2D 1H and 13C NMR evidence for stereoselective formation of a new bond C-N, C-S or C-C in the reaction of ivalin acetate with substituted pyrimidines.

Article abstract of DOI:10.1016/S1386-1425(97)00245-X

Several pyrimidine derivatives of ivalin acetate were synthesized as potential anti HIV agents. High stereoselective Michael addition to ivaline acetate was observed and a new C-C, C-N or C-S bond was formed. 2D NMR 1H and 13C as well as X-ray crystallographic studies were performed on the compounds herein described to establish the structure and stereochemistry.

Full text of DOI:10.1016/S1386-1425(97)00245-X

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Spectrochimica Acta Part A 54 (1998) 567–574
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2D H and C NMR evidence for stereoselective formation of
a new bond C–N, C–S or C–C in the reaction of ivalin
acetate with substituted pyrimidines
E. Diaz a,*, J.L. Nava a, H. Barrios a, B. Quiroz a, A. Guzman a, L. Leo´n G. b,
A. Fuentes B. b
a Uni6ersity Nacional Autonoma de Me´xico, Instituto de Qu´ımica, Circuito Exterior Ciudad Uni6er., Me´xico D.F. 04410, Me´xico
b Facultad de Qu´ımica UAEM. Toluca, Toluca E. de Me´xico CP 050000, Me´xico
Received 7 June 1997; received in revised form 4 October 1997; accepted 4 October 1997
Abstract
Several pyrimidine derivatives of ivalin acetate were synthesized as potential anti HIV agents. High stereoselective
1
Michael addition to ivaline acetate was observed and a new C–C, C–N or C–S bond was formed. 2D NMR H and
13C as well as X-ray crystallographic studies were performed on the compounds herein described to establish the
structure and stereochemistry. © 1998 Elsevier Science B.V. All rights reserved.
Keywords: Ivalin acetate; Substituted pyrimidines; Stereoselective formation
From recent studies, the configuration of the
carbon attached to the uracil moieties appears
important for the antiviral activities of nucleoside
analogues [6]. Compelling evidence has supported
the notion that some analogues with the i-L
configuration in the hetero-substituted nucleoside
derivatives [7–9] show potent anti-HIV and anti-
HBV activities and have been used for treatment
of AIDS and hepatitis B infections [10].
1. Introduction
Dideoxynucleoside analogues are amongst the
most important inhibitors of reverse transcriptase
(RT), a key enzyme encoded by HIV and involved
in its replication [1].
Recently, new classes of non-nucleosides [1,2]
HIV RT inhibitors have been described as TIBO
[1,2] and nevirapine [3] known as a variety of
heterocycles with a benzodiazepine moiety. In ad-
dition, several uracil and cytosine derivatives
bearing a phenylthio moiety [4] and structurally
related to HEPT [5] have emerged as potent non-
nucleoside inhibitors of the HIV RT.
In view of recent isolation of a novel germacra-
nolide aminoacid adduct dimer [11] as well as the
structure determination of the adduct of alanto-
lactone with (Z)-L-Cys-Ala-OMe it seemed inter-
esting to explore the 1,4-addition of pyrimidine
derivatives to the h,i-unsaturated system of ivalin
acetate (1b).
* Corresponding author.
1386-1425/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.
PII S1386-1425(97)00245-X

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E. Diaz et al. / Spectrochimica Acta Part A 54 (1998) 567–574
Scheme 1.
k-butyrolactone moiety was stereoselectively func-
Ivaline (1a) is a well-known eudesmanolide that
tionalized with the pyrimidine derivative to ad-
ducts 2–11 in good yield (see Scheme 2). These
adducts were formed as only one stereoisomer as
has been studied mainly as an antileukemic com-
pound [12]. In order to take advantage of the
previous knowledge about its biological activity
and because such a compound possesses an h,i-
unsaturated, k-lactone moiety that presents well
known affinity for Michael additions, we have
synthesized several nucleoside derivatives of ivalin
acetate (1b). According to the above consider-
ations, the conjugate addition of pyrimidine
derivatives was first examined under various con-
ditions but poor results were obtained.
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detected by H NMR. We have evidence of the
stereochemistry of the created stereocenter in
which the relative stereochemistry was well deter-
mined by NOESY studies (see Fig. 1). A more
rigorous proof of the assignment of stereochem-
istry was provided by the X-ray data (details of
X-ray crystallographic study will be reported else-
where) for the derivative 7 (Fig. 2).
The desired addition was successful under two
reaction conditions: Method A involves phase-
transfer conditions using Arquad S-50/CH2Cl2/
NaOH, and method B using Triton B/THF/H2O
(see Section 3). Both methods were extremely
useful for the synthesis of pyrimidine derivatives
from ivalin acetate (1b). From these reactions we
were able to isolate adducts (2–11, Scheme 1),
where the pyrimidine ring is coupled to the CH2-
13 moiety of the k-lactone. The highly substituted
2. Results and discussion
In the studies herein described and depending
on the chosen pyrimidine derivative, we have
identified the obtained compounds as adducts ei-
ther as C-alkylation (2), N-alkylation (3–10) or
S-alkylation (11). In this paper, we report the
complete proton assignment and the detailed

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E. Diaz et al. / Spectrochimica Acta Part A 54 (1998) 567–574
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Scheme 2.

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570
E. Diaz et al. / Spectrochimica Acta Part A 54 (1998) 567–574
Fig. 1. 500 MHz NOESY spectrum of compound 7 recorded in CDCl3/DMSO-d6 solution.
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analysis of the 500 MHz H–1H dipolar correla-
tion (NOESY) spectra of the different adducts as
well as the 13C assignments of all the products
that we have synthesized. The numbering scheme
we employ for compounds 2–11 is shown in
Scheme 1.
CDCl3 which demonstrate the existence of inter-
actions of 8-H with 7-H and 11-H, with both
detected in all the NOESY spectra (Fig. 1). The
resulting cross peaks exhibit an opposite phase
relative to the diagonal, and some intensity and
phase anomalies, observed as small antiphase
residual connectivities, were observed for the H-7
and 11-H cross peaks.
The 7-H, 11-H and 13-CH2 multiplets of the
adducts lie in the range 1.92–4.98 ppm in CDCl3
at 500 MHz, and the network of dipolar coupled
nuclei is not very extended. Since 7-Hh and 8-Hh
The full proton assignment of the adducts in
CDCl3 suggested by COSY and selective decou-
pling experiments are reported in Table 1.
The assignments of the 13C resonances of the
synthesized products were carried out in CDCl3
by determining (i) the signal multiplicities by ed-
ited DEPT experiments [15]; (ii) the H, C correla-
tions [16].
3
are known to be cis, the value of J7,11=6.3–6.6
Hz, found in the derivatives 2–11 and measured
by selective decoupling experiments, suggested
that these two protons are in the cis configuration
[13]. However, some of the eremophilanolides de-
scribed in the literature, and structurally related
3
to eudesmanolides, showed a J7,11 in the range
The complete 1H and 13C assignments of
molecules were achieved by the means of proton-
proton and proton-carbon correlation methods.
As is well known, an HMQC experiment allowed
9–12 Hz for either cis or trans geometry of the
two protons [14]. Consequently, we decided to
perform phase sensitive NOESY experiments in