Synthesis of cinnamate ester-AZT conjugates as potential dual-action HIV-1 integrase and reverse transcriptase inhibitors

Article abstract of DOI:10.1016/j.tet.2014.09.045

Synthetic approaches to a series of novel cinnamate ester-AZT conjugates have been explored and a successful pathway has finally been developed. α-(Halomethyl)cinnamate esters, obtained in high yield by treating benzyl-protected salicylaldehde-derived Bay

Full text of DOI:10.1016/j.tet.2014.09.045

Tetrahedron 70 (2014) 9449e9455
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Tetrahedron
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Synthesis of cinnamate estereAZT conjugates as potential
dual-action HIV-1 integrase and reverse transcriptase inhibitors
*
Temitope O. Olomola, Rosalyn Klein, Perry T. Kaye
Department of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2014
Received in revised form 3 September 2014
Accepted 15 September 2014
Available online 20 September 2014
Synthetic approaches to a series of novel cinnamate estereAZT conjugates have been explored and
a successful pathway has finally been developed. a-(Halomethyl)cinnamate esters, obtained in high yield
by treating benzyl-protected salicylaldehde-derived BayliseHillman adducts with acetyl bromide at low
temperature, have been treated with propargylamine to afford substrates for click chemistry reactions
with azidothymidine (AZT) in the presence of in situ generated Cu(I) catalyst to produce the title
compounds.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Dual-action inhibitors
HIV-1 Integrase/reverse transcriptase
BayliseHillman reaction
Cinnamate esters
Azidothymidine (AZT)
1. Introduction
potential, dual-action HIV-1 PR/RT inhibitors6,7 and, in this paper,
we report progress on the development of novel, dual-action HIV-1
The BayliseHillman (or MoritaeBayliseHillman) reaction is
now a well established, atom-economical method for coupling
suitably activated alkenes with aldehydes and related electrophilic
systems.1e3 Our own research in this area has involved applications
of BayliseHillman methodology in the construction of benzannu-
lated heterocyclic systems,4 including quinolines, chromenes and
coumarins and, more recently, in the structural elaboration of these
systems to access compounds with medicinal potential.5e7 The
global health challenges presented by the spread of HIV/AIDS,
particularly in Sub-Saharan Africa,8 have been compounded by the
emergence of drug resistance, now being addressed by the use of
combination regimens, known as HAART (Highly Active Anti-
Retroviral Therapy), in which an HIV-1 protease (PR) inhibitor is
administered together with nucleoside and non-nucleoside HIV-1
reverse transcriptase (RT) inhibitors.9 Unfortunately, patient non-
compliance remains problematic even with HAART regimens,10
and an alternative approach to combination therapies is attract-
ing attention. This involves the use of Designed Multiple Ligands
(DMLs)11e13 or ‘portmanteau’ drugs,14 in which different bioactive
moieties are linked within a single compound. We have, in fact,
recently reported the synthesis and preliminary evaluation of
BayliseHillman-derived coumarineAZT conjugates (e.g., 1) as
integrase/reverse transcriptase (IN/RT) inhibitors.
The presence of cinnamate ester moieties,15,16 in both caffeic
acid phenethyl ester 2 and -chicoric acid 3 has been presumed to
L
be responsible for their reported HIV-1 IN inhibition activity, while
azidothymidine (AZT) is, of course, a well established HIV-1 RT
inhibitor.17 Compound 4 has been reported by Wang et al.14 as
a dual-action HIV-1 RT/IN inhibitor, which exhibits IC50 values in
the nanomolar range for both enzymes. In our own research pro-
gramme, attention has been focussed on developing cinnamate
estereAZT conjugates 12 (Scheme 1) as potential HIV-1 IN/RT
inhibitors.
2. Results and discussion
The proposed route to the desired cinnamate estereAZT con-
jugates 12 may be summarised by the formal retrosynthetic anal-
ysis outlined in Scheme 1. Thus, BayliseHillman reactions of
variously substituted salicylaldehydes 5 with tert-butyl acrylate 6
were expected to afford the isolable BayliseHillman adducts 7,
which, as
a,
b-unsaturated esters, should be susceptible to conju-
gate addition by propargylamine 8 to afford
b
-hydroxy products 9,
dehydration of which would lead to cinnamate esters 10. A ‘click
chemistry’ reaction18 between the alykynyl derivative 10 and AZT
11 would then deliver the target molecules 12.
The BayliseHillman adducts 7aee were successfully prepared
* Corresponding author. Tel.: þ27 46 6037030; fax: þ27 466225109; e-mail ad-
dress: P.Kaye@ru.ac.za (P.T. Kaye).
using established methodology,19 and underwent conjugate
http://dx.doi.org/10.1016/j.tet.2014.09.045
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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T.O. Olomola et al. / Tetrahedron 70 (2014) 9449e9455
Scheme 1.
addition of propargylamine 8 to afford, after flash chromatography,
the alkynylated compounds 9aee as single diastereomers in ex-
cellent yield (88e99%).20 However, attempted dehydration of the
conjugate addition product 9e, using 1-ethyl-3-[3-(dimethylamino)
propyl]carbodiimide (EDC) as a dehydrating agent21 in the presence
of a catalytic quantity of CuCl2 gave little evidence of the expected
cinnamate ester 10e (Scheme 2). An alternative approach was then
explored involving reaction of the O-benzylated salicylaldehydes 13
with methyl acrylate (Scheme 3). Whereas the tert-butyl acrylate-
derived BayliseHillman adducts are isolable, the methyl acrylate-
derived analogues are not and require benzylation of the phenolic
group to prevent spontaneous cyclisation to mixtures of coumarin
and chromene derivatives.19
2-(Benzyloxy)benzaldehydes 13aee, obtained in yields of
88e99% by treating the salicylaldehydes 5aee with benzyl bromide
in the presence of potassium carbonate and sodium iodide in ab-
solute ethanol, were then reacted with methyl acrylate 14 using
DABCO as catalyst and purified CHCl3 as solvent (The CHCl3 was
passed through basic alumina to remove contaminating HCl and
thus prevent the acid-catalysed deprotection of the benzylated
salicylaldehydes.). After stirring at rt for 21 days, the crude mixtures
were flash chromatographed to afford the O-benzylated Bay-
liseHillman adducts 15aee in yields of up to 94%.
Bartoli et al. have reported the CeCl3$7H2O/NaI-catalysed dia-
stereoselective dehydration of b
-hydroxycarbonyl compounds.22 In
order to explore this route to cinnamate esters, the O-benzylated
BayliseHillman adduct 15b was first reacted with propargylamine
to give compound 16b as a single diastereomer in 92% yield after
flash chromatography.20 Unfortunately, attempts to dehydrate the
b-hydroxycarbonyl compound using Bartoli’s method proved un-
successful, and attention was again turned to an alternative ap-
proach, viz., acetylation of the hydroxyl group to facilitate its
elimination. Thus, the 5-bromo adduct 15b was treated with acetyl
chloride in the presence of pyridine in dry DCM for 4 h to afford
compound 18b in 55% yield following flash chromatography. In an
attempt to increase the yield in the acetylation reaction, acetyl
bromide was used in place of acetyl chloride. The BayliseHillman
adducts 15a,cee were treated with acetyl bromide at 0 ꢀC in the
presence of pyridine in dry DCM for 4 h. Flash chromatography of
the products afforded, unexpectedly, the 2-bromomethyl cinna-
mate esters 19a,cee23 in yields of up to 94%, instead of the expected
acetylated derivatives 18a,cee, thus obviating the need for an

T.O. Olomola et al. / Tetrahedron 70 (2014) 9449e9455
9451
Scheme 2.
Scheme 3.
additional elimination step in accessing cinnamate esters! The (Z)-
3. Experimental
3.1. General
stereochemistry is assumed by analogy with related systems.23
Reaction of the acetylated 5-bromo adduct 18b with prop-
argylamine and K2CO3 in acetonitrile afforded the alkynylated
0
product 20b in 82% yield via conjugate additioneelimination or SN
The synthesis of the BayliseHillman adducts 7aee, benzylated
salicylaldehydes 13aee, the O-benzylated adducts 15aee and the
acetylated adduct 18b has been reported previously.19,25,26 The in-
termediates 9aee, 16b, 19a,cee and 20aee and the cinnamate
estereAZTconjugates 22aee are all new and were obtained as follows.
pathways (Scheme 4). The corresponding analogues 20a,cee,
however, were obtained in yields of up to 89% via direct nucleo-
philic substitution (SN) reactions of the 2-bromomethyl derivatives
0
19a,cee; in one case, the isomeric SN reaction product 21 was
isolated in 20% yield. The (E)-stereochemistry is assumed by anal-
ogy with related systems.23 In the final, ‘click chemistry’ step, the
propargylamino derivatives 20aee were each reacted with AZT in
aqueous THF in the presence of a Cu(I) catalyst generated in situ
from the sodium ascorbate reduction of Cu(II). The expected
products 22aee were obtained in yields of 87e92% following flash
chromatography, and were fully characterised.
In conclusion, efficient access to a series of cinnamate estereAZT
conjugates as potential dual-action HIV-1 IN/RT inhibitors has been
achieved in three steps from the corresponding O-benzylated
BayliseHillman adducts. The action of AZT as a nucleoside analogue
pro-drug requires in vivo triphosphorylation.24 Research on the
preparation of triphosphorylated analogues of these compounds
has been initiated in order to facilitate in vitro evaluation of their
nucleoside reverse transcriptase inhibition (NRTI) potential.
3.2. General procedure for the aza-Michael reaction of Bay-
liseHillman adducts 7aee with propargylamine
Propargylamine (0.3 mL, 4 mmol) was added to a solution of the
tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)-2-methylenepropanoate
(7aee) (2.2 mmol) in dry THF (5 mL) and the mixture stirred at rt
for 48 h. The reaction mixture was then concentrated in vacuo and
flash chromatographed [on silica gel; elution with hexane/EtOAc
(1:1)] to afford the tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)-2-[(2-
propynylamino)methyl]propanoate (9).
3.2.1. tert-Butyl 3-hydroxy-3-(2-hydroxyphenyl)-2-[(2-propynyl-
amino)methyl]propanoate 9a. A white solid (0.67 g, 99%), mp
68e70 ꢀC. HRMS: m/z calculated for C17H24NO4 (MHþ) 306.1705.

9452
T.O. Olomola et al. / Tetrahedron 70 (2014) 9449e9455
Scheme 4.
Found 306.1698; nmax/cmꢁ13458(OH)and1709(C]O); dH (400 MHz;
CDCl3) 1.28 [9H, s, C(CH3)3], 2.26 (1H, t, J¼2.4 Hz, C^CH), 3.03 (1H, dt,
J¼7.4 and 4.6 Hz, CHCO), 3.08e3.18 (2H, series of signals, CHCH2), 3.41
(2H, d, J¼2.4 Hz, CH2C^CH), 5.21 (1H, d, J¼7.4 Hz, CHOH), 6.77 (1H, dt,
J¼7.5 and 1.0 Hz, ArH), 6.82 (1H, dd, J¼8.1 and 1.0 Hz, ArH), 6.98 (1H,
dd, J¼1.6 and 7.5 Hz, ArH) and 7.13 (1H, dt, J¼8.1 and 1.6 Hz, ArH); dC
(100 MHz; CDCl3) 27.8 [C(CH3)3], 37.8 and 48.7 (CH2), 50.1 (CHCO),
72.8 and 81.5 (C^CH), 77.2 (CHOH), 80.0 [C(CH3)3],117.0,119.3,125.3,
127.9 and 129.0 (ArC), 156.0 [ArC(OH)] and 171.1 (C]O).
350.1967. Found 350.1953; nmax/cmꢁ1 3356 (OH) and 1740 (C]O);
dH (400 MHz; CDCl3) 1.41e1.45 [12H, overlapping s and t, C(CH3)3
and OCH2CH3], 2.20 (1H, t, J¼2.3 Hz, C^CH), 2.72 (1H, dd, J¼12.2
and 3.9 Hz, CHCHa), 3.05 (1H, dd, J¼9.1 and 5.0 Hz, CHCO), 3.19 (1H,
dd, J¼12.2 and 5.0 Hz, CHCHb), 3.30 (1H, dd, J¼17.1 and 2.3 Hz,
CHaC^CH), 3.43 (1H, dd, J¼2.3 and 17.1 Hz, CHbC^CH), 3.69 (3H, s,
OCH3), 4.09 (2H, q, J¼7.0 Hz, OCH2), 5.44 (1H, d, J¼5.0 Hz, CHOH),
6.76e6.83 (2H, m, ArH), and 6.94 (1H, dd, J¼7.2 and 1.8 Hz, ArH); dC
(100 MHz; CDCl3) 14.4 (OCH2CH3), 27.9 [C(CH3)3], 38.1 and 47.3
(CH2), 48.9 (CHCO), 64.5 (OCH2), 72.1 and 80.8 (C^CH), 73.5
(CHOH), 81.2 [C(CH3)3], 110.9, 119.2, 119.4 and 127.8 (ArC), 142.9 and
145.9 [ArC(OH) and ArC(OEt)] and 172.3 (C]O).
3.2.2. tert-Butyl 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-2-[(2-
propynylamino)methyl]propanoate 9b. A white solid (0.76 g, 90%),
mp 136e138 ꢀC. HRMS: m/z calculated for C17H2179BrNO4 (MꢁH)þ
382.0654. Found 382.0660; nmax/cmꢁ1 3260 (OH) and 1724 (C]O);
dH (400 MHz; DMSO-d6) 1.24 [9H, s, C(CH3)3], 2.71 (1H, dd, J¼14.9
and 8.4 Hz, CHCHa), 2.81 (2H, q, J¼8.4 Hz, CHCO and CHCHb), 3.04
(1H, s, C^CH), 3.25 (2H, s, CH2C^CH), 5.01 (1H, d, J¼5.7 Hz, CHOH),
6.71 (1H, d, J¼8.6 Hz, ArH), 7.20 (1H, dd, J¼8.6 and 2.3 Hz, ArH) and
7.35 (1H, d, J¼2.3 Hz, ArH); dC (100 MHz; DMSO-d6) 27.6 [C(CH3)3],
37.5 and 46.9 (CH2), 51.8 (CHCO), 67.4 (CHOH), 73.8 and 82.7
(C^CH), 79.5 [C(CH3)3], 109.9, 117.3, 130.4, 130.6 and 131.8 (ArC),
153.6 [ArC(OH)] and 171.4 (C]O).
3.2.5. tert-Butyl 3-(5-chloro-2-hydroxyphenyl)-3-hydroxy-2-[(2-
propynylamino)methyl]propanoate 9e. A white solid (0.68 g, 91%),
mp 125e126 ꢀC. HRMS: m/z calculated for C17H23ClNO4 (MHþ)
340.1316. Found 340.1331; nmax/cmꢁ1 3549 (OH) and 1697 (C]O);
dH (400 MHz; DMSO-d6) 1.25 [9H, s, C(CH3)3], 2.70 (1H, q, J¼8.8 Hz,
CHCHa), 2.78e2.84 (2H, m, CHCO and CHCHb), 3.04 (1H, t, J¼2.3 Hz,
C^CH), 3.25 (2H, t, J¼2.3 Hz, CH2C^CH), 5.02 (1H, d, J¼5.7 Hz,
CHOH), 6.77 (1H, s, ArH), 7.09 (1H, dd, J¼8.6 and 2.7 Hz, ArH) and
7.23 (1H, d, J¼2.7 Hz, ArH); dC (100 MHz; DMSO-d6) 27.6 [C(CH3)3],
37.5 and 46.8 (CH2), 51.7 (CHCO), 67.4 (CHOH), 73.8 and 82.7
(C^CH), 79.5 [C(CH3)3], 116.7, 122.2, 127.5, 127.7 and 131.3 (ArC),
153.1 [ArC(OH)] and 171.4 (C]O).
3.2.3. tert-Butyl 3-hydroxy-3-(2-hydroxy-3-methoxyphenyl)-2-[(2-
propynylamino)methyl]propanoate 9c. A yellow solid (0.65 g, 88%),
mp 67e69 ꢀC. HRMS: m/z calculated for C18H26NO5 (MHþ) 336.1811.
Found 336.1827; nmax/cmꢁ1 3356 (OH) and 1714 (C]O); dH
(400 MHz; CDCl3) 1.24 [9H, s, C(CH3)3], 2.14 (1H, s, C^CH),
2.67e2.72 (1H, m, CHCHa), 2.94e3.02 (2H, m, CHCO and CHCHb),
3.22 (2H, q, J¼17.1 Hz, CH2C^CH), 3.69 (3H, s, OCH3), 5.22 (1H, s,
CHOH), 6.61e6.68 (2H, m, ArH), and 6.75e6.78 (1H, m, ArH); dC
(100 MHz; CDCl3) 27.4 [C(CH3)3], 37.6 and 46.9 (CH2), 49.2 (CHCO),
55.5 (OCH3), 71.8 (CHOH), 72.8 and 80.52 (C^CH), 80.50 [C(CH3)3],
109.7, 118.6, 119.3 and 127.4 (ArC), 142.9 and 146.6 [ArC(OH) and
ArC(OMe)] and 171.8 (C]O).
3.3. Procedure for the synthesis of methyl 3-[2-(benzyloxy)-5-
bromophenyl]-3-hydroxy-2-[(2-propynylamino)methyl]prop-
anoate 16b
Propargylamine (0.3 mL, 4.4 mmol) was added to a solution of
methyl 3-(2-benzyloxy-5-bromophenyl)-3-hydroxy-2-methylenepro-
panonate 15b (0.83 g, 2.2 mmol) in dry THF (5 mL) and the mixture was
stirred at rt for 48 h. The reaction mixture was then concentrated in
vacuo and flash chromatographed [on silica gel; elution with hexane/
EtOAc (1:1)] to afford methyl 3-[2-(benzyloxy)-5-bromophenyl]-3-
hydroxy-2-[(2-propynylamino)methyl]propanoate 16b as a white solid
(0.87 g, 92%), mp 97e99 ꢀC. HRMS: m/z calculated for C21H2379BrNO4
3.2.4. tert-Butyl 3-(3-ethoxy-2-hydroxyphenyl)-3-hydroxy-2-[(2-
propynylamino)methyl]propanoate 9d. A brown solid (0.73 g, 95%),
mp 48e50 ꢀC. HRMS: m/z calculated for C19H28NO5 (MHþ)

T.O. Olomola et al. / Tetrahedron 70 (2014) 9449e9455
9453
(MHþ) 432.0810. Found 432.0809; nmax/cmꢁ1 1719 (C]O); dH
3.5. General procedure for the synthesis of methyl (E)-3-[2-
(400 MHz; CDCl3) 2.19 (1H, s, C^CH), 2.88 (1H, dd, J¼4.5 and 11.9 Hz,
CHCO), 3.10 (1H, dd, J¼4.1 and 8.6 Hz, CHCHa), 3.16 (1H, dd, J¼4.1 and
11.9 Hz, CHCHb), 3.36 (2H, q, J¼17.1 Hz, CH2eC^CH), 3.54 (3H, s, OCH3),
5.08 (2H, q, J¼11.7 Hz, OCH2), 5.34 (1H, d, J¼4.5 Hz, CHOH), 6.79 (1H, d,
J¼8.6 Hz, ArH), 7.31e7.42 (6H, overlapping m, ArH) and 7.56 (1H, s,
ArH); dC (100 MHz; CDCl3) 37.9 and 48.4 (NCH2), 49.7 (CHCO), 51.3
(CH3), 69.3 (CHOH), 71.8 (OCH2), 70.2 and 81.2 (C^CH), 113.0, 113.3,
127.1,128.0,128.6,129.9,130.8,132.7 and 136.2 (ArC),153.9 [ArC(OBn)]
and 173.4 (C]O).
(benzyloxy)phenyl]-2-[(2-propynylamino)methyl]-2-propen-
oates 20a,cee
Propargylamine (0.3 mL, 4 mmol) was added to a solution of the
methyl 3-[2-(benzyloxy)phenyl]-2-(bromomethyl)-2-propenoate
(19a,cee) (2.2 mmol) and K2CO3 (0.35 g, 2.5 mmol) in CH3CN (5 mL)
and the mixture stirred at rt for 12 h. The reaction mixture was then
neutralised by pouring into 0.5 N HCl (20 mL) and extracted using
CHCl3 (3ꢂ20 mL). The extracts were combined, washed with brine
(2ꢂ20 mL), concentrated in vacuo and flash chromatographed
[on silica gel; elution with hexane/EtOAc (4:1)] to afford the methyl
(E)-3-[2-(benzyloxy)-2-[(2-propynylamino)methyl]-2-propenoate
(20).
3.4. General procedure for the synthesis of methyl (Z)-3-[2-
(benzyloxy)phenyl]-2-(bromomethyl)-2-propenoates 19a,cee
Acetyl bromide (0.3 mL, 4.1 mmol) was slowly added to a cooled
(ice-bath) solution of methyl 3-(2-benzyloxyphenyl)-3-hydroxy-2-
methylenepropanoate (15a,cee) (0.39 g, 1.3 mmol) in dry DCM
(10 mL) (CAUTION! Exothermic reaction). Pyridine (0.1 mL) was
then added and the mixture left to stir at rt for 4 h. The crude
mixture was concentrated in vacuo and flash chromatographed [on
silica gel; elution with hexane/EtOAc (9:1)] to afford the methyl (Z)-
3-[2-(benzyloxy)phenyl]-2-(bromomethyl)-2-propenoates (19).
3.5.1. Methyl
methyl]-2-propenoate 20a. A yellow oil (0.57 g, 77%). HRMS: m/z
calculated for C21H22NO3 (MHþ) 336.1600. Found 336.1602; nmax
(E)-3-[2-(benzyloxy)phenyl]-2-[(2-propynylamino)-
/
cmꢁ1 3291 (NH) and 1709 (C]O); dH (600 MHz; CDCl3) 1.66 (1H, br
s, NH), 2.16 (1H, t, J¼2.4 Hz, C^CH), 3.42 (2H, d, J¼2.4 Hz, CH2C^C),
3.64 (2H, s, NCH2), 3.82 (3H, s, OCH3), 5.14 (2H, s, OCH2), 6.94 (1H, d,
J¼8.3 Hz, ArH), 6.98 (1H, t, J¼7.5 Hz, ArH), 7.28e7.42 (6H, series of
signals, ArH), 7.54 (1H, d, J¼7.5 Hz, ArH) and 8.06 (1H, s, 3-H); dC
(150 MHz; CDCl3) 38.0 and 45.4 (NCH2), 52.0 (CH3), 70.3 (OCH2),
71.3 and 81.9 (C^CH), 112.3, 120.8, 124.6, 127.0, 127.9, 128.6, 129.9,
130.4, 130.6,130.8 and 138.4 (C]CH and ArC), 156.8 [ArC(OBn)] and
168.4 (C]O).
3.4.1. Methyl (Z)-3-[2-(benzyloxy)phenyl]-2-(bromomethyl)-2-
propenoate 19a. A yellow oil (0.39 g, 83%). Found: C, 59.65; H,
4.74. C18H17BrO3 requires: C, 59.85; H, 4.74%; nmax/cmꢁ11711 (C]O);
dH (400 MHz; CDCl3) 3.88 (3H, s, OCH3), 4.39 (2H, s, CH2Br), 5.15 (2H,
s, OCH2Ph), 6.98 (1H, d, J¼8.3 Hz, ArH), 7.08 (1H, t, J¼7.5 Hz, ArH),
7.33e7.42 (6H, overlapping m, ArH), 7.72 (1H, d, J¼7.5 Hz) and 8.12
(1H, s, 3-H); dC (100 MHz; CDCl3) 27.4 and 70.3 (CH2), 52.3 (OCH3),
112.5, 121.0, 123.9, 127.0, 128.0, 128.4, 128.6, 129.6, 131.1, 136.5 and
138.9 (C]CH and ArC), 157.1 [ArC(OBn)] and 166.6 (C]O).
3.5.2. Methyl (E)-3-[2-(benzyloxy)-3-methoxyphenyl]-2-[(2-
propynylamino)methyl]-2-propenoate 20c. A white solid (0.68 g,
85%), mp 54e56 ꢀC. HRMS: m/z calculated for C22H24NO4 (MHþ)
366.1705. Found 366.1710; nmax/cmꢁ1 3296 (NH) and 1709 (C]O);
dH (600 MHz; CDCl3) 1.72 (1H, br s, NH), 2.17 (1H, s, C^CH), 3.40
(2H, s, CH2C^C), 3.53 (2H, s, NCH2), 3.80 and 3.90 (6H, s, 2ꢂOCH3),
4.99 (2H, s, OCH2), 6.96 (1H, d, J¼7.9 Hz, ArH), 7.07 (1H, t, J¼7.9 Hz,
ArH), 7.11 (1H, d, J¼7.7 Hz, ArH), 7.29e7.41 (5H, series of signals,
ArH) and 7.87 (1H, s, 3-H); dC (150 MHz; CDCl3) 38.1 and 45.4
(NCH2), 51.9 and 55.9 (OCH3), 71.3 and 81.9 (C^CH), 75.3 (OCH2),
113.3, 122.0, 124.0, 128.1, 128.3, 128.7, 130.0, 130.7, 137.2, 138.3 and
146.3 (C]CH and ArC), 152.8 [ArC(OBn)] and 168.2 (C]O).
3.4.2. Methyl (Z)-3-[2-(benzyloxy)-3-methoxyphenyl]-2-(bromometh-
yl)-2-propenoate 19c. A brown oil (0.48 g, 94%). Found: C, 58.33; H,
4.89. C19H19BrO4 requires: C, 58.45; H, 4.99%; nmax/cmꢁ1 1712 (C]O);
dH (400 MHz; CDCl3) 3.88 and 3.94 (6H, 2ꢂs, 2ꢂOCH3), 4.24 (2H, s,
CH2Br), 5.05 (2H, s, OCH2Ph), 7.05 (1H, d, J¼7.9 Hz, ArH), 7.19 (1H, t,
J¼8.0 Hz, ArH), 7.27 (1H, d, J¼7.7 Hz), 7.32e7.39 (5H, overlapping m,
ArH) and 7.90 (1H, s, 3-H); dC (100 MHz; CDCl3) 26.9 and 75.2 (CH2),
52.1 and 55.7 (OCH3), 113.6, 120.5, 124.3, 128.06, 128.09, 128.7, 128.8,
129.3,136.6 and 139.1 (C]CH and ArC),146.1 and 152.7[ArC(OBn) and
ArC(OMe)] and 166.1 (C]O).
3.5.3. Methyl (E)-3-[2-(benzyloxy)-3-ethoxyphenyl]-2-[(2-
propynylamino)methyl]-2-propenoate 20d. A yellow solid (0.74 g,
89%), mp 52e53 ꢀC. HRMS: m/z calculated for C23H26NO4 (MHþ)
380.1862. Found 380.1861; nmax/cmꢁ1 3180 (NH) and 1707 (C]O);
dH (600 MHz; CDCl3) 1.48 (3H, t, J¼7.0 Hz, OCH2CH3), 1.77 (1H, br s,
NH), 2.17 (1H, t, J¼2.4 Hz, C^CH), 3.40 (2H, d, J¼2.4 Hz, CH2C^C),
3.55 (2H, s, NCH2), 3.81 (3H, s, OCH3), 4.11 (2H, q, J¼7.0 Hz,
OCH2CH3), 5.02 (2H, s, OCH2Ph), 6.95 (1H, d, J¼8.0 Hz, ArH), 7.05
(1H, t, J¼8.0 Hz, ArH), 7.10 (1H, d, J¼7.5 Hz, ArH), 7.30e7.43 (5H,
series of signals, ArH) and 7.90 (1H, s, 3-H); dC (150 MHz; CDCl3)
14.9 (CH2CH3), 38.0 and 45.3 (NCH2), 51.9 (OCH3), 64.4 and 75.2
(OCH2), 71.3 and 81.9 (C^CH),114.4,121.9,123.9,128.0,128.2,128.6,
130.0, 130.6, 137.3, 138.4 and 146.5 (C]CH and ArC), 152.0
[ArC(OBn)] and 168.2 (C]O).
3.4.3. Methyl (Z)-3-[2-(benzyloxy)-3-ethoxyphenyl]-2-(bromometh-
yl)-2-propenoate 19d. A brown oil (0.46 g, 88%). Found: C, 59.66; H,
5.42. C20H21BrO4 requires: C, 59.27; H, 5.22%; nmax/cmꢁ1 1712 (C]
O); dH (400 MHz; CDCl3) 1.50 (3H, t, J¼7.0 Hz, CH2CH3), 3.85 (3H, s,
OCH3), 4.14 (2H, q, J¼7.0 Hz, CH2CH3), 4.21 (2H, s, CH2Br), 5.03 (2H,
s, OCH2Ph), 7.00 (1H, d, J¼8.0 Hz, ArH), 7.13 (1H, t, J¼8.0 Hz, ArH),
7.22 (1H, d, J¼7.6 Hz), 7.29e7.36 (5H, overlapping m, ArH) and 7.87
(1H, s, 3-H); dC (100 MHz; CDCl3) 14.9 (CH2CH3), 27.0, 64.4 and 75.3
(CH2), 52.2 (OCH3), 114.9, 120.7, 124.3, 128.2, 128.9, 129.5, 137.0 and
139.3 (C]CH and ArC), 146.5 and 152.2 [ArC(OBn) and ArC(OEt)]
and 166.4 (C]O).
3.5.4. Compounds 20e and 21. The procedure described for the
3.4.4. Methyl (Z)-3-[2-(benzyloxy)-5-chlorophenyl]-2-(bromometh-
yl)-2-propenoate 19e. A yellow solid (0.47 g, 91%), mp 80e81 ꢀC.
Found: C, 54.40; H, 4.24. C18H16BrClO3 requires: C, 54.64; H, 4.08%;
nmax/cmꢁ11697 (C]O); dH (600 MHz; CDCl3) 3.88 (3H, s, OCH3), 4.33
(2H, s, CH2Br), 5.13 (2H, s, OCH2Ph), 6.89 (1H, d, J¼8.8 Hz, ArH), 7.29
(1H, d, J¼8.8 Hz), 7.33e7.39 (5H, overlapping m, ArH), 7.68 (1H, s,
ArH) and 7.97 (1H, s, 3-H); dC (150 MHz; CDCl3) 26.5 and 70.8 (CH2),
52.5 (OCH3),113.8,125.4,126.1,127.0,128.2,128.7,129.1,129.6,130.6,
136.1 and 137.4 (C]CH and ArC),155.6 [ArC(OBn)] and 166.3 (C]O).
synthesis
of
methyl
(E)-3-[2-(benzyloxy)phenyl]-2-[(2-
propynylamino)methyl]-2-propenoate 20a was followed, using
propargylamine (0.3 mL, 4 mmol) and methyl (Z)-3-[2-(benzyloxy)-
5-chlorophenyl]-2-(bromomethyl)-2-propenoate 19e (0.87 g,
2.2 mmol) in dry THF (5 mL). Work-up afforded two products.
Product 1. Methyl (E)-3-[2-(benzyloxy)-5-chlorophenyl]-2-[(2-
propynylamino)methyl]-2-propenoate 20e: A yellow solid (0.61 g,
75%), mp 51e53 ꢀC. HRMS: m/z calculated for C21H21ClNO3 (MHþ)
370.1210. Found 370.1205; nmax/cmꢁ1 3301 (NH) and 1697 (C]O);

9454
T.O. Olomola et al. / Tetrahedron 70 (2014) 9449e9455
dH (600 MHz; CDCl3) 1.77 (1H, br s, NH), 2.20 (1H, s, C^CH), 3.44
(2H, s, CH2C^C), 3.61 (2H, s, NCH2), 3.82 (3H, s, OCH3), 5.11 (2H, s,
OCH2), 6.85 (1H, d, J¼8.8 Hz, ArH), 7.24 (1H, d, J¼8.8 Hz, ArH),
7.32e7.48 (5H, series of signals, ArH), 7.59 (1H, s, ArH) and 7.95 (1H,
s, 3-H); dC (150 MHz; CDCl3) 37.8 and 45.1 (NCH2), 52.1 (CH3), 70.6
(OCH2), 71.6 and 81.6 (C^CH), 113.5, 125.8, 126.1, 127.0, 128.0, 128.6,
129.9, 130.2, 131.0, 136.3 and 136.9 (C]CH and ArC), 155.3
[ArC(OBn)] and 168.1 (C]O).
Product 2. Methyl 3-[2-(benzyloxy)-5-chlorophenyl]-3-(2-
propynylamino)-2-methylenepropanoate 21: A yellow solid (0.16 g,
20%), mp 66e68 ꢀC. HRMS: m/z calculated for C21H21ClNO3 (MHþ)
370.1210. Found 370.1209; nmax/cmꢁ1 3271 (NH) and 1707 (C]O);
dH (600 MHz; CDCl3) 1.84 (1H, br s, NH), 2.11 (1H, s, C^CH), 3.34
(2H, s, CH2C^C), 3.67 (3H, s, OCH3), 5.07 (2H, s, OCH2), 5.29 (1H, s,
CHNH), 5.80 and 6.36 (2H, 2ꢂs, C]CH2), 6.84 (1H, d, J¼8.7 Hz, ArH),
7.16 (1H, d, J¼8.7 Hz, ArH) and 7.31e7.43 (6H, series of signals, ArH);
dC (150 MHz; CDCl3) 36.5 (NCH2), 51.8 (CH3), 55.0 (CHN), 70.6
(OCH2), 71.5 and 81.7 (C^CH), 113.4 and 126.0 (ArC), 126.7 (C]
CH2), 127.4, 128.0, 128.2, 128.4, 128.5, 131.0 and 136.5 (ArC), 140.3
(C]CH2), 154.9 [ArC(OBn)] and 166.6 (C]O).
CHaOH), 3.81 (3H, s, OCH3), 3.93 (1H, dd, J¼10.3 and 1.8 Hz, CHbOH),
4.29e4.31 (1H, m, OCHCHN), 5.13 (2H, s, OCH2Ph), 5.34e5.38 (1H,
m, OCHCH2OH), 6.26 (1H, t, J¼6.4 Hz, OCHN), 6.94 (2H, t, J¼8.0 Hz,
ArH), 7.27e7.31 (2H, overlapping m, ArH), 7.34e7.41 (5H, series of
signals, ArH), 7.53 (1H, s, ArH), 7.57 (1H, s, ArH) and 8.05 (1H, s,
PhCH]C); dC (150 MHz; CDCl3) 14.5 (CH3Ar), 37.6 (CH2CHN), 43.7
and 45.3 (CH2N), 52.1 (OCH3), 59.0 (CHN), 61.1 (CH2OH), 70.2
(OCH2Ph), 85.1 (HOCH2CHO), 87.4 (NCHO), 111.0, 112.4, 120.6, 121.8,
124.4, 127.0, 127.8, 128.5, 129.6, 130.3, 130.4, 136.6, 137.3, 138.7,
146.6, 150.5, 156.6, 164.1 and 168.3 (ArC, C]C and C]O).
3.7.2. Cinnamate estereAZT conjugate 22b. A pale yellow solid
79
(0.75 g, 92%), mp 96e97 ꢀC. HRMS: m/z calculated for C31
H BrN6O7
34
(MHþ) 681.1672. Found 681.1669; nmax/cmꢁ1 1681 (C]O); dH
(600 MHz; CDCl3) 1.90 (3H, s, CH3), 2.88 (2H, t, J¼6.5 Hz, CH2CHN),
3.56 and 3.91 (4H, s, 2ꢂNCH2), 3.72 (1H, d, J¼11.9 Hz, CHaOH), 3.81
(3H, s, OCH3), 3.96 (1H, d, J¼11.9 Hz, CHbOH), 4.33e4.35 (1H, m,
OCHCHN), 5.11 (2H, s, OCH2Ph), 5.37 (1H, dd, J¼11.9 and 6.7 Hz,
OCHCH2OH), 6.22 (1H, t, J¼6.4 Hz, OCHN), 6.82 (1H, d, J¼8.8 Hz,
ArH), 7.29e7.36 (6H, series of signals, ArH), 7.48 (1H, s, ArH), 7.61
(1H, s, ArH), 7.67 (1H, s, ArH) and 7.93 (1H, s, PhCH]C); dC
(150 MHz; CDCl3) 12.4 (CH3Ar), 37.5 (CH2CHN), 44.0 and 45.6
(CH2N), 52.2 (OCH3), 59.1 (CHN), 61.4 (CH2OH), 70.6 (OCH2Ph), 85.2
(HOCH2CHO), 88.2 (NCHO), 111.2, 112.8, 114.1, 121.9, 126.6, 127.0,
128.1, 128.6, 130.8, 132.8, 133.0, 136.2, 137.2, 137.6, 146.9, 150.4,
155.8, 163.8 and 168.0 (ArC, C]C and C]O).
3.6. Procedure for the synthesis ofmethyl(E)-3-[2-(benzyloxy)-
5-bromophenyl]-2-[(2-propynylamino)methyl]-2-propenoate
20b
Propargylamine (0.3 mL, 4 mmol) was added to a solution of
methyl 3-acetoxy-3-[(2-benzyloxy-5-bromophenyl)-2-methylene]-
propanoate 18b (0.92 g, 2.2 mmol) and K2CO3 (0.35 g, 2.5 mmol) in
CH3CN (5 mL) and the mixture stirred at rt for 12 h. The reaction
mixture was then neutralised by pouring into 0.5 N HCl (20 mL)
and extracted using CHCl3 (3ꢂ20 mL). The extracts were combined,
washed with brine (2ꢂ20 mL), concentrated in vacuo and
flash chromatographed [on silica gel; elution with hexane/EtOAc
(4:1)] to afford methyl (E)-3-[2-(benzyloxy)-5-bromophenyl]-2-[(2-
propynylamino)methyl]-2-propenoate 20b as a yellow solid (0.75 g,
82%), mp 53e54 ꢀC. HRMS: m/z calculated for C21H2179BrNO3 (MHþ)
414.0705. Found 414.0700; nmax/cmꢁ1 3296 (NH) and 1697 (C]O);
dH (400 MHz; CDCl3) 1.81 (1H, br s, NH), 2.21 (1H, s, C^CH), 3.44
(2H, s, CH2C^C), 3.61 (2H, s, NCH2), 3.82 (3H, s, OCH3), 5.10 (2H, s,
OCH2), 6.80 (1H, d, J¼8.7 Hz, ArH), 7.30e7.40 (6H, overlapping m,
ArH), 7.74 (1H, s, ArH) and 7.95 (1H, s, 3-H); dC (100 MHz; CDCl3)
37.7 and 45.0 (NCH2), 52.0 (CH3), 70.4 (OCH2), 71.6 and 81.6 (C^CH),
113.0, 113.8, 126.5, 126.9, 128.0, 128.5, 131.0, 132.8, 133.0, 136.2 and
136.7 (C]CH and ArC), 155.7 [ArC(OBn)] and 167.9 (C]O).
3.7.3. Cinnamate estereAZT conjugate 22c. A light brown solid
(0.68 g, 89%), mp 82e84 ꢀC. HRMS: m/z calculated for C32H37N6O8
(MHþ) 633.2673. Found 633.2670; nmax/cmꢁ1 1681 (C]O); dH
(600 MHz; CDCl3) 1.89 (3H, s, CH3), 2.84e2.88 (2H, m, CH2CHN), 3.52
and 3.85 (4H, s, 2ꢂNCH2), 3.71 (1H, d, J¼12.4 Hz, CHaOH), 3.79 and
3.89 (6H, s, 2ꢂOCH3), 3.93 (1H, d, J¼12.4 Hz, CHbOH), 4.29e4.31 (1H,
m, OCHCHN), 4.98 (2H, s, OCH2Ph), 5.35 (1H, dd, J¼12.4 and 6.3 Hz,
OCHCH2OH), 6.21 (1H, t, J¼6.4 Hz, OCHN), 6.93e6.96 (2H, series of
signals, ArH), 7.04 (1H, t, J¼7.9 Hz, ArH), 7.28e7.38 (5H, series of
signals, ArH), 7.48 (1H, s, ArH), 7.58 (1H, s, ArH) and 7.81 (1H, s,
PhCH]C); dC (150 MHz; CDCl3) 12.4 (CH3Ar), 37.5 (CH2CHN), 44.0
and 45.4 (CH2N), 52.1 and 55.9 (OCH3), 59.0 (CHN), 61.3 (CH2OH),
75.3 (OCH2Ph), 85.2 (HOCH2CHO), 88.2 (NCHO), 111.1, 113.2, 121.6,
122.0, 124.1, 128.1, 128.3, 128.7, 129.8, 130.5, 137.1, 137.6, 138.7, 146.0,
146.6, 150.4, 152.8, 163.8 and 168.1 (ArC, C]C and C]O).
3.7.4. Cinnamate estereAZT conjugate 22d. A light brown solid
(0.69 g, 89%), mp 91e93 ꢀC. HRMS: m/z calculated for C33H39N6O8
(MHþ) 647.2829. Found 647.2833; nmax/cmꢁ1 1684 (C]O); dH
(600 MHz; CDCl3) 1.45 (3H, t, J¼7.0 Hz, OCH2CH3), 1.85 (3H, s, CH3),
2.78e2.87 (2H, m, CH2CHN), 3.52 and 3.83 (4H, s, 2ꢂNCH2), 3.70
(1H, d, J¼2.1 and 12.1 Hz, CHaOH), 3.78 (3H, s, OCH3), 3.91 (1H, d,
J¼2.1 and 12.1 Hz, CHbOH), 4.08 (2H, q, J¼7.0 Hz, OCH2CH3),
4.28e4.30 (1H, m, OCHCHN), 4.98 (2H, s, OCH2Ph), 5.36 (1H, dd,
J¼8.4 and 5.8 Hz, OCHCH2OH), 6.24 (1H, t, J¼6.4 Hz, OCHN), 6.93
(2H, d, J¼7.9 Hz, ArH), 7.00 (1H, m, ArH), 7.27e7.39 (5H, series of
signals, ArH), 7.54 (1H, s, ArH), 7.60 (1H, s, ArH) and 7.83 (1H, s,
PhCH]C); dC (150 MHz; CDCl3) 12.3 (CH3Ar), 14.9 (CH2CH3), 37.6
(CH2CHN), 44.0 and 45.4 (CH2N), 52.0 (OCH3), 59.0 (CHN), 61.1
(CH2OH), 64.3 (OCH2CH3), 75.1 (OCH2Ph), 85.2 (HOCH2CHO), 87.5
(NCHO), 111.0, 114.3, 121.5, 121.9, 124.0, 128.0, 128.2, 128.6, 129.7,
130.4, 137.2, 137.4, 138.6, 146.2, 146.8, 150.5, 152.1, 164.1 and 168.2
(ArC, C]C and C]O).
3.7. General procedure for the synthesis of cinnamate ester-
AZT conjugates 22aee27
30-Azido-30-deoxythymidine (AZT) (0.61 g, 2.3 mmol) was dis-
solved in H2O/THF (1:1; 12 mL) and the methyl (E)-3-[2-(benzy-
loxy)phenyl]-2-[(2-propynylamino)methyl]-2-propenoate (20aee)
(2.3 mmol), sodium ascorbate (96 mg, 0.49 mmol) and CuSO4$5H2O
(17 mg, 68
mmol) were added to the solution. After stirring for
24 h at rt, the mixture was extracted with CH2Cl2 (2ꢂ100 mL) and
washed sequentially with H2O (50 mL) and brine (30 mL). The or-
ganic layers were combined, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The crude material was purified by flash
chromatography [on silica gel; elution with EtOAc and then with
methanol/DCM (1:4)] to afford the cinnamate estereAZT conjugate
(22).
3.7.1. Cinnamate estereAZT conjugate 22a. A pale yellow solid
(1.21 g, 87%), mp 92e94 ꢀC. HRMS: m/z calculated for C31H35N6O7
(MHþ) 603.2567. Found 603.2574; nmax/cmꢁ1 1681 (C]O); dH
(600 MHz; CDCl3) 1.87 (3H, s, CH3), 2.78e2.87 (2H, m, CH2CHN),
3.63 and 3.87 (4H, s, 2ꢂNCH2), 3.72 (1H, dd, J¼10.3 and 1.8 Hz,
3.7.5. Cinnamate estereAZT conjugate 22e. An off white solid
(0.69 g, 90%), mp 92e93 ꢀC. HRMS: m/z calculated for C31H34ClN6O7
(MHþ) 637.2178. Found 637.2180; nmax/cmꢁ1 1689 (C]O); dH
(600 MHz; CDCl3) 1.85 (3H, s, CH3), 2.77e2.88 (2H, m, CH2CHN),
3.56 and 3.89 (4H, s, 2ꢂNCH2), 3.73 (1H, d, J¼11.9 Hz, CHaOH), 3.79

T.O. Olomola et al. / Tetrahedron 70 (2014) 9449e9455
9455
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(3H, s, OCH3), 3.92 (1H, d, J¼11.9 Hz, CHbOH), 4.29e4.31 (1H, m,
OCHCHN), 5.09 (2H, s, OCH2Ph), 5.35e5.39 (1H, m, OCHCH2OH),
6.26 (1H, t, J¼5.7 Hz, OCHN), 6.85 (1H, d, J¼8.9 Hz, ArH), 7.20 (1H, d,
J¼7.5 Hz, ArH), 7.27e7.36 (5H, series of signals, ArH), 7.47 (1H, s,
ArH), 7.57 (1H, s, ArH), 7.65 (1H, s, ArH) and 7.92 (1H, s, PhCH]C);
dC (150 MHz; CDCl3) 12.3 (CH3Ar), 37.6 (CH2CHN), 43.9 and 45.4
(CH2N), 50.4 (OCH3), 59.1 (CHN), 61.1 (CH2OH), 70.6 (OCH2Ph), 85.2
(HOCH2CHO), 87.3 (NCHO), 111.0, 113.7, 122.0, 125.4, 126.0, 127.0,
127.1, 128.0, 128.6, 129.9, 130.0, 130.5, 136.2, 137.3, 146.5, 150.6,
155.2, 164.1 and 168.0 (ArC, C]C and C]O).
Acknowledgements
18. Kolb, H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8, 1128e1137.
19. Kaye, P. T.; Musa, M. A.; Nocanda, X. W. Synthesis 2003, 4, 531e534.
20. On occasions in a cognate study on analagous systems, preparative layer
chromatography has permitted isolation of the minor diastereomers.
21. Sai, H.; Ogiku, T.; Ohmizu, H. Tetrahedron 2007, 63, 10345e10353.
22. Bartoli, G.; Bellucci, M. C.; Petrini, M.; Marcantoni, E.; Sambri, L.; Torregiani, E.
Org. Lett. 2000, 2, 1791e1793.
The authors thank Rhodes University for a bursary (to T.O.O.),
the South African Medical Research Council (MRC) and Rhodes
University for generous financial support. T.O.O. gratefully
acknowledges Obafemi Awolowo University, Ile-Ife, Nigeria for
study leave.
23. NOTE: The configurations about the double bond in compounds 19a,cee and
20aee are assumed by analogy with related systems [papers in preparation and
published (Idahosa, K. C.; Lee, Y.-C.; Nyoni, D.; Kaye, P. T.; Caira, M. R. Tetrahe-
dron Lett. 2011, 52, 2972e2976)], in which the configurations have been
established X-ray crystallographically.
References and notes
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2. Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581e1588.
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2575e2589.
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51, 6325e6328.
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24. Bourdais, J.; Biondi, R.; Sarfati, S.; Guerreiro, C.; Lascu, I.; Janin, J.; Veron, M. J.
Biol. Chem. 1996, 271, 7887e7890.
25. Kaye, P. T.; Musa, M. A. Synth. Commun. 2003, 33, 1755e1770.
26. Ahn, S.-H.; Lim, H. N.; Lee, K.-J. J. Heterocycl. Chem. 2008, 45, 1701e1706.
27. The systematic name for the parent system 22a is: 4-{(E)-5-[2-(benzyloxy)
phenyl]-4-methoxycarbonyl-2-aza-4-pentenyl}-1-[(2R,4S,5S)-5-(5-methyl-2,4-
dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-2-(hydroxymethyl)tetrahydrofuran-3-
yl]-1H-1,2,3-triazole.