Ringopening
NOH HO
NHOH O
Tauto-merization
H
H
46
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
CbzHNO
HN
Me Me
O
N
OH
NHNMOM
O
N
O
CbzHNO
HN
Me Me
O
N
OCbz
NHNMOM
O
N
O
Cl
Cl
1) CbzCl (5 equiv.) NaHCO3(aq)/ 1,4-dioxane (1:2) 35% over 2 steps
2) NCS (4 equiv.) CCl4/THF (1:1), 60oC NCS:
N
O
O
Cl
47
CbzHNO
HN
Me Me
O
N
OCbz
NHNMOM
O
N
O
Cl
Cl CbzHNO
HN
Me Me
O
N
OH
NHNH
O
N
O
Cl
Cli) BCl3 (5 equiv.) DCM, -78oC
ii) NaOH 10%, THF 25oC
75% over 2 steps
N
Cl
O
BCl2
Cl
N
Cl
O
BCl2
Me MeCl
N
Cl
O BCl2-MeCl
NaOH
HOBCl2
N
Cl
ONa
-CH2O
+H3O+NH
Cl
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
48
Synthesis of Diazonamide ANicolaou’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12888
CbzHNO
HN
Me Me
O
N
OH
NHNH
O
N
O
Cl
ClDIBAL-H
(100 equiv. added portionwise5 x 20 equiv.)
O
NTHF, -78 25oC56%
CbzHNO
HN
Me Me
O
N
ONH
NH
ClO
N Cl
DIBAL-H: AlH
49
Synthesis of Diazonamide ANicolaou’s Group
CbzHNO
HN
Me Me
O
N
ONH
NH
ClO
N Cl
1) H2 (2 atm), Pd(OH)2/C (cat.) EtOH2) EDC (5 equiv.), HOBt (5 equiv.) NaHCO3 (15 equiv.), DMF
OHHOO
MeMe
(5 equiv.)
82% over 2 steps
HN
O
HN
Me Me
O
N
ONH
NH
ClO
N Cl
OHO
Me Me
Diazonamide A!
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
CN N
N
EDC:
NN
N
OH
HOBt:
50
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
39 steps synthesis 31 steps in the longest linear sequence (overall yield: 0.01% !!)
First example of an heteropinacol cyclization cascade in the formation of a macrocycle
Surprising concomitant Reduction/Oxidation reaction using Pearlman’s catalyst
Overview of Nicolaou’s Group Synthesis
Nicolaou, K. C. Angew. Chem., Int. Ed. 2003, 42, 1753Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12897
51
Harran’s Synthetic Strategy
OH
HN CO2H
NH
HNO2HC
NH
HO2C
NH
Me Me
CO2HHO
Me Me
CO2HHN
[O]
[O] Cl+
Cl+
Harran’s synthesis is inspired by his hypothesis on the biosynthesis of the natural Diazonamide A
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
52
Retrosynthetic Analysis of the Diazonamide ARobinson-Gabriel Cyclodehydration /
Oxidation
RHN
O
O
NHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Photoinducedelectron transfer
cyclization
O
HN
Me MeH
O
N
ONH
NH
Br
Electronsource
RHNO
HN
Me MeH
O
N
ONH Br
CO2Me
Oxidative''cycloaddition''
RHNO
HN
Me MeH
O
NCO2Me
NH Br
OH
Peptide coupling
RHNO
HN
Me MeH
O
N
ONH Br
NH
NH
OAc
Electronsink
Robinson-Gabriel Cyclodehydration /
Oxidation
RHN
O
O
NHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Photoinducedelectron transfer
cyclization
O
HN
Me MeH
O
N
ONH
NH
Br
Electronsource
RHNO
HN
Me MeH
O
N
ONH Br
CO2Me
Oxidative''cycloaddition''
RHNO
HN
Me MeH
O
NCO2Me
NH Br
OH
Peptide coupling
RHNO
HN
Me MeH
O
N
ONH Br
NH
NH
OAc
Electronsink
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
Robinson-Gabriel Cyclodehydration /
Oxidation
RHN
O
O
NHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Photoinducedelectron transfer
cyclization
O
HN
Me MeH
O
N
ONH
NH
Br
Electronsource
RHNO
HN
Me MeH
O
N
ONH Br
CO2Me
Oxidative''cycloaddition''
RHNO
HN
Me MeH
O
NCO2Me
NH Br
OH
Peptide coupling
RHNO
HN
Me MeH
O
N
ONH Br
NH
NH
OAc
Electronsink
Robinson-Gabriel Cyclodehydration /
Oxidation
RHN
O
O
NHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Chlorination
Photoinducedelectron transfer
cyclization
O
HN
Me MeH
O
N
ONH
NH
Br
Electronsource
RHNO
HN
Me MeH
O
N
ONH Br
CO2Me
Oxidative''cycloaddition''
RHNO
HN
Me MeH
O
NCO2Me
NH Br
OH
Peptide coupling
RHNO
HN
Me MeH
O
N
ONH Br
NH
NH
OAc
Electronsink
53
Retrosynthetic Analysis of Diazonamide A
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
H2N
Me MeH
O
NCO2Me
NH Br
HBr
OH
RHNO
OH
+
OH
RHNO
HN
Me MeH
O
NCO2Me
NH Br
Peptidecoupling
54
Yonemitsu oxidation
DDQ:O
O
Cl
Cl
CN
CN
Synthesis of the 3-Oxazoylindole H2N
Me MeH
O
NCO2Me
NH Br
HBr
CO2Me
NH2
NHBr
HCl
NClMe Me
CbzHNOH
O
, DCM
N
Me Me
CbzHN
HN
O
CO2Me
NH
Br
Me Me
CbzHNCl
O
76%
1) DDQ (2.3 equiv), THF 70oC, 2h
90%
2) 33% HBr in AcOH94%
H2N
Me MeH
O
NCO2Me
NH Br
HBr
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961Yonemistsu, O. Heterocycles 1979, 12, 1457
55
Yonemistu Oxidation Proposed Mechanism
Yonemistsu, O. Heterocycles 1979, 12, 1457
NH
HNR'
O
N
HNR'
O
OH
OH
Cl CN
CNCl
R
R
O
O
Cl
Cl CN
CNN
HNR'
OR
H
O
O
Cl CN
CNCl++
P.T.
N
HNR'
OR
O
OH
Cl CN
CNCl+
N
HNR'
OR
O
OH
Cl CN
CNCl
HH
+
+
56
Yonemistu Oxidation Proposed Mechanism
N
HNR'
O
H2O
NH
HNR'
O
HO
DDQ
N
HNR'
O
HO
NH
HNR'
O
O
Tautomerization
Anhydrous
NH
NO
R'
DDQ
Tautomerization
R
R
R
R
R
N
NO
R'
R
NH
NO
R'
R
Yonemistsu, O. Heterocycles 1979, 12, 1457
If R' is electron-donating: cyclization goes faster
If R has a carbonyl substituent: tautomerization is facilitate
57
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
H2N
Me MeH
O
N CO2Me
NH Br
HBr
TBTU, (iPr)2NEt, DMF
91%
NH
OMeMe
ArO2SHN
HO
O
NCO2Me
NH
BrAr= 2-NO2Ph
OH
ArO2SHNO
OH
TBTU:
NN
N
ON
N-BF4
58
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
NH
OMeMe
ArO2SHN
HO
O
NCO2Me
NH
BrAr= 2-NO2Ph
ArO2SHNO
HN
Me MeH
O
N
ONH Br
CO2Me
PhI(OAc)2 (1.1 equiv)LiOAc (2 equiv)CF3CH2OH-20oC
ArO2SHNO
HN
Me MeH
O
N
O
CO2Me
NH Br
H
N
MeMe
O
NCO2Me
NH
Br
OArO2SHN
O
20-25%7-8% ~15% (1:1)
H
59
Oxidative Formal Cycloaddition Proposed MechanismGeneration of the Phenoxenium Ion
PhI(OAc)2 AcOHR
OH
R
OIPh
OAc
Dissociation
R
O
+ PhI + AcO-
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961Antus, S.; Pelter, A. J. Chem. Soc., Perkin Trans. 1 1999, 379
60
Oxidative Formal Cycloaddition Proposed Mechanism
Calculations have shown preference for a left handed conformation
Major
Minor
Left handed conformation
Right handed conformation
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
-H+
-H+
O
NH
Br
N
O
CO2Me
O
N
O
CO2Me
NH
N
O
CO2Me
NHO
O
N
ONH Br
CO2Me
H
Br Br
NH
Br
N
O
CO2Me
O
N
O
CO2Me
NH
N
O
CO2Me
NHOBr BrO
O
N
O
CO2Me
NH Br
H
* ** *
* ** *
61
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
ArO2SHNO
HN
Me MeH
O
N
ONH Br
CO2Me
Ar=2-NO2Ph
1) PhSH, Na2CO3, DMF2) Teoc-Cl, DCM, K2CO3(aq)
80% (2 steps) TeocHNO
HN
Me MeH
O
N
ONH Br
CO2H
3) LiOH, MeOH(aq)99%
Teoc: OSi
O
TeocHNO
HN
Me MeH
O
N
ONH Br
HN
O
NH
OAc
1) TBTU, (iPr)2NEt (2 equiv.), DMF
NH
OH
NH2
HCl
(1.1 equiv.)
91%
2) Ac2O, Pyridine, DCM/THF
95%Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
62
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
TeocHNO
HN
Me MeH
O
N
ONH Br
HN
O
NH
OAc
DDQ (2.2 equiv)
THF/H2O (9:1)86%
TeocHNO
HN
Me MeH
O
N
ONH Br
HN
O
NH
OAc
O
PPh3, (CCl3)2, NEt3, DCM
55%
TeocHNO
HN
Me MeH
O
N
ONH Br
O
N
NH
OAc
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
63
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Single atropisomer
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
TeocHNO
HN
Me MeH
O
N
ONH Br
O
N
NH
OAc
hv (300nm), CH3CN/H2O (3:1) 3 mM
LiOH (2 equiv.)r.t, 3h
TeocHNO
HN
Me MeH
O
N
ONH
NH
O
N
OH72%
64
TeocHNO
HN
Me MeH
O
N
ONH Br
O
N
NH
OO
LiOH(aq) TeocHNO
HN
Me MeH
O
N
ONH Br
O
N
NH
O
NHBr
O
NH
O
N
hv (300nm)
NHBr
O
NH
O
N
LiLiOH(aq)
-LiBr
NH
NH
O
N
O
H
Tautomerization
NH
NH
O
N
OH
* * *
*
Proposed Mechanism of the Photoinduced Macrocycle Formation
Conformational rigidity places the two arenes in the right position to generate only one atropisomer
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
65
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
TeocHNO
HN
Me MeH
O
N
ONH
NH
O
N
OH
1) O
O2N
SCF3
O O
K2CO3, DMF87%
2) 20% Pd/C, 1atm H2 EtOAc/MeOH
96%
TeocHNO
HN
Me MeH
O
N
ONH
NH
O
N
TeocHNO
HN
Me MeH
O
N
ONH
NH
O
N
OS
CF3
OO
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
66
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
TeocHNO
HN
Me MeH
O
N
ONH
NH
O
N
TeocHNO
HN
Me MeH
O
N
ONH
NTeoc
O
N
i) O O O
O O
NEt3, THFii) Teoc-Cl, NEt3iii) Pd(PPh3)4 (5 mol%) Morpholine (5 equiv.), 0oC
78%
Teoc: OSi
O
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
67
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961Guetté, J.-P.; Lemaire, M.; Guy, A. Tetrahedron 1982, 38, 2339
TeocHNO
HN
Me MeH
O
N
ONH
NTeoc
O
N
TeocHNO
HN
Me MeH
O
N
ONH
NTeoc
O
N Cl
Cl
OCl
ClCl
ClCl
Cl
DMF30-50%
68
Synthesis of Diazonamide AHarran’s Group
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
TeocHNO
HN
Me MeH
O
N
ONH
N
O
N Cl
Cl
H2NO
HN
Me MeH
O
N
ONH
NH
O
N Cl
Cl
TAS-F (5 equiv.)DMF
TAS-F:
NS
N
N+
SiF
F
-
O
SiMe3
O
- SiFMe3- CH2CH2- CO295%
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
69
Synthesis of Diazonamide AHarran’s Group
H2NO
HN
Me MeH
O
N
ONH
NH
O
N Cl
Cl
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
OH
OHO
Me Me
(1.1 equiv.)P
O
EtO OEtCN
N
O
, DMF
90%
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Diazonamide A!
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
70
Overview of Harran’s Group Synthesis
HN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Convergent synthesis of 19 steps 9 steps in the longest linear sequence (overall yield: 8%)
Synthesis based on the possible biosynthesis of the natural product
Key steps: - Annulation involving phenoxenium ion- Photoinduced macrocycle formation
Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961
71
Conclusion
Structure revisionHN
OHO
Me Me
O
HN
Me MeH
O
N
ONH
NH
ClO
N Cl
Actual structure
K. C. Nicolaou’s group synthesis: -39 steps - Unprecedented hetero pinacol macrocyclization
P.G. Harran’s group synthesis: -19 steps - Inspired by the biosynthesis of the molecule
HN
OH2N
Me Me
O
HN
Me MeH
O
N
ONH
ClO
N Cl
OHOH
Originally proposed structure
72
Acknowledgment
Prof Keith Fagnou
David LapointeMarc LafranceBenoit LiegaultDaniel BlackDave Stuart
Megan ApSimonNicole BlaquiereDerek SchipperLaurence Caron
Mégan Bertrand-LaperleDaniel Shore
Sophie RousseauxChris Whipp
Malcolm HuestisCatherine Lebel
Ho-Yan SunDoris Lee