misassigned natural products and the role of chemical synthesis in modern structure ilucidation:...
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Misassigned Natural Products and Misassigned Natural Products and the Role of Chemical Synthesis in the Role of Chemical Synthesis in
Modern Structure Ilucidation: Modern Structure Ilucidation: Total Synthesis of (+)-Total Synthesis of (+)-
HexacyclinolHexacyclinol
Jolaine Savoie, 18 Mars 2008Department of Chemistry, Université de Montréal,
C.P. 6128 Station Downtown, Montréal, Québec, H3C 3J7, Canada
Summary
1. Introduction2. The state of modern structure elucidation
Total synthesis of (+)-hexacyclinol by La Clair Formation of endoperoxides Stability endoperoxides Using the endoperoxide as a synthetic intermediate Total synthesis of (+)-hexacyclinol by Porco &
Rychnovsky3. Conclusion
Molecules of Mistaken Identity & Total Synthesis
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Structural Hypotheses
What’ s the Role of Total Synthesis Today?
Before World War II Degradation Derivatization
Today Multidimensional NMR SpectroscopyHigh-Resolution Mass SpectroscopyX-Ray Crystallography
Scale up for biological testing Structural assignment
Molecules of Mistaken Identity & Total Synthesis
A CLASSICAL MISASSIGNMENT: Wieland and Windaus, two researchers in Germany, won the Nobel Prize in Chemistry in 1927-1928 because of the
proposed structure of cholesterol
Me
Et
OHMe
MeMe
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Molecules of Mistaken Identity & Total Synthesis
Number of inaccuracies in the core structure was revealed in 1932 by Bernal, who obtained on X-Ray cristal structure of ergosterol.
Structure of Ergosterol (1932)Verified by X-Ray Crystal Analysis
Correct Structure of
Cholesterol (1932)
HO
H HHO
H H
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Molecules of Mistaken Identity & Total SynthesisIn 1962, Büchi and his colleagues at the Massachussetts Institute of
Technology (MIT), obtaining synthetic material that fully corresponded to authentic patchouli alcohol.
H
-Patchoulene
H
O
H2O
H+
H
OHOH
1) Ac2O, py,
2) 300oC, 30 min
3) H2, PtO2H
OH
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Molecules of Mistaken Identity & Total SynthesisIn 1963, Dunitz and his colleagues at Eidgenössische Technische Hochschule
Zürich, used the X-Ray Crystal Analysis of patchouli alcohol and reassigned the structure.
H
-Patchoulene
H
O
H2O
H+
1) Ac2O, py,
2) 300oC, 30 min
3) H2, PtO2
OH OHOH
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Molecules of Mistaken Identity & Total Synthesis
Surprisingly, the examples outlined in the Nicolaou’s review cover virtually every compound class : stereods, terpenes, indole alkaloids and peptides and
encompass molecules of all sizes and levels of stereochemical complexity.
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Proposed Structure
Method Original
Assignment
Revised StructureBasis for Revision
Verified ByTotal Synthesis
Why do so many errors occur?
Molecules of Mistaken Identity & Total Synthesis
The answer from Nicolaou is : The number of errors simply reflects the fact that every method of assignment has its weaknesses, some of which can not be resolved even if every tool for structural elucidation is also applied.
X-Ray Crystal Analysis Does not reveal the hydrogen atoms (discern between O and N) Confuse the identity of atoms within certain functional groups (cyano vs diazo)
High –Resolution Mass Spectroscopy Ionisation (Fast –Atom Bombardment (FAB) vs Electron Spray Ionisation (ESI)
IR SpectroscopyStructural information
K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed., 2005, 44, 1012-1044
Total Synthesis of (+)-Hexacyclinol: La Clair
1. Introduction2. The state of modern structure elucidation
Total synthesis of (+)-hexacyclinol by La Clair Formation of endoperoxides Stability endoperoxides Using the endoperoxide as a synthetic intermediate Total synthesis of (+)-hexacyclinol by Porco &
Rychnovsky3. Conclusion
Story of (+)-Hexacyclinol
Panus Rudis
Biological Data
Isolated by Gräfe and co-workers , in 2002.
From basidiospores collected from Panus Rudis (Mushrooms growing on dead wood).
Biosynthesis of hexacyclinol occurs via the terpenoid pathway.
Moderate antibiotic activity.
Showed an antiproliferative effect.
Inhibitory activity against (P. Falciparum). (antimalariale)
OO O
OO
OH
O
Story of (+)-Hexacyclinol
OO O
OO
OH
O
2
OO O
OO
OH
O
1
O
OO
OH
O
3
In vacuo, neat, 95%
O2, rose bengal, MeOH, h, 0oC, 89%
German fungal cultures provided a strain of P. rudis that was able to do the biosynthesis of 1, 2 and
3.
Retrocycloaddition of 1 and 2 released oxygen to afford 3.
[2+2+2] cycloaddition of 3 with singlet O2 returned to a mixture of 1 and 2.
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Retrosynthetic Analysis for Hexacyclinol
OO O
OO
OH
O
2
O
OO
OH
O
3
O
OO
OH
O
J
O
OO
OH
i
O
OOH
HO
OOH
G
O
OOH
F
O
OH
E
OH
D C B A
Retrosynthetic Analysis for Hexacyclinol: Jolaine
OO O
OO
OH
O
2
O
OO
OH
O[2+2+2]
O
OO
OH
O
OH
OO
O
O
O
O
OGP
OO
O
OO
O
PGO
PGO
1. [O]2.Julia
1. Hydrolyse2. -Elimiation
1. -Thiolation2. [O]3. Julia
O
O
O SOPh
OO
O
PGOPGO H
O
O
SOPh
O
O
OH
O
PGO H
O
O
O
OGP
PhS
O
TBSO H
O
OO
O
OGP
O
OO
OH
TBSO CN
1. Ring opening via esterification2. Thermolysis
O
Aldol
Acetal clivage
SN2 cyclization
a b
c
de
f
g hi
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Cyclization Via SN2
Isomerisation
OAc
HO OAc
OH
TBSO ONs
OH
TBSO CN
1)TBSCl, imidazole,DMAP(cat), DCM
2)NH3, MeOH, RT
3) NsCl,pyridine,0oC--> RT
NaCN (1,5 eq)DMSO, 85oC,32h
72% (4 steps)
4 5 6
O
TBSO CN
7
O
Br
2)2,6-lutidine (2 eq), DCM0oC-->RT, 67%
O
TBSO
8a: R1=CN, R2=H8b: R1=H, R2=CN
O
R2R1
NaHMDS, THF, -78oC-->RT
1) NaHMDS, THF, -78oC-->-40oC
1)methylvinyl ether, Br2
3:2( 8a:8b)
2) Ph3CCO2H,THF, 67% (3 steps)
O
TBSO
8a: R1=CN, R2=H8b: R1=H, R2=CN
O
R2R1
11:1( 8a:8b)
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Cyclization Via Mitsunobu Reaction
O
TBSO
8a: R1=CN, R2=H8b: R1=H, R2=CN
O
R2R1
O
TBSO
O
HO
DIBAL-H, Toluene-78oC-->RT
9
O
TBSO
O
H
10S S
OH
TBSO H
11
S S
H
O
TBSO H
13
S S
O
O
ZnBrDCM, 59% (2 steps)
HCl in aq. THF
Ag2O in paraffin, DCM , RT
PPh3, DIAD, DCM, RT, 16h, 68%(4steps)
LiOH aq. THF
11:1(8a:8b)
SSTMS TMS
OH
TBSO H
12
S S
HO
O
D. Picq, I. Drivas, G. Carret, D. Anker, Tetrahedron, 1985, 41,13, 2681-2690, J. Attaghrai, D. Picq, D. Anker, Carbohydr. Res. 1987, 159,159
O
OH
OMOM
O
O OMOM
O
Li
O
15 17
TPAP (cat.)NMO, DCM
92%
Et2O-pentane(8:1v/v),
-78oC-->0oC, 12, 89%
O
O
OMOM
O
18
Kinetic Resolution of Epoxyde
Synthesis of Precursor 18
O OMOM
N
O
O
OMOM1) HNAll22) MsCl
OMs
O OMOM
NO
O OMOM
NH2
OH
O OMOM
NMe2
OH
O
O
OMOM
ACN dry,rfx, 5h
KOH/H2OEtOH, r.t.30 min
EtOH, H2OAcOH, Pd-Crfx, 20h
O OMOM
NOH
Formic acidFormaldehyderfx,CHCl3:MeOH(1:1)
O OMOM
NMe3
OH
Acetone, MeI10 min, r.t.
I
Ag2O,H2O20h, r.t.
O
O
OMOM
PhO
O
OH NaO
PhHO
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Combination of 14 & 18 follow by Mitsunobu
(1:4,5)
TBSO H
13
S S
O
O
TBSO H
14
S S
O
OLi
O
O
OMOM
O
18
TBSO H
19a
S S
O
O
O
OMOMHO
OTBSO H
19b
S S
O
O
O
OMOMHO
OTBSO H
20
S S
O
OO
OMOM
PhS
O
1)LDA (1.1 eq)HMPA (3 eq)THF, -78oC
2)n-BuLi(1.1 eq)-78oC--> -60oC
2h
1)-78oC, 18, THF, 2h2)-78oC --> RT, 62%
PhSH, PEt3, DEAD, DCM, 45oC, 24h, 94%
PhSH, PEt3, DEAD, DCM, 45oC, 24h
Li
Since 19a didn’t react, that result suggested that the C6-carbinol was too hindered to form the required alkoxyphosphonium
intermediate.
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
PhSO
TBSO H
20
S S
O
O
O
OMOM
PhS
O
TBSO H
21
S S
O
OO
OMOMSPh
O
TBSO H
22
O
O
O
OMOM
O
1)LDA (1.1 eq), THF;-78oC--> -50oC
2)CH3COCN, -78oC-78oC--> RT,12h, 92%
O
2)CSA (0,2 eq),RT, t-BuOMe, 6h, 94%
TBSO H
23a
O
O
O
O
SOPh
OH
O
TBSO H
23b
O
O
SOPh
O
O
OH
O
TMSCl (1.2 eq), H2O (5.0 eq.), DCM, 0oC, 97%
1)mCPBA (3 eq), DCMO O
OO
Tandem Ring Opening & Closing Via Cleavage MOM Group
Cyclization
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Ring Closing via Aldol Reaction
23b
TBSO H
O
O
SOPh
O
O
X
O
OH
Add MsCl (1 eq) and Et3N(1 eq) in DCM once an hour 5h at -10oC, -10oC -->RT,
16h, 76%
24a X= OMs24b X=Cl
O
O
O SOPh
OO
O
TBSO
OO
SOPh
O
OO
O
TESO
TBSOO
O
O
OO
O
TESO
TBSO
1) PhSNa (0.2 eq.), MeOH
2)TESOTf, 2,6-lutidine, DCM, -20oC-->RT,
82% (2 steps)
252627
60-70oC, DMF, 16h, 92%
TBSO H
O
O
SOPh
O
O
OH
O
O
Ring opening via esterification
Thermolysis
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Intermolecular Cyclization Via Julia-Kocienski Olefination
-Thiolation
OO
O
OO
O
TESO
TBSO
27
OO
O
OO
O
TESO
TBSO
28
BtSO O
OO
O
OO
O
TESO
O
29
BtSO O
OO
O
O
O
O
OTES
31
O
OO
O
O
O
O
OTES
30
1)KHMDS (1.1eq), THF, -78oC-->-50oC2)(BtS)2, -78oC,
-78oC-->0oC, 12h
3)oxone, 1,4-dioxane, 87%(2 steps)
1)TBAF, THF, 0oC-->RT
2) Dess-Martin Periodinane,DCM, 0oC-->RT
DBU (1.2 eq), DMAP (cat.),THF, -40oC-->RT,10h,
72% ( 4steps)
Ph3CCOOH, L-(+)-diisopropyltartratetoluene, DCM, (3:1v:v)
O
O
OTES
32
O
KOTMS,THF,-10oC--> 35oC,
5h, 69%
OH
OOO
O
O
O
O
OTES
31
O
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Mechanism
Tandem Hydrolysis & -Elimination Ring Opening
OO
O
O
MeO
O
O
OTES
31
O O
O
OTES
32
O
O
O
OTMS
O
O
O
O
O
OTES
O
-CO2
O
O
OTES
32
O
OH
O
O
O
OTES
33
O
O
O
O
O
OTES
35
O
O
OO O
OO
OH
O
2
MnO2, DCM, RT
N
N NH
NS
OO34
1) 34, KHMDS, -78oCthen -78oC--> -30oC, 2h
2) 33, -78oC-78oC-->RT, 12h
76% (2 steps)
O2, rose bengal, MeOHh, 0oC, 82%
[2+2+2]
O
O
OH
3a
O
O
H2SiF6aq. cat.CH3CN/tBuOH(9:1 v/v)
r.t., 78%
OO O
OO
OH
O
1
J. J. La Clair, Angew. Chem. Int. Ed., 2006, 45, 2769-2773
Cycloadditon [2+2+2]
Allylic Oxidation Julia-KocienskiOlefination
(8:1)
0,6% for 37 steps
Natural
Synthetic D= 131,5o c= 0,40,
D= 130,5o c= 0,403
1. Introduction2. The state of modern structure elucidation
Total synthesis of (+)-hexacyclinol by La Clair Formation of endoperoxides Stability of endoperoxides Using the endoperoxide as a synthetic
intermediate Total synthesis of (+)-hexacyclinol by Porco &
Rychnovsky3. Conclusion
T.C.T. Chang, M. Roseblum, J. Org. Chem., 1981, 46, 4105-4107P. M. O’Neill, S. L. Rawe, R. C. Storr, S. A. Ward, G. H. Posnet, Tetrahedron Lett., 2005, 46, 3029-3032
O
O
HO
PGG2
PGH2
O
O
OO
H
H
OArtemisinin: antimalarial
O O
O
F
F
Fenozan : antimalarial
O O
OO
tetraoxane: antimalarial
O
OBn
OSO2Ph
synthetic peroxide: antimalarial
COOH
O
O
HOO
COOH
O
O
OO
H
H
O
MeO
H
H
O
MeO
O
1)O2, Rose Bengal in MeOH-78oC, h, 4h,
2) dry HCl, 70% HClO4 in Et2O28h, 10%
J. S. Yadav, R. Satheesh Babu, G. Sabitha, Tetrahedron lett., 2003, 44, 387-389
Direct Nucleophilic Attack on O2
O
O
O
N
OO
O
O
O
N
O2
[4+2]
Thebaine is known to produce exclusively the adduct resulting from cycloaddition on the less hindered face of the diene
PhPh OO
Ph
PhDye, CH2Cl2O2, h, < 0oC
P. M. O’Neill, S. L. Rawe, R. C. Storr, S. A. Ward, G. H. Posnet, Tetrahedron Lett., 2005, 46, 3029-3032D. Lopez, E. Quinoa, R. Riguera, J. Org. Chem., 2000 , 65, 15, 4671-4678
Diels-Alder
Thebaine
A. Rostami, Y. Wang, A. M. Arif, R. McDonald, F. G. West, Org. Lett., 2007 , 9, 4, 703-706
Nazarov
Me
Ph
O
N3-78oC -->0oC (72%)
N
OBF3
Me
Ph
O21,5-H
5 : 5 : 1
BF3 Et2O
N
O
Ph
Me
N
OPh
H O O
Me
N
OH
Ph O O
Me
OO
O
H
TMSOOTMS
OO
HO
O
HO
1) TiCl4 (3-4 eq)-78oC, CH2Cl2
2)0.5M K2CO3,0oC, 1h, then HCl/MeOH
OO
O
H
TMSOOTMS
OO
O
TMSO
1) TiCl4 (3-4 eq)-78oC, CH2Cl2
2) pyridine (21eq)-20oC -->-30oC11h
70%
70%
OO
O
TMSO
13%
TMSO
A. M. Szpilman, E. Korshin, H. Rozenberg, M. D. Bachi, J. Org. Chem., 2005, 70, 9, 3618-3632
Mukayama Aldol
O
O
OO
H
H
O
Grubbs 1 (10%)CH2Cl2 (0.3M)
83%
O
O
OO
H
H
O
O
O
OO
H
H
O
O
O
OO
H
H
CF3
OO
O
OO
H
H
CF3
OO
O
OO
H
H
CF3
O
Grubbs 1(5%)rfx, CH2Cl2, 1.5h
71%
ratio (E:Z);(90:10)
F. Grellepois, B. Crousse, D. Bonnet-Delpon, J.-P. Bégué, Org. Lett., 2005, 7, 23, 5219-5222
Metathesis
V. K.-Y. Lo, Y. Liu, M.-K. Wong, C.-M. Che, Org. Lett., 2006, 8, 8, 1529-1532
O
O
OO
H
H
O
H
NH
+ + Ph H
1a, H2O, N2
40oC, 24h
O
O
OO
H
H
N
Ph
H
a: 59%b: 13%
1a
O
N N
OAu Cl
Gold Coupling
H.-X. Jin, H.-H. Liu, Q. Zhang, Y. Wu, J. Org. Chem., 2005, 70, 4240-4247 B. J. Kim, T. Sasaki, J. Org. Chem., 2004, 69, 3242-3244
O
O
OO
H
H
OAc
BrHO
TMS triflate (0.1 eq)dry CHCl3, rt
89%O
O
OO
H
H
O
Br
Acetalization
O OO OO
O OOHO
LiBH4 (2.0eq)Et2O
0oC, 24 min91%
Reduction
HH
O O HO OHHO O
Komblum-DeLaMareRearrangement
Enantioselectivedesymmetrisation
reaction
Mechanism
Example
BnO OBn
OO
BnO OBn
OHO
1(10 mol%) r.t, 24h
N
N
OAc
HO
1
Kornblum DeLaMare Rearrangement
S. T. Staben, X. Linghu, F. D. Toste, J. Am. Chem. Soc, 2006, 128, 12658-12659
HH
O O
B
O O
B H
HO O
I. Erden, N. Öcal, J. Song, C. Gleason, C. Gärtner, Tetrahedron, 2006, 62, 10676-10682
Mechanism
Example
O O
1. O2, -78oC
NH2. HN
DBU O
82%
Endoperoxide Isomerisation: 2-Vinyl-2-Cyclopentenone
RR
O O
1. O2, -78oC
NH2. HN
DBU O R
H
O O
DBUR H
R
H
O OH
H R
O OH
HR
O
B
H
B.W. Greatrex, D.K. Taylor, J. Org. Chem, 2004, 69, 2577-2579T. V. Robinson, D. K. Taylor, E. R.T. Tiekink, J. Org. Chem, 2006, 71, 19, 7236-7244
Ring Contraction
3,6-Dihydro-1-2-dioxine
OO
c-C6H11 O
PPh3, CHCl360oC, 5h
97% O
Oc-C6H11
OO
PPh3, CHCl360oC, 3h
63% Oc-C6H11
H H
c-C6H11
Epoxy-1-2-dioxine
OO Br
BrOO
Co(II)[SALEN]2 (5 mol%), THF, 3-12h
91%O BrHO
Br
O O
(95:5)
C. Fattorusso, G. Campiani, B. Catalanotti, M. Persico, N. Basilico, S. Parapini, D. Taramelli, C. Campagnuolo, E. Fattorusso, A. Romano, O. Taglialatela-Scafiati, J. Med. Chem, 2006, 49, 24, 7088-7094
T. V. Robinson, D. K. Taylor, E. R.T. Tiekink, J. Org. Chem, 2006, 71, 19, 7236-7244
Reduction of Endoperoxide
OO
COOCH3
Zn/AcOHEt2O
OHHO
COOCH3
O
HH
LiAlH4Et2O
OO
COOCH3
O
HH
OH CH2OHHO
OH
OH CH2OHHO
OH
OO OTBDMS
TBDMSOOHHO
HOOH OTBDMS
TBDMSOOHHO
5%Pd-C (10%w/w)H2, MeOH
90%
T. V. Robinson, D. K. Taylor, E. R.T. Tiekink, J. Org. Chem, 2006, 71, 19, 7236-7244
Reduction of Endoperoxide
OOn-Pr n-Pr
OHHO
HOOH
n-Pr n-Pr
OHHO
10%Pt-C (10%w/w)H2, MeOH
69%
OO n-Pr
n-PrOHHO
HOOH n-Pr
n-PrOHHO
Mg(5mmol)I2, MeOH, 24h
77%
OO n-Pr
n-PrOHHO
HOOH n-Pr
n-PrOHHO
Thiourea(5mmol)MeOH, 3-5 days, 66%
1. Introduction2. The state of modern structure elucidation
Total synthesis of (+)-hexacyclinol by La Clair Formation of endoperoxides Stability of endoperoxides Using the endoperoxides as a synthetic
intermediate Total synthesis of (+)-Hexacyclinol by Porco
&Rychnovsky3. Conclusion
J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, 5790-5792
What is the wrong with the structure of (+)-hexacyclinol ?
Proposed a new structure of (+)- hexacyclinol based :
1.On calculated 13C NMR chemical shift correlation.2.From an acid catalyzed rearrangement panepophenanthrin. (ubiquitin activating enzyme inhibitor)
OO O
OO
OH
O Gräfre’ s proposed structure
La Clair’s synthesis
O
OOH
H
MeO
OO
O
O
O OH
H
O
OH
OHO
OH
H
Pabepophenanthrin
J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, 5790-5792
Revised Retrosynthetic Analysis for Hexacyclinol
O
OOH
H
MeO
OO
O
O
OOH
H
MeO
O
O
OH
OMe
OMe
O
O
OH
2 4 5
[4+2]
Synthesis of Precursor 7 Via Oxidation Reaction
A. B. Hughes, M. V. Sargent, J. Chem. Soc. Perkin Trans 1, 1989, 10, 1787-1791 X. Lei, R. P. Johnson, J. A. Porco, Jr., Angew. Chem. Int. Ed., 2003, 42, 3913-3917
Chelation-controlled reduction was attempted using DiBAL-H or Zn(BH4)2
to induce the anti-epoxy alcohol, but it’s showed no diastereoselectivity (1:1).In contrast, the reduction with the Super-Hydride cleanly afforded syn-epoxy alcohol.
OMe
OAc
H
OMe
OAc
Br
OH
BrBr2, AcOH
NaOAc any, 93%
KOH/H2OMeOH, 45 min,
r.t., 96%
OMe
O
Br
OMeOMe
O
BrOO
PhI(OAc)2MeOH, r.t.1h, 96%
1,3-propanediol,BF3 Et2O,
DME, r.t., 2h75%
O
BrOO
O
Ph3COOH, NaHMDS (1M in THF),
L-DIPT, 4A molecular sieves,Toluene, -55oC,
48h, 80%, 95%ee
OH
BrOO
O
1)LiEt3BH, THF, -78oC, 1h
2) PPh3, DIAD,4-nitrobenzoic acidTHF, -50oC-->R.T.10h, 80%( 2steps)7
9 introduce via Stille Coupling
J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, 5790-5792L. T. Scott, G. J. DeCicco, J. L. Hyun, G. Reinhardt, J. Am. Chem. Soc., 1985, 107, 6546-6555
H.X. Zhang, F. Guibé, G. Balavoine, J. Org. Chem., 1990, 55, 1857
OO
O
OH
BrO
OTES
Br
O1) K10 clay, DCM
6h, 98%
2) Et3SiCl, 2,6-lutidineDMAP(cat), DCM, 83%
SnBu3
MeO
Pd2(dba)3, AsPH3, Toluene, 110oC, 1h, 96%
O
OTES
OMeO
7 8 10
9
Hydrostannylation of propargyl alcohol ( 9)
SnBu3
MeO
9
OH OMea) NaH, dry DMF
0oC, 3h
H H
b) (MeO)2SO2,2h, r.t., 80%
PdCl2(PPh3)2dry THF, Bu3SnH
J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, 5790-5792
Diels-Alder Reaction & SN2’ substitution/Cyclization
10 partially dimerized upon standing without solvent (25oC). The Diels-Alder ‘s product was
cleanly obtained in 87% yield as a single diastereoisomer.
O
OTES
OMeO
10
O
OOH
H
MeO
OO
O
O
OOH
H
MeO
O
O
OH
OMe
24
1)Et3N-HF, CH3CN0oC--> RT, 15 min
K10 clay, EtAcO, RT, 99%
2) neat, RT,72h, 87%(two steps)
28% for 11 steps
J. A. Porco, S. Su, X. Lei, S. Bardham, S. D. Rychnovsky, Angew. Chem. Int. Ed., 2006, 45, 5790-5792
X-Ray Crystal Structure Analysis of Synthetic 2
SN2’ cyclization places the prenyl substituent at C-5 in a pseudo equatorial orientation,
which minimizes steric interactions on the envelope
conformation of the tetreahydrofuran ring.
O
OOH
H
MeO
OO
O
2
C-5 position
C-5 position
D= 133,3o c= 0,40
D= 130,5o c= 0,403
Porco & Rychnovsky
La Clair
D= 133,3o c= 0,40, MeOH
D= 131,5o c= 0,40,
Conclusion
La Clair Porco & Rychnovsky No 13C data or
experimental protocols in the supporting information.
[]D & 1H NMR similar to the natural product.
Proof on his structure: release of O2 .
Fugal cultures can make hexacyclinol & desoxyhexacyclinol.
[]D & 1H NMR similar to the natural product.
13 C NMR data matched the natural product.
X-Ray Crystal obtained synthetic material (not natural product).
Proposed that hexacyclinol is an artifact obtained during the isolation procedure.
No mention of O2 release.