Transcript Διαφάνεια 1

o-Quinone Methides of Bis-naphthalene and Perylene
as Alkylating Agents of Selected Peptides
2A.
Saravanos, 1Y. Sarigiannis, 1G. Stavropoulos, 2P. Tsoungas and 2P. Cordopatis
1Department
University of Patras
of Chemistry and 2Department of Pharmacy, University of Patras, 265 00 Patras, Greece,
Introduction
a.CuCl2xH2O +Al2O3
+H2O
0
b.100 C, 40h, P
OMe
o-Quinone methides (o-QMs) 1 are highly reactive and ephemeral
intermediates extensive harnessed by nature. A variety of plants, animals
OMe
electrophiles,
nucleophiles
or
(hetero)
Diels
–
80%
THF, TMEDA,
BuLi inHex, RT
DMF,H2O
Alder
cycloadditions [1]. The driving force inherent in these transformations and
CHO
Et2O, TMEDA,
BuLi inHex, RT
DMF,H2O
significance in organic synthesis emanates from their versatile reactivity
towards
OMe
Hex, TMEDA,
BuLi inHex, RT,
DMF,H2O
Al2O3/CuCl2xH2O,
Benz. 500C,5h
and insects capitalize upon them as a means of defense. Their
cHex, TMEDA,
BuLi inHex, RT,
DMF,H2O
72%
MeI, K2CO3, DMF,
RT, O.N.
MeI, NaH60%in oil, DMF,
RT, O.N.
68%
CHO
DMF, POCl3
H 2O
OMe
OMe
Br
OMe
the propensity of 1 to “revert to type” (i.e. restore its aromaticity).
MeI, NaH60%in oil, DMF,
RT, O.N.
66%
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
Br
OMe
varying complexity.
In biology, on the other hand, the significance of 1 rests upon its mode of
NBS, TBAB,1000C,
H2O, O.N.
action being the reactive site of various structures on cellular
68.3%
among the major biochemical processes taking place [3-7]. It has been
CH3COOH, Br2, I2,
H 2O-Na2S2O 5, NaHCO 3
observed at very low temperatures [8] or when highly hindered [9] and has
Br
B(OH)2
O
O
been isolated only when metal stabilized [9,10]. Under ordinary conditions,
the intermediacy of 1 is inferred by trapping reactions. A plethora of
50%
Br
70%
OMe
THF, TrisopropylBorate,
-780C 2h, HCL, RT
MeI, K2CO3, DMF,
RT, O.N.
54%
macromolecules such us DNA or proteins. Alkylation or cross – linking are
OMe
OH
OH
O
O
N
N
methods have been developed for its generation, mainly as a precursor to
NaH, THF, ClOCbH,
RT, 24h
various heterocycles, natural products among them. The activity in the
field has been reflected on a number of reviews, which have subsequently
CHO
a. Et2O, nBuLi in Hex
b.DMF inEt2O, H2O, O.N.
75%
72%
appeared, as early as mid 60’s right through to the present days [1]. There
2M NaOH, Et2O
has been a resurgence of interest in the chemistry and biology of 1,
recently. This has focused primarily on its photogeneration, metal
MeI, K2CO3,DMF
RT
O
64%
complexation and its effect on biomacromolecules.
CHO
82%
substituted naphthol 3, are useful intermediates for alkylation / X-linking of
MeI, NaH, DMF
RT
simple amino acids right through to cellular macromolecules such as DNA,
proteins and peptides. This reaction is already known to be responsible for
Br
CHO
50%
CHO
74%
Br
72%
THF, TrisopropylBorate,
-780C 2h, HCL, RT
a broad spectrum of activity of these molecules.
TBAB,NBS,
1000C,4h,
H2O, O.N.
MeI, DCM, (Bu) 4NOH,
NaOH, RT
o-QMs of types 5 and 8, prepared by coupling of an appropriately
OH
OH
O
CHO
OH
CHO
B(OH)2
Y :Br, B(OH)2
Scheme: Part of the Synthetic Route for the preparation of o-Quinone methides
3
O
O
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
Nu
Nu
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
O
O
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
5
8
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7. (a) Gaudiano G., Frigerio M., Bravo, P., and Koch, T., J. Am. Chem. Soc. 1990, J Org. Chem. 1996, 61,
Aknowledgements
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.
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.
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