Synthesis and antibiotic activity of the tricyclic furo[3,2-c] isochromen-2-trione unit of the pyranonaphthoquinones

Article abstract of DOI:10.1016/j.bmcl.2003.11.015

The elaboration and biological activity of 15, containing the proposed pharmacophore for the antibiotic activity of the pyranonaphthoquinones, are reported. The synthetic strategy involved acid-catalyzed lactonization of mandelate 17 for isochroman ring formation, in combination with a Wittig-oxa-Michael functionalization of isochroman-3-ol derivative 20, a lactonization involving configurational inversion of a benzylic alcohol and a final AgO oxidation. Compound 15 showed activity against Staphylococcus aureus and Bacillus subtilis with MIC of 64 and 32 μg/mL, respectively.

Full text of DOI:10.1016/j.bmcl.2003.11.015

Bioorganic & Medicinal Chemistry Letters 14 (2004) 757–760
Synthesis and antibiotic activity of the tricyclic furo[3,2-c]
isochromen-2-trione unit of the pyranonaphthoquinones
Darıo A. Bianchi,a Emma G. Sutichb and Teodoro S. Kaufmana,*
a
´
Instituto de Quımica Organica de Sıntesis (CONICET-UNR), Facultad de Ciencias Bioquımicas y Farmaceuticas,
´
´
´
Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Repu´blica Argentina
´
b
´
Departamento de Microbiologıa, Facultad de Ciencias Bioquımicas y Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531,
´
´
S2002LRK Rosario, Repu´blica Argentina
Received 12 September 2003; revised 26 October 2003; accepted 11 November 2003
Abstract—The elaboration and biological activity of 15, containing the proposed pharmacophore for the antibiotic activity of the
pyranonaphthoquinones, are reported. The synthetic strategy involved acid-catalyzed lactonization of mandelate 17 for isochroman
ring formation, in combination with a Wittig–oxa-Michael functionalization of isochroman-3-ol derivative 20, a lactonization
involving configurational inversion of a benzylic alcohol and a final AgO oxidation. Compound 15 showed activity against Sta-
phylococcus aureus and Bacillus subtilis with MIC of 64 and 32 mg/mL, respectively.
# 2003 Elsevier Ltd. All rights reserved.
The
3,3a,5,9b-tetrahydro-furo[3,2-c]isochromen-2-
active against Gram positive microorganisms, including
Staphylococcus and Bacillus (Fig. 1).
trione moiety (1) is a key structural element of a number
of biologically important natural products, mainly of
fungal origin. Some representative compounds display-
ing this framework include the antifungal agent kala-
fungin (2),1 arizonin A1 (3), a kalafungin-type antibiotic
isolated from Actinoplanes arizonaensis,2a frenolicin B
(4), an interesting anticoccidial agent from Streptomyces
roseofulvus AM-38672b and medermycin (5), a platelet
aggregation inhibitor3 from Streptomyces tanashiensis
K73,4 with potent anticancer activity as well as highly
Other pyranonaphthoquinones displaying this feature
are the novel antibiotic mederrhodin A (6) produced by
recombinant DNA techniques,5 the antimicrobial gri-
seusin A (7) from Streptomyces griseus K-63,6a,b
nanaomycin D (8) the enantiomer of kalafungin, the
unique human platelet aggregation inhibitor Sch 38519
(9) from Thermomonospora spp,6c (+)-granaticin (10), an
RNA synthesis inhibiting compound from Streptomyces
Figure 1.
* Corresponding author. Tel./fax:+54-341-437-0477; e-mail: tkaufman@fbioyf.unr.edu.ar
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.015

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D. A. Bianchi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 757–760
olivaceous7 and g-actinorhodin (11), produced by
Streptomyces coelicolor8a and representative of the
dimeric pyranonaphthoquinone antibiotics, which also
include some of the crisamycins.8b The wide therapeutic
potential of these natural products and the significant
synthetic challenge represented by their complex struc-
tures have attracted considerable attention from the
organic chemistry community and different approaches
for their partial or total syntheses have been reported.9
Experiments with several naphthocyclinones, polycyclic
pyranonaphthoquinones structurally related to the acti-
norhodins, demonstrated their inhibitory properties
against Gram positive bacteria, suggesting that the
minimal structure 12 (Fig. 2) is required for activity;1c,15
their benzylic oxygen functionality was also linked to
bioactivity.16 In addition, benzoisochroman-5,8-diones
of general structure 13 were prepared from condensa-
tion of 1,4-dimethoxy-b-phenethyl alcohols with alde-
hydes followed by oxidative demethylation of the
resultant pyrans,17 and tricyclic lactones such as 14 have
also been synthesized,10b but their activity has not been
tested.
The 3,3a,5,9b-tetrahydro-furo[3,2-c] isochromen-2-
trione moiety, characteristic of these pyrano naphtho-
quinone natural products, has been elaborated in
various imaginative ways; Giles and co-workers have
recently disclosed an intramolecular version of the
Mukaiyama reaction capable of yielding iso-
chromans,10a which was conveniently modified to fur-
nish the furo[3,2-c]isochromen-2-one system,10b while
the groups of Kraus and Semmelhack11 have designed a
palladium mediated alkoxy-carbonylation of suitably
functionalized allylic alcohols and Brimble and co-
workers have devised for this purpose an interesting,
and very effective furo[3,2-b]naphtho[2,1-d]furan oxida-
tive rearrangement,9a,12 all of which complement earlier
developments made by the teams of Kraus13 and Li,14
involving intramolecular additions of oxygen-bearing
functional groups to intermediate species carrying con-
jugated double bonds.
We report here the elaboration of 3,3a,5,9b-tetrahydro-
furo[3,2-c]isochromen-2-trione 15 from the easily
available glyoxylate 16,18 employing an acid-catalyzed
lactonization and
a
one-pot Wittig–oxa-Michael
sequence for isochroman ring formation and functiona-
lization, followed by a mesylate-assisted lactonization
sequence for the elaboration of the five-membered lac-
tone; we also disclose results of the antimicrobial activ-
ity of 15 and its aromatic precursor against
Staphylococcus aureus and Bacillus subtilis.
To access 15, glyoxylate 16 was selectively reduced with
sodium cyanoborohydride in EtOH furnishing mande-
late 17 which, when submitted to camphorsulfonic acid-
promoted lactonization in MeOH, smoothly afforded a-
hydroxylactone 18 as the sole product in 89% isolated
yield, as shown in Scheme 1. Garner and Ramakanth
observed that during the Wittig olefination of a-
hydroxy carbonyls the starting material can rearrange,
furnishing other carbonyl substances, which in turn are
able to undergo olefination, leading to diminished yields
of the desired product.19 Therefore, 18 was protected as
the TBDMS ether 19 under conventional conditions,
and this was then carefully and efficiently reduced to
lactol 20 with 1.1 equivalents of DIBAL-H in toluene at
ꢀ78 ꢁC.20
Figure 2.
Scheme 1. Reagents and conditions: (a) NaCNBH3, AcOHgl, EtOH, rt, overnight (96%); (b) CSA (0.5 equiv), MeOH, 40 ꢁC, 6 h (89%);
(c) TBDMSCl, imidazole, DMAP, DMF, rt, 4 h (87%); (d) DIBAL-H, toluene, ꢀ78 ꢁC, 10 min (93%); (e) PPh3¼CHCO2Et, MeCN, reflux, 40 min;
(f) KtBuO (0.1 equiv), 2 min (76%, overall); (g) TBAF, THF, rt, 1 h (90%); (h) TEA, CH2Cl2, rt, overnight (80%); (i) AgO, 6 N HNO3, 5 min (55%).

D. A. Bianchi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 757–760
759
Submission of 20 to olefination with (carbethoxy meth-
ylene) triphenylphosphorane in refluxing MeCN gave
intermediate ester 21 as the sole product, to which the
Z-configuration was attributed based on analysis of
the chemical shifts and coupling constants of the diag-
nostic benzylic (d 5.71, dd, J=0.6 and 11.2 Hz) and
olefinic protons a- and b- to the carbonyl moiety [d 6.60
(dd, J=0.6 and 9.0 Hz) and d 6.47 (dd, J=9.0 and 11.2
Hz), respectively]. Without purification, 21 was treated
in situ with potassium tert-butoxide, selectively provid-
ing isochroman ester 22 in 70% yield from 19. The
expected trans stereochemistry of the substituents in 22,
probably formed through a chair-like transition state,
agreed with literature reports21 and was further con-
firmed by the value of JH3ꢀH4=8.1 Hz. Interestingly,
Martın and co-workers have recently shown in analo-
gous systems that when the E-isomers undergo oxa-
Michael cyclization, cis-substituted pyran derivatives
are preferentially obtained, while cyclization of the Z-ole-
fins give rise mainly to the trans-substituted oxacycles.22
Table 1. MIC and MBC of tricyclic lactones 15 and 24 against
Staphylococcus aureus and Bacillus subtilis27
Compda
S. aureus
B. subtilis
MIC
MBC
MIC
MBC
15
24
64
128
>128
>128
32
128
128
>128
a MIC and MBC are given in mg/mL.
(MBC) in liquid media, with results (Table 1) indicating
that both lactones are capable of inhibiting bacterial
growth, being 15 more potent than 24. These observa-
tions confirm the previous supposition regarding the
structure of the pharmacophore of the pyr-
anonaphthoquinone antibiotics and underscore the
importance of the quinone functionality for their anti-
biotic activity.
In conclusion, a facile synthesis of the 3,3a,5,9b-
tetrahydro-furo[3,2-c] isochromen-2-trione 15, which
embodies the tricyclic ring system found in many pyr-
anonaphthoquinone natural products with antibiotic
activity, was achieved from glyoxylate–acetate 16. Key
steps of the synthesis were acid-catalyzed lactonization
of mandelate 17, Wittig–oxa-Michael functionalization
of isochroman-3-ol 20, lactonization of 23 with config-
urational inversion and final AgO-mediated oxidation.
Compound 15 proved to be active against S. aureus and
B. subtilis.
Protection of the benzylic alcohol in 18 proved to be
crucial to the success of the sequence, because it pre-
vented hydroxyl group participation in side reactions23
during the lactone reduction and Wittig olefination
steps and also improved stereochemical control of the
oxa-Michael product. Simultaneous experiments carried
out without protection of 18 evidenced difficulties in
accomplishing the reduction of this hydroxylactone and
lead to a 1.15:1 mixture of 23 and 24 in 16% overall
yield.
Next, exposure of silyl ether 22 to tetrabutyl ammonium
fluoride resulted in mild and efficient desilylation and
isolation of the expected alcohol 23, which failed to
undergo a retro-Michael–Michael addition–lactoniza-
tion sequence upon treatment with potassium tert-but-
oxide or with camphorsulfonic acid in toluene at
70 ꢁC.9c Therefore, an alternative lactonization strategy
was devised, consisting in a one pot reaction of 23 with
MsCl in CH2Cl2–triethylamine containing one equivalent
of KOH; this smoothly afforded isochroman-g-lactone
24 in 80% yield, presumably by carboxylate displace-
ment of an intermediate mesylate.
Acknowledgements
The authors acknowledge the financial support pro-
vided by ANPCyT, CONICET, SECyT-UNR and
Fundacion Antorchas and thank Dr. Jorgelina F. Perez
for her capable assistance. D.A.B. thanks CONICET
for a doctoral fellowship.
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1
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56.37 (OMe), 60.99 (C-5), 68.57 (C-9b), 72.24 (C-3a),
107.46 (C-8), 132.94 (C-5a), 141.82 (C-9a), 158.38 (C-7),
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of stock solutions (2000 mg/mL in MeOH) with Mueller–
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