Studies towards the synthesis of atp analogs as potential glutamine synthetase inhibitors

Article abstract of DOI:10.1080/00397911.2010.501473

In research directed at the development of adenine triphosphate (ATP) analogs as potential glutamine synthetase (GS) inhibitors, adenine and allopurinol derivatives have been synthesized either as novel ATP analogs or as scaffolds for the construction of

Full text of DOI:10.1080/00397911.2010.501473

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Studies Towards the Synthesis of
ATP Analogs as Potential Glutamine
Synthetase Inhibitors
Sheriff Salisu a , Colin Kenyon b & Perry T. Kaye a
a Department of Chemistry and Centre for Chemico- and
Biomedicinal Research , Rhodes University , Grahamstown , South
Africa
b CSIR BIO/CHEMTEK , Modderfontein , South Africa
Published online: 25 May 2011.
To cite this article: Sheriff Salisu , Colin Kenyon & Perry T. Kaye (2011) Studies Towards the
Synthesis of ATP Analogs as Potential Glutamine Synthetase Inhibitors, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:15, 2216-2225,
DOI: 10.1080/00397911.2010.501473
To link to this article: http://dx.doi.org/10.1080/00397911.2010.501473
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Synthetic Communications1, 41: 2216–2225, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.501473
STUDIES TOWARDS THE SYNTHESIS OF ATP
ANALOGS AS POTENTIAL GLUTAMINE
SYNTHETASE INHIBITORS
Sheriff Salisu,1 Colin Kenyon,2 and Perry T. Kaye1
1Department of Chemistry and Centre for Chemico- and Biomedicinal
Research, Rhodes University, Grahamstown, South Africa
2CSIR BIO=CHEMTEK, Modderfontein, South Africa
GRAPHICAL ABSTRACT
Abstract In research directed at the development of adenine triphosphate (ATP) analogs as
potential glutamine synthetase (GS) inhibitors, adenine and allopurinol derivatives have
been synthesized either as novel ATP analogs or as scaffolds for the construction of such
analogs.
Keywords Adenine; allopurinol; Baylis–Hillman products; glutamine synthetase
inhibitors
Although Tuberculosis (TB) has been viewed as a preventable disease, it remains a
major international health challenge with the highest mortality rates being recorded
in the poorest parts of the world. The problem has been exacerbated by the increased
susceptibility of AIDS-infected patients to TB[1] and by the emergence of multidrug-
resistant (MDR-TB)[2] and, very recently, extremely drug-resistant (XDR-TB)
strains.[3–5] Mycobacterium tuberculosis (M.tb.) is the tubercle bacillus responsible
for TB,[6,7] and the type II M.tb. glutamine synthetase enzyme (MTB-GS) has been
shown to be essential, inter alia, for the formation of the cell wall of M.tb.[8] Adenine
triphosphate (ATP; Fig. 1) is a critical GS substrate, and our research has focused on
the development ATP mimics capable of binding to the active site of MTB-GS and
thus inhibiting normal enzymatic function. The first step in exploring this hypothesis
has involved the synthesis of such mimics, and in a collaborative program, we have
Received December 10, 2009.
Address correspondence to Perry T. Kaye, Department of Chemistry and Centre for Chemico- and
Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa. E-mail: P.Kaye@ru.ac.za
2216

SYNTHESIS OF ATP ANALOGS
2217
Figure 1. Major structural features of ATP.
examined various approaches to their synthesis. These include (i) replacement of the
adenine moiety (Fig. 1) by different heterocyclic sytems;[9] (ii) the use of ‘‘truncated’’
adenine derivatives;[10] and (iii) replacement of the polar sugar and triphosphate moi-
eties in ATP by, for example, penta-acetylgluconyl or polyoxygenated alkylphospho-
nate groups.[9,10] In this communication, we report the results of preliminary studies
directed toward the preparation of adenine and allopurinol derivatives.
It was anticipated that deprotonation of adenine followed by reaction with suit-
able electrophiles would afford novel ATP analogs or scaffolds for the construction of
such analogs. When adenine 1 was treated with NaH in dimethylformamide (DMF),
Scheme 1. Reagents: i) NaH, DMF; ii) CH2¼CHCH2Br; iii) SnCl4, CH3CN.

2218
S. SALISU, C. KENYON, AND P. T. KAYE
followed by allyl bromide (Scheme 1), both the monoallylated product 2 and the
diallylated analog 3 were obtained in very poor yields (12% and 2% respectively), with
monoallylation in the former compound occurring preferentially at the 6-amino group
rather than on the purine nucleus at N-9. Preliminary attempts to couple deprotonated
adenine with 2-(chloroethoxy)ethanol, acetoxyacetyl chloride, and chloroacetyl
chloride all proved unsuccessful. However, SnCl4-catalyzed N-glycosidation using
specially prepared[11] penta-acetylated glucopyranose in acetonitrile[12] afforded
3,4,5-triacetoxy-6-acetoxymethyl-2-(6-aminopurin-9-yl)pyran 5 in 30% yield. NMR
analysis of this product confirmed the presence of the anomeric proton, resonating
at 5.88 ppm (0.4 ppm upfield of the corresponding signal in the penta-acetylated pre-
cursor), and the anomeric carbon, resonating at 80.3 ppm—an upfield shift of 8.8 ppm.
Attention was also given to the use of allopurinol 5 as a structural analog of
adenine. Since it was again the intention to react the deprotonated heterocyclic sub-
strate with various electrophiles, the allopurinol hydroxyl group was protected as
the 2-pyranyl ether[13] to avoid competition between the NH and OH groups. The pro-
tected allopurinol 6 was deprotonated using sodium hydride in tetrahydrofuran (THF)
and then treated with allyl bromide[14] under reflux to afford the N-allylated derivative
7 in 87% yield (Scheme 2). We had previously developed access to various coumarin
derivatives using Baylis–Hillman methodology,[15] and it was decided to explore the
use of 3-(chloromethyl)coumarins as alkylating agents to afford compounds 8 and
9. The coumarin moiety is common in nature,[16] and has the potential to undergo
nucleophilic ring opening.[17]
In the present study, the requisite Baylis–Hillman adducts 12 and 13 were
obtained as outlined in Scheme 3, the former accompanied by a trace amount of
the 2H-chromene-3-carboxylate ester 14. Cyclization of the Baylis–Hillman adduct
13 in a refluxing mixture of HCl and CH3COOH[15] yielded the desired 6-bromo-
3-(chloromethyl)coumarin 15 in 31% yield together with two side products,
Scheme 2. Reagents: i) PTSA, DMF; ii) NaH, DMF; iii) CH2¼CHCH2Br; iv) See Scheme 3.

SYNTHESIS OF ATP ANALOGS
2219
Scheme 3. Reagents: (i) CH2¼CHCO2But, DABCO, CHCl3; (ii) HCl, CH3CO2H; (iii) CH3CO2H;
(iv) H2O; (v) NaH, THF then 15; (vi) NaH, THF, then 12 or 13.
Scheme 4. Proposed mechanism for the formation of the allopurinol-coumarin products.

2220
S. SALISU, C. KENYON, AND P. T. KAYE
3-(acetoxymethyl)-6-bromocoumarin 16 (<2%) and 6-bromo-3-(hydroxymethyl)-
coumarin 17 (7%). Formation of the acetate ester 16 may be attributed to direct
conjugate addition by acetic acid on the substrate 13 and=or nucleophilic
displacement of chloride in the major product 15 by acetate, while the formation
of the alcohol 17 may be attributed to the hydrolysis of the ester 16 during workup
(Scheme 3).
Two routes to the allopurinol-coumarin product 8 were followed (Scheme 3).
In the first, the allopurinol ether 6 was deprotonated and reacted with 6-bromo-3-
(chloromethyl)coumarin 15 using direct nuceophilic displacement, affording the
required product 9 in 31% yield. In the second approach, use of the Baylis–Hillman
adduct 13, as the electrophile, involved a tandem conjugate addition–cyclization
sequence to afford the product 9 in 14% yield. The second approach was also used
to prepare compound 8 directly from the corresponding Baylis–Hillman adduct 12.
A mechanistic rationalization for the conjugate addition–cyclization sequence is
outlined in Scheme 4. Thus, conjugate addition of the deprotonated alloprinol
derivative 18 to the Baylis-Hillman adducts 12 and 13, followed by intramolecular
trans-esterification of the deprotonated aza-Michael adducts 18 and 19 and dehy-
dration, is expected to afford products 8 and 9, respectively. The conjugate addition
of amines to Baylis–Hillman esters has been observed previously in our group.[18,19]
CONCLUSIONS
Although yields have not been optimized, the N-allylated derivatives 2 and 7,
the N-glycosylated derivative 4, and the allopurinol-coumarin adducts 8 and 9
represent useful scaffolds for structural elaboration. The successful coupling of the
protected allopurinol 6 to Baylis–Hillman adducts suggests that aza-Michael addition
might well provide effective access to various N-substituted adenine and allopurinol
systems. It is expected that this methodology and the potential of some of the pro-
ducts as glutamine synthetase inhibitors will be explored in future investigations.
EXPERIMENTAL
Low-resolution mass spectra (LRMS) were obtained on a Finnegan Mat GCQ
spectrometer, whereas high-resolution mass spectra (HRMS) were recorded by the
University of Witwatersrand Mass Spectrometry Unit. NMR spectra were recorded
on a Bruker 400 MHz Avance spectrometer and were referenced using solvent sig-
nals (dH: 7.26 ppm for residual CHCl3; dC: 77.0 ppm for CDCl3). Melting points were
determined using a hot-stage apparatus and are uncorrected. The penta-acetylated
glucose,[11] the allopurinol 2-pyranyl ether 6,[13] the Baylis–Hillman adducts 12
and 13,[15] and the coumarin derivatives 14 and 15[15,18] are known. Synthetic meth-
ods and the characterization of new compounds prepared in this study are detailed.
6-(N-Allylamino)purine 2 and 9-Allyl-6-(N-allylamino)purine 3
NaH (60% dispersion in mineral oil; 100 mg, 4.0 mmol) was added, in small
portions to permit controlled evolution of hydrogen, to a stirred solution of adenine
1 (300 mg, 2.2 mmol) in dry DMF (20 mL) under nitrogen at 0 ꢀC. Allyl bromide

SYNTHESIS OF ATP ANALOGS
2221
(230 mL, 2.7 mmol) was then added through a septum, and the resulting solution was
refluxed for ca. 6 h. The reaction was quenched by the addition of water (25 mL). The
solvent was evaporated in vacuo, and the aqueous residue was extracted with CHCl3
(2 ꢁ 25 mL). The organic extracts were combined, washed sequentially with saturated
aqueous NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), and brine (2 ꢁ 50 mL). The aque-
ous washings were extracted with CHCl3, and the organic layers were combined and
dried (anhydrous MgSO4). The solvent was evaporated in vacuo, and the residue was
flash chromatographed [on silica; elution with EtOH–EtOAc (1:20)] to afford two
fractions.
6-(N-Allylamino)purine 2. Yellow solid (45 mg, 12%), mp 165–167 ꢀC (found
Mþ: 175.085842. C8H9N5 requires, M: 175.085795); nmax (solid deposit=cmꢂ1) 3382
(NH); dH=ppm (400 MHz; CDCl3) 4.91 (2H, d, J ¼ 5.8 Hz, CH2CH), 5.25 (1H, d,
=
=
J ¼ 17.1 Hz, CH2CH CHZ), 5.35 (1H, d, J ¼ 10.2 Hz, CH2CH CHE), 6.07 (1H,
tdd, J ¼ 16.1, 10.4 and 5.8 Hz, CH2CH), 8.43 (1H, s, Ar-H), 8.70 (1H, s, Ar-H),
10.01 (1H, d, J ¼ 10.0 Hz, 6-NH), and 11.12 (1H, d, J ¼ 9.4 Hz, 9-NH); dC=ppm
(100 MHz; CDCl3) 46.1 (CH2CH), 119.6, 120.4, 131.2, 144.2, 149.3, 151.9 and
=
152.5 (CH CH2 and Ar-C).
9-Allyl-6-(N-allylamino)purine 4. Yellow solid (8.0 mg, 2.0%), mp 103–105 ꢀC
(found Mþ: 215.118412. C11H13N5 requires, M: 215.117096); nmax (thin film=cmꢂ1
)
3383 (NH); dH=ppm (400MHz; CDCl3) 4.80 (4H, d, J ¼ 5.3 Hz, 2 ꢁ CH2CH), 5.19
=
=
(2H, m, CH CH2NH), 5.30 (2H, d, J ¼ 8.0 Hz, CH CH2), 6.02 (2H, m, 2 ꢁ CH2CH),
7.77 (1H, s, Ar-H) and 8.40 (1H, s, Ar-H); dC=ppm (100 MHz; CDCl3) 45.7
=
(2ꢁ CH2CH), 116.4, 118.9, 119.6, 131.9, 134.3, 139.7, 152.5, 153.2 and 154.7 (CH CH2
and Ar-C).
3,4,5-Triacetoxy-6-acetoxymethyl-2-(6-aminopurin-9-yl)pyran 4
Tin tetrachloride (1.0 mL, 9.3 mmol) was added to a stirred solution of adenine
1 (0.5 g, 4 mmol) and acetylated glucose[11] (1.4 g, 3.5 mmol) in acetonitrile (20 mL),
and the reaction mixture was refluxed under argon for ca. 6 h. The reaction was
quenched with saturated aqueous NaHCO3 (50 mL). The solvent was evaporated
in vacuo, and the aqueous residue extracted with EtOAc (2 ꢁ 25 mL). The organic
extracts were combined and washed sequentially with saturated aqueous NaHCO3
(2 ꢁ 50 mL) and brine (2 ꢁ 50 mL). The aqueous washings were extracted with
EtOAc, and the organic layers were combined and dried (anhydrous MgSO4). The
solvent was evaporated in vacuo, and flash chromatography of the residual oil [on
silica; elution with EtOH-CHCl3 (1:19)] afforded 3,4,5-triacetoxy-6-acetoxymethyl-
2-(6-aminopurin-9-yl)pyran 4 as yellow crystals (510 mg, 30%), mp 63–65 ꢀC (found
Mþ: 465.14892. C19H23N5O9 requires, M: 465.14958); nmax (solid deposit=cmꢂ1
)
=
3339 (NH2) and 1744 (C O); dH=ppm (400 MHz; CDCl3) 2.00–2.08 (12H, series
of singlets, 4 ꢁ CH3), 4.02–5.58 [6H, series of multiplets, CH2 and pyran 3-,4-,5-
and 6-H], 5.76 (2H, s, NH2), 5.88 (1H, d, J ¼ 9.5 Hz, pyran 2-H), 8.00 (1H, s,
Ar-H) and 8.36 (1H, s, Ar-H); dC=ppm (100 MHz; CDCl3) 20.1, 20.5, 20.6, and
20.7 (5 ꢁ CH3), 61.6 (CH2), 67.9 (C-5), 70.4 (C-3), 72.9 (C-4), 75.1 (C-6), 80.3
(C-2), 119.2, 138.3, 150.7, 153.4 and 155.4 (Ar-C), 169.0, 169.4, 169.8 and 170.5
=
(4 ꢁ C O).

2222
S. SALISU, C. KENYON, AND P. T. KAYE
7-Allyl-4-(tetrahydropyran-2-yloxy)pyrazolo[3,4-d]pyrimidine 7
NaH (60% dispersion in mineral oil; 40 mg, 0.91 mmol) was added in small
portions to a stirred solution of protected allopurinol 6[13] (200 mg, 0.91 mmol) in
dry THF (50 mL) under nitrogen to permit controlled evolution of hydrogen. Allyl
bromide (80 mL, 0.91 mmol) was then added through a septum, and the resulting
solution was refluxed for ca. 6 h. The reaction was quenched by the addition of water
(50 mL). The solvent was evaporated in vacuo, and the aqueous residue was extracted
with CH2Cl2 (2 ꢁ 50 mL). The organic extracts were combined and washed sequen-
tially with water (2 ꢁ 100 mL) and brine (2 ꢁ 100 mL). The aqueous washings were
extracted with CH2Cl2, and the organic layers were combined and dried
(anhydrous MgSO4). Evaporation of the solvent in vacuo afforded 7-allyl-4-(tetrahy-
dropyran-2-yloxy)pyrazþolo[3,4-d]-pyrimidine 7 as a pale yellow solid (210 mg, 87%),
mp 60–62 ꢀC (found M : 260.12774. C13H16N4O2 requires, M: 260.12733); dH=ppm
(400 MHz; CDCl3) 1.61–4.10 [8H, series of multiplets, (CH2)4], 4.61 (2H, m,
=
=
=
CH2CH CH2), 5.21 (1H, d, CH2CH CHZ), 5.28 (1H, dd, CH2CH CHE), 5.83
(1H, dd, OCHO), 5.94 (1H, tdd, CH¼CH2), 7.94 (1H, s, Ar-H) and 8.12 (1H, s,
Ar-H); dC=ppm (100 MHz; CDCl3) 22.7 (C-50), 24.9 (C-40), 29.3 (C-30), 47.8
=
(CH2CH CH2), 68.2 (C-6 ), 82.9 (OCHO), 106.3, 118.9, 132.1, 135.8, 149.0, 151.7
0
=
and 156.8 (CH CH2 and Ar-C).
6-Bromo-3-(chloromethyl)coumarin 15, 3-(Acetoxymethyl)-6-
bromocoumarin 16, and 6-Bromo-3-(hydroxymethyl)coumarin 17
A mixture of t-butyl 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-2-methylene
propanoate 13 (2.0 g, 6.1 mmol), concentrated HCl (10 mL), and glacial acetic acid
(10 mL) was boiled under reflux for 2.5 h. The reaction mixture was allowed to cool
to room temperature. Ice-cold water (40 mL) was then added and the reaction
mixture was stirred for 30 min. The mixture was allowed to stand at 0 ꢀC for 24 h,
and the pink solid was filtered off and flash chromatographed [on silica; elution with
hexane–EtOAc (7:3)] to afford three products.
6-Bromo-3-(chloromethyl)coumarin 15. White powder (0.52 g, 31%), mp
102–104 ꢀC (lit.[15] 104–106 ꢀC).
3-(Acetoxymethyl)þ-6-bromocoumarin 16. White powder (33 mg, 1.8%),
mp 119–121 ꢀC (found M : 297.966202. C12H981BrO4 requires, M: 297.96637); nmax
(solid deposit=cmꢂ1) 1720 (C O), dH=ppm (400 MHz; CDCl3) 2.16 (3H, s, CH3),
5.06 (1H, d, CH2), 7.22 (1H, d, 8-H), 7.61 (1H, dd, 7-H) and 7.64 (2H, m, 5-H
=
and 4-H); dC (100 MHz; CDCl3) 20.8 (CH3), 60.9 (CH2), 117.2, 118.4, 120.3,
=
125.0, 130.2, 134.5, 138.9 and 152.3 (Ar-C), 159.5 and 170.4 (2 ꢁ C O).
6-Bromo-3-(hydroxþymethyl)coumarin 17. White powder (0.11 g, 7.3%),
mp 147–149 ꢀC (found: M , 253.959816. C10H779BrO3 requires, M: 253.95781); nmax
(solid deposit=cmꢂ1) 3409 (OH) and 1632 (C O); dH=ppm (400 MHz; DMSO-d6)
4.36 (2H, m, CH2), 5.52 (1H, t, OH), 7.37 (1H, d, 8-H), 7.71 (1H, dd, 7-H), 7.94
=
(1H, d, 4-H) and 8.05 (1H, d, 5-H); dC (100 MHz; DMSO-d6) 58.1 (CH2), 116.1,
=
118.2, 121.0, 130.1, 130.5, 133.3, 135.6 and 151.3 (Ar-C) and 159.1 (C O).

SYNTHESIS OF ATP ANALOGS
2223
7-[(2H-Chromen-2-on-3-yl)methyl]-4-(tetrahydropyran-2-yloxy)-
pyrazolo[3,4-d]pyrimidine 8
NaH (60% dispersion in mineral oil; 21 mg, 0.88 mmol) was added to a stirred
solution of protected allopurinol 6 (110 mg, 0.49 mmol) in dry THF (10 mL) under
nitrogen in small portions to permit controlled evolution of hydrogen. The resulting
solution was refluxed for 1 h and then cooled to room temperature before adding
t-butyl 3-hydroxy-3-(2-hydroxyphenyl)-2-methylene propanoate 12 (120 mg,
0.49 mmol). The reaction mixture was refluxed for ca. 6 h. Water (30 mL) was added
to quench the reaction. The organic solvent was evaporated in vacuo, and the aqueous
residue was extracted with CH2Cl2 (2 ꢁ 30 mL). The combined organic extracts were
washed sequentially with water (2 ꢁ 60 mL) and brine (2 ꢁ 60 mL). The aqueous wash-
ings were extracted with CH2Cl2, and the organic layers were combined and dried
(anhydrous MgSO4). Evaporation of the solvent in vacuo afforded a pale yellow solid,
flash chromatography of which [on silica; elution with hexane–EtOAc (3:7)] afforded
7-[(2H-chromen-2-on-3-yl)methyl]-4-(tetrahydropyran-2-yloxy)pyrazolo[3,4-d]-
pyrimidine 8 as a white powder (45 mg, 24%), mp 210–212 ꢀC (found Mþ: 378.132008.
C20H18N4O4 requires, M: 378.132805); nmax (solid deposit=cmꢂ1) 1698 (C O);
=
dH=ppm (600 MHz; CDCl3) 1.59–4.10 [8H, m, (CH2)4], 5.03 (2H, s, NCH2), 5.84
(1H, dd, OCHO), 7.29 (2H, m, Ar-H), 7.52 (2H, m, Ar-H), 8.075 (1H, s, Ar-H),
8.078 (1H, s, Ar-H) and 8.46 (1H, s, Ar-H); dC=ppm (150 MHz; CDCl3) 22.7
(C-500), 24.8 (C-400), 29.4 (C-300), 45.7 (CH2), 68.3 (C-600), 82.8 (C-200), 106.2, 116.6,
118.7, 121.9, 124.8, 128.5, 132.3, 135.6, 144.5, 150.2, 151.8, 153.7 and 157.4 (Ar-C)
=
and 161.4 (C O).
7-[(6-Bromo-2H-chromen-2-on-3-yl)methyl]-3-(tetrahydropyran-2-
yloxy)-pyrazolo[3,4-d]pyrimidine 9
Method 1. NaH (60% dispersion in mineral oil; 24 mg, 0.99 mmol) was added
to a stirred solution of protected allopurinol 6 (120 mg, 0.55 mmol) in dry THF
(10 mL) under nitrogen in small portions to permit controlled evolution of hydrogen.
The resulting solution was refluxed for 1 h and then cooled to room temperature
before adding 6-bromo-3-(chloromethyl)chromen-2-one 15 (150 mg, 0.55 mmol).
The reaction mixture was refluxed for ca. 6 h. Water (30 mL) was added to quench
the reaction. The organic solvent was evaporated in vacuo, and the aqueous residue
extracted with CH2Cl2 (2 ꢁ 30 mL). The combined organic extracts were washed
sequentially with water (2 ꢁ 60 mL) and brine (2 ꢁ 60 mL). The aqueous washings
were extracted with CH2Cl2, and the organic layers were combined and dried (anhy-
drous MgSO4). Evaporation of the solvent in vacuo afforded a pale yellow solid,
flash chromatography of which [on silica; elution with hexane–EtOAc (1:1)] afforded
7-[(6-bromo-2H-chromen-2-on-3-yl)methyl]-3-(tetrahydropyran-2-yloxy)pyrazolo[þ3,
4-d]pyrimidine 9 as a white powder (77 mg, 31%), mp 210–212 ꢀC (found M :
458.041200. C20H8171BrN4O4 requires, M: 458.04141); nmax (solid deposit=cmꢂ1) 1720
=
(C O); dH=ppm (400 MHz; CDCl3) 1.60–4.10 [8H, series of multiplets, (CH2)4],
5.02 (1H, s, NCH2), 5.83 (1H, dd, OCHO), 7.19 (1H, d, 8-H), 7.60 (1H, dd, 7-H),
7.66 (1H, d, 5-H), 8.00 (1H, s, Ar-H), 8.08 (1H, s, Ar-H), and 8.42 (1H, s, Ar-H);
dC=ppm (100MHz; CDCl3) 22.7 (C-500), 24.8 (C-400), 29.3 (C-300), 45.7 (NCH2), 68.3

2224
S. SALISU, C. KENYON, AND P. T. KAYE
(C-600), 82.8 (C-200), 106.1, 117.4, 118.3, 120.2, 123.0, 130.7, 135.0, 135.6, 143.2, 150.0,
=
151.7, 152.4 and 157.3 (Ar-C), and 160.7 (C O).
Method 2. The procedure described for the preparation of compound 8 was
followed using the Baylis–Hillman adduct 13 and the protected allopurinol 6 to
afford compound 9 in 14% yield.
ACKNOWLEDGMENTS
We are grateful to the South African Department of Science and Technology
(DST) Innovation Fund for a bursary (S. S.) and the Department of Science and
Technology and Rhodes University for generous financial support.
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