Synthesis of the isocoumarin portion of the rubromycins

Article abstract of DOI:10.1016/S0040-4039(01)00524-X

A synthesis of the isocoumarin found in the rubromycin class of natural products is reported. The isocoumarin ring system is formed via Heck coupling of a pyruvate synthon with a terephthalic acid derivative followed by an intramolecular acid-catalyzed cyclization. The requisite terephthalic acid precursor is generated by carboxylation of catechol and then desymmetrization of the aromatic ring by halogenation. The isocoumarin derivative that has been produced is an appropriate precursor for the synthesis of γ-rubromycin, purpuromycin, and heliquinomycin.

Full text of DOI:10.1016/S0040-4039(01)00524-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3567–3570
Synthesis of the isocoumarin portion of the rubromycins
Stephen P. Waters and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA
Received 9 March 2001; revised 23 March 2001; accepted 28 March 2001
Abstract—A synthesis of the isocoumarin found in the rubromycin class of natural products is reported. The isocoumarin ring
system is formed via Heck coupling of a pyruvate synthon with a terephthalic acid derivative followed by an intramolecular
acid-catalyzed cyclization. The requisite terephthalic acid precursor is generated by carboxylation of catechol and then
desymmetrization of the aromatic ring by halogenation. The isocoumarin derivative that has been produced is an appropriate
precursor for the synthesis of g-rubromycin, purpuromycin, and heliquinomycin. © 2001 Elsevier Science Ltd. All rights reserved.
g-Rubromycin (1),1 purpuromycin (2),2 and heliquino-
mycin (3)3 are a set of structurally related pigments
consisting of naphthazarin and isocoumarin ring struc-
tures linked through a 5,6-spiroketal. The synthesis of
this unique class of antitumor antibiotic compound has
yet to be achieved although they display a range of
biological activity. g-Rubromycin (1) exhibits activity
against the reverse transcriptase of human immunodefi-
ciency virus-14 and against human telomerase which is
overproduced in cancer cells;5 purpuromycin (2) is a
potential topical agent for vaginal infections6 and
heliquinomycin (3) is an inhibitor of DNA helicase.3
Due to the recent report of a synthesis of the isocou-
marin portion of heliquinomycin,7 we were prompted
to report our efforts toward the synthesis of a common
isocoumarin precursor 5 which could be employed in
the syntheses of 1–3 (Fig. 1). Activation of 5 as the
tosylate 4 would provide the isocoumarin precursor for
g-rubromycin and heliquinomycin, while oxidation of
alcohol 5 to the aldehyde 6 would provide the requisite
precursor for purpuromycin (3).
The synthesis of isocoumarin 5 began with catechol (7),
which was subjected to carbon dioxide under high
pressure to produce dihydroxyterephthalate 8 (Scheme
1).8 Fischer esterification and protection of the phenols
of 8 provided the dimethyl 2,3-dimethoxyterephthalate
Keywords: isocoumarin; rubromycin; purpuromycin; antitumor;
antibiotic.
* Corresponding author.
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00524-X

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S. P. Waters, M. C. Kozlowski / Tetrahedron Letters 42 (2001) 3567–3570
Scheme 1. (a) i. NaOH, ii. CO2, 80 atm, 200°C, 48 h, 54% overall yield; (b) i. MeOH, HCl, 75%, ii Me2SO4, K2CO3, 100%; (c)
i. AgNO3, TFAA, ii. H2, Raney Ni, iii. H+, NaNO2, KI, 86% overall yield; (d) i. BBr3, ii. BnBr, K2CO3, 86% overall yield; (e)
Pd(PPh3)4, CuI, Et3N, 93–97%; (f) i. LiOH, H2O/THF or KOH, H2O/MeOH, D.
a nucleophile, thereby eliminating the regioselection
problem during cyclization. A palladium catalyzed
Heck-type coupling of ortho-iodo benzoates with acryl-
ate derivatives provided the necessary construction
(Scheme 3, 20 to 21).12 Exercising this strategy on
diester 10 would lead to a compound with three methyl
esters which would be difficult to selectively functional-
ize. As such, the regioselective saponification discovered
earlier of the less hindered methyl ester (meta to the
iodide) of 10 using LiOH in wet THF was applied to
generate 19. Chemoselective reduction of the resulting
carboxylic acid to the corresponding alcohol13 and sub-
sequent protection as the silyl ether afforded 20 in 87%
overall yield from 10.
(9). At this point, the symmetry of 9 was broken via
iodination to 10. Direct iodination of arene 9 was not
viable due to the deactivating influence of the aromatic
ring substituents towards a positive source of iodine.
Instead, a three-step sequence was employed: nitration
of the ring according to the method of Crivello9 was
followed by reduction to the aniline and Sandmeyer
reaction to afford aryl iodide 10 efficiently (86% yield
for three steps).10
Initial efforts have been directed toward protecting the
catechol derivatives as the corresponding bis-methyl
ethers (i.e. 10). However, difficulties may arise in
removing the methyl ethers in any synthesis of 1–3, due
to the potential sensitivity of the molecule towards the
standard Lewis acidic conditions (BBr3, for example).
Thus, we have shown that aryl iodide 10 can be trans-
formed to its corresponding bis-benzyl ether 11 via a
two-step sequence in 80% overall yield. The lability of
benzyl ethers towards catalytic hydrogenolysis offers a
mild alternative that should prove compatible with the
remaining functionality in 1–3.
Application of the Heck coupling with the methyl enol
ether of methyl pyruvate and 20 provided 71% of the
coupled 21 along with 23% recovered starting material
(Scheme 3). Acid catalyzed intramolecular condensa-
tion of 21 in 5% HCl/MeOH resulted in formation of
isocoumarin along with concomitant removal of the
silyl ether to provide isocoumarin precursor 5 directly
in 83% yield.
Sonagashira coupling of propargyl alcohol (12a) or its
silyl ether derivative (12b) to arene 11 was readily
accomplished; however, hydrolysis of the hindered ester
group in 14 proved impossible at this stage (Scheme 1).
Without the free carboxylate, cyclization to an isocou-
marin did not proceed. As a solution to this problem,
hydrolysis of the esters was undertaken prior to Son-
agashira coupling (Scheme 2). Both methyl esters could
be cleaved to provide bisacid 16 even though hydrolysis
of the ester flanked by two ortho substituents required
forcing conditions (KOH, H2O/MeOH, D). Son-
agashira coupling of the resultant iodide 16 with
propargyl alcohol was then undertaken in the presence
of ZnCl2. Even though this protocol had been shown to
provide the isocoumarins in related systems,11 only the
isophthalide product 18 from 5-exo dig cyclization was
observed in this more functionalized case.
At this point, 5 possesses the appropriate functionality
for introduction of the isocoumarin subunit into 1–3
(Fig. 1). The isocoumarin portion of the griseorhodins14
In order to generate the desired isocoumarin isomer, a
modified approach was employed in which the latent
lactone carbonyl would act as an electrophile instead of
Scheme 2. (a) i. LiOH, H2O/THF, ii. KOH, H2O/MeOH, D,
100% overall yield; (b) Pd(PPh3)4, ZnCl2, Et3N.

S. P. Waters, M. C. Kozlowski / Tetrahedron Letters 42 (2001) 3567–3570
3569
Scheme 3. (a) LiOH, THF/H2O; (b) i. BH3, THF, ii. TBSCl, imidazole, 87% from 10; (c) Pd(PPh3)4, K2CO3, 71%+23% 20; (d)
5% HCl/MeOH, 83%.
could also be obtained via this route by substituting
acetone enol ether in place of methyl pyruvate enol
ether during the Heck coupling. Further progress
towards these natural products and derivatives thereof
will be reported in due course.
143.3, 152.7, 157.0, 154.5, 160.8; HRMS (CI) m/z calcd
for C14H15O7 (MH+) 295.0809, found 295.0810. 10: IR
(film) 2949, 1736, 1391, 1281 cm−1; 1H NMR (CDCl3, 500
MHz) l 3.87 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.94 (s,
3H), 7.90 (s, 1H); 13C NMR l (CDCl3, 125 MHz) l 52.5,
52.9, 61.6, 61.8, 83.4, 128.6, 135.8, 139.3, 151.4, 153.2,
164.3, 166.5; HRMS (CI) m/z calcd for C12H13IO6 (M+)
379.9738, found 379.9741. 11: IR (film) 2949, 1735, 1278
cm−1; 1H NMR (CDCl3, 500 MHz) l 3.87 (s, 3H), 3.89 (s,
3H), 5.10 (s, 2H), 5.11 (s, 2H), 7.32–7.43 (m, 10H), 8.00
(s, 1H); 13C NMR (CDCl3, 125 MHz) l 52.5, 52.9, 76.4,
76.6, 84.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 129.2,
136.2, 139.8, 150.7, 152.1, 164.2, 166.5; HRMS (CI) m/z
calcd for C24H21IO6 (M+) 532.0356, found 532.0360. 16:
Acknowledgements
Financial support was provided by the University of
Pennsylvania, Merck Research Laboratories, Pharma-
cia-Upjohn, and DuPont.
1
mp 144°C, IR (film) 3331, 1737 cm−1; H NMR (acetone-
d6, 500 MHz) l 5.17 (s, 2H), 5.22 (s, 2H), 7.38–7.53 (m,
10H), 8.10 (s, 1H); 13C NMR (acetone-d6, 125 MHz) l
76.5, 76.7, 83.9, 128.6, 128.7, 128.8, 128.9, 129.8, 136.8,
137.1, 137.2, 141.3, 150.6, 152.7, 164.6, 167.0; HRMS
(CI) m/z calcd for C22H17IO6 (M+) 504.0069, found
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504.0072. 18: IR (film) 3366, 1776, 1637 cm−1; H NMR
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(s, 3H), 3.94 (s, 3H), 4.70 (s, 2H), 7.64 (s, 1H); 13C NMR
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119.2, 124.4, 126.4, 128.9, 137.2, 146.1, 149.2, 149.7,
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S. P. Waters, M. C. Kozlowski / Tetrahedron Letters 42 (2001) 3567–3570
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