The Hexacyclinol Incident Adam Hoye Current Literature Sept. 16th, 2006 La Clair, J. J., Angew. Chem. Int. Ed., 2006, 45, 2769-2773 + supporting info. Rychnovsky, S. D., Org. Lett. 2006, 8, 2895-2898 Porco, J. A. Jr.; Su. S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D., Angew. Chem. Int. Ed. 2006, 45, 5790-5792
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The Hexacyclinol Incident
Adam HoyeCurrent LiteratureSept. 16th, 2006
La Clair, J. J., Angew. Chem. Int. Ed., 2006, 45, 2769-2773 + supporting info.Rychnovsky, S. D., Org. Lett. 2006, 8, 2895-2898
Porco, J. A. Jr.; Su. S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D., Angew. Chem. Int.Ed. 2006, 45, 5790-5792
Hexacyclinol (Gräfe)
Isolated in 2002 as a metabolite from fungal strain Ranus rudis HKI 0254(Antiproliferative activity against L-929 cells and inhibition of respiratory burstactivity in PMNL)
Structure determined by mass spectrometry, 1D and 2D NMR spectroscopy (1H, 13C,DEPT, COSY, HMQC, HMBC, NOESY), and IR.
OO
CH3
H3C
H
O
OH
CH3
H3C OCH3
O
H
O
H
H
Schlegel, B.; Härtl, A.; Dahse, H-M; Gollmick, F. A.; Gräfe, U.; J. Antibiot. 2002, 55, 814
La Clair- Initial Hexacyclinol Observations
J. J. La Clair- previously unpublished results
O
OH
OO
O
OOO
OR
OO
O
O
OH
OO
O
OO
in vacuo, neat, 95%
O2, rose bengal, h!,89%
desoxohexacyclinol 5-epi-hexacyclinol hexacyclinol
La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769-2773
La Clair’s Synthesis
OAcHO
OAcOtBu
OAcAcO
OAc Enzymatic Hydrolysis
1. AcOH, AcO2, perchloric acid2. O3
3. NaBH44. Ac2O/pyridine
28%
7% recovered yield, 95%ee
12 3
(from norbornadiene)
Baumgarten, H. E., Org Synth. 1973, 5, 151Tanaka, M.; Norimine, Y.; Fujita, T.; Suemune, H. J. Org. Chem. 1996, 61, 6952-6957
OAcHO
OAc
1. TBSCl, imid., DMAP2. NH3, MeOH
3. NsCl, pyr.ONsTBSO
OH NaCN, DMSO, 85°C
CNTBSO
OH
72% from 3
methyl vinyl ether,Br2, then 5, 2,6-lutidine67%
CNTBSO
O
O
Br1. NaHMDS, THF,-78°C to rt
2. NaHMDS, THF,-78°C to -40°C, thenPh3CCO2H
67%
TBSO
O
O
HCNH
11:1 ratio of cyanide diastereomers
DIBAL-H, toluene,-78°C to rt
TBSO
O
O
HO
(TMSSCH2)2CH2,ZnBr2, CH2Cl2
TBSO
O
O
H SS
59% from 7
1. HCl, THF (aq)
TBSO
O
O
H SS
68% (4 steps)
34
5
67
8
9 9a
TBSO
O
O
H SS
10
1. LiOH, THF (aq.)
2. PPh3, DIAD, CH2Cl22. slow add'n of Ag2Oin parrafin, CH2Cl2
La Clair’s Synthesis
TBSO
O
O
H SS
LDA, HMPA, -78°C
TBSO
O
H SS
OLi
Lithen nBuLi,
-78°C to -60°C, 2 hr
O
OOMOM
Li
O
O
OMOMHO
O
O
OMOMO
O
TPAP, NMO
Slow add'n
TBSO
O
HS
S
O
O
OMOM
O
HO
TBSO
O
HS
S
O
O
OMOM
O
HO
PhSH, PEt3,
DEAD, CH2Cl2
94%
TBSO
O
HS
S
O
O
OMOM
O
PhS
62%
19%
10 11
12
1314
15a
15b
16
La Clair’s Synthesis
TBSO
O
HSS
O
O
OMOM
O
PhSLDA
1. mCPBA
2. CSA (0.2 eq),tBuOMe (aq)
TBSO
O
HSS
O
O
OMOM
O
PhS
R
TBSO
O
H
O
O
OMOM
O
S
R
OR=COCH3
R=COCH3
O
Ph
then CH3COCN
TMSCl, H2O97%
94%92%
TBSO
O
H
OR
O
R=COCH3
SOPh
OH
OO
TBSO
O
H
O
SOPh
O
O
OH
O
TBSO
O
H
O
SOPh
O
O
X
O
OH
MsCl, NEt3
TBSO
O
H
O O
O
O
SOPh
X=OMs, Cl
1. PhSNa, MeOHTESO
TBSO O O
SPh O
O
OO
O60-70°C, DMF
92%
TESO
TBSO O O
O
OO
O
16
1718
19a19b
20 21 22
76%
2.TESOTf, 2,6-lutidine82%
13
17
1813
17
18
19
19
6
6
18
18
O
O
La Clair’s Synthesis
1. KHMDS, then (BtS)2
2. oxone, wet 1,4-dioxane
87%
TESO
O O
O
OO
O
BtS
OO
TBSO
1. TBAF
2. DMP
TESO
O O
O
OO
O
BtS
OO
O
DBU, DMAP (slow add'n),-40°C to rt72% from 23
O O
O
O
O
OR
O
O O
O
O
O
OR
OO
O
OR
OO
O
HO
O
OR
OO
O
O
KHMDS, -78°ˇC then 28, -78°C to rt2. cat. H2SiF2 (aq.),CH3CN/tBuOH
SO O
O
OH
OO
OO2, rose bengal
MeOH, h!
82%O
OH
OO
O
OO
KOTMS, THF
-10°C to 35°C69%
R = TESR = TES
R = TES
76% from 27
NN
NN
Ph
TESO
TBSO O O
O
OO
O
2223 24
2526
27
28
29
5-epi-Hexacyclinol (30)
5
Bt= Benzothiazole
MnO2
1.
R = TES
Ph3COOH,L-diisopropyltartrate
CH2Cl2, PhMe
La Clair’s Synthesis
O
OH
OO
O
OOO
OR
OO
O
O
OH
OO
O
OO
in vacuo, neat, 95%
O2, rose bengal, h!,89%
desoxohexacyclinol 5-epi-hexacyclinol hexacyclinol
Overall a 0.8% yielding 39 step synthesis
…but several unusual features…
-Authorship:
Google search for Bionic Bros. GmbH, Germany yields:- Recently released a new Role PlayingGame based on the basic elements of life- Address shares that of a yoga studio in Berlin
…but several unusual features…
Quantities synthesized:
so to make 3.6 g of final product (9.3 mmol) from 1 mol of diacetatecompound, which is synthesized in 1% yield from norbornadiene,which corresponds to 100 moles or 10,700 grams ($0.31/g, so$3,320 for s.m.)
Questionable Steps:
TBSO
O
HS
S
O
O
OMOM
O
HO
TBSO
O
HS
S
O
O
OMOM
O
HO
PhSH, PEt3,
DEAD, CH2Cl2
94% TBSO
O
HS
S
O
O
OMOM
O
PhS
15a
15b
16
O
OH
OO
O
OOO
OR
OO
O
O
OH
OO
O
OO
in vacuo, neat, 95%
O2, rose bengal, h!,89%
desoxohexacyclinol 5-epi-hexacyclinol hexacyclinol
…but several unusual features…
Supporting information:
3.6 grams synthesized and no 13C NMR spectrum? Intermediate characterization?
not included
1H NMR Spectra
synthetic hexacyclinol
natural hexacyclinol
Rychnovsky, S. D. Org. Lett. 2006, 8, 2895-2898
Rychnovsky’s Investigation
Validation of the structure of Hexacyclinol:Using 13C NMR data:
-chemical shifts are spread over a wide range -relatively insensitive to solvent changes-sensitive to steric and electronic influences in the structure
Precedence:David Forsyth applied MM3 geometry and evaluated NMR shiftsusing GIAO with the B3LYP method and a specialized basis setto achieve an average 2.3 ppm deviation from experimentalvalues. Bifulco found that the HF/6-31G(d) method was superiorfor nonpolar compounds, however highly oxygenated compounds(like hexacyclinol) had not been investigated.
13C NMR calculation data
-5
-4
-3
-2
-1
0
1
2
3
4
5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
ppm
-3
-2
-1
0
1
2
3
4
5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ppm
-5
-4
-3
-2
-1
0
1
2
3
4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
ppm
O
OH
O
Me
MeH
MeH
Me
Elisapterosin B
O
O
Me
O
O
OMe
Me
Maoecrystal V
H
Me
O
O
Me
OH
Me H
Me
Me
Elisabethin A
∆ δ= 1.9 ppm (3.8 ppm max)
∆ δ= 1.2 ppm (3.7 ppm max)
∆ δ= 1.4 ppm (3.8 ppm max)
13C NMR calculation data
-20
-15
-10
-5
0
5
10
15
20
25
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
ppm
∆ δ= 6.8 ppm (22.0 ppm max)
O
O O O
O
OH
O
H
Gräfe Hexacyclinol
Structure proposal
Isolation artifact:
O
OH
H
O
O
OOH
OH
OH
O
OH
H
O
O
HO
O
OH
OH
O
OH
H
O
O
HO
O
O
O
OH
H
O
O
O
O
H H H
HO
OH
H
O
O
O
OH
O
panepophenanthrin(x-ray structure)
H+
H+MeOH
Proposed strcture for Hexacyclinol
Proposed structure validation
-12
-10
-8
-6
-4
-2
0
2
4
6
8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
ppm
-6
-4
-2
0
2
4
6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
ppm
OO
OH
H
OO
O
O
∆ δ= 2.8 ppm (9.5 ppm max)
∆ δ= 1.8 ppm (5.2 ppm max)
Porco’s Initial Investigation
Therefore hexacyclinol not an isolation artifact of panepophenantherin
O
OH
H
O
O
OOH
OH
OH
O
OH
H
O
O
HO
O
OH
OH
O
OH
H
O
O
HO
O
O
O
OH
H
O
O
O
O
H H H
HO
OH
H
O
O
O
OH
O
panepophenanthrin(x-ray structure)
H+
H+MeOH
Proposed strcture for Hexacyclinol
O
OH
H
O
O
OOH
OH
OH
H
H+, MeOH
OO
OH
H
OO
O
O
Porco, J. A. Jr.; Su, X.; Lei, X.; Bardhan, S.; Rychnovsky, S. D.; Angew. Chem. Int. Ed. 2006, 45, 5790-5792
Porco’s Panepophenanthrin
Lei, X.; Johnson, R. P,; Porco, J. A. Jr. Angew. Chem. Int. Ed., 2003, 42, 3913-3917
OOBr
OTBS
OOO
OTBS
O
Me
MeHO
OH
O
Me
MeHO
O
OH
O
Me
Me
O
HO
O
Me MeOH
Me MeO
OH
OOO
OHH
O
O
O
OH
OH
H
O
OHH
O
O
OOH
OH
OH
H
[4+2]
HF, CH3CN
Pd(OAc)2, Ag2CO3
2-methyl-3-buten-2-ol,DMF, 90°C
80%
OMeBr
OHO
BrOO1. PhI(OAc)2, 96%
2. 1,3-propanediol,BF3·ˇOEt2, 75%
1. Ph3COOH, NaHMDS,L-DIPT, 4-Å MS, 80%
2. LiEt3BH, 98%3. DIAD, 4-nitrobenzoic acid,then NaOMe, MeOH, 80%4. TBSCl, imidazole, 90%
H+
-H2O
40%
OH
O
Me
MeHO
O
20%
OO
HO
H
R
O
OH
OHR
HH
8 step synthesis, 16.2% yieldKey [4+2] dimerization
Porco’s Hexacyclinol
-13C NMR data matches that of authentic material-10 steps, 38% overall yield
OOBr
OH
O
Br
OTES
O
O
SnBu3Me
MeMeO
OTBS
O
OMe
Me
MeO1. K10 clay, 98%
2. Et3SiCl, 2,6-lutidine,DMAP, 83%
Pd2dba3, AsPh3,96%
O
OH
H
O
O
MeO
O
OH
OMe
H
1. Et3N·HF, CH3CN2. neat, rt, 87% (2 steps)
OO
OH
H
OO
O
O
K10 clay, EtOAc
99%
(+)-Hexacyclinol
Conclusion
- Structure of Hexacyclinol was confirmed by computational methodscombined with synthesis- matches (13C NMR) data of authentic material-Following Porco publication, La Clair re-named ‘deoxohexacyclinol’ asdesoxoudol- claiming the 2 structures gave rise to similar 1H NMR spectradue to similar functionality and connectivity-La Clair has said a future publication is forthcoming to address voicedconcerns of original synthesis (1 year).
from www.xenobe.org
Lessons we can take home from this?
C & E News, July 31, 2006, p. 11
"Occasionally, blatantly wrong science ispublished, and to the credit of syntheticchemistry, the corrections usually come quicklyand cleanly," comments Harvard Universitychemistry professor E. J. Corey
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