nmr prediction and its use to determine the structure of hexacyclinol
DESCRIPTION
NMR Prediction and its Use to Determine the Structure of Hexacyclinol. Dec. 18, 2008. Structure Elucidation. NMR is an extremely powerful tool for structural elucidation but it is still up to the chemist to interpret this data and derive structural information. - PowerPoint PPT PresentationTRANSCRIPT
NMR Prediction and its Use to Determine the Structure of Hexacyclinol
OO
OO
OH
O
O
Dec. 18, 2008
O
O
O
O
O
O
HOH
1
1H, 13C, 15N, 17O, 31P1H, 13C, 15N, 17O, 31P
Structure Elucidation
Cimino, P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson. Chem. 2004, 42, S262
NMR is an extremely powerful tool for structural elucidation but it is still up to the chemist to interpret this data and derive structural information.
DFT is becoming a powerful tool and can be used to calculate the chemical shift values of several nuclei for complex molecules.
OO
OO
OH
O
O
Structure Elucidation
3
ChemDraw NMR Predictor
O
O
O
O
O
O
HOH
O
O
O
O
O
O
HOH
O
O
O
O
OO
O
H H HOH
HHO
H
OH
OHHO
H H H H
H
H
OH
OH
OH
HMe
MeH
HG H I J K
L M
5152
50
53
55
544948
O
O
O
O
OO
O
H H HOH
HHO
H
OH
OHHO
H H H H
H
H
OH
OH
OH
HMe
MeH
HG H I J K
L M
5152
50
53
5554
4948
O
O
O
O
OO
O
H H HOH
HHO
H
OH
OHHO
H H H H
H
H
OH
OH
OH
HMe
MeH
HG H I J K
L M
5152
50
53
55
544948
O
O
O
O
OO
O
H H HOH
HHO
H
OH
OHHO
H H H H
H
H
OH
OH
OH
HMe
MeH
HG H I J K
L M
5152
50
53
55
544948
O
O
O
O
OO
O
H H HOH
HHO
H
OH
OHHO
H H H H
H
H
OH
OH
OH
HMe
MeH
HG H I J K
L M
5152
50
53
55
544948
O
O
O
O
OO
O
H H HOH
HHO
H
OH
OHHO
H H H H
H
H
OH
OH
OH
HMe
MeH
HG H I J K
L M
5152
50
53
55
544948
4
NMR Prediction in the LiteratureStructure of the GHIJKLM Domain of Maitotoxin
Nicolaou, K. C.; Frederick, M. O. Angew. Chem. Int. Ed. 2007, 46, 5278.
Originally Proposed Stereochemistry
Reversed Stereochemistry at C51 - C52
Reversed Stereochemistry at C50 - C55
Hexacyclinol
Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814. 5
OO
OO
OH
O
O
The Journal of Antibiotics
Published September, 2002
Udo Gräfe
Hans-Knöll-Institute for Natural Products Research
Gräfe’s Proposed Structure:
OO
OO
OH
O
O
Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814.
- Isolated from basidiospores of the mushroom Panus rudis strain HKI 0254- Antiproliferative metabolite- Potent inhibitor of L-929 and K-562 cells
6
Isolation and Structure Elucidation of Hexacyclinol
Structure elucidated by MS, IR, 1H and 13C NMR, DEPT, COSY, HMQC, HMBC and NOESY
OO
OO
OH
O
O
OO
OO
OH
O
OO
O
OO
OH
O
OO
O
OO
OH
O
O
Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814. 7
Proposed Structure of Hexacyclinol
OO
OO
OH
O
O
Schlegel, B.; Härtl, A.; Dahse, H.-M.; Gollmick, F. A.; Gräfe, U.; Dörfelt, H.; Kappes, B. J. Antibiot. 2002, 55, 814. 8
Proposed Structure of Hexacyclinol
The First Total Synthesis of Hexacyclinol
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769. 9
Angewandte Chemie International Edition
Published Online Feb 9, 2006
James J. La Clair
Xenobe Research Institute
OO
OO
OH
O
O
Hexacyclinol
OO
OH
O
OO
O
OO
OH
O
O
h, O2Rose BengalMeOH, 0 °C
89 %
HexacyclinolDesoxohexacyclinol
in vacuo95 %
OO
OH
O
OO
O
OO
OH
O
O
h, O2Rose BengalMeOH, 0 °C
89 %
HexacyclinolDesoxohexacyclinol
37 Linear Step Synthesis0.9 % Overall Yield
42 Linear Step Synthesis0.06 % Overall Yield
The First Total Synthesis of Hexacyclinol
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769. 10
OAc
OAcHOStarting From: 5 Steps
6.2 %Yield
Key Step: [2+2+2] Cycloaddition with Singlet O2
Biological Activity of Intermediates
11
O
O
H
OO
H
OArtemisinin
Inhibition of P. Berghei ED50 (mg/kg)
IC50 (nM) 2.5 0.9
4.3
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769.
OO
OO
OH
O
O
OO
OH
O
OHO
OO
OH
O
OO
O
OO
OH
O
OO
O
O
Hexacyclinol
Inhibition of P. Berghei ED50 (mg/kg)
IC50 (nM) 9.3 2.6
8.9
6.1 1.5
1.6
2.1 0.7
5.2
La Clair’s Synthesis of Hexacyclinol
12La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769
La Clair’s Synthesis of Hexacyclinol
13La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769
La Clair’s Synthesis of Hexacyclinol
14La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769
La Clair’s Synthesis of Hexacyclinol
15La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769
La Clair’s Synthesis of Hexacyclinol
16
OAc
OAcHO
OO
OH
O
O
Desoxohexacyclinol3a
4
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769
La Clair’s Synthesis of Hexacyclinol
17La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769
La Clair’s Synthesis of Hexacyclinol
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769 18
1H NMR Spectrum of Synthetic Hexacyclinol
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769 19
OO
OO
OH
O
O
Note: CDCl3
Signal @ 7.5 ppm
OO
OO
OH
O
O
Key Steps in La Clair’s Synthesis
OO
OO
OH
O
O
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769. 20
HO
TBSO
SS
H
H
O
TBSO
SS
H
O
OSlow addition of Ag2O
in paraffin
CH2Cl2r.t.
HO
TBSO
SS
H
HO
O
TBSO
SS
H
O
O
LiOH aq. THF
PPh3 DIAD
CH2Cl2r.t.
16 h68 %
(over 3 steps)
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769. 21
O
TBSO SS
OHO
HOMOM
O
PhSHPEt3
DEADCH2Cl245 °C24 h
O
TBSO SS
OPhS
HOMOM
O
94 %Complete inversion of
hindered tertiary alcohol via Mitsunobu-type conditions
Key Steps in La Clair’s Synthesis
OO
OO
OH
O
O
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
SH
NNH
O
O
EtOOEt
PEt3
S
SS
HOR
SS
OR
PEt3
HN
NH
O
O
EtOOEt
OMOM
O
OMOM
O
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
SH
NNH
O
O
EtOOEt
PEt3
S
SS
HOR
OMOM
O
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
SH
NNH
O
O
EtOOEt
PEt3
S
SS
HO
SS
OR
PEt3
HN
NH
O
O
EtOOEt
OMOM
O
OMOM
O
S
X
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
SH
NNH
O
O
EtOOEt
PEt3
S
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
SH
NNH
O
O
EtOOEt
PEt3
S
SS
HOR
SS
OR
PEt3
HN
NH
O
O
EtOOEt
OMOM
O
OMOM
O
S
PEt3O
PhSPhS
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769. 22
Mechanism of Mitsunobu-type Inversion of Tertiary Alcohol
O
OMOMO
R
S S OOMOM
O
R
SS
Possible Intermediate
OO
OO
OH
O
O
NN
O
O
EtOOEt
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3N
N
O
O
EtOOEt
PEt3
NN
O
O
EtOOEt
PEt3
SH
SS
PhSR
OMOM
O
Rychnovsky’s Structural Revision
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 23
Organic Letters
Published Online Jun 1, 2006
“Recently, a provocative synthesis of hexacyclinol was reported, and interest in the paper triggered my reexamination
of the original structure assignment”
Scott D. RychnovskyUniversity of California - Irvine
Principles of Nuclear Magnetic Resonance
24
Each nucleus has a magnetic moment arising from its angular momentum.
When placed in a magnetic field, the nuclei precess around the axis of the applied magnetic field, Bo with a “Larmor Frequency”, νL.
Atkins, P.; de Paula, J. Physical Chemistry, 4th ed.; W. H. Freeman and Co.: New York, 2002
Principles of Nuclear Magnetic Resonance
Atkins, P.; de Paula, J. Physical Chemistry, 4th ed.; W. H. Freeman and Co.: New York, 2002 25
νL =γBo 2π
This frequency will depend on the local magnetic field of each nucleus.
σ is known as the Shielding Constant.
νL = (1 - σ)γBo 2π
In order to compare NMR spectra, chemists use the Chemical Shift (δ) to compare the shielding constant of a nucleus with a reference value.
δ = σ - σref
Introduction to NMR Calculations
Cimino, P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson. Chem.2004, 42, S26 26
Step 1: Geometry optimization to identify an energy minimum
Introduction to NMR Calculations
Cimino, P.; Gomez-Paloma, L.; Duca, D.; Riccio, R.; Bifulco, G. Magn. Reson. Chem. 2004, 42, S26Modern Methods and Algorithms of Quantum Chemistry, Grotendorst, J.; ed. John von Neumann Institute for Computing: Jülich, 2000, p. 541
27
Step 2: Perform single-point chemical shift calculations
Gauge-Including Atomic Orbital (GIAO) method
σ is an electronic property that can be accessed by quantum chemical calculation for every nucleus
Chemical Shift δ is then calculated based on a suitable reference.
Rychnovsky’s NMR Prediction Method
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 28
Step 1:Lowest energy conformation identified using Monte
Carlo MMFF
Step 2:The energy of the optimized species was recalculated using the
HF/3-21G method
Step 3:The 13C NMR shifts were calculated by GIAO using the
mPW1PW91/6-31G(d,p) DFT method
The calculations took approximately 12h of CPU time and were performed on an inexpensive Linux
computer with a 3.06 GHz Intel Pentium 4 processor.
Validating Bifulco’s Method Using Structurally Similar Molecules
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 29
O
OHO
HMe
Me
Me
HMe
Elisapterosin B
O
Me
Me
O OO
O
Me
Maoecrystal V
OMe
MeO
MeOH
HMe
HMe
Elisabethin A
Each compound’s structure is conformationally rigid and has been confirmed by X-ray analysis
Rychnovsky’s NMR Prediction Model Studies
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 30
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Elisapterosin B
Carbon Number
Δδ
(ppm
)
O
OHO
HMe
Me
Me
HMe
3
1
4
5
11 1210
7
6
19
18
1716
1514
13
9 20
2
8
Average Δδ = 1.9 ppm
Maximum Δδ = 3.8 ppm
Rychnovsky’s NMR Prediction Model Studies
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 31
O
Me
Me
O OO
O
Me
3
1
4 5
11
1210
7
61918
17
16
15
14
139
2 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Maoecrystal V
Carbon Number
Δδ
(ppm
) Average Δδ = 1.1 ppm
Maximum Δδ = 3.7 ppm
Rychnovsky’s NMR Prediction Model Studies
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 32
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Elisabethin A
Carbon Number
Δδ
(ppm
)
OMe
MeO
MeOH
HMe
HMe3
1
45
11
12
10
76
19
18
1716
15
14
13
9
20
2
8
Average Δδ = 1.5 ppm
Maximum Δδ = 3.8 ppm
Average Δδ = 6.8 ppm
Maximum Δδ = 22.0 ppm
OO
OO
OH
O
O
31
45
1112
107
619
18
17
1615
14
13 9
20 22
21 23
2
8
OO
OO
OH
O
O
31
45
1112
107
619
18
17
1615
14
13 9
20 22
21 23
2
8
Average Δδ = 6.8 ppm
Maximum Δδ = 22.0 ppm
Rychnovsky’s Structural Revision
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 33
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Hexacyclinol (Originally Proposed Structure)
Carbon Number
Δδ
(ppm
)
Predicted 13C NMR shifts for Gräfe’s structure of Hexacyclinol do not fit well with experimental data
What is the Correct Structure of Hexacyclinol?
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 34
OO
OO
OH
O
O
HexacyclinolMolecular Weight: 416.46
Chemical Formula: C23H28O7Isolated From
Panus rudis HKI 0254
OOH
OH
OH
O
H
H O
OH
Panepophenanthrin
O
Molecular Weight: 420.45Chemical Formula: C22H28O8
Isolated From Panus rudis Fr. IFO8994
Could Hexacyclinol be an artifact of the isolation of Panepophenanthrin?
OOH
OH
OH
O
H
H O
OH OOH
OH
O
H
H O
OH
HO
H
O
O
H
H O
OH
HO
O
H
O
O
H
H O
OH
O
- H2O
O O O
O
- H2O
SiO2 / MeOH
OOH
OH
OH
O
H
H O
OH OOH
OH
O
H
H O
OH
HO
H
O
O
H
H O
OH
HO
O
H
O O O- H2O
SiO2 / MeOH
OOH
OH
OH
O
H
H O
OH OOH
OH
O
H
H O
OH
HO
O O
SiO2 / MeOH
Hexacyclinol = Isolation Artifact of Panepophenanthrin??
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 35
Panepophenanthrin
Hexacyclinol?
O
O
O
O
O
O
HOH
OOH
OH
OH
O
H
H O
OH
O
OOH
OH
OH
O
H
H O
OH OOH
OH
O
H
H O
OH
HO
H
O
O
H
H O
OH
HO
O
H
O
O
H
H O
OH
O
- H2O
MeOH
O
O
H
H O
OH
O
OMe
O O O
OO
- H2O
SiO2 / MeOH
O
O
O
O
O
O
HOH
Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 36
Stereochemistry?
Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895
O
O
O
O
O
O
HOH
H H
HnOe
no nOe
37
Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 38
O
O
O
O
O
O
HOH
H
HH
Average Δδ = 4.2 ppm
Maximum Δδ = 18.5 ppm
Average Δδ = 4.2 ppm
Maximum Δδ = 18.5 ppm
O
O
O
O
O
O
HOH
3
14
5
11
12
10
7619
18
1716
1514
13
9
20
2221
23
2
8O
O
O
O
O
O
HOH
3
14
5
11
12
10
7619
18
1716
1514
13
9
20
2221
23
2
8
Rychnovsky’s Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 39
C9’s calculated shift is ~ 17 ppm too low while C12 is ~ 18 ppm too high.Possible HMQC misassignment in isolation paper?
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Hexacyclinol (Revised, Conformation 1)
Carbon Number
Δδ
(ppm
)
C9 and C12 do not fit well with
experimental shifts
C12C9C12
Rychnovsky’s Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 40
C9’s calculated shift is ~ 17 ppm too low while C12 is ~ 18 ppm too high.Possible HMQC misassignment in isolation paper?
H9, H12
C9 ?
O
O
O
O
O
O
HOH
129
O
O
O
O
O
O
HOH
3
14
5
11
12
10
7619
18
1716
1514
13
9
20
2221
23
2
8
Rychnovsky’s Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 41
O
O
O
O
O
O
HOH
3
14
5
11
12
10
7619
18
1716
1514
13
9
20
2221
23
2
8
Getting better, but can we make the prediction even more accurate?
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Hexacyclinol (Revised, C9, C12 Exchanged)
Carbon Number
Δδ
(ppm
)
C2 and C5 still do not fit well with
experimental shifts
Average Δδ = 2.9 ppm
Maximum Δδ = 9.5 ppm
Average Δδ = 2.9 ppm
Maximum Δδ = 9.5 ppm
Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 42
O
O
O
O
O
O
HOH
H
HJ3 = 10.1 Hz
Lowest calculated energy conformation
shows these H’s have a dihedral angle of 65º
J3 = 10.1 Hz suggests a dihedral angle closer to 180º
The Karplus Equation
J3 = A(cos2φ) + B(cosφ) + C
Revised Structure of Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 43
There is another conformer 1.6 kcal/mol higher in energy with a H4-H5 dihedral angle of 159º
O
O
O
O
O
O
HOH
3
14
5
11
12
10
7619
18
1716
1514
13
9
20
2221
23
2
8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
-25.0-20.0-15.0-10.0-5.00.05.0
10.015.020.025.0
Hexacyclinol (Revised, Conformation 2)
Carbon Number
Δδ
(ppm
) Average Δδ = 1.8 ppm
Maximum Δδ = 5.2 ppm
Revised vs. Originally Proposed Hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895 44
O
O
O
O
O
O
HOH
3
14
5
11
12
10
7619
18
1716
1514
13
9
20
2221
23
2
8
Average Δδ = 1.8 ppm
Maximum Δδ = 5.2 ppm
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Revised vs. Originally Proposed Hexacylinol
Carbon Number
Δδ
(ppm
)
OO
OO
OH
O
O
31
45
1112
107
619
18
17
1615
14
13 9
20 22
21 23
2
8
Average Δδ = 6.8 ppm
Maximum Δδ = 22.0 ppm
Two Proposed Structures for Hexacyclinol
45
OO
OO
OH
O
O
O
O
O
O
O
O
HOH
Gräfe’s Proposed Structure of Hexacyclinol
Rychnovsky’s Proposed Structure of Hexacyclinol
Synthetically confirmed by La Clair
Supported by NMR PredictionNo synthetic corroboration
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Porco, J. A.; Su, S.; Lei, X.; Bardham, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 46
O
O
O
O
O
O
HOH
“In light of our prior synthesis of Panepophenanthrin and access to the natural product as well as chiral, nonracemic epoxyquinol monomer precursors, we
initiated studies to prepare the revised structure of Hexacyclinol.”
John A. Porco Jr.Boston University
Angewandte Chemie International Edition
Received July 18, 2006Published Online July 27, 2006
O
O
O
O
O
O
HOH
OOH
OH
OH
O
H
H O
OH
O
OOH
OH
OH
O
H
H O
OH
O
O
O
O
O
O
O
HOHO
O
H
H O
OH
O
O
O
Hexacyclinol = Isolation Artifact of Panepophenanthrin?
Rychnovsky, S. D.; Org. Lett. 2006, 8, 2895 47
PanepophenanthrinHexacyclinol?
O
O
H
H O
OH
O
O
O
Hexacyclinol From Acid-Catalyzed Rearrangement of Panepophenanthrin?
Porco, J. A.; Su, S.; Lei, X.; Bardham, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 48
O
O
O
O
O
O
HOH
OOH
OH
OH
O
H
H O
OH
O
SiO2 / MeOHor
K10 Clay / MeOHor
CHCl3 / MeOH Recovered Starting Material
Hemi-acetal “locks” the structure and prevents ring opening
The revised Hexacyclinol could not have come from Panepophenanthrin directly, but they might share a common biosynthetic intermediate
Attempted validation of Rychnovsky’s hypothesis
Panepophenanthrin
HOO
OH
OHO
O OH
O
[4+2]Dimerization
OOH
OH
OH
O
H
H O
OH
O
OOH
OH
H
H O
OH
O
OHO
HemiacetalFormation
Panepophenanthrin via[4+2] Dimerization
49
O
O
O
O
O
O
HOH
Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913
HOO
OH
O
[4+2]Dimerization
OOH
OH
OH
O
H
H O
OH
O
OOH
OH
H
H O
OH
O
OHO
HemiacetalFormation
Panepophenanthrin
O
O H
OH OH
O
OH
H
HOO
O
O H
OH OH
O
OH
H
HOO
HH
HH
O
O
O
OH
H
OHH
HO
OH
O
Total Synthesis of Panepophenantrin via Spontaneous [4+2] Dimerization
50
O
O
O
O
O
O
HOH
Dimerization reaches 80% after standing neat for 24 h.
80 %
Could Hexacyclinol be formed from a similar epoxyquinol monomer intermediate?
Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913
MeOO
OH
O[4+2]
Dimerization
OOH
OMe
H
H O
OH
O
OMeO Acid-Catalyzed
net-SN2' EliminationO
O
O
OMe
O
O
HOH
HOO
OH
O[4+2]
Dimerization
OOH
OH
OH
O
H
H O
OH
O
OOH
OH
H
H O
OH
O
OHO
HemiacetalFormation
Hexacyclinol
Hexacyclinol From[4+2] Dimerization?
51
O
O
O
O
O
O
HOH
Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913
Panepophenanthrin
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Hughes, A. B.; Sargent, M. V. J. Chem Soc. Perkin Trans. 1 1989, 1787Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913 52
O
O
O
O
O
O
HOH
OMe
OAc
OMe
OAc
BrOMe
OH
BrBr2
NaOAc
HOAcRT
36 h93 %
H2O / MeOHRT
45 min
KOH
96 %
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 53
O
O
O
O
O
O
HOH
OMe
OH
Br
O
BrMeO OMe
OOBr
O
PhI(OAc)2
MeOHRT1 h
96 %
HO OHBF3 • Et2O
DMERT2 h
75 %
Ph3COOHNaHMDSL-DIPT4Å MS
Toluene- 55 °C
48 h
OOBr
O
O80 %
95 % ee
Oxidation of Phenols with PhI(OAc)2
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677 54
O
O
O
O
O
O
HOH
OMe
OH
Br
O
BrMeO OMe
PhI(OAc)2
MeOHRT1 h
96 %
OMe
OH
Br
PhI
OAc
OMe
O
Br
IPh
HOAc
MeOH
O
BrMeO
PhIHOAc
OAc
OAc
OMe
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 55
O
O
O
O
O
O
HOH
OMe
OH
Br
O
BrMeO OMe
OOBr
O
PhI(OAc)2
MeOHRT1 h
96 %
HO OHBF3 • Et2O
DMERT2 h
75 %
NaHMDSL-DIPT4Å MSToluene- 55 °C
48 h
OOBr
O
O80 %
95 % ee
OPhPh
PhOH
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Lei, X.; Johnson, R. P.; Porco, J. A. Angew. Chem. Int. Ed. 2003, 42, 3913Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 56
O
O
O
O
O
O
HOH
OOBr
O
OH
OOBr
O
O
LiEt3BH
THF-78 °C
1 h
OOBr
O
O
PPh3DIAD
O2N
OH
O
98 %
THF-50 °C - RT
1 h
O
NO2
NaOMe(1M)
MeOHRT
30 min
OOBr
O
OH
80 %(over 2 steps)
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 57
O
O
O
O
O
O
HOH
OOBr
O
OH
K10 Clay(Montmorillonite)
CH2Cl2RT6 h
BrO
OH
O
98 %
Et3SiCl2,6-lutidine
DMAP (cat.)
CH2Cl2RT3 h
BrO
OTES
O
83 %
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 58
O
O
O
O
O
O
HOH
Me
MeMeO
O
OTES
OToluene110 °C
1 h
Pd2(dba)3AsPh3
Me
MeMeO
SnBu3
96 %
Me
MeMeO
PdCl2(PPh3)2n-Bu3SnH
THFRT
35 min
BrO
OTES
O
67 %
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790 59
O
O
O
O
O
O
HOH
MeOO
OTES
O
MeOO
OH
OEt3N • 3 HF
CH3CN0 °C - RT
15 min
Both intermediates partially dimerize upon standing without solvent at RT
exo-[4+2] Dimerization
60
O
O
O
O
O
O
HOH
Dimerization is complete after standing neat for 72 h.
87 % from silyl-protected
alcohol “Pre-Hexacyclinol”
O
O H
OH OMe
O
OMe
H
HOO
O
O H
OH OMe
O
OMe
H
HOO
HH
HH
O
O
O
OH
H
OHH
MeO
OMe
O
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790
Porco’s Synthesis of the RevisedStructure of Hexacyclinol: Endgame
61
O
O
O
O
O
O
HOH
O
O
O
OH
H
OHH
MeO
OMe
O
K10 clay(Montmorillonite)
EtOAcRT
3 min
O
O
O
OMe
O
O
HOH
99 %O
O
O
OH
OHH
MeO
O
"Pre-Hexacyclinol" Hexacyclinol
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790
14 Linear Steps27 % Overall Yield
Porco’s Synthesis of the RevisedStructure of Hexacyclinol
62
“Synthetic Hexacyclinol was confirmed to be identical to spectral data (1H, 13C NMR) reported by Gräfe and co-workers. X-ray crystal structure analysis fully confirmed the
structural framework”
O
O
O
O
O
O
HOH
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790
X-Ray Crystal Structure of Synthetic Hexacyclinol
63
O
O
O
O
O
O
HOH
Porco, J. A.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790
Conclusions
64
OO
OO
OH
O
O
O
O
O
O
O
O
HOH
Gräfe’s Proposed Structure of Hexacyclinol
Rychnovsky’s Proposed Structure of Hexacyclinol
Synthetically Preparedby La Clair
Synthetically Preparedby Porco
Structure Confirmed byX-Ray Crystallography
Conclusions
Chemical and Engineering News, July 31, 2006, p. 11
“Occasionally, blatantly wrong science is published, and to the credit of
synthetic chemistry, the corrections usually come quickly and cleanly.”
- Elias J. Corey
65
Conclusions
Feynman, R. Surely You’re Joking, Mr Feynman!: Adventures of a Curious Character; W. W, Norton: New York; 1997
“We’ve learned from experience that the truth will come out. Other experimenters will repeat your experiment
and find out whether you were wrong or right…although you may gain some temporary fame and excitement,
you will not gain a good reputation as a scientist if you haven’t tried to be very careful in this kind of work.”
- Richard Feynman
66