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The porphyrin handbook - Kadish K.M.

Kadish K.M. The porphyrin handbook - Academic press, 2000. - 368 p.
Download (direct link): kadishsmishgulilard2000.djvu
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In order to investigate the effect of various electron-withdrawing
groups at different positions of the macrocycle on the migratory
aptitudes of the pinacol-pinacolone
rearrangement, Pandey and coworkers233 extended this study to various
purpurin 18-N-alkylimide, isoimide and chlorin p6 systems. In their
initial studies, 3-formyl-3-devinyl-chlorin p6 trimethyl ester 193 was
used as substrate, which in turn was obtained by reacting chlorin p6
trimethyl ester with 0s04/NaI04 under modified reaction conditions
(dioxane was eliminated from the conventional protocol).229 Reaction of
203 with 0s04 produced v/c-dihydroxy-3-formyl-bacteriochlorin p6
trimethyl ester 204 in 70% yield, as a diastereomeric mixture (vi'c-
dihydroxy groups up or down relative to pyrrolic ring D, see Scheme 51).
After repeated chromatography, two diastereomers, of 204 (vie-dihydroxy
groups up or down) were separated and characterized by 'H NMR
spectroscopy. Both isomers possessed a long-wavelength absorption at 765
nm. Under
Scheme 52. Alkyl ether analogues of bacteriochlorin imides.
CHO Me Me Et

cis-diol up CHO Me OhX,01- down
Me-<^ Y " VEt
1 t C02Bu
(mixture of two isomers)
cis-diol up or down
216 (mixture of two isomers)
cis-diol up or down
1 t C02Bu
217 R1 = O, R2 = N-Hexyl; or R1 = N-Hexyl, R2 = (mixture of four
Me^ ^O-Heptyl
218b (777 nm) isomeric mixture
Pandey and Zheng
H2S04 treatment, diol 204a (as a diastereomeric mixture) afforded 7-keto-
bacteriochlorin 205 and 8-ketobacterio-chlorin 206 in 2:1 ratio. In the
electronic absorption spectra, compared to ketobacteriopurpurins 198 and
199 (in which a 45-nm shift was observed at their long-wavelength
absorptions), the 3-formyl-ketobacteriochlorin p6 201 (738 nm) and 202
(741 nm) did not show such a remarkable difference. From these studies it
seems that besides the electronic nature of various substituents present
at the perpheral positions of the vic-dihydroxyporphyrins and
bacteriochlorins, the fused anhydride ring also exerts significant
influence on the rearrangement of the alkyl substituents under pinacol-
pinacolone conditions.
To further investigate the effect caused by small structural
variations on the migratory aptitude under pinacol-pinacone-reaction
conditions, v/c-dihydroxypur-purins containing isoimide ring systems 207
and 208 were reacted with 0s04 and the corresponding 7-ketobacterio-
chlorins 211 (750 nm) and 8-ketobacteriochlorins 213 (723nm) were
obtained in a 3:2 ratio (Scheme 51). Under similar reaction conditions,
diol 210 gave a mixture of ketochlorins 212 and 214 in a ratio of 2 to 1.
From these studies, it can be concluded that it is not a simple matter
to define the general substituent migratory aptitudes in chlorin and
bacteriochlorin systems, because distant conjugated peripheral
substituents can dramatically affect the stability of carbocation
intermediates and hence the products. The facility of the rearrangement
of various substituents depends not only on the intrinsic nature of the
migratory group but also on the electronic and steric factors present
elsewhere on the tetrapyrrolic systems.
Among the v/c-dihydroxy-bacteriochlorins discussed so far, most were
found to have rapid in vivo clearance and thus have poor tumor
localization. Recently, Pandey et al. successfully converted the
aspartic-acid derivative of 3-formyl-3-devinylpurpurin-18 215 into the
corresponding vi'c-dihydroxy-bacteriopurpurin 216.234 This compound, as
an isomeric mixture, was found to be an effective long-wavelength-
absorbing photosensitizer (813nm) if the mice were treated with light at
3 hours postinjection of the drug. However, no activity was observed at
24 hours postinjection. This clearly indicates a rapid in vivo clearance
presumbly caused by either the hydrophilic character of the diol
functionality or the formation of more hydrophilic
Scheme 53. Reaction of organolithiums with octaethylporphyrinone.
43 / Porphyrins as Photosensitizers in Photodynamic Therapy
dicarboxylic bacteriochlorin analogue formed by in vivo cleavage of the
anhydride ring system.
In order to determine the effect of hydrophobicity in in vivo
efficacy, v/c-dihydroxybacteriochlorin 218b was obtained by
osmiumtetroxide reaction of the related chlorins (Scheme 52). We have
previously discussed that the fused-anhydride-ring system present in
purpurin-18 can be replaced by imide and isoimide ring systems containing
N-substituted alkyl groups with variable carbon units. In certain types
of photosensitizers, replacement of the methyl ester functionality (at
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