300-th anniversary of the birth of
Mikhail Lomonosov
“Chemistry – our life,
our future”
«Историк, Ритор, Механик, Химик, Минералог,
Художник, Стихотворец – он все испытал и все проник»
А.С. Пушкин
Усть-Рудицкая фабрика
1753-1765
150-th anniversary of the Butlerov’s the modern theory of the
chemical structure of organic compounds.
Synthesis of enediyne systems and their
application in medicinal chemistry
Irina A. Balova
Saint-Petersburg State University,
Department of Organic Chemistry
St-Petersburg State Polytechnical University
6–th December 2011
Naturally Occurred Enediyne Antibiotics
MeO
HO
O
OH
O
O
O
AcHN
S
O
S
S
O
Me
O
MeO
O
O
Sugar
Me
O
OH
Calicheamicin
NHMe
OH
Neocarsinostatin
K.C. Nicolaou, G. Zuccarello, C. Riemer, V.A. Estevez, W.M. Dai. J. Am. Chem. Soc., 1992
I.A. Maretina, B.A. Trofimov, Russ. Chem. Rev., 2006, 75, 825.
1
Enediynes biological mode of action
.
Me
R'SH
S
S
HO
O
AcHN
S
O
AcHN
. .
.
HO
O
O
Sugar
.
.
S
HO
H-donor
Sugar
.
Bergman
DNA cleavege
O2
O
S
Sugar
OH-donor
AcHN
.
R. R. Jones, R. G. Bergman JACS , 1972; 660.
Myers, A. G.; Dragovich, P. S.; Kuo, E.Y. J. Am. Chem. Soc. 1992, 114, 9369.
Nicolaou, K.C.; Dai, W. -M. Angew. Chem. Int. Ed. Engl. 1991, 30, 1387
HO
O
S
O
Sugar
AcHN
2
Enediyne systems fused to heterocyclic core
• Heterocycles possessing an enediyne moiety are
promising objects for the medicinal chemistry as
analogs of naturally occurred enediyne antibiotics.
• Enediyne system fused to a various heterocicles are
promising objects for the investigation of general
patterns of action and structure-activity relationships
3
Proposed strategy for synthesis of
Enediyne systems fused to heterocyclic core
I. Richter-type cyclization
Br
II. Electrophilic cyclization
R
X
LG
HBr
z
N
N
X
R
-ILG
-HLG
2 R
R'
I2
N=N
=
X
=
O, S, NMe,
N(Et)Ph
=
LG
=
Me, Bn
I
O
O
R'
Pdo / Cu (I)
Pdo / Cu(I)
R'
X
R
4
I. Richter type cyclizaton of buta-1,3-diynylarenediazoniume salts
II. electrophilic cyclization of ortho-functionalized buta-1,3-diynylarenes
III. synthesis of 10-membered cyclic endiyne system fused to cinnoline
6
Richter cyclization
Hal
R
R
Nu
NaNO2, HHal
N
N
H2O
+
N2
R
Nu = Hal
R
NH2
Hal = Cl, Br
-
Hal Nu = H2O
N
N
R
R
20eq 1M HHal
N
O
OH
N
N
H
N
N R'
R"
V. von Richter, Ber. Dtsch. Chem. Ges. 1883, 16, 677.
S.F. Vasylevsky, E.V. Tretyakov , Leibigs Ann. 1995, 775.
. S.Brase, S. Dahmen, J. Heuts, Tetrahedron Lett. 1999, 40, 677
7
Richter-type cyclization of
diacetylene derivatives
z
z
NH2
N=N-N(Et)Ph
R
R
z
R
)2
(
Hal
z
+
N2 Hal-
N
R
N
8
Sequential “Diacetylen zipper” and
Sonogashira cross-coupling
LAETA
( )n
( )
n
X
( )
2n
X = Li
X=H
n=2-5
CH3 1. LAETA,
15 -180 C, 10 min
H3C
LAETA =
Eur. J. Org. Chem. 2005, 882
Mendeleev Commun., 2011, 19.
H2N
-
NH
Li
Ar(Ht)I
Pd0/Cu(I)
Ar(Ht)
( )
2n
H2O
H3C
H3CH3C
CH3
Li3
CH
+
10
Richter-type cyclization of
(buta-1,3-diynyl)arenediazonium salts
R
R
R
2
X
A-E
2
X
Cl
X
+
NH2*HCl
Y
X= H, Br, CH3, NO2, COOMe
Y= H, H, Br, H,
H
Y
N Cl2
N
O
R
X
N
Y
R
2
X
+
N
Y
N
+
Y
10-54%
A: NaNO2, HCl; B: BuONO, H2S04; C: NaNO2,
HCl, THF; D: NaNO2, HCl, Et2O /hexane;
E: NaNO2, HCl, MeOH
Tetrahedron Lett. 2007, 48, 4907.
Russ.Chem. Bull. 2008, 57, 1693
Collaboration with Prof. S. F. Vasilevsky, Institute of Chemical Kinetics
and Combustion RA S, Novosibirsk, Russia
11
Richter-type cyclization of
diynylaryltriazene as a short and effective
rout to 4-bromo-3-ethynylcinnolines
Ph
N
N
Et
R
R
N
2
X
N
HBr (48%), aceton
N
X
Br
20 oC, 15 min
Y
Y
X = H, Br; Y = H, Me, COOMe
R=Alk, Ph
Tetrahedron Lett. 2009, 6358
75-87%
12
Reactivity of 3-ethynyl-4-halocinnolines
H2N
R
Ph
N
R
Y
N
N
Ph
Y
N
X
N
MeNH2
H3C
Y
R
Hal
NH2NH2
Pd / Cu
N
N
X
X
R
N
Na2S
MeSH
Y
N
X
R
N
S
SMe
Y
C 8H17
MeOOC
N
S
N
N
N
I2 MeOOC
X
Hal = Cl, Br
Tetrahedron Lett. 2009, 6358
C 8H17
I
N
N
X = H, Br; Y = H, Me, COOMe
13
Electrophilic cyclization
R?
E = I2, Br2, ICl, IPy2BF4
Larock, R. C. in Acetylene Chemistry, Wiley-VCH, 2005, 51
Mehta S., Larock R. // J. Org. Chem., 2010, 75, 1652.
14
Iodocyclization of ortho-functionalized
(buta-1,3-diynyl)arenes
X
LG
2 R
X
=
LG =
O, S, NMe,
I
O
O
R
Me
I
R
Me, Bn
R
S
X
I2 (ICl)
R
R
N
I
O
O
O
I
I
Synlett. 2011, 517
Collaboration with Prof. S. Brase , Karlsruhe Institute of Technology, Germany
15
Synthesis of enediyne systems
fused to five-membered heterocycles
X
X
R
R
Pd/Cu
I
R'
12 examples 47-83%
Some examples
O
Ph
S
OH
S
C 8H17
SiMe 3
N
OH
SiMe 3
O
SiMe 3
16
Synthesis of cinnolinoendiyne
J. Org. Chem., 2011, 76, 6937
Collaboration with Prof. Vladimir V. Popik, University of Georgia, Athens, USA
17
Synthesis of cinnolinoenediyne
J. Org. Chem., 2011, 76, 6937
Collaboration with Prof. Vladimir V. Popik, University of Georgia, Athens, USA
18
Bergman cyclization of cinnolinoenediyne
OH
1.0
N N
11
11
Relative Concentration
89
OH
Single-strand break
0.8
Supercoiled DNA
0.6
1
2
3
4
Cleavage of φX174 plasmid DNA by
cinnolinoenediyne.
0.4
0.2
lane 1: DNA alone incubated for 24 h at 400C;
lanes 2 - 4: DNA incubated with enediyne 9
(200 μM, 2 mM, and 4 mM )
0.0
0
10
20
30
40
50
Time / h
The rates of the Bergman cyclization (2-propanol, 750C) of cinnolinoenediyne 9
(kdecay= (4.15±0.19)x10-5 s-1) and benzo-fused analog 11 (kdecay=
(9.14±0.28)x10-6 s-1 .
J. Org. Chem., 2011, 76, 6937
Collaboration with Prof. Vladimir V. Popik, University of Georgia, Athens, USA
20
Conclusions
• The halocyclization of ortho-functionalized (buta-1,3-diynyl)arenes is
a direct and effective approach towards heterocycles with both
halogen and ethynyl moieties, which are precursors of various
enediyne systems fused to heterocyclic core
Acknowledgements
Prof. S. F. Vasilevsky
Prof. S. Bräse
Prof. V. V. Popik
Dr. V. Sorokoumov,
Dr. O. Vinogradova,
Dr. N. Danilkina,
BSc. E. Gorbunova
Saint-Petersburg State University,
DAAD foundation,
National Science Foundation (CHE-0449478)
and Georgia Cancer Coalition
for financial support
.
Thank you for attention