Synthesis of a benzomacrolactone-based somatostatin mimetic

Article abstract of DOI:10.1021/ol202528k

The benzomacrolactone is a framework found in numerous natural products. The synthesis of an orthogonally functionalized benzomacrolactone from d-glucosamine and a salicylic acid derivative is described. This macrolactone was used for the synthesis of a somatostatin mimetic that has submicromolar affinity for the human somatostatin receptor 4 (hSSTR4).

Full text of DOI:10.1021/ol202528k

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5716–5719
Synthesis of a Benzomacrolactone-Based
Somatostatin Mimetic
Jian Zhou,†,‡ Marie-Christine Matos,‡ and Paul V. Murphy*,†,‡
School of Chemistry, National University of Ireland Galway, University Road, Galway,
Ireland, and Centre for Synthesis and Chemical Biology & UCD School of Chemistry and
Chemical Biology, University College Dublin, Dublin 4, Ireland
paul.v.murphy@nuigalway.ie
Received June 3, 2011
ABSTRACT
The benzomacrolactone is a framework found in numerous natural products. The synthesis of an orthogonally functionalized benzomacrolactone
from D-glucosamine and a salicylic acid derivative is described. This macrolactone was used for the synthesis of a somatostatin mimetic that has
submicromolar affinity for the human somatostatin receptor 4 (hSSTR4).
A recent analysis of scaffolds investigated in organic
chemistry has shown that a small number of frame-
works are found in a large number of all known
compounds.1 This could, at least partially, explain
why the diversity of scaffolds in a set of known drugs
is considered to be low.2 Hence the exploitation of
frameworks less used to date in medicinal chemistry
might ultimately lead to increased success in drug
discovery. If the scaffolds are “natural product like”,
they could have increased biological importance.3
The low bioavailability and poor pharmacokinetics of
somatostatin 1 has led to interest in nonpeptide mimetics
which may be better drug candidates.4 During the early
1990s, Hirschmann and colleagues at the University of
Pennsylvania introduced the use of β-D-glucose, its enan-
tiomers, and a diastereomer (β-D-mannose) asscaffolds for
the synthesis of ligands for the somatostatin, the substance
† National University of Ireland Galway.
‡ University College Dublin.
(4) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278.
(5) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.;
Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III; Strader,
C. D.; Cascieri, M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.;
Maechler, L. J. Am. Chem. Soc. 1992, 114, 9217.
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25, 97. (b) Meutermans, W.; Le, G. T.; Becker, B. ChemMedChem 2006,
1, 1164. (c) Murphy, P. V.; Dunne, J. L. Curr. Org. Synth. 2006, 3, 403
and references cited therein.
(1) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F.;
Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443.
(2) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887.
(3) (a) 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 91À111. (b) Koch,
M. A.; Waldmann, H. Drug Discovery Today 2005, 10, 471.
r
10.1021/ol202528k
Published on Web 10/11/2011
2011 American Chemical Society

P, and the β2-adrenergic receptors.5 Since this contribu-
tion, monosaccharides,6 due to their polyfunctional
nature, have been a basis for generating a wide range
of compounds for screening. The glucopyranoside 3
(Scheme 1) prepared by the Hirschmann group, and
containing the lysine, tryptophan, and phenylalanine
side chains of 1, was found to be a ligand for somatos-
tatin receptors, indicating that truncated mimetics are of
interest. Other research has also indicated that interac-
tions of the side chains of the Trp-Lys fragment of the
hormone somatostatin 1 seem to be important for the
recognition of SSTRs.7
The preparation of 4 was envisaged (Scheme 1) from
salicylic acid 5 and the alcohol 6. The incorporation of
azide, OTIPS, and OPMB(PMB = 4-methoxybenzyl) was
based on providing the potential to introduce modifica-
tions selectively at these sites, with previous experience
indicating orthogonality between the groups.10
Scheme 2
Scheme 1
The synthesis of 6 (Scheme 2) commenced from
D-glucosamine 7. The fully acetylated 2-azido-2-deoxy-
D-glucopyranose was obtained as a mixture of anomers
(R:β, 2:1) after diazo transfer and subsequent per-O-
acetylation.11 A thioglycoside was then prepared,12 and
subsequent de-O-acetylation followed by reaction with
dimethylanisaldehyde acetal and CSA gave 8.13 A TIPS
protecting group was then introduced, and subsequent
partial reductive cleavage gave 9. Next, 9 was hydro-
lyzed.14 If too high a proportion of water was used, it led
to decomposition. The hemiacetal intermediate on reac-
tion with NaBH4 in EtOH/H2O then gave 10.15 The 1,
2-diol of 10 was protected as a benzylidene acetal, and a
pivalyl group was then introduced at the free alcohol
group; subsequent partial reductive cleavage of the
benzylidene acetal gave 11. The allylation of the free
alcohol was carried out using sodium hydride and allyl
iodide. The pivalyl ester16 was removed to give 6.
Herein we were interested in presenting groups on a
benzomacrolactone scaffold that could mimic the interac-
tions of the Trp-Lys fragment and selected2 and analogues
of 2 as targets for synthesis. There is no crystal structure
available of somatostatin receptors binding to any ligands,
but we hypothesized that the scaffold in 2 may span a
larger surface of a protein receptor compared with a
monosaccharide, which could lead to a ligand of higher
affinity. Benzomacrolactones are common in nature (e.g.,
zearalenone,8 Scheme 1), having a range of interesting
biological properties,9 and analogues would be of interest
for screening. Herein we describe the synthesis of soma-
tostatin mimetics from a suitably decorated benzomacro-
lactone 4.
(10) Murphy, P. V.; O’Brien, J. L.; Gorey-Feret, L. J.; Smith, A. B.,
III. Tetrahedron 2003, 59, 2259.
(11) Yan, R. B.; Yang, F.; Wu, Y. F.; Zhang, L. H.; Ye, X. S.
Tetrahedron Lett. 2005, 46, 8993.
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hedron Lett. 2004, 45, 6433.
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S.; Lopez, J. C. Carbohydr. Res. 2005, 340, 1872.
(7) (a) Angeles, A. R.; Neagu, I.; Birzin, E. T.; Thornton, E. R.; Smith,
A. B., III; Hirschmann, R. Org. Lett. 2005, 7, 1121. (b) Chagnault, V.; Lalot,
J.; Murphy, P. V. ChemMedChem 2008, 3, 1071.
(15) Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 2776.
(16) Nagorny, P.; Fasching, B.; Li, X. C.; Chen, G.; Aussedat, B.;
Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, 5792.
(17) Rountree, J. S. S.; Murphy, P. V. Org. Lett. 2009, 11, 871.
(8) Stob, M.; Baldwin, R. S.; Tuite, J.; Andrews, F. N.; Gillette, K. G.
Nature 1962, 196, 1318.
(9) For a review of resorcylic acid lactones see: Wissinger, N.;
Barluenga, S. Chem. Commun. 2007, 22.
Org. Lett., Vol. 13, No. 21, 2011
5717

The preparation of the aromatic precursor 5 was next
carried out (Scheme 3)17,18 from commercially available
12. Formation of the acetonide was first carried out, the
resulting phenol was converted to its triflate, and a sub-
sequent palladium-catalyzed coupling19 with potassium
vinyltrifluoroborate gave 13. The acetonide 13 was then
hydrolyzed to give 5. Reaction of 5 with the sorbitol
derivative 6 by a Mitsunobu esterification20 promoted by
triphenylphosphine in the presence of DIAD gave 14. It is
worth noting that the yield from the esterification de-
creased dramatically (from 83 to 45%) if the coupling
was carried out starting from the benzyl ether 15. The pKa
of 5 is lower than that of 15 due to intramolecular
H-bonding in 5, which explains the increased yield. The
phenol was converted to its benzyl ether and then RCM21
using the HoveydaÀGrubbs II catalyst in CH2Cl2 under
argon gave 4 (85% from 14). When 14 was directly
subjected to RCM using the catalyst, the yield of the
ring-closed product was low (∼40%). The optimum con-
ditions for RCM were established after investigation of a
variety of conditions,22,23 and the HoveydaÀGrubbs II
catalyst24 was chosen. Separation of the catalyst from the
product was difficult. Chromatography using toluene/
CH3CN (200:1) as a solvent led to separation of the
catalyst and isolation of 4 (92%).
group, and there was evidence of decomposition under
such conditions. Various N-benzyl derivatives were
prepared, but these approaches were ultimately unpro-
ductive, and finally, the use of potassium bis(t-butoxy-
carbonyl)amine (Boc2NK) succeeded; its reaction with 19
giving 22 (77%).28
Scheme 4
To obtain somatostatin mimetics, side chains containing
an amino group and indole group were installed on the
scaffold (Scheme 4). First, the azide of 4 was reduced using
PMe3,25 which was more effective than PBu3 or PPh3. The
resulting amine wasthencoupled with indol-3-ylacetic acid
1626 to give 17. Next, the TIPS group was removed using
TBAF in THF, and the resulting hydroxyl group alkylated
using 1,4-dibromo-trans-2-butene 18 in the presence of
Ag2O27 gave 19. A variety of attempts to alkylate the
secondary hydroxyl group using 20/21 failed. With the
bromide 19 in hand, an amine surrogate then needed to
be introduced. The Gabriel reagent (potassium phtha-
limide) was avoided as strongly basic conditions would
have been possibly needed for removal of the phthalyl
Scheme 3
(18) Matos, M. C.; Murphy, P. V. J. Org. Chem. 2007, 72, 1803.
(19) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107.
(20) Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991,
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Chem. 2000, 65, 7990.
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Chem. Soc. 2005, 127, 17160.
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5718
Org. Lett., Vol. 13, No. 21, 2011

Deprotection of 22 combined with reduction of the
alkene groups was next investigated. In order to minimize
the number of deprotection steps, trifluoroacetic acid
(TFA) was first chosen as it could potentially remove the
benzyl group from the phenol, as well as the Boc and PMB
protecting groups in one pot.29 The reaction of 22 with
TFA in the presence of cation scavengers (PhSH, anisole,
thioanisole) was screened,30 and it was found that the use
of thioanisole as a cosolvent with TFA led tothe formation
of 24 (60%), an analogue of 2. The reduction of the alkene
groups of 22 was next investigated. Hydrogenation (5 or
10% PdÀC with AcOH or HCl in MeOH; 5% Pd(OH)2,
AcOHÀMeOH; Wilkinson’scatalyst, EtOH, etc.) of22led
to decomposition. Moreover, it was found for some re-
agents that reduction of the indole ring31 of 22 (as evi-
denced by MS analysis) was a problem, possibly due to the
presence of a Boc group on the indole nitrogen. Hence a
variety of conditions were screened (H2O, heat;32 Cs2CO3,
imidazole, CH3CN;33 MeONa, MeOH) in order toremove
the Boc group. Finally, the indole Boc and a second Boc
group from the aminobutylene were removed from 22
(Ki ∼ 1 μM). Compound 24 (>95% purity) was a ligand for
hSSTR4 (Ki = 0.58 μM) and hSSTR5 (Ki = 1.1 μM). As
the benchmark, 1 had Ki values of 0.52 nM (hSSTR4) and
0.75 nM (hSSTR5), whereas the mannosamine derivative 26
Figure 1. Somatostatin mimetics and affinities for hSSTR4.
(Figure 1, synthesis not shown) was inactive (Ki > 100 μM)
against these receptor subtypes. Previous work from the
Hirschmann group showed that 3 is a ligand for hSSTR4
with a Ki = 1.1 μM,35 and work from our own group
showed that 25 has a Ki = 3.3 μM against this receptor.7b
In summary, somatostatin mimetics based on benzoma-
crolactone scaffolds have been prepared. The approach
could be extended to other peptidomimetics or other
compounds for screening and broadens the potential for
benzomacrolactone as a framework in bioorganic and
medicinal chemistry.
using Zemplen conditions34 at 40 °C to provide 23. Sub-
ꢀ
sequent attempts at hydrogenation reactions with 23 were
still problematic when PdÀC or Pd(OH)2 was used. For-
tunately, hydrogenation from 23 using PtO2 gave the
desired intermediate, and subsequent treatment with
TFA and thioanisole gave the target mimetic 2.
Somatostatin regulates the endocrine system and affects
neurotransmission and cell proliferation via interaction with
G-protein-coupled receptors (SSTRs). A sample of 2
(<95% purity) showed activity as a ligand for hSSTR4
Acknowledgment. The authors thank the Higher Edu-
cation Authority’sProgrammefor ResearchinThirdLevel
Institutions Cycle 3 (M.-C.M.), IRCSET (J.Z.), and
Science Foundation Ireland (PI/IN1/B966) for support.
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Brennan, P. E.; Cappi, M. W.; Heer, J. P.; Helgen, C.; Kori, M.;
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Supporting Information Available. NMR spectra,
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new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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