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adjusted model, we reconsider simple 1,2-dyotropic reactions with the introduction of a
concept based on the intramolecular dynamics of a tetrahedron (van ’t Hoff modeling). In fact the
dyotropic reactions are strongly related to conversions originated from neighbouring
group participation or anchimeric assistance, defined as the interaction of a
center with a lone pair of electrons in an atom and the electrons present in aδor π bond. The researchful 1,2-dyotropic reactions, based on the
1,2-interchange of halogens, methyl and hydrogen taking place in a concerted
fashion, are in competition with the two-step reaction in which the
neighbouring group participation or anchimeric assistance comes to full
expression by ionic dissociation of the other exchangeable (halogen) atom. As
to be expected there is an essential difference between halogen or methyl
exchange regarding the number of electrons participating in the transition state.
This aspect becomes evident in the geometries of the corresponding transition
state geometries. In this paper we refer to ab
initio MO calculations and VB considerations. We consider the 1,2-halogen
exchange as a combination of two SN2 reactions each containing four
electrons. The van ’t Hoff dynamics appears a useful model in order to illustrate the
computations in a straightforward manner.
This study was directed on the B- into Z-DNA isomerization with alternating CG sequences monitored
with artificial DNA model-systems based on methylation of the phosphate backbone.
The chemical concept for this transition wherein shielding of the oxygen anions
of the backbone phosphates plays an essential role, resulted in the preparation of the phosphatemethylated d(CpG). Even on this primitive level of only two base pair long, the B-Z conformational
aspects of this self-complementary duplex could be described in solution
with nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements.
The exclusivity of this choice became clear after synthesizing phosphatemethylated
DNA with longer alternating CG fragments. It could be shown that conflicting
conformational effects of the CG and GC fragments resulted in an overall B
structure of the phosphatemethylated
tetramer d(CPGPCPG). From our model
considerations, it is clear that the internal stress introduced by the
alternating CG sequences will be promoted by a complete shielding of the
phosphate backbone. Elimination of this effect may be realized by a site-specific phosphate shielding. The role of the anti-syn isomerization of G in
the CG fragments is clarified by methylation of the phosphate group. This anti-syn transition is absent in
corresponding methylphosphonates, suggesting an exclusive role for
base-backbone coordination via hydrogen bonding. In addition, we propose that
the B- into Z-DNA interconversion may offer a mechanistic view for differences
in dynamics between cytosine and its epigenetic derivative 5-methylcytosine.
This mechanism has been extended to the demethylation of 5-methylcytosine and
the exchange of information
between the new epigenetic base, 5-hydroxymethylcytosine and the DNA backbone
via an intramolecular phosphorylation. The role of 5-hydroxymethylcytosine in
Alzheimer disease has been briefly discussed. In our opinion, this study
can be considered as a new dynamic concept for epigenetics based on the
dynamics of the B-Z transition in natural and phosphatemethylated DNA.