o-Quinone Methides of Bis-naphthalene and Perylene as Alkylating Agents of Selected Peptides
1
o-Quinone Methides of Bis-naphthalene and Perylene as Alkylating Agents of Selected Peptides 2 A. Saravanos, 1 Y. Sarigiannis, 1 G. Stavropoulos, 2 P. Tsoungas and 2 P. Cordopatis 1 Department of Chemistry and 2 Department of Pharmacy, University of Patras, 265 00 Patras, Greece, University of Patras Introduction o-Quinone methides (o-QMs) 1 are highly reactive and ephemeral intermediates extensive harnessed by nature. A variety of plants, animals and insects capitalize upon them as a means of defense. Their significance in organic synthesis emanates from their versatile reactivity towards electrophiles, nucleophiles or (hetero) Diels – Alder cycloadditions [1]. The driving force inherent in these transformations and the propensity of 1 to “revert to type” (i.e. restore its aromaticity). O 1 Either acting as a highly polarized species or as heterodiene, 1 has been the prototype for the construction of diverse heterocyclic frameworks of varying complexity. In biology, on the other hand, the significance of 1 rests upon its mode of action being the reactive site of various structures on cellular macromolecules such us DNA or proteins. Alkylation or cross – linking are among the major biochemical processes taking place [3- 7]. It has been observed at very low temperatures [8] or when highly hindered [9] and has been isolated only when metal stabilized [9,10]. Under ordinary conditions, the intermediacy of 1 is inferred by trapping reactions. A plethora of methods have been developed for its generation, mainly as a precursor to various heterocycles, natural products among them. The activity in the field has been reflected on a number of reviews, which have subsequently appeared, as early as mid 60’s right through to the present days [1]. There has been a resurgence of interest in the chemistry and biology of 1, recently. This has focused primarily on its photogeneration, metal complexation and its effect on biomacromolecules. o-QMs of types 5 and 8, prepared by coupling of an appropriately substituted naphthol 3, are useful intermediates for alkylation / X-linking of simple amino acids right through to cellular macromolecules such as DNA, proteins and peptides. This reaction is already known to be responsible for a broad spectrum of activity of these molecules. References 1. Van De Water, R.W. and Pettus, T.R.R., Tetrahedron 2002, 58, 5367 and references cited therein. 2. Boger, D.L., Nishi, T. and Teergarden, B.R., J. Org. Chem. 1994, 59, 4943 3. (a) Chatterjee, M. and Rokita, S.E., J. Am. Chem. Soc. 1994, 116, 1690. (b) Zeng, Q, and Rokita, S.E., J Org. Chem. 1996, 61, 90 4. (a) Skibo, E.B., J Org. Chem. 1992, 57, 587. (b) Quyang, A., and Skibo, E.B. ibid 1998, 63, 1983 5. Nikolaou, K.C., Dai, W., J Am. Chem. Soc. 1992, 114, 8908 6. Bolton, J.L., Sevestre, H., Ibe, B.O. and Thompsom, J.A. Chem. Res. Toxicol. 1990, 3, 65 7. (a) Gaudiano G., Frigerio M., Bravo, P., and Koch, T., J. Am. Chem. Soc. 1990, J Org. Chem. 1996, 61, 90, 6704. (b) Angle, S.R. and Yong, W. J. Am. Chem. Soc. 1990, 112, 4524 8. (a) Tomioka, H., Pure Appl Chem, 1997, 69, 837. (b) Qiao, G.G., Lenghaus, K., Solomon, D.H. Reisinger, A, Bytheway, I. and Wentriep, C. J. Org Chem., 1998, 63, 9806 9. Kopach, M.E., and Harman, W.D., J. Am. Chem. Soc. 1994, 116, 6581. (b) Vigalok, A., and Milstein, D., ibid 1997, 119, 7873 (ESF), Operational Program for Educational and Vocational Training II (EPEAEK II) and particularly the Program PYTHAGORAS II for funding the above work. O O Nu 5 O O Nu 8 OH CHO Y :Br,B(O H) 2 3 Scheme: Part of the Synthetic Route for the preparation of o-Quinone methides OH N aH,TH F, ClO CbH , RT,24h O O N a.Et 2 O , nBuLiin H ex b.DM F inEt 2 O ,H 2 O,O .N . O O N CHO OH CHO 2M N aO H ,Et 2 O TBA B,N BS, 100 0 C,4h, H 2 O,O.N. OH CHO Br O CHO Br M eI, K 2 CO 3, DMF RT M eI,NaH , DMF RT M eI, D CM , (Bu) 4 NOH, N aO H ,RT 75% 72% 74% 82% 64% 72% TH F,TrisopropylBorate, -78 0 C 2h, H CL,RT 50% O CHO B(O H) 2 OMe M eI, K 2 CO 3, D M F, RT, O .N . M eI,N aH 60% in oil , D M F, RT,O .N . 68% 72% a.C uCl 2 xH 2 O +Al 2 O 3 +H 2 O b.100 0 C ,40h,P Al 2 O 3 /CuC l 2 xH 2 O, B enz.50 0 C,5h OMe OMe 80% cH ex,TM ED A , B uLiinH ex,R T, DM F,H 2 O H ex, TM EDA, B uLiinH ex, R T, DM F,H 2 O Et 2 O ,TM ED A , BuLiinH ex,RT DM F,H2O THF,TM EDA, B uLiinH ex,RT DM F,H2O D M F,PO Cl 3 H 2 O OMe OMe CHO CHO M eI,N aH 60% in oil , D M F, RT,O .N . 66% OMe OMe Br Br OH Br N B S,TBA B,100 0 C, H 2 O , O.N. 54% CH 3 C O O H ,B r 2, I 2 , H 2 O-N a 2 S 2 O 5 ,N aH CO 3 70% M eI,K 2 CO 3, DM F, RT,O .N . OMe Br 68.3% TH F,TrisopropylBorate, -78 0 C 2h, H C L,RT 50% OMe B(O H) 2
-
Upload
rahim-freeman -
Category
Documents
-
view
34 -
download
3
description
o-Quinone Methides of Bis-naphthalene and Perylene as Alkylating Agents of Selected Peptides. 2 A. Saravanos, 1 Y. Sarigiannis, 1 G. Stavropoulos, 2 P. Tsoungas and 2 P. Cordopatis. 1 Department of Chemistry and 2 Department of Pharmacy, University of Patras, 265 00 Patras, Greece,. - PowerPoint PPT Presentation
Transcript of o-Quinone Methides of Bis-naphthalene and Perylene as Alkylating Agents of Selected Peptides
o-Quinone Methides of Bis-naphthalene and Peryleneas Alkylating Agents of Selected Peptides
2A. Saravanos, 1Y. Sarigiannis, 1G. Stavropoulos, 2P. Tsoungas and 2P. Cordopatis 1Department of Chemistry and 2Department of Pharmacy, University of Patras, 265 00 Patras, Greece,
University of Patras
Introductiono-Quinone methides (o-QMs) 1 are highly reactive and ephemeral
intermediates extensive harnessed by nature. A variety of plants, animals
and insects capitalize upon them as a means of defense. Their
significance in organic synthesis emanates from their versatile reactivity
towards electrophiles, nucleophiles or (hetero) Diels – Alder cycloadditions
[1]. The driving force inherent in these transformations and the propensity
of 1 to “revert to type” (i.e. restore its aromaticity).
O
1
Either acting as a highly polarized species or as heterodiene, 1 has been
the prototype for the construction of diverse heterocyclic frameworks of
varying complexity.
In biology, on the other hand, the significance of 1 rests upon its mode of
action being the reactive site of various structures on cellular
macromolecules such us DNA or proteins. Alkylation or cross – linking are
among the major biochemical processes taking place [3-7]. It has been
observed at very low temperatures [8] or when highly hindered [9] and has
been isolated only when metal stabilized [9,10]. Under ordinary conditions,
the intermediacy of 1 is inferred by trapping reactions. A plethora of
methods have been developed for its generation, mainly as a precursor to
various heterocycles, natural products among them. The activity in the
field has been reflected on a number of reviews, which have subsequently
appeared, as early as mid 60’s right through to the present days [1]. There
has been a resurgence of interest in the chemistry and biology of 1,
recently. This has focused primarily on its photogeneration, metal
complexation and its effect on biomacromolecules.
o-QMs of types 5 and 8, prepared by coupling of an appropriately
substituted naphthol 3, are useful intermediates for alkylation / X-linking of
simple amino acids right through to cellular macromolecules such as DNA,
proteins and peptides. This reaction is already known to be responsible for
a broad spectrum of activity of these molecules.
References
1. Van De Water, R.W. and Pettus, T.R.R., Tetrahedron 2002, 58, 5367 and references cited therein.
2. Boger, D.L., Nishi, T. and Teergarden, B.R., J. Org. Chem. 1994, 59, 4943
3. (a) Chatterjee, M. and Rokita, S.E., J. Am. Chem. Soc. 1994, 116, 1690. (b) Zeng, Q, and Rokita, S.E., J
Org. Chem. 1996, 61, 90
4. (a) Skibo, E.B., J Org. Chem. 1992, 57, 587. (b) Quyang, A., and Skibo, E.B. ibid 1998, 63, 1983
5. Nikolaou, K.C., Dai, W., J Am. Chem. Soc. 1992, 114, 8908
6. Bolton, J.L., Sevestre, H., Ibe, B.O. and Thompsom, J.A. Chem. Res. Toxicol. 1990, 3, 65
7. (a) Gaudiano G., Frigerio M., Bravo, P., and Koch, T., J. Am. Chem. Soc. 1990, J Org. Chem. 1996, 61,
90, 6704. (b) Angle, S.R. and Yong, W. J. Am. Chem. Soc. 1990, 112, 4524
8. (a) Tomioka, H., Pure Appl Chem, 1997, 69, 837. (b) Qiao, G.G., Lenghaus, K., Solomon, D.H.
Reisinger, A, Bytheway, I. and Wentriep, C. J. Org Chem., 1998, 63, 9806
9. Kopach, M.E., and Harman, W.D., J. Am. Chem. Soc. 1994, 116, 6581. (b) Vigalok, A., and Milstein, D.,
ibid 1997, 119, 7873
10. (a) Amouri, H., Besace, Y. and Le Bras, J., J. Am. Chem. Soc. 1998, 120, 6171. (b) Amouri, H. and
Vaissermann, J., Organometallics, 2000, 19, 5143. (c) Amouri, H., and Vaissermann, J., Rager, M.N. and
Grotjiahn, D.B. ibid 2000, 19, 1740. (d) Vigalok, A. and Milstein, D., Acc. Chem. Res., 2001, 34, 798
Aknowledgements
We thank the European Social Fund (ESF), Operational Program for Educational and Vocational Training II (EPEAEK II) and particularly the Program PYTHAGORAS II for funding the above work.
O
O
Nu
5
O
O
Nu
8
OH
CHO
Y :Br, B(OH)2
3
Scheme: Part of the Synthetic Route for the preparation of o-Quinone methides
OH
NaH, THF, ClOCbH,RT, 24h
O
O
N
a. Et2O, nBuLi in Hexb.DMF inEt2O, H2O, O.N.
O
O
N
CHO
OH
CHO
2M NaOH, Et2O
TBAB,NBS,1000C,4h,H2O, O.N.
OH
CHO
Br
O
CHO
Br
MeI, K2CO3,DMFRT
MeI, NaH, DMFRT
MeI, DCM, (Bu)4NOH,NaOH, RT
75%72%
74%82%
64%
72%
THF, TrisopropylBorate, -780C 2h, HCL, RT
50% O
CHO
B(OH)2
OMe
MeI, K2CO3, DMF,RT, O.N.
MeI, NaH60%in oil, DMF,RT, O.N.
68%
72%
a.CuCl2xH2O +Al2O3 +H2O
b.1000C, 40h, P
Al2O3/CuCl2xH2O, Benz. 500C,5h
OMe
OMe
80%
cHex, TMEDA,BuLi inHex, RT,DMF,H2O
Hex, TMEDA,BuLi inHex, RT,DMF,H2O
Et2O, TMEDA,BuLi inHex, RTDMF,H2O
THF, TMEDA,BuLi inHex, RTDMF,H2O
DMF, POCl3H2O
OMe
OMe
CHO
CHO
MeI, NaH60%in oil, DMF,RT, O.N.
66%
OMe
OMe
Br
Br
OH
Br
NBS, TBAB,1000C,H2O, O.N.
54%
CH3COOH, Br2, I2, H2O-Na2S2O5, NaHCO3
70%
MeI, K2CO3, DMF,RT, O.N.
OMe
Br
68.3%
THF, TrisopropylBorate, -780C 2h, HCL, RT
50%
OMe
B(OH)2
![Open Access The p53-dependent apoptotic pathway of breast … · 2017-04-11 · [16,17]. In the case of di-aziridinyl-substituted quinone, this highly cytotoxic bifunctional alkylating](https://static.fdocuments.us/doc/165x107/5f8bd5c85d9f4e6898592404/open-access-the-p53-dependent-apoptotic-pathway-of-breast-2017-04-11-1617.jpg)
