Synthesis of a novel polyhydroxylated salicylic acid lactone framework

Article abstract of DOI:10.1021/ol802852r

The facile preparation of a novel 8-membered polyhydroxylated salicylic acid lactone from 2,6-dihydroxybenzoic acid and sodium thio-D-glucose is described. The key step involved a sodium hydride promoted intramolecular lactonization in the presence of excess TMSCl, which led to isolation of the "natural product like" lactone.

Full text of DOI:10.1021/ol802852r

ORGANIC
LETTERS
2009
Vol. 11, No. 4
871-874
Synthesis of a Novel Polyhydroxylated
Salicylic Acid Lactone Framework
J. S. Shane Rountree† and Paul V. Murphy*,†,‡
UCD School of Chemistry and Chemical Biology and Centre for Synthesis and
Chemical Biology, UniVersity College Dublin, Belfield, Dublin 4, Ireland, and
School of Chemistry, National UniVersity of Ireland, Galway,
UniVersity Road, Galway, Ireland
paul.V.murphy@nuigalway.ie
Received December 10, 2008
ABSTRACT
The facile preparation of a novel 8-membered polyhydroxylated salicylic acid lactone from 2,6-dihydroxybenzoic acid and sodium thio-D-
glucose is described. The key step involved a sodium hydride promoted intramolecular lactonization in the presence of excess TMSCl, which
led to isolation of the “natural product like” lactone.
As part of our wider research into the preparation of
macrolide structures with desirable biological activities for
use as biochemical probes or potential medicinal agents,1
we were interested in the preparation of novel salicylate-
based lactones. Some naturally occurring compounds of this
type, such as apicularen A 1 (from a variety of strains of
myxobacterial Chondromyces),2 salicylhalamide A 2 (from
marine sponge Haliclona sp.),3 and lobatamide C 3 (from
marine tunicate Aplidium lobatum),4 exhibit antitumor activi-
ties. In particular, apicularen A 1 exhibits extremely potent
cytostatic activity against a variety of human cancer cell lines
and is also an inhibitor of angiogenesis.5 Structurally, the
compound is interesting as it contains an embedded pyran
ring, an inner 10-membered lactone ring, and an outer 12-
membered lactone ring. Resorcylic acid lactones, which are
closely related to salicylic acid lactones, have 14-membered
lactone rings and also have interesting biological activities.6
The diverse biological effects displayed by these agents
suggest that the inherent benzolactone motif is a privileged7
or evolutionarily selected scaffold8 that encodes properties
† University College Dublin.
‡ National University of Ireland, Galway.
(1) (a) Matos, M.-C.; Murphy, P. V. J. Org. Chem. 2007, 72, 1803–
1806. (b) Anquetin, G.; Rawe, S. L.; McMahon, K.; Murphy, E. P.; Murphy,
P. V. Chem.sEur. J. 2008, 14, 1592–1600. (c) Anquetin, G.; Horgan, G.;
Rawe, S.; Murray, D.; Madden, A.; MacMathuna, P.; Doran, P.; Murphy,
P. V. Eur. J. Org. Chem. 2008, 195, 3–1958.
(4) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A.,
Jr. J. Am. Chem. Soc. 2003, 125, 7889–7901.
(2) (a) Kunze, B.; Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075–1080. (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; Hofle, G. Eur. J. Org. Chem. 2000, 91, 3–919.
(5) Kwon, H. J.; Kim, D. H.; Shim, J. S.; Ahn, J. W. J. Microbiol.
Biotechnol. 2002, 12, 702–705.
(3) Xie, X.-S.; Padron, D.; Liao, X.; Wang, J.; Roth, M. G.; De
Brabander, J. K. J. Biol. Chem. 2004, 279, 19755–19763.
(6) For a recent review, see: Winssinger, N.; Barluenga, S. Chem.
Commun. 2007, 22–36.
10.1021/ol802852r CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

for binding to proteins. Carbohydrates are also privileged
structures,9 having been applied widely as scaffolds for the
development of bioactive compounds.10 This approach has
been in part successful because the carbohydrate framework
contains hydroxyl groups that provide sites for attachment
of pharmacophoric groups. A recent analysis of scaffolds
investigated in organic chemistry showed that a small number
of frameworks are found in a large number of all known
compounds, indicating that there is considerable scope for
the generation of new frameworks that will provide a basis
for future drug discovery.11 If these scaffolds are “natural
product like” they may be more biologically relevant.12
Hence, we describe a concise synthesis of a novel
polyhydroxylated salicylic acid lactone framework 4 contain-
ing an inner 8- and an outer 12-membered ring that resembles
the natural salicylic acid lactones (Figure 1). The retrosyn-
thetic analysis of 4 is outlined in Scheme 1.
ing. The alkoxide generated by reaction of 6 with sodium
hydride would act as a nucleophile at the salicylate ester
and could give 4 or 5 after deprotection, generating two novel
natural product inspired frameworks. Intramolecular lacton-
ization reactions of this type have previously been utilized
by others in order to prepare various lactones with yields
varying from 33 to 77%.4,14
The benzylic bromide 9 was first prepared as described
previously.13 Reaction of this bromide with sodium thio-D-
glucose in methanol proceeded smoothly and gave the
thioglycoside 7 in good yield (84%, Scheme 2). The 4- and
Scheme 2. Preparation of 6 and Initial Lactonization Attempts
Figure 1. Structures 1-4.
6-OH groups of the tetrol 7 were protected as the benzylidene
acetal by reaction with benzaldehyde dimethyl acetal and
catalytic (()-10-camphorsulfonic acid (1 mol %) in freshly
distilled acetonitrile to give 6 (99%). The formation of an
8- or 9-membered ring lactone was next investigated. When
diol 6 was treated with excess sodium hydride in DMF or
THF and water was added (to react with excess hydride
during workup), acid 11 was the only product isolated.
During the course of the reactions, the reaction mixture was
analyzed by ESI-MS, which suggested that a lactone,
presumably 10 based on observations described below, was
Scheme 1. Retrosynthetic Analysis
(7) Structural analogues based on the same scaffold which bind to more
than one type of receptor are known as privileged structures. See:
Hirschmann, R. Angew. Chem., Int. Ed. 1991, 30, 1278–1301.
(8) Koch, M. A.; Waldmann, H. Drug DiscoVery Today 2005, 10, 471–
483.
(9) Hirschmann, R.; Cichy-Knight, M. A.; van Rijn, R. D.; Sprengler,
P. A.; Spoors, P. G.; Shakespere, W. C.; Pietranico-Cole, S.; Barbosa, J.;
Liu, J.; Yao, W.; Roher, S.; Smith, A. B., III. J. Med. Chem. 1998, 41,
1382–1391.
(10) For recent reviews on carbohydrates as scaffolds, see: (a) Dunne,
J. L.; Murphy, P. V. Curr. Org. Synth. 2006, 3, 403–437. (b) Velter, I.; La
Ferla, B.; Nicotra, F. J. Carbohydr. Chem. 2006, 25, 97–138. (c) Becker,
B.; Condie, G. C.; Le, G. T.; Meutermans, W. Mini-ReV. Med. Chem. 2006,
6, 1299–1309. (d) Meutermans, W.; Le, G. T.; Becker, B. ChemMedChem
2006, 1, 1164–1194.
It was envisaged that reaction of sodium thio-D-glucose 8
and known salicylic acid derivative 913 would give 7. After
benzylidene acetal protection of the sugar moiety to give 6,
we envisaged that a study of the regioselectivity of the
intramolecular lactonization reactions of 6 would be interest-
(11) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F.,
III.; Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443–4451.
872
Org. Lett., Vol. 11, No. 4, 2009

formed initially and that it was subsequently hydrolyzed after
water had been added to the reaction mixture.
isolation of the lactone. The reactions of 6 with 6 equiv of
sodium hydride in DMF, followed by the addition of 4 equiv
of TMSCl after 15 min, resulted in the isolation of silylated
compounds 14 and 15 (Figure 2). The presence of a signal
The lactonization reaction was next carried out in the pre-
sence of benzyl bromide with a view to trapping the lactone
12. It was believed that the incorporation of the relatively
apolar groups onto the free hydroxyl groups in the presence
of the lactone would protect the lactone from basic hydrolysis
by increasing steric hindrance and by decreasing solubility
of the lactone in water. Thus, when diol 6 was treated with
sodium hydride in DMF for 5 min, with subsequent addition
of benzyl bromide, the 8-membered ring lactone 12 (29%)
was isolated as the major product along with the di-O-
benzylated derivative 13 (12%) (Scheme 3). The 500 MHz
Figure 2
.
Silylated lactones 14 and 15.
1
for a phenolic proton in the H NMR spectrum (500 MHz)
of 15 in CDCl3 at δ 9.11 ppm confirmed that the TMS group
was located on the thioglucose residue.
Scheme 3. Lactonization in the Presence of Benzyl Bromide
When the amount of TMSCl in these reactions was
increased to 10 equiv, the 8-membered lactone 10 (44%)
was the major product (Scheme 4). The isolation of 10
Scheme 4. Preparation of Lactone 10 and Deprotection to 4
1H and COSY NMR data in CDCl3 for lactone 12 clearly
showed that the chemical shift of the signal for H-2 on the
sugar ring shifted by ∼1 ppm downfield when compared with
the signal for the H-2 of both 6 and 13, supporting the
assignment of the 8-membered ring structure to 12. It is
generally accepted that medium size rings including 8-mem-
bered ring lactones are difficult to prepare.15 However, there
is literature precedent for the formation of an 8-membered
ring salicylic acid lactone by intramolecular reaction with
alkoxide generated by sodium hydride.16
required careful workup involving the addition of saturated
aqueous sodium bicarbonate solution 30 min after the
addition of TMSCl, followed by dilution with water after a
further 20 min and extraction into diethyl ether, before drying
the organic phase (magnesium sulfate) and subjecting it to
flash chromatography. Under these conditions, the reaction
was replicated successfully several times.
As the use of benzyl bromide in the lactonization had some
success it was decided to investigate the use of TMSCl to
likewise trap the intermediates of the reaction and facilitate
(12) For selected publications on “natural product like” compounds, see:
(a) Smith, A. B., III.; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int. Ed.
2008, 47, 7082–7086. (b) Milroy, L.-G.; Zinzalla Giovanna, Pr.; Giuseppe
Michel, P.; Ley, S. V.; Gunaratnam, M.; Beltran, M.; Neidle, S. Angew.
Chem., Int. Ed. 2007, 46, 2493–2496. (c) Ganesan, A. Combinatorial
Synthetic Design: The Balance of Novelty and Familiarity. In Exploiting
Chemical DiVersity for Drug DiscoVery; Bartlett, P. A., Entzeroth, M., Eds.;
RSC Biomolecular Sciences, Royal Society of Chemistry : Cambridge, UK,
2006; pp 91-111. (d) Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8, 281–
286.
It is interesting to note that after using these favorable
workup conditions, almost none of the starting material was
(14) (a) Bhattacharjee, A.; De Brabander, J. K. Tetrahedron Lett. 2000,
41, 8069–8073. (b) Holloway, G. A.; Hugel, H. M.; Rizzacasa, M. A. J.
Org. Chem. 2003, 68, 2200–2204. (c) Nicolaou, K. C.; Kim, D. W.; Baati,
R.; O’Brate, A.; Giannakakou, P. Chem.sEur. J. 2003, 9, 6177–6191. (d)
Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6, 1289–1292.
(15) (a) Rousseau, G. Tetrahedron 1995, 51, 2777–2849. (b) Parenty,
A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006, 106, 911–939. (c)
Shiina, I. Chem. ReV. 2007, 107, 239–273.
(13) From 2,6-dihydroxybenzoic acid, acetonidation: (a) Hadfield, A.;
Schweitzer, H.; Trova, M. P.; Green, K. Synth. Commun. 1994, 24, 1025–
1028. Triflation: (b) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto,
Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517–
5520. For methylation and benzylic bromination, see ref 4.
(16) Under similar reaction conditions, Shen et al. reported the formation
of an undesired 8-membered ring lactone in preference to a desired 15-
membered ring lactone. See ref 4.
Org. Lett., Vol. 11, No. 4, 2009
873

observed by TLC analysis. However, 6 was generated after
employing other workup conditions. In these cases, the
starting material was isolated with high recovery (30-50%),
suggesting that the lactone intermediate of the reaction can
be hydrolyzed back to give 6 (Figure 3). The reversible
(i.e., ester migration from 2-OH to either the 3-, 4-, or 6-OH)
had not occurred under the acidic conditions. The preparation
of 4 from 2,6-dihydroxybenzoic acid was achieved in 10%
overall yield for the eight steps (37% in four steps from
sodium thio-D-glucose).
In summary, we have described the concise synthesis of
a novel hybrid of a saccharide and salicylic acid lactone that
contains an 8-membered ring. Naturally occurring medium-
sized lactones are considered to be rare in organic chemistry,
possibly due to the difficulty of their biosynthesis.15a,c Those
that occur do exhibit interesting biological properties. Lactone
4 exhibits some structural similarity with (-)-ovatolide 18,
which is a naturally occurring indole alkaloid found in the
leaves of Bridelia oVata, which are used in traditional Thai
medicine as a laxative, febrifuge, and astringent (Figure 4).17
Figure 3. Formation of 14 and 15.
Figure 4. Structures of (-)-ovatolide 18 and 4.
formation of intermediate 16 or a protonated variant thus
seems plausible, since its silylated variant 14 was observed
and 6 can be recovered after certain workup conditions.
The reason for the removal of TMS under the conditions
that led to 10 is not understood and would need to be
investigated more thoroughly. One possibility is that when
TMSCl (10 equiv) is in excess compared to sodium hydride
(6 equiv) HCl is generated due to the presence of residual
water in the solvent. If enough water is present, acid-
catalyzed hydrolysis of the hemiacetal of 16 may result and
lead to removal of any acid-sensitive TMS groups from
intermediates such as 14 or 15 to yield 10. It is not
inconceivable that the addition of bicarbonate during workup
contributes to this scenario.
The approach described herein may be helpful in the
synthesis of other natural product-like medium size lactones
that are fused to organic structures, expanding further the
number of frameworks available for investigations into
bioactive compound discovery. Lactone 4 did not show
ability to inhibit the proliferation of tumor cells in preliminary
biological studies. However, more diverse and detailed
biological studies of 4 and derivatives may be interesting.
Acknowledgment. The authors are grateful to the UCD
NMR and MS Centres. The research was funded by a
Government of Ireland Postdoctoral Fellowship (Irish Re-
search Council for Science, Engineering and Techology) and
Science Foundation Ireland (PI/IN1/B966, 03/IBN/B352).
The benzylidene acetal was successfully removed from
10 using 80% acetic acid to give the polyhydroxylated
derivative 4 in quantitative yield (Scheme 4). The NMR data
for 4 was carefully analyzed to confirm that transesterification
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Delgado, A.; Clardy, J. J. Org. Chem. 1993, 58, 2862–2866.
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