An efficient synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one - A protected fragment of novenamine

Article abstract of DOI:10.1016/j.tet.2005.08.083

The high-yielding six-step synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4- d]oxazol-4-one 17 from commercially available 2,4-dihydroxy-3-methylacetophenone is described. Coumarin 17 constitutes a useful synthon for coumarin antibiotic synthesis. A new methodology for oxazole formation applicable to 3-aminocoumarins has been developed, and a mechanistic rationalization is proposed.

Full text of DOI:10.1016/j.tet.2005.08.083

Tetrahedron 61 (2005) 10683–10688
An efficient synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]
oxazol-4-one—a protected fragment of novenamine
*
David W. Gammon, Roger Hunter and Seanette A. Wilson
Department of Chemistry, University of Cape Town, Private Bag, Rondebosch, Cape Town 7701, South Africa
Received 24 June 2005; revised 4 August 2005; accepted 19 August 2005
Available online 19 September 2005
Abstract—The high-yielding six-step synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one 17 from commercially available
2,4-dihydroxy-3-methylacetophenone is described. Coumarin 17 constitutes a useful synthon for coumarin antibiotic synthesis. A new
methodology for oxazole formation applicable to 3-aminocoumarins has been developed, and a mechanistic rationalization is proposed.
q 2005 Published by Elsevier Ltd.
1. Introduction
The coumarin-containing antibiotics are powerful inhibitors
of DNA-gyrase, which is a type II topoisomerase and an
essential prokaryotic enzyme.3 Since DNA-gyrase has no
counterpart in eukaryotes, it is a very attractive drug-target
for antibiotics. Recently, novobiocin has also been
identified as an antitumour agent in that it is an inhibitor
of the 90 kDa heat shock protein, Hsp90.4,5
Novenamine 1 is the glycosylated 3-aminocoumarinyl sub-
unit of novobiocin 2, a naturally occurring antimicrobial
agent that was first isolated in 1956 from several
Streptomyces species including S. spheroides and S. niveus
(Fig. 1).1
Novobiocin, together with the structurally related coumarin
antibiotics, clorobiocin 3, and coumermycin A1 4, show
potent activity against Gram-positive bacteria, including
methicillin-resistant strains of staphylococcus species
(Fig. 1).2
There are only two published total syntheses of the
coumarin moiety of novenamine, neither of which were
used in the coupling to noviose.6,7
The first of these (Scheme 1), published in 1958, started
Figure 1. Structure of novenamine 1, novobiocin 2, clorobiocin 3 and coumermycin A1 4.
Keywords: Novobiocin; Coumarin antibiotics; Oxazoles; Robinson–Gabriel mechanism; POCl3/pyridine.
*
Corresponding author. Tel.: C27 21 650 2544; fax: C27 21 689 7499; e-mail: roger@science.uct.ac.za
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.08.083

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D. W. Gammon et al. / Tetrahedron 61 (2005) 10683–10688
Scheme 3. Reagents and conditions: (i) Acetic anhydride, pyridine, 110 8C,
24 h, 65%.
Scheme 1. Reagents and conditions: (i) 10% Pd/C, 2.5 N HCl, H2, ethanol,
no yield given.
Furthermore, Ueda et al. reported successful cleavage of the
oxazole of 10 using mildly acidic conditions, without
destruction of the glycosidic bond.11 This therefore
prompted us to develop a novel synthesis of 3-amino-4,7-
dihydroxy-8-methyl coumarin with the 3-amino and
4-hydroxyl groups protected as an oxazole as in 17 (Fig. 2).
from 2-methylresorcinol and concerned the synthesis of
novobiocinic acid 7, with the aim of elucidating the
structure of the coumarin moiety.6 The synthesis was very
low-yielding (!7%), with the 3-amino functionality being
introduced via reduction of the unstable nitroso intermediate
5 to form the ammonium salt 6.
The second report, published in 1984, described a synthesis
from 2,4-dihydroxy-3-methylacetophenone, of two 3-acyl-
amino-4,7-dihydroxy-8-methylcoumarin
derivatives
(Scheme 2) and their subsequent biological testing.7 In
this instance, the introduction of the 3-amido functionality
involved preparation and reduction of the 3-phenylazo
derivative 8, followed by N-acylation of the resulting
ammonium salt 9.
Figure 2. Structure of target molecule, 2,6-dimethyl-7-hydroxychro-
meno[3,4-d]oxazol-4-one 17.
It was considered that this derivative would be a promising
coupling partner to the carbohydrate unit of novenamine,
noviose, which has been synthesized in our laboratories
recently.12
2. Results and discussion
A retrosynthetic analysis of 17 revealed commercially
available 2,4-dihydroxy-3-methylacetophenone 11 to be an
appropriate starting material. The envisaged strategy
involved formation of the 4-hydroxycoumarin unit, intro-
duction of the 3-amino functionality via reduction of a nitro
group regioselectively installed at C-3, and finally oxazole
formation.
Scheme 2. Reagents and conditions: (i) Sodium dithionite, sodium acetate,
ethanol, water, reflux, 90%.
To this end, chemoselective benzylation of 2,4-dihydroxy-
3-methylacetophenone gave the 4-benzyloxy derivative 12
in 88% yield,13 presumably as a result of the 4-hydroxyl
group being less sterically hindered than the 2-hydroxyl
group, as well as not being involved in hydrogen-bonding to
the acetyl oxygen (Scheme 4). The o-hydroxyacetophenone
derivative 12 was then converted directly into the
4-hydroxycoumarin 13 in 76% yield using diethyl carbonate
and sodium hydride, methodology first described by Barker
et al.14 Nitration at the C-3 position with fuming nitric acid
in chloroform at room temperature,15 furnished 14 in nearly
quantitative yield. The insolubility of 14 in a range of
standard solvents contributed to numerous failed attempts
to reduce the nitro functionality via the following reagents:
Traditionally, the total syntheses of novenamine and its
derivatives have involved coupling the sugar moiety to 4-O-
protected-4,7-dihydroxy-8-methylcoumarin prior to the
introduction of the C-3 amino functionality thereby
necessitating further post-glycosylation steps.8,9 In con-
templating a synthetic strategy towards novenamine, which
would minimize such post-glycosylation steps, it was noted
that a derivative of novenamine with the vicinal hydroxy-
amine protected as an oxazole 10 was formed and isolated
by Hinman et al. via cleavage of the amide bond in novo-
biocin 2 with acetic anhydride and pyridine (Scheme 3).10

D. W. Gammon et al. / Tetrahedron 61 (2005) 10683–10688
10685
Scheme 4. Reagents and conditions: (i) BnCl, K2CO3, KI, acetone, 56 8C, 88%; (ii) NaH, CO(OEt)2, toluene, 110 8C, 76%; (iii) HNO3, H2SO4, CHCl3, room
temperature, 93%; (iv) Zn, AcOH, 110 8C, 86%; (v) POCl3, pyridine, THF, 66 8C, 87%; (vi) 10% Pd/C, H2, THF/CH2Cl2, room temperature, 74%.
(i) sodium dithionite in pyridine;7 (ii) Pd/C, H2; (iii) Fe, 1 M
HCl, MeOH; (iv) Fe, 1 M HCl, THF; (v) Zn dust, 1 M
NaOH, EtOH. Ultimately, however, conversion of the nitro
group to acetamide 15 could be achieved in a gratifyingly
high yield (86%) using zinc in refluxing acetic acid,
involving a slight modification of the method developed
by Okumura to reduce 4,7-dihydroxy-3-phenylazocoumarin
to the corresponding 3-acetamido-4,7-dihydroxy-
coumarin.16 The work-up and product isolation of the
nitration and reduction steps simply involved filtration of
the solid from the cooled reaction medium and recrystalliza-
tion, making this strategy an attractive choice for the
introduction of an amino group at C-3.
In a recent and independent study, Nicolaou et al. found that
pyridine-buffered POCl3 was effective in converting
hindered ketoamides into oxazoles,21 although their study
did not extend to the coumarin series or related structures.
The mechanism for the PCl5-promoted Robinson–Gabriel
cyclodehydration of ketoamides was determined by
Wassermann and Vinick in 1973 with the use of oxygen-
18 labelling. Their experiments established that the amide
oxygen is the one incorporated into the oxazole ring and that
the ketone carbonyl oxygen is expelled.20 In keeping with
the Robinson–Gabriel mechanism, and in view of the
3-amido-4-hydroxycoumarin structure of 15 having its
‘ketone’ carbonyl already fixed as an enol in conjugation
with the coumarin carbonyl group, it seemed reasonable to
postulate a nucleophilic substitution mechanism via a
Michael addition/elimination sequence to account for
cyclization. It was also considered reasonable to postulate
prior activation of the enolic hydroxyl group as a superior
chlorophosphate leaving group, since this was in keeping
with the rapid reaction observed (5–10 min).
Numerous methods are available for conversion of 3-amino-
4-hydroxycoumarin derivatives into the corresponding
oxazole including (i) heating 3-amino-4-hydroxycoumarin
as its hydrochloride with the appropriate carboxylic acid
in polyphosphoric acid for 3.5 h at 160–200 8C;17
(ii) condensing 3-amino-4-hydroxycoumarin derivatives
with aromatic aldehydes to yield the corresponding Schiff
bases which, by heating in nitrobenzene, undergo cycliza-
tion and H2 elimination to afford the corresponding oxazole
derivatives18 and (iii) heating 3-amino-4-hydroxycoumarin
derivatives with the appropriate anhydride in pyridine.19 An
examination of these methods revealed that they invariably
require high temperatures, long reaction times and often
give unsatisfactory yields.
This activation step has been postulated by Meyers et al. in
the condensation of carboxylic acids with amino alcohols to
form oxazolines using Ph3P–CCl4–Et3N, whereby the
intermediate hydroxy amide reacts with Ph3PClCCCl3K at
An alternative method was therefore investigated using
phosphorus oxychloride (POCl3) and pyridine in refluxing
tetrahydrofuran, which pleasingly converted acetamide 15
into its corresponding oxazole 16 in a Robinson–Gabriel-
type cyclodehydration reaction.20 The reaction times were
typically between 5 and 10 min, with yields of greater than
85% following recrystallization. Evidence for the formation
of the oxazole was provided by the 1H NMR spectrum of 16,
which revealed a downfield shift in one of the methyl
singlets from dH 2.11 in 15 to 2.56 as well as the
disappearance of the amide proton. In the 13C NMR of 16,
the oxazole carbon C-2 resonated at dC 162.6 whereas the
carbonyl carbon of the acetamide 15 resonated at dC 171.2,
revealing an upfield shift for this carbon in the oxazole
structure. The IR spectrum of 16 revealed the absence of a
signal in the NH region as well as the amide carbonyl bands,
a further indication that oxazole formation had taken place.
Scheme 5. Proposed mechanism for oxazole formation via nucleophilic
substitution.

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D. W. Gammon et al. / Tetrahedron 61 (2005) 10683–10688
the hydroxyl group, with subsequent displacement by the
amide carbonyl oxygen.22 Our postulated mechanism is
depicted in Scheme 5.
which gave the anticipated NMR spectroscopic and
microanalytical information as reported in Section 4.
3. Conclusion
Mechanistic studies were carried out by investigating the
cyclization of two model compounds 18 and 19 (Scheme 6).
A protected coumarin fragment of novenamine has been
synthesized in only six steps from commercially available 2,
4-dihydroxy-3-methylacetophenone 11 and in 40% overall
yield. Only one of the six steps required an aqueous work-
up, and the purification of each product was achieved in
high yield by recrystallization, with no chromatography
being necessary. New methodology has been developed for
oxazole formation applicable to 3-aminocoumarins, provid-
ing a useful alternative protecting-group strategy in the
synthesis of coumarin antibiotics. Work is currently
underway to couple 17 to 3-O-carbamoyl-C-4-epi-noviose,
the C-4-epimer of 3-O-carbamoyl noviose.
Scheme 6. Reagents and conditions: (i) (a) POCl3, pyridine, THF, reflux;
(b) MeOH, reflux, 18% over two steps.
4. Experimental
4.1. General
The two substrates were chosen as having varying degrees
of electron-deficiency in their aromatic rings, so as to probe
the importance of this parameter, and the cyclization
conditions were kept the same as for 15. Neither structure
afforded an oxazole, highlighting the importance of a
strongly electron-withdrawing group to promote the
Michael-addition step. However, 19 did furnish a phosphate
derivative 20, derived by substitution of the dichlorophos-
phate intermediate with methanol. Dimethoxyphosphate
ester 19 could be isolated and characterized by 1H, 13C and
31P NMR spectroscopy, lending support for formation of
a similar transient chlorophosphate in the mechanism
postulated in Scheme 5 for cyclization of 15.
All moisture-sensitive reactions were performed in flame-
dried glassware equipped with a rubber septun under a
positive pressure of nitrogen. THF was distilled from
sodium benzophenone under nitrogen and CH2Cl2 over
P2O5. Silica-gel 60 and DC-Alufolien 60 F254 were used for
column chromatography and analytical TLC, respectively.
Melting points were determined on a Reichert Jung hot-
stage microscope and are uncorrected. Microanalyses were
performed with a Fisons EA 110 CHN analyzer and high-
resolution mass spectrometry were obtained using a VG70-
SEQ micromass spectrometer. NMR were recorded on
either a Varian VXR-300 or Varian Unity 400 spectrometer.
Chemical shifts (d) are reported in ppm and J values
are given in hertz. The IR spectra were recorded on a
Perkin-Elmer Paragon 1000 FT-IR spectrometer and the
Apart from Nicolaou’s work, only one other literature
analogy for the use of this reagent was found. This involved
conversion of methyl 2-benzoylamino-3-arylaminopro-
penoate 21 with phosphorus oxychloride and pyridine into
4-arylaminomethylene-2-phenyl-2-oxazolin-5-one 22
(Scheme 7).23 The relatively few number of literature
analogies was confirmed by a recent review detailing the
synthesis of oxazole-containing natural products by Yeh in
2004.24
frequencies are given in cmK1
.
4.1.1. 7-Benzyloxy-4-hydroxy-8-methylchromen-2-one
(13). Acetophenone 1213 (0.50 g, 1.9 mmol) was dissolved
in toluene (10 ml) and added to sodium hydride (60% in oil,
0.17 g, 4.3 mmol) suspended in toluene (10 ml). Diethyl
carbonate (0.31 ml, 2.5 mmol) was added and the mixture
refluxed for 2 h before being cooled to 0 8C, quenched with
water and extracted with ethyl acetate (!1). The aqueous
phase was acidified with 1 M HCl and extracted with ethyl
acetate (!3). The combined organic extracts from the
acidic extractions were dried over anhydrous magnesium
sulphate, filtered and evaporated under reduced pressure.
The residue was crystallized from methanol to give 13
(0.42 g, 76%) as colourless crystals: mp 233–234 8C (lit.7
mp 233–236 8C); IR nmax(CH2Cl2)/cmK1 1514, 1587
(aromatic C]C), 1723, 1667 (C]O stretch); 1H NMR
(300 MHz, DMSO-d6) d 2.19 (s, 3H, ArCH3), 5.22 (s, 2H,
–CH2C6H5), 5.44 (s, 1H, H-3), 7.07 (d, 1H, H-6, JZ8.7 Hz),
7.31–7.47 (m, 5H, –CH2C6H5), 7.62 (d, 1H, H-5, JZ
8.7 Hz), 12.20 (br, 1H, –OH); 13C NMR (75.5 MHz,
DMSO-d6) d 8.2 (ArCH3), 69.9 (–CH2C6H5), 88.5 (C-3),
108.3 (C-6), 109.3 (C-4a), 112.6 (C-8), 121.3 (C-5), 127.3,
127.8, 128.4, 136.7 (–CH2C6H5), 152.5 (C-8a), 159.3 (C-4),
Scheme 7. Reagents and conditions: (i) POCl3, pyridine, 70 8C, 83%.
In the final step, debenzylation of oxazole 16 furnished the
desired 7-hydroxycoumarin 17 in 74% yield (Scheme 4).
Compound 17 has been prepared previously by refluxing
3-acetamido-7-acetoxy-4-hydroxy-8-methylcoumarin, iso-
lated from novobiocin, in acetic anhydride followed by
acetate saponification but no NMR data was reported.25
Accordingly, a full characterization of 17 was carried out,

D. W. Gammon et al. / Tetrahedron 61 (2005) 10683–10688
10687
162.2 (C-7), 166.1 (C-2); HRMS m/z 282.0883 (MC),
C17H14O4 requires 282.0892. Anal. Calcd for C17H14O4: C,
72.33%; H, 5.00%. Found: C, 72.16%; H, 4.82%.
2.56 (s, 3H, –CH3), 5.10 (s, 2H, –CH2C6H5), 6.88 (d, 1H,
H-8, JZ8.8 Hz), 7.29–7.34 (m, 5H, –CH2C6H5), 7.48 (d,
1H, H-9, JZ8.8 Hz); 13C NMR (100 MHz, CDCl3) d 8.8
(ArCH3), 14.1 (–CH3), 70.79 (–CH2C6H5), 105.1 (C-9a),
108.9 (C-8), 115.8 (C-6), 118.9 (C-9), 122.4 (C-3a), 127.1,
128.2, 128.7, 136.3 (–CH2C6H5), 152.1 (C-5a), 156.2
(C-1a), 156.3 (C-7), 159.3 (C-4), 162.6 (C-2). Anal. Calcd
for C19H15NO4: C, 71.02%; H, 4.71%; N, 4.36%. Found: C,
70.96%; H, 4.56%; N, 4.34%.
4.1.2. 7-Benzyloxy-4-hydroxy-8-methyl-3-nitrochromen-
2-one (14). Concentrated sulphuric acid (1.61 ml,
22.1 mmol) and concentrated nitric acid (1.00 ml,
18.4 mmol) were mixed slowly at 0 8C and then added,
over a period of 15 min, to 13 (2.08 g, 7.4 mmol) suspended
in CHCl3. After an additional 1 h, the solvent was
evaporated under reduced pressure and 1 M HCl (30 ml)
was added. The yellow solid was filtered, rinsed well
with methanol, and crystallized from glacial acetic acid
to give 14 (2.23 g, 93%) as yellow plates: mp 205–208 8C;
IR nmax(KBr pellet)/cmK1 1325 and 1530 (NO stretch),
1754 (C]O stretch), 3540 (OH stretch); 1H NMR
(300 MHz, DMSO-d6) d 2.18 (s, 3H, ArCH3), 5.07 (br,
1H, –OH), 5.22 (s, 2H, –CH2C6H5), 7.06 (d, 1H, H-6, JZ
9.0 Hz), 7.30–7.48 (m, 5H, –CH2C6H5), 7.77 (d, 1H, H-5,
JZ9.0 Hz); 13C NMR (75.5 MHz, DMSO-d6) d 8.2
(ArCH3), 69.9 (–CH2C6H5), 108.1 (C-6), 112.2 (C-3),
113.9 (C-4a), 119.5 (C-8), 123.9 (C-5), 127.3, 127.8,
128.5, 136.8 (–CH2C6H5), 151.3 (C-8a), 157.0 (C-4),
159.7 (C-7), 166.4 (C-2). Anal. Calcd for C17H13NO6: C,
62.39%; H, 4.00%; N, 4.28%. Found: C, 62.14%; H, 3.88%;
N, 4.31%.
4.1.5. 2,6-Dimethyl-7-hydroxychromeno[3,4-d]oxazol-4-
one (17). 10% Pd/C (0.50 g, 0.05 mmol) was added to
compound 16 (0.15 g, 0.5 mmol) in a mixture of THF
(10 ml) and CH2Cl2 (5 ml) and the solution stirred for 3 h at
room temperature in an atmosphere of H2 using a balloon.
The excess solvent was evaporated after removing the Pd/C
by filtration (rinsing with hot methanol). The product was
recrystallized with methanol to yield 17 (0.08 g, 74%) as
colourless crystals: mp 330–332 8C (decomp.) (lit.25 mp
295–303 8C (decomp.) from water/dimethylformamide); IR
nmax(CH2Cl2)/cmK1 1503, 1584, 1604 (aromatic C]C),
1647 (coumarin C]C), 1749 (C]O stretch), 3150 (OH
stretch); 1H NMR (400 MHz, CDCl3) d 2.17 (s, 3H, ArCH3),
2.59 (s, 3H, –CH3), 6.91 (d, 1H, H-8, JZ8.4 Hz), 7.48
(d, 1H, H-9, JZ8.4 Hz), 10.55 (s, 1H, –OH); 13C NMR
(100 MHz, CDCl3) d 9.0 (ArCH3), 14.4 (CH3), 103.5
(C-9a), 112.5 (C-6), 113.3 (C-8), 119.8 (C-9), 120.8 (C-3a),
152.8 (C-5a), 156.2 (C-1a), 157.0 (C-7), 159.5 (C-4), 163.0
(C-2). Anal. Calcd for C12H9NO4: C, 62.34%; H, 3.92%; N,
6.06%. Found: C, 62.13%; H, 3.99%; N, 5.98%.
4.1.3. N-(7-Benzyloxy-4-hydroxy-8-methyl-2-oxo-(2H)-
chromen-3-yl)-acetamide (15). Compound 14 (1.00 g,
3.1 mmol) and Zn (1.00 g, 15.5 mmol) were refluxed in
acetic acid (10 ml) for 1 h, in which time the solution turned
deep purple and then colourless. The Zn salts were filtered
and rinsed well with hot acetic acid. The filtrate was cooled
to room temperature, allowing the amide to precipitate. The
product was filtered and crystallized with ethyl acetate to
yield 15 (0.87 g, 86%) as colourless crystals: mp 240–
243 8C; IR nmax(CH2Cl2)/cmK1 1500 (aromatic C]C),
1572 (amide I), 1598 (aromatic C]C), 1632 (amide II),
1686 (C]O stretch), 3288 (NH stretch), 3500 (OH stretch);
1H NMR (300 MHz, CDCl3) d 2.11 (s, 3H, –NHCOCH3),
2.23 (s, 3H, ArCH3), 5.24 (s, 2H, –CH2C6H5), 7.16 (d, 1H,
H-6, JZ9.0 Hz), 7.38–7.48 (m, 5H, –CH2C6H5), 7.68
(d, 1H, H-5, JZ9.0 Hz), 9.42 (s, 1H, –NH), 12.2 (br, 1H,
–OH); 13C NMR (75.5 MHz, CDCl3) d 8.1 (ArCH3), 22.6
(–NHCOCH3), 69.9 (–CH2C6H5), 101.4 (C-3), 108.9 (C-6),
109.7 (C-4a), 112.5 (C-8), 121.7 (C-5), 127.3, 127.9, 128.4,
136.7 (–CH2C6H5), 150.1 (C-8a), 157.4 (C-4), 158.9 (C-7),
160.3 (C-2), 171.2 (–COCH3). Anal. Calcd for C19H17NO5:
C, 67.25%; H, 5.05%; N, 4.13%. Found: C, 67.27%; H,
4.94%; N, 4.07%.
4.1.6. Dimethyl (2-acetamido)phenyl phosphate (20).
2-Acetamidophenol (0.20 g, 1.32 mmol) was suspended in
THF (10 ml). Pyridine (0.43 ml, 5.29 mmol) and POCl3
(0.25 ml, 2.65 mmol) were added and the mixture refluxed
for 1 h. Methanol was added and the reaction mixture was
refluxed for a further 20 min before being diluted with water
and the aqueous phase extracted with ethyl acetate (!1).
The combined organic extracts were dried over anhydrous
magnesium sulphate, filtered and evaporated under reduced
pressure. The crude product (0.44 g) was purified by column
chromatography (10 g silica, 50% ethyl acetate/hexane) to
afford 20 (0.06 g, 18%) as colourless crystals: mp 65–67 8C;
IR nmax(CH2Cl2)/cmK1 1637 (C]O); 1H NMR (400 MHz;
DMSO-d6) d 2.05 (3H, s, –NHCOCH3), 3.79 (6H, d,
JHPZ11.2 Hz, –OCH3), 7.16 (2H, m, Ar-H), 7.27 (1H, m,
Ar-H), 7.69 (1H, d, JZ6.4 Hz, Ar-H), 9.40 (1H, s,
–NHCOCH3); 13C NMR (100 MHz, DMSO-d6) d 24.1
(–NHCOCH3), 55.7 (d, JCPZ6 Hz, 2!–OCH3), 120.6,
125.7, 126.0, 126.2 (aromatics), 130.1 (C-2), 143.1 (C-1),
169.1 (C]O); 31P NMR (300 MHz, DMSO-d6) d 0.87
(PO(OCH3)2OR).
4.1.4. 7-Benzyloxy-2,6-dimethylchromeno[3,4-d]oxazol-
4-one (16). Amide 15 (2.06 g, 6.1 mmol), pyridine
(1.72 ml, 18.3 mmol) and POCl3 (2.96 ml, 30.4 mmol)
were suspended in tetrahydrofuran (50 ml) and refluxed
for 10 min. After cooling to room temperature, the mixture
was filtered, the excess solvent evaporated under vacuum
and the remaining slurry azeotroped with toluene (!3) to
remove traces of pyridine. The product was crystallized
with ethyl acetate to yield 16 (1.70 g, 87%) as colourless
crystals: mp 206–207 8C; IR nmax(CH2Cl2)/cmK1 1503,
1605 (aromatic C]C), 1647 (coumarin C]C), 1748 (C]O
stretch); 1H NMR (400 MHz, CDCl3) d 2.33 (s, 3H, ArCH3),
Acknowledgements
This work was supported by the National Research
Foundation (NRF) as well the Equity Development
Programme of the Department of Chemistry, University of
Cape Town.

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Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett. 2000,
10, 161–165.
References and notes
10. Hinman, J. W.; Caron, E. L.; Hoeksema, H. J. J. Am. Chem.
Soc. 1957, 79, 3789–3800.
1. (a) Wallik, H.; Harris, D. A.; Reagan, M. A.; Ruger, M.;
Woodruff, H. B. Antibiot. Annu. 1955–1956, 3, 909–917.
(b) Lin, F. K.; Coriell, L. L. Antibiot. Med. 1956, 2, 268–276.
2. Musicki, B.; Periers, A. M.; Laurin, P.; Ferroud, D.; Benedetti,
Y.; Lachaud, S.; Chatreaux, F.; Haesslein, J.; Iltis, A.; Pierre,
C.; Khider, J.; Tessot, N.; Airault, M.; Demassey, J.; Vicat, P.;
Klich, M. Bioorg. Med. Chem. Lett. 2000, 10, 1695–1699.
3. (a) Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H. J.; Weston,
S. A.; Barth, P. T.; Taylor, I. W. F.; Paupit, R. A.; Timms, D.
Biochemistry 1997, 36, 9663–9673. (b) Lewis, R. J.; Singh,
O. M.; Smith, C. V.; Skarzynski, T.; Maxwell, A.; Wonacott,
A. J.; Wigley, D. B. EMBO J. 1996, 15, 1412–1420. (c) Freel
Meyers, C. L.; Oberthur, M.; Xu, H.; Heide, L.; Kahne, D.;
Walsh, C. T. Angew. Chem., Int. Ed. 2004, 43, 67–70.
(d) Albermann, C.; Soriano, A.; Jiang, J.; Vollmer, H.;
Biggins, J. B.; Barton, W. A.; Lesniak, J.; Nikolov, D. B.;
Thorson, J. S. Org. Lett. 2003, 5, 933–936.
11. Ueda, Y.; Chuang, J. M.; Crast, L. B.; Partyka, R. A. J. Org.
Chem. 1988, 53, 5107–5113.
12. Gammon, D. W.; Hunter, R.; Wilson, S. Tetrahedron Lett.
2002, 43, 3141–3144.
13. Raphael, R. A.; Ravenscroft, P. J. Chem. Soc., Perkin Trans. 1
1988, 1823–1828.
14. Barker, W. M.; Hermodson, M. A.; Link, K. P. J. Med. Chem.
1971, 14, 167–169.
15. Klosa, J. Pharmazie 1953, 8, 221–223.
16. Okumura, K., Tanabe Seiyaku Co. JP 37004874.
17. (a) Merchant, J. R.; Venkatesh, M. S. Chem. Ind. (London)
1979, 478–479. (b) Colotta, V.; Catarzi, D.; Varano, F.;
Cecchi, L.; Filacchioni, G.; Martini, C.; Giusti, L.; Lucacchini,
A. II Farmaco 1998, 53, 375–381.
18. Merchant, J. R.; Desai, H. K. Indian J. Chem. 1973, 11,
433–436.
4. Blagosklonny, M. V. Leukaemia 2002, 16, 455–462.
5. Adams, J.; Elliot, P. J. Oncogene 2000, 19, 6687–6692.
6. Spencer, C. F.; Stammer, C. H.; Rodin, J. O.; Walton, E.;
Holly, F. W.; Folkers, K. J. Am. Chem. Soc. 1958, 80,
140–143.
19. Merchant, J. R.; Venkatesh, M. S.; Martyres, G. Indian
J. Chem., Sect. B 1981, 20, 711–712.
20. Wasserman, H. H.; Vinick, F. J. J. Org. Chem. 1973, 38,
2407–2408.
21. Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Bheema Rao, P.;
Rassias, G.; Snyder, S. A.; Huang, X.; Chen, D. Y.-K.;
Brenzovich, W. E.; Giuseppone, N.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897–12906.
22. Meyers, A. I.; Hoyer, D. Tetrahedron Lett. 1985, 26,
4687–4690.
7. Patonay, T.; Litkei, G.; Bognar, R.; Erdei, J.; Miszti, C.
Pharmazie 1984, 39, 86–91.
8. (a) Vaterlaus, B. P.; Kiss, J.; Spiegelberg, H. Helv. Chim. Acta
1964, 47, 381–390. (b) Vaterlaus, B. P.; Doebel, K.; Kiss, J.;
Rachlin, A. I.; Spiegelberg, H. Helv. Chim. Acta 1964, 49,
390–398. (c) Vaterlaus, B. P.; Spiegelberg, H. Helv. Chim.
Acta 1964, 47, 508–514.
23. Singh, M. K.; Singh, R. S.; Singh, R. M. Indian J. Chem., Sect.
B 1999, 38, 920–924.
9. Periers, A. M.; Laurin, P.; Ferroud, D.; Haesslein, J.; Klich,
M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne, P.;
24. Yeh, V. S. C. Tetrahedron 2004, 60, 11995–12042.
25. Stammer, C. H. J. Org. Chem. 1960, 25, 460–461.