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Diazonamide A: The Long Story of a Misunderstood Molecule. Seminar presented by Elisia Villemure February 14, 2008. The Origin of Diazonamide. Isolated from the colonial ascidian Diazona angulata Collected from the ceilings of caves along the northwest coast of Siquijor

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diazonamide a the long story of a misunderstood molecule
Diazonamide A: The Long Story of a Misunderstood Molecule

Seminar presented by Elisia Villemure

February 14, 2008

the origin of diazonamide
The Origin of Diazonamide
  • Isolated from the colonial ascidian

Diazona angulata

  • Collected from the ceilings of caves

along the northwest coast of Siquijor

Island in the Philippines

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

why is this molecule so interesting
Why Is this Molecule So Interesting?

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.

  • 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

Initially proposed structure

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

structure determination of diazonamide a and b
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

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

strategy for structure elucidation
Strategy for Structure Elucidation

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.

evidence of the presence of an hemiacetal in diazonamide a and b
Evidence of the Presence of an Hemiacetal in Diazonamide A and B

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

evidence on the structure of diazonamide a and b
Evidence on the Structure of Diazonamide A and B

Diazonamide A

Diazonamide B

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

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

evidences on the structure of diazonamide a and b
Evidences on the Structure of Diazonamide A and B

Diazonamide A

Diazonamide B

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

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

crystal structure of diazonamide b
Crystal Structure of Diazonamide B

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

first synthesis by harran s group
First Synthesis by Harran’s Group

In 2001, P. G. Harran published the first synthesis of ‘’Diazonamide A’’.

Spectroscopic data didn’t match the natural product assignment!!!

24 step synthesis

Revision of the structure is proposed!

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4765

structural misassignment in literature

Wiedemannic Acid

Structural Misassignment in Literature

A search in the literature between January 1990 to April 2004 revealed 300 structural revisions of natural products

Kinamycin C:

(+)-tolyporphin A:

Sauer, E., Barriault, L. Org. Lett.2004, 19, 3329

Nicolaou, K. C. Angew. Chem., Int. Ed.2005, 44, 1012

diazonamide structure revision
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

x ray crystallography
X-Ray Crystallography

Scattered X-Ray

Incident X-Ray

Atom

X-Ray generator

Electron cloud

Crystal

Diffraction pattern

Nucleus

  • Every atom scatters X-Ray differently depending on its size
  • Hydrogen atoms are almost invisible in X-Ray

Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.

Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

x ray crystallography1
X-Ray Crystallography

X-Ray

Phasing

Fitting

Crystal

Diffraction

patterns

Electron

density map

Atomic

model

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

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

Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.

Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

x ray crystallography2
X-Ray Crystallography

X-Ray

Phasing

Fitting

Crystal

Diffraction

patterns

Electron

density map

Atomic

model

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

Thermal ellipsoids size:

Debye-Waller factor (B-factor): -Accounting

for the thermal motion of the atom

- Numeric representation of the size of the ellipsoid

Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.

Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

x ray crystallography3
X-Ray Crystallography

Collected information

  • Structure in the space
  • Stereochemistry
  • Bond lengths
  • Bond angles
  • Debye-Waller factor (B-factor)

Clegg, W.; Blake, A.J.; Gould, R.O.; Main, P. Crystal Structure Analysis Principles and Practice, Oxford Science Publication 2001, 265p.

Massa, W. Crystal Structure Determination, Spinger 2004, 210 p.

diazonamide structure revision1

C10

(4.83)

C12

(4.83)

C8

(4.33)

C17

(4.53)

C7

(4.49)

C11

(5.13)

O2

(5.46)

O3

(7.42)

Diazonamide Structure Revision

Natural Diazonamide bicyclic core

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

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

diazonamide structure revision2

C10

(4.83)

C12

(4.83)

C8

(4.33)

C17

(4.53)

C7

(4.49)

C11

(5.13)

O2

(5.46)

O3

(7.42)

Diazonamide Structure Revision

Natural Diazonamide bicyclic core

  • O3 has a large thermal motion compared with O2
  • X-Ray analysis of the synthetic Diazonamide B

B(eq) : O2 = 6.00 Å2

O3 = 5.35 Å2

The bond length and the B-factor are consistent the hypothesis of

O3 being a Nitrogen

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

diazonamide structure revision3

C10

(4.83)

C12

(4.83)

C8

(4.33)

C17

(4.53)

C7

(4.49)

C11

(5.13)

O2

(5.46)

O3

(7.42)

Diazonamide Structure Revision

Natural Diazonamide bicyclic core

In X-Ray, the scattering power of an atom is proportional

to its atomic number. Neighboring atoms in the periodic

table differ slightly from one another, like O and N

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

comparison of the assignments
Comparison of the Assignments

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

diazonamide structure revision4
Diazonamide Structure Revision

To be consistent with the molecular formula, C40H35N6O6Cl2, one oxygen atom is missing

and there is one extra nitrogen

5 oxygens

7 nitrogens

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

diazonamide structure revision5
Diazonamide Structure Revision

Acid digests of diazonamide A do not produce valine, but indicates

the presence of two isopropyl groups

  • N7 protons are reported as a sharp
  • one-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

diazonamide structure revision6
Diazonamide Structure Revision

Dehydrated form of the originally

proposed structure

Growth inhibition determined for human adenocacinoma OVCAR-3

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 470

find the differences
Find the differences!

Latervalidated by

total synthesis

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12888

Nicolaou, K. C. Angew. Chem., Int. Ed.2002, 41, 3495

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

diazonamide a timeline discovery
Diazonamide A Timeline Discovery

Fenical, W.; Clardy, J. J. Am. Chem. Soc.1991, 113, 2303

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12888

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4765

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Nicolaou, K. C. Angew. Chem., Int. Ed.2002, 41, 3495

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

nicolaou s synthetic strategy

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Nicolaou’s Synthetic Strategy

Formation of the

Heterocyclic core

Macrolactamization

synthesis of indole oxazole building block

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Indole-OxazoleBuilding Block

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 10162

synthesis of indole oxazole building block1

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Indole-OxazoleBuilding Block

Li, J. J. Name Reactions in Heterocyclic Chemistry, Wiley-Interscience 2005, 557p.

synthesis of indole oxazole building block2

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Indole-OxazoleBuilding Block

Miyaura, N. J. Org. Chem.1995, 60, 7508

synthesis of the aryl bromide coupling partner1

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of the Aryl Bromide Coupling Partner

Padwa, A. J. Am Chem. Soc.1975, 97, 1837

synthesis of diazonamide a nicolaou s group1

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Most accessible

aldehyde

Parikh-Doering

oxidation

synthesis of diazonamide a nicolaou s group2

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Mixture of 8 diastereomers

hetero pinacol sequence proposed mechanism
Hetero Pinacol Sequence Proposed Mechanism

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

synthesis of diazonamide a nicolaou s group3

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Mixture of 4 diastereomers

synthesis of diazonamide a nicolaou s group4

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Mixture of 2 diastereomers

synthesis of diazonamide a nicolaou s group5

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Mixture of 2 diastereomers

synthesis of diazonamide a nicolaou s group6

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Only one diastereomer cyclizes:

the desired one

synthesis of diazonamide a nicolaou s group7

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Substrate specific:

Doesn’t work with

other model substrates

!!!

proposed mechanism for the oxidation with pearlman s catalyst
Proposed Mechanism for the Oxidation with Pearlman’s Catalyst

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

synthesis of diazonamide a nicolaou s group10

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Synthesis of Diazonamide ANicolaou’s Group

Nicolaou, K. C. J. Am. Chem. Soc. 2004, 126, 12888

overview of nicolaou s group synthesis

Nicolaou, K. C. Angew. Chem., Int. Ed.2003, 42, 1753

Nicolaou, K. C. J. Am. Chem. Soc.2004, 126, 12897

Overview of Nicolaou’s Group Synthesis
  • 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

harran s synthetic strategy
Harran’s Synthetic Strategy

Harran’s synthesis is inspired by his hypothesis on the

biosynthesis of the natural Diazonamide A

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

Harran, P. G. Angew. Chem., Int. Ed.2001, 40, 4770

retrosynthetic analysis of the diazonamide a
Retrosynthetic Analysis of the Diazonamide A

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

retrosynthetic analysis of diazonamide a3
Retrosynthetic Analysis of Diazonamide A

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of the 3 oxazoylindole
Synthesis of the 3-Oxazoylindole

Yonemitsu oxidation

Yonemistsu, O. Heterocycles1979, 12, 1457

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

yonemistu oxidation proposed mechanism
Yonemistu Oxidation Proposed Mechanism

Yonemistsu, O. Heterocycles1979, 12, 1457

yonemistu oxidation proposed mechanism1
Yonemistu Oxidation Proposed Mechanism

Yonemistsu, O. Heterocycles1979, 12, 1457

synthesis of diazonamide a harran s group
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group1
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

oxidative formal cycloaddition proposed mechanism generation of the phenoxenium ion
Oxidative Formal Cycloaddition Proposed MechanismGeneration of the Phenoxenium Ion

Antus, S.; Pelter, A. J. Chem. Soc., Perkin Trans. 1 1999, 379

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

oxidative formal cycloaddition proposed mechanism
Oxidative Formal Cycloaddition Proposed Mechanism

-H+

Major

Left handed

conformation

Calculations have shown preference for a left handed conformation

-H+

Minor

Right handed

conformation

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group2
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group3
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group4
Synthesis of Diazonamide AHarran’s Group

Single atropisomer

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

proposed mechanism of the photoinduced macrocycle formation
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

synthesis of diazonamide a harran s group5
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group6
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group7
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

Guetté, J.-P.; Lemaire, M.; Guy, A. Tetrahedron1982, 38, 2339

synthesis of diazonamide a harran s group8
Synthesis of Diazonamide AHarran’s Group

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

synthesis of diazonamide a harran s group9
Synthesis of Diazonamide AHarran’s Group

Diazonamide A!

Harran, P. G. Angew. Chem., Int. Ed.2003, 42, 4961

overview of harran s group synthesis
Overview of Harran’s Group Synthesis
  • 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

conclusion
Conclusion
  • 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

acknowledgment
Acknowledgment

Prof Keith Fagnou

David Lapointe

Marc Lafrance

Benoit Liegault

Daniel Black

Dave Stuart

Megan ApSimon

Nicole Blaquiere

Derek Schipper

Laurence Caron

Mégan Bertrand-Laperle

Daniel Shore

Sophie Rousseaux

Chris Whipp

Malcolm Huestis

Catherine Lebel

Ho-Yan Sun

Doris Lee