generation of diverse molecular complexity from cyclooctatetraene_defense

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


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


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


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%)


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

generation of diverse molecular complexity from cyclooctatetraene_defense

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