Generation Of Diverse Molecular Complexity
From Cyclooctatetraene
Marquette University
ByMohamed El Mansy
04/03/2014
Diversity-oriented synthesis
Preparation of structurally complex and diverse compounds from simple starting materials.
OSi
NH2
iPriPr
OOHC NC
HOOCHN Ar
O
HN
N
O
OHN
Br
O
OSi
iPr
iPr
HO
H
N
N
O
ON
Br
OH
O
HH
Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett., 2000, 2, 709-712.
How to generate molecular diversity?
Reagent-based approach Common starting material
Substrate-based approach
Common reagents
Diversity-Oriented Synthesis: Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology, 2013 John Wiley & Sons, Inc.
Cyclooctatetraene (COT)
Simple compound C8H8. Commercially available.
Reppe, W.; Schichting, O.; Klager, K.; Toepel, T. Ann 1948, 560, 1-92. Barnes, C. E. U.S. Patent 2 579 106, 1951.Shvo, Y.; Hazum, E. J. Chem. Soc., Chem. Comm. 1975, 829-830.
HHNi (cat.)
CaC22000oC
H2O
Reaction of (COT)Fe(CO)3 with electrophiles
Fe(CO)3Fe(CO)5(CH3)3NO
(100%)
HH
Fe(CO)3BF4
Fe(CO)3
Ph
O
Ph
Fe(CO)3PF6
El= H+El=
El= PhCO+
Broadley, K.; Connelly, N. G.; Graham, P. G.; Howard, J. A. K.; Risse, W.; Whiteley, M. W.; Woodward, P. J. Chem. Soc. Dalton Trans. 1985, 777-781.
Charles, A. D.; Diversi, P.; Johnson, B. F. G.; Karlin, K. D.; Lewis, Rivera, A. V.; Scheldrick, G. M. J. Organomet. Chem. 1977, 128, C31-C34.
Davison, A.; McFarlane, W.; Pratt, L.; Wilkinson, G. J. Chem. Soc. 1962, 4821-4829.
i) PhCOCl / AlCl3ii) NH4
+ PF6-
(74%)HBF4/Ac2O(92%)
(75%)[C7H7]+B-F4/Pyridine
HH
Fe(CO)3
HH
Fe(CO)3
HH
Fe(CO)3
OPh
Mechanism for formation
H
Fe(CO)3
Fe(CO)3O
Ph
Ph
O
Fe(CO)3
[1,4]-shift
[3,3]
Fe(CO)3
H
H
Broadley, K.; Connelly, N. G.; Graham, P. G.; Howard, J. A. K.; Risse, W.; Whiteley, M. W.; Woodward, P. J. Chem. Soc. Dalton Trans. 1985, 777-781.
Charles, A. D.; Diversi, P.; Johnson, B. F. G.; Karlin, K. D.; Lewis, Rivera, A. V.; Scheldrick, G. M. J. Organomet. Chem. 1977, 128, C31-C34.
Fe(CO)3
El
Fe(CO)3
HH
Fe(CO)3
El
HH
El
Fe(CO)3
El HH
Fe(CO)3BF4
El= H+
El= PhCO+
El=
Objectives
Different
Scaffolds
OH
OHOH
OH
H2N
OH
NH2
H H
HO
OHOH
HO
Potential glycosida
ses inhibitors
Glycosidic bond
The glycosidic bond is very stable towards hydrolysis.
Glycosidase enzymes catalyze the hydrolysis reaction.
OHOHO
OH
HOO
OH
OHO
OH
HO
O
OH
HO
OH
HO
HOGlycosidases2
H2O
glycosidic linkage.
http://www.chem.qmul.ac.uk/iupac/2carb/33.html
Glycosidase inhibitors
O
OR
HOHO
OH
HO
OHOHO
OH
HOO
O
OHOHO
OH
HOOH
HO O
O
O
d
d O O
O
O
O O
HOHH2O ROH
HO O
O
O
5.5 Å
Hydrolysis of glycosidic bond with retention of configuration at anomeric carbon.
Zechel, D. L.; Withers, S. G. Acc. Chem. Res. 2000, 33, 11-18.
OHOHO
OH
HOHOR
HO
NH3+
HO
HOHO
Examples of known aminocyclitols
OH
OHH2N OH
HO
validamine
OH
OHH2N O
H
OHHO
valiolamine
NH2
OHOH
HO
HO NH2
OHOH
HO
HO NH2
OHOH
MeO
HO
OH
OH
OHH2N
HOOH
OH
OHH2N
HO
6-Membered Ring Cyclitols
7-Membered Ring Cyclitols
Hooper, R. In “Aminoglycoside Antibiotics”; Umezawa, H., Hooper, I. R., Eds.; Springer, Berlin, 1981; p 7.
Girard, E.; Desvergnes, V.; Tarnus, C.; Landais, Y. Org. Biomol. Chem. 2010, 8, 5628–5634.
Casiraghi, G. et. Al. J. Org. Chem., 2003, 68, 5881-5885.
Aminocycloheptitols: Previous work
O O
OBnO
O O
BnO
N
OBoc
H
OH
NBocTBSO
OH
OHOH
OH
H2N
OHSnCl4, Et2O
(80%)
Casiraghi, G. et. Al. J. Org. Chem., 2003, 68, 5881-5885.
12 steps , overall yield is 23 %.One optically pure compound
BF4
SiMe2Ph
(PhMe2Si)2Zn THF
(61%)
OH
OH
OHH2N
HO
Girard, E.; Desvergnes, V.; Tarnus, C.; Landais, Y. Org. Biomol. Chem. 2010, 8, 5628–5634.
Aminocycloheptitols: Previous work
11 steps , overall yield is 15 %Racemic product
Our work
Ph
NPhth
i) K+ - NPhthii) CAN/ MeOH
(81%)
Ph
Fe(CO)3
Ph
Fe(CO)3BF4
HBF4/Ac2O
(88%)
(±) (±) (±)
H OO
Ph H5'
H5
PhthN
H4 H6
H3H7Ph H5'
H5
PhthN
H4
OR
OR
1O2, TPP Zn, AcOH
(92%) R = H R = Ac (82%)
Ac2Op-TsCl
Ph
NPhth
OO
Ph
NPhth
RO OR
(±) (±)=2.73ppm
=2.11ppm
Ph
NPhth
iii) Pb(OAc)4
NaBH3CNTHF/AcOH
i) AD-mix
NPhthH
HO OH
TBDPSO
HO OH
H
(±)-R=CHO
(±)-R= CH2OH (100%)(±)
TBDPSClImidazole
OsO4/NMO
NPhthH
HO OH
TBDPSO
HO OH
H
(±)
(±) (±)
(63%) (91%)
(94%) (88%)
NPhthH H
OO
R
ii) 1O2, TPP, hv
NPhthH H
OO
TBDPSO
(±)
NPhthH H
HO OH
TBDPSO+
Zn/HOAc
6:1
11 steps, 26% overall yield11 steps , overall yield is 15 %
Racemic product12 steps , overall yield is 23 %.One optically pure compound
Org. Biomol. Chem. 2010, 8, 5628–5634. J. Org. Chem., 2003, 68, 5881-5885.
Optically active tetraols
Ph
NPhth
(±)
i) AD-mix /t-BuOH/H2O/MeSO2NH2
Ph
NPhthH H
HO
OHPh
NPhthH H
HO
OH
OO O
O
(+) (48%) (+) (44%)
ii) 1O2, TPP, hv
Ph
NPhth
(±)
i) AD-mix
Ph
NPhthH H
HO
OHPh
NPhthH H
HO
OH(-) (+)
Pb(OAc)4 Pb(OAc)4
NPhthH H
OO
OHCNPhthH H
OO
OHC
93% 73%
NPhthH H
OO
HOH2CNPhthH H
OO
HOH2C
NaBH3CNNaBH3CN82%
78%
(+)
(+)
(-)
(-)
1O2, TPP
i)PTAD
75%
NN
Ph
NPhthH H
RO
OR
NO OPh
ii)DNBCl
Anobick Sar
Optical purity
NPhthH
OO
HO
H
(S) Mosher's acid/DCC/DMAP
(100%) NPhthH
OO
O
HF3C
O
PhMeO
NPhthH
OO
O
HF3C
O
PhMeO(S) Mosher's acid/DCC/DMAP
(94%)NPhthH
OO
HO
H
(+)
(-)
PPM6.66.46.26.05.85.65.45.25.04.84.64.44.24.03.83.6
SpinWorks 3:
file: ...ectra\151-200\ml190acetone.fid\fid block# 1 expt: "s2pul"transmitter freq.: 399.747950 MHztime domain size: 26264 pointswidth: 6410.26 Hz = 16.0357 ppm = 0.244070 Hz/ptnumber of scans: 8freq. of 0 ppm: 399.745551 MHzprocessed size: 65536 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 56.574 ppm/cm: 0.14152
NPhthH
OO
O
HF3C
O
PhMeO
PPM6.66.46.26.05.85.65.45.25.04.84.64.44.24.03.83.6
SpinWorks 3:
file: ...ectra\201-250\ml201acetone.fid\fid block# 1 expt: "s2pul"transmitter freq.: 399.747950 MHztime domain size: 26264 pointswidth: 6410.26 Hz = 16.0357 ppm = 0.244070 Hz/ptnumber of scans: 8freq. of 0 ppm: 399.745551 MHzprocessed size: 65536 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 56.011 ppm/cm: 0.14011
NPhthH
OO
O
HF3C
O
PhMeO
(>94% d.e.)
(>96% d.e.)
=6.22 ppm
=6.31 ppm
(+)
NPhthH
HO OH
TBDPSO
HO OH
H
NPhthH H
OO
HOH2CNPhthH H
OO
HOH2C
79%
NPhthH
HO OH
TBDPSO HNPhth
H
HO OH
TBDPSO H
i) TBDPSCl/Imidazole
OsO4/NMO
NPhthH
HO OH
TBDPSO H
OHHO
(-)
OsO4/NMO
ii) Zn/HOAc90%
(88%) (88%)
i) TBDPSCl/Imidazoleii) Zn/HOAc
(+)
(+) (-)
(-)
11 steps, 15% overall yield
11 steps, 12% overall yield
Bicyclic cyclitolsOH
OH
HO
HO
H
H
OH
OH
OH
OH
HO
THNso
H
H
OH
OH
OH
OH
HO
HO
H
H
bis-homoinositol
conduramine D-2 analogue
bis-homoconduritol A
OH
OH
HO
HO
H
H
CO2Me
OR
OR
RO
RO
H
H
CO2Me
NH2HO
OHHO
HOKi=0.541MIC50=80 M
Kelebekli, L.; Kara, Y.; Balci, M.; Carbohydrate Res., 2005, 340, 1940-1948.Kara, Y.; Balci, M. Tetrahedron, 2003, 59, 2063-2066.
Sengu, M.; Menzek, A.; Sahin, E.; Arik, M.; Saracoglu, N. Tetrahedron, 2008, 64, 7289–7294Wang,Y.; Bennet, A. Org. Biomol. Chem., 2007, 5, 1731–1738
Fe(CO)2PPh3
HH
BF4NPhth
i) K+ - NPhthii) DDQ
(73%)H H
Fe(CO)2PPh3Fe(CO)3
PPh3/TMANO
(93%)
HBF4/Ac2O(92%)
(±)
Fe(CO)5(CH3)3NO
(100%)
O
O
Cl
Cl
CN
CN
DDQ
N
O
O-NPhth
N O
TMANO
Synthesis of Bicyclicdiene
Exhaustive Dihydroxylation
NPhth
H H
OsO4, NMO
(49%)
NPhth
H H
HO
OHOHHO
(±)
NPhth
H H
HO
OHOHHO
(±)(±)
(21%)
(~ 3 eq.)
N
O
ON-Methylmorpholine N-oxide
Monohydroxylation
NPhth
H H
NPhth
H H
NPhth
H H
+
OsO4NMO (1 equ.)
(±) (56%) (±) (29%)(±)
HO
HOOH
OH
NPhth
H H
HO
HOO
CF3CO3H(83%)
(±)
Fürst-Plattner Rule
Fürst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275.
R RH
RH
ORCO3H
NuNu
HR
Nu
O
R
Nu
OH
Disfavored by 5 Kcal/mol
Epoxide opens to trans diaxial
Epoxide ring opening
NPhth
H H
HO
HOO
H2O, CBr4 NPhth
H H
HO
HOOH
OH
(±)(±)
(63%)
Epoxidation
NPhth
H H
NPhth
H H
NPhth
H H
O
+m-CPBA
(±) (70%) (±) (12%)(±)
O
Mechanism of Enone formation
NPhth
H H
NPhth
H H
OO
H+
NPhth
H H
HONPhth
H H
HO
H
NPhth
H H
OH
-H+
1,2-Hydride shift
NPhth
H H
O
NPhth
H H
O
OHOH
NPhth
H H
HO
OHOHHO
OsO4, NMO
(97%)
H2O, CBr4
(66%)
(±) (±)(±)
e
e e
NPhth
H H
O
(±)
NPhth
H H
O
O
(±)
NPhth
H H(±)
NPhth
H H
HO
OHOHHO
H2O, CBr4
(46%)(±)
HO OH
OH
NPhth
OH(±) (18%)
e
e e
a
a
Ring Expansion Mechanism
NPhth
H H
O
O
(±)
H+/H2O
HO OH
OH
NPhth
OH(±)
NPhth
H H
O
OHOH
H+
NPhth
H H
O
OHOHH
H2O
-H+
H2O, CBr4
NPhth
H H
O
OH
H2O
HOO
NPhth
OH(±)
-H+
H+
H+/H2O
AB
Formation of endoperoxide
NPhth
H H(±)
1O2, TPP
(86%)
Zn, AcOH
(98%)
(±) (±)
NPhth
H H
OO
NPhth
H H
HO
OH
Sun light
H4O
O
H3'H3
H4
H1H
H3'H3OH
OHPhthN
H2
PhthNH2
NPhth
H H
HO
OHOH
HO
OsO4/NMO(79%)
(±)
NPhth
H H
O
O
(±)
Hg lamp, C6H6(67%)
H
OR2
R1 R3
OsO4
Kishi model
NPhth
H H
O
OH
NPhth
H H
HO
OH
NaBH4/CeCl3
(±)
(±)
(94%)
(±)
NPhth
H H
O O Et3N
NPhth
H H
HO
OHOH
HO
OsO4/NMO
(34%)(±)
NPhth
H H
HO
OHOH
HO
(±)
(28%)
(95%)
Kornblum–DeLaMare rearrangement
Preparation of Epoxyendoperoxide
(99%)
(±)
NPhth
H H
OO CF3CO3H
(±)H H
OO
O
NPhth
X-ray
(94%)
Zn/ AcOH
(±)H H
HO
OHO
NPhth
H H
HO
OHOHHO
H2O, CBr4
(92%)
(±)
NPhth
Ring Contraction
(±)
NPhth
H H
HO
OHCF3CO3H
(±)
NPhth
H H
HO
OHO
(85%)
H2O, THFCBr4 OHC
OH
NPhth
H H(45%)
Proposed Ring Contraction Mechanism
NPhth
H H
HO
OHO
H+
-H2O
OHC
OH
NPhth
H H
NPhth
H H
HO
OHOH
OH
NPhth
H HO
HHO
H
OH
NPhth
H HO
HHOH-H+
Generated Tetraols Out of 16 possible isomers, we synthesized 8. Assignments were made by NMR and single crystal X-
ray diffraction.
NPhth
H H
HO
OHOHHO
A
53 2
14
X-ray
NPhth
H H
HO
OHOHHO
H
53 2
14
NPhth
H H
HO
OHOHHO
C
53 2
14
X-ray
NPhth
H H
HO
OHOH
HO
F
53 2
14
NPhth
H H
HO
HOOH
OH
G
53 2
14
NPhth
H H
HO
OHOH
HO
E
53 2
14
NPhth
H H
HO
OHOHHO
B
53 2
14 NPhth
H H
HO
OHOHHO
D
53 2
14
X-ray
Testing of the generated tetraols
β-Glucosidase was selected as enzyme to be initially testing the protected bicyclic tetraols.
Validation of assay is done by using different enzyme concentrations.
Testing a known inhibitor and reproduce inhibition data.
OHOHO
OH
HO ONO2
Glycosidase enzyme OHOHO
OH
HO OH
HONO2
+
determined colorimetrically
Glucosidase Validation Curve
0 50 100 150 200 250
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
f(x) = 0.00165904070999085 x + 0.121740383572049R² = 0.999288630050026
f(x) = 0.00218072425141492 x + 0.101205783420139R² = 0.998926925348967f(x) = 0.00116576128229274 x + 0.0958652870327817R² = 0.997445982859077
f(x) = 0.000878638941185093 x + 0.0635441050809969R² = 0.998436756380225
f(x) = 0.00046675204626423 x + 0.0290250363557235R² = 0.99910202134682
f(x) = 1.58748644609038E-05 x − 0.00284808614979621R² = 0.967642027019055
f(x) = 0.000229626974637258 x + 0.013163359268852R² = 0.999483971982093
Glucosidase Validation Curve
Time (s)
Abso
rban
ce (
406
nm)
Assay Results
-5.0 -4.5 -4.0 -3.5 -3.0 -2.570
80
90
100
110
MML 286_f1 Dose Response (4 pt)
log([X],M)
% A
ct
NPhth
H H
HO
OHOHHO
IC50=1.68mM
NPhth
H H
HO
OHOHHO
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.560
70
80
90
100
110
MML286_f2 Dose Response
log([X],M)
%A
ctiv
ity
IC50= 156.8µM
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.570
80
90
100
110
MML 326_f2 Dose Response
log([X],M)
%A
ctiv
ity NPhth
H H
HO
HOOH
OH
IC50= 41.66µM
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.570
80
90
100
110
MML 278_f2 Dose Response
log([X],M)
%A
ct.
IC50= 1.904mM
NPhth
H H
HO
OHOHHO
Assay Results
NPhth
H H
HO
OHOHHO
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.570
80
90
100
110
MML292_f1 Dose Response
log([X],M)
%A
ctiv
ity
IC50= 430µM
NPhth
H H
HO
OHOH
HO
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.570
80
90
100
110
120
MML 216 Dose Response
log([X],M)
%A
ct.
IC50= 914.2µM
Assay Results
NPhth
H H
HO
OHOH
HO
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.570
80
90
100
110
MML 278_f2 Dose Response
log([X],M)
%A
ct.
IC50= 1.904mM
NPhth
H H
HO
OHOHHO
-5.0 -4.5 -4.0 -3.5 -3.0 -2.560
70
80
90
100
110
120
MML 316_f2 Dose Response- Trial II (4-pt)
log([X],M)
% A
ct.
IC50=74.76µM
Assay Results
Formation of polycyclic structures using olefin metathesis approach
M. F. El-Mansy , A. Sar , S. Chaudhury , N. J. Wallock and W. A. Donaldson , Org. Biomol. Chem., 2012,10, 4844-4846
Fe(CO)3
Ph
O
PF6
Ph
O
Ph
O
5% G-I0.014 M(62%)
H
H
i) Allyl malonateii) CAN
(95%)
E E
E=CO2Me
EE
H
Ph
ONTs
i) K+ - N(allyl)SO2Tolii) CAN
(70%)
N
Ph
Ts
O
5% G-I0.005 M(80%)
H
H
H
Ph
Fe(CO)3BF4
M. F. El-Mansy , A. Sar , S. Chaudhury , N. J. Wallock and W. A. Donaldson , Org. Biomol. Chem., 2012,10, 4844-4846
N
Ph
Tsii)CAN/ MeOH
(44%)
N Ts
N Ts
5% G-II0.08 M
Isomerizes
(82%)
i) K+ - N(allyl)SO2Tol
Ph
E
(64%)
5% G-I0.04 M
Isomerizes
(88%)
E
E
E
E
E
i) Allyl malonateii) CAN
E=CO2Me
Formation of polycyclic structures using olefin metathesis approach
Fe(CO)2PPh3
HH
BF4i) Allyl malonateii) CAN
(95%)
H H
H
EE
H HE
E
15% G-I0.014 M
74%
E=CO2Me
NTs
i) K+ - N(allyl)SO2Tolii) DDQ
(58%)H H
NTs
NTs
15% G-I 0.008 M(76%)
M. F. El-Mansy , A. Sar , S. Chaudhury , N. J. Wallock and W. A. Donaldson , Org. Biomol. Chem., 2012,10, 4844-4846
X
Ru
H H
H H
H
NTs
H H
2
Ru=CH2
H2C=CH2
N
H H
X
Ru
H H
X
Ru
H H
X
Ru
H H
Ru
H H
EE
A
E
D
C
B
Ru=CHPh
1
1
2
2
EE
H HE
E Ts
2
or
X=CE2 or NTs
Intermolecular
Interamolecular
Hoye, T.; Jeon, J.; Tennakoon, M. Angew. Chem. Int. Ed. 2011, 50, 2141-2143.
Conclusion
N
Ph
Ts
O
H
H
N Ts
NTs
NTs
NPhth
H H
HO
OHOH
HO
** * *
(+)
NPhthH
HO OH
TBDPSO H
OHHO
NPhthH
HO OH
TBDPSO
HO OH
H
(-)
NPhthH
HO OH
TBDPSO
HO OH
H(±)
Acknowledgment
Supervisor
Professor William A. Donaldson
Committee members
Professor Daniel Sem
Professor Chae S. Yi
Professor Christopher Dockendorff
Thank you