Synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin scaffold

Article abstract of DOI:10.1021/jo051454n

A novel synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin (DMJ) scaffold has been developed. This involved development of a route suitable for the strategic grafting of pharmacophoric tryptophan and lysine side chains to the nitrogen a

Full text of DOI:10.1021/jo051454n

Synthesis of Somatostatin Mimetics Based on the
1-Deoxymannojirimycin Scaffold
Sebastien G. Gouin and Paul V. Murphy*
Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology,
Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
paul.v.murphy@ucd.ie
Received July 14, 2005
A novel synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin (DMJ) scaffold
has been developed. This involved development of a route suitable for the strategic grafting of
pharmacophoric tryptophan and lysine side chains to the nitrogen atom of the piperidine ring and
to the primary hydroxyl group of DMJ, respectively. The novel peptidomimetics were found to bind
with higher affinity to sst4 receptors than to sst5 receptors.
1. Introduction
sugar amino acids,7 and disaccharides.8 Although no drug
has yet been developed, potent ligands for receptors have
been identified9 and it has been shown that pyranoside
derivatives can have improved cellular permeability over
There has been recent progress in the application of
pyranosides and related scaffolds as platforms for drug
discovery since the first experimental application by
researchers at the University of Pennsylvania, which
showed that novel ligands (peptide â-turn mimetics) for
peptide hormone receptors could be developed based on
â-D-glucopyranose.1 In this example, pharmacophoric
groups, which correspond to amino acid side chains, were
grafted to the pyranose, which acted as a replacement
for the peptide backbone. Interest in this area has since
extended2 to the wider application of pyranosides as
peptidomimetics3 and as scaffolds for the solid-phase
synthesis of prospecting combinatorial libraries.4 There
has been interest in syntheses of pyranose-based sugar
amino acids (SAAs)5 and incorporation of such motifs into
molecules of biological interest. Investigations have
included (amino)sugar scaffolds, including L-sugars,6
(2) For reviews of sugar scaffolds see: (a) Sofia, M. J. Mol. Diversity
1998, 3, 75. (b) Sofia, M. J. Med. Chem. Res. 1998, 8, 362. (c) Sofia, M.
J.; Silva, D. J. Curr. Opin. Drug Discov. Dev. 1999, 2, 365. (d)
Schweizer, F.; Hindsgaul, O. Curr. Opin. Chem. Biol. 1999, 3, 29. (e)
Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002,
102, 491. (f) Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 231. (g)
Marcaurelle, L. A.; Seeberger, P. H. Curr. Opin. Chem. Biol. 2002, 6,
289. (h) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K.
J. Chem. Sci. 2004, 116, 187. (i) Schweizer, F. Trends Glycosci.
Glycotechnol. 2003, 15, 315.
(3) The first nonpeptidal peptidomimetic was reported in 1986,
which recognized the opiate receptor for which it was designed. See:
Belanger, P. C.; Dufresne, C. Can. J. Chem. 1986, 64, 1514.
(4) (a) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.;
Kunz, H. Angew. Chem., Int. Ed. 1998, 37, 2503. (b) Sofia, M. J.;
Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.; Wang, H. M.; Gange,
D. J. Org. Chem. 1998, 63, 2802. (c) Jain, R.; Kamau, M.; Wang, C.;
Ippolito, R.; Wang, H.; Dulina, R.; Anderson, J.; Gange, D.; Sofia, M.
Bioorg. Med. Chem. Lett. 2003, 13, 2185. (d) Opatz, T.; Kallus; C.;
Wunberg, T.; Schmidt, W.; Henke, S.; Kunz, H. Carbohydr. Res. 2002,
337, 2089. (e) Opatz, T.; Kallus, C.; Wunberg, T.; Schmidt, W.; Henke,
S.; Kunz, H. Eur. J. Org. Chem. 2003, 1527. (f) Opatz, T.; Kallus, C.;
Wunberg, T.; Kunz, H. Tetrahedron 2004, 60, 8613.
(5) (a) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed.
Engl. 1994, 33, 670. (b) Kessler, H.; Diefenbach, B.; Finsinger, D.;
Geyer, A.; Gurrath, M.; Goodman, S. L.; Holzemann, G.; Haubner, R.;
Jonczyk, A.; Muller, G.; Graf von Roedern, E.; Wermuth, J. Lett. Pept.
Sci. 1995, 2, 155.
(6) Hirschmann, R.; Cichy-Knight, M. A.; van Rijn, R. D.; Sprengler,
P. A.; Spoors, P. G.; Shakespeare, W. C.; Pietranico-Cole, S.; Barbosa,
J.; Liu, J.; Yao, W.; Roher, S.; Smith, A. B., III. J. Med. Chem. 1998,
41, 1382.
(7) Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann, M.;
Kessler, H. J. Am. Chem. Soc. 1996, 118, 10156.
(1) (a) 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. (b) Nicolaou, K. C.;
Salvino, J. M.; Raynor, K.; Pietranico, S.; Reisine, T.; Freidinger, R.
M.; Hirschmann, R. In Peptides - Chemistry, Structure, and Biology,
Proceedings of the 11th American Peptide Symposium; Rivier, J. E.,
Marshall, G. R., Eds.; ESCOM: Leiden, 1990; pp 881-884. (c)
Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino,
J.; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakepseare, W. C.;
Sprengler, P. A.; Hamley, P.; Smith, A. B.; Reisine, T.; Raynor, K.;
Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri, M.
R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550.
10.1021/jo051454n CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/13/2005
J. Org. Chem. 2005, 70, 8527-8532
8527

Gouin and Murphy
peptides.10 Both of these are objectives for peptidomimetic
research.11 Progress is continually dependent on advances
in synthetic carbohydrate chemistry both in solution and
on solid phase. These include the development of or-
thogonal protecting group strategies, strategies for regio-
selective manipulation of pyranoside hydroxyl groups,
and the chemoselective manipulation of functional groups.
The application of iminosugar-based scaffolds as pep-
tidomimetics has been less well-developed although some
work has been carried out by Le Merrer and co-workers12
and, more recently, by researchers from our group.13 This
is presumably because such scaffolds are not as readily
available as pyranosides and the synthesis of iminosug-
ars is not trivial.14 Iminosugars themselves have been of
significant interest as glycosidase inhibitors15 and some
have found clinical use.16 The use of iminosugars as
scaffolds for bioorganic and medicinal chemistry offers
the possibility, not available to pyranosides, of incorpo-
rating a charged hydrogen bond donor through protona-
tion of the ring nitrogen atom which would occur at
physiological pH. In addition, pharmacophoric groups can
be grafted to the nitrogen atom. Herein we describe an
approach to the synthesis of somatostatin mimetics
derived from 1-deoxymannojirimycin.
CHART 1
co-workers, is based on the â-D-glucopyranoside scaffold
(Chart 1). We proposed the working out of a synthesis of
2, a structural analogue of 1, from 1-deoxymannojirimy-
cin (DMJ) scaffold. This required the development of a
strategy for grafting the pharmacophoric tryptophan and
lysine side chains to the nitrogen atom of the piperidine
ring and to the primary hydroxyl group, respectively. The
piperidine 2 lacks the benzyl groups found in 1 and in
iminosugars synthesized by Le Merrer. The branching
positions on the scaffold would lead to a different spatial
distance between the indole and pentylamino groups.
2.2. Synthesis of Somatostatin Mimetics. The
synthesis of 2 commenced from 3 which was prepared,
as previously described,17 from DMJ.18,19 Preliminary
efforts to introduce a TIPS or TBDPS group on the
primary hydroxyl group of 3 were unsuccessful. However,
the reaction of 3 in acetone using a catalytic amount of
PPTS gave, in a regioselective manner, 4 in 70% yield.20
The formation of the diacetonide 5 was also observed;
the yield of 5 varied from 2 to 10% in a number of
experiments. The TBS group was then introduced regio-
selectively at the primary hydroxyl group to give 6 using
TBSCl and imidazole in DMF. The introduction of the
benzyl or methoxyphenylmethyl (MPM) protecting at the
remaining free hydroxyl group of 6 was not achieved in
our hands; however, the MOM protecting group was
introduced to this hydroxyl group by the reaction of
6 with MOMCl, diisopropylethylamine (DIPEA) in di-
chloromethane giving 7 in 89% yield (Scheme 1).
Conditions for the regioselective removal of protecting
groups from 7 were investigated next (Scheme 2). It was
possible to remove the TBS protecting group using TBAF
in THF to give 9; however, the yield was only 47%. This
was due to the basicity of the TBAF, which led to the
removal of the CBz group as well. Indeed it has recently
been shown that TBAF can remove carbamate protecting
groups.21 The removal of the TBS group was, however,
achieved in a selective fashion using HF-pyridine and 9
was obtained in 75% yield after 18 h. Selective depro-
tection of the CBz group by stirring a mixture of 7 and
Pd-C in THF in the presence of H2 gave 8 in a
quantitative yield.
2. Results and Discussion
2.1. Design of Somatostatin Mimetics. Somato-
statin is a cyclic peptide that regulates the release of
growth hormone and other pituitary hormones and plays
a role in neuronal transmission. A number of receptor
subtypes for this hormone have been identified. The
somatostatin antagonist 1, developed by Hirschmann and
(8) For some recent syntheses of disaccharide libraries see: (a) Sofia,
M. J.; Allanson, N.; Hatzenbuhler, N. T.; Jain, R.; Kakarla, R.; Kogan,
N.; Liang, R.; Liu, D. S.; Silva, D. J.; Wang, H. M.; Gange, D.; Anderson,
J.; Chen, A.; Chi, F.; Dulina, R.; Huang, B. W.; Kamau, M.; Wang, C.
W.; Baizman, E.; Branstrom, A.; Bristol, N.; Goldman, R.; Han, K. H.;
Longley, C.; Midha, S.; Axelrod, H. R. J. Med. Chem. 1999, 42, 3193.
(b) Baizman, E. R.; Branstrom, A. A.; Longley, C. B.; Allanson, N.;
Sofia, M. J.; Gange, D.; Goldman, R. C. Microbiology-SGM 2000, 146,
3129. (c) Castoldi, S.; Cravini, M.; Micheli, F.; Piga, E.; Russo, G.;
Seneci, P.; Lay, L. Eur. J. Org. Chem. 2004, 2853. (d) Venot, A.;
Swayze, E. E.; Griffey, R. H. Boons, G.-J. ChemBioChem 2004, 5, 1228.
(9) Prasad, V.; Birzin, E. T.; McVaugh, C. T.; van Rijn, R. D.; Rohrer,
S. P.; Chicci, G.; Underwood, D. J.; Thornton, E. R.; Smith, A. B., III;
Hirschmann, R. J. Med. Chem. 2003, 46, 1858.
(10) El Oualid, F.; Burm, B. E. A.; Leroy, I. M.; Cohen, L. H.; van
Boom, J. H.; van den Elst, H.; Overkleeft, H. S.; van der Marel, G. A.;
Overhand, M. J. Med. Chem. 2004, 47, 3920.
(11) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278.
(12) (a) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.;
Geoffroy, S.; Foglietti, M.-J. Bioorg. Med. Chem. Lett. 1997, 6, 11667.
(b) Le Merrer, Y.; Poitout, L.; Depezay, J.-C. In Methods in Molecular
Medicine: Peptidomimetics Protocols. Kazmierski., W. M., Ed.; Hu-
mana Press Inc.: Totowa, NJ, 1999; Vol. 23.
(13) (a) Chery, F.; Murphy, P. V. Tetrahedron Lett. 2004, 45, 2067.
(b) Chery, F.; Cronin, L.; O’ Brien, J. L.; Murphy, P. V. Tetrahedron
2004, 60, 6597.
(14) For a recent review on synthesis of iminosugars containing six-
membered rings see: Afarinkia, K.; Bahar, A. Tetrahedron Asymmetry
2005, 16, 1239.
Grafting of the alkylamino side chain to the primary
hydroxyl group of 9 was explored next. The triflate 12
(15) For reviews on glycosidase inhibition by iminosugars and
related compounds see: (a) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep.
1994, 135. (b) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2,
199. (c) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (d) Heightman, T.
D.; Vasella A. T. Angew. Chem., Int. Ed. 1999, 38, 750. (e) Lillelund
V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515.
(f) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top.
Med. Chem. 2003, 3, 513. (g) Asano, N.; Nash R. J.; Molyneaux, R. J.;
Fleet, G. W. J. Tetrahedron Asymmetry 2000, 11, 1645.
(17) Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter, W.
Liebigs Ann. Chem. 1990, 953.
(18) For a synthesis of DMJ from our own group see: O’Brien J. L.;
Tosin, M.; Murphy, P. V. Org Lett. 2001, 3, 3353.
(19) For a five-step synthesis of DMJ from D-fructose see: Spreitz,
J.; Stu¨tz, A. E.; Wrodnigg, T. Carbohydr. Res. 2002, 337, 183.
(20) Schueller, A. M.; Heiker, F. R.; Bayer, A.-G. Carbohydr. Res.
1990, 203, 308.
(16) Kingma, P. J.; Menheere, P. P.; Sels, J. A.; Nieuwenhuijzen
Kruseman, A. C. Diabetes Care 1992, 15, 478.
(21) Jacquemard, U.; Be´ne´teau, V.; Lefoix, M.; Routier, S.; Me´rour,
J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039.
8528 J. Org. Chem., Vol. 70, No. 21, 2005

Synthesis of Somatostatin Mimetics
SCHEME 1
SCHEME 4
SCHEME 2
The azide derivative 15 was freshly prepared as
described previously,1c,6 and the alkylation of 9 with this
electrophile in dichloromethane gave 16 in 77% yield.
This experiment was conducted in absence of base and
under vacuum, according to the protocol previously
described by Hirschmann and co-workers.6 The CBz
group was removed in the presence of the azide group
and the other protecting groups by heating 16 in etha-
nolic potassium hydroxide to give 17. The triflate 19,
freshly prepared from its alcohol precursor 18,1c on
reaction with 17 in the presence of sodium hydride gave
the indole derivative 20 in 47% yield (Scheme 4).
SCHEME 3
Next, the benzensulfonyl group was removed from 20
by heating in the presence of 5 M aqueous NaOH-EtOH;
the azide was converted to the amine using catalytic
hydrogenation to give 21. The MOM and isopropylidene
groups were finally removed under acidic conditions to
give the target compound 2 (Scheme 5).
2.3. Biological Evaluation. Compounds 2 and 21
were investigated for their effects in an in vitro nonselec-
tive sst receptor binding assay23 and in in vitro selective
sst424 and sst525 receptor binding assays. The results are
summarized in Table 1. In the nonselective assay the Ki
values determined for 2 and 21 were 26 and 21 µM,
respectively. Both iminosugar derivatives showed pref-
erential binding to sst4 receptors than to sst5 receptors.
Compounds 2 and 21 inhibited binding of the control to
sst4 receptors by 46% and 48% (both at 1.0 µM), respec-
tively, whereas they did not show any binding to sst5
receptors at this concentration, and only displayed
significant inhibition of the binding at 1.0 × 10-4 M.
was first prepared from phthalamide derivative 111c and
attempts to use this as an electrophile in reactions with
9 were unsuccessful. The attempted reaction of 12 with
9 in the presence of sodium hydride led to formation of
the cyclic carbamate 1422 which occurs via 13 (Scheme
3). Attempts to effect the desired alkylation reaction of
12 in absence of base were not successful.
(23) Brown, P. J.; Lee, A. B.; Norman, M. G.; Presky, D. H.;
Schonbrunn, A. J. Biol. Chem. 1990, 265, 17995.
(24) Rohrer, L.; Raulf, F.; Bruns, C.; Buettner, R.; Hofstaedter, F.;
Schu¨le, R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 4196.
(25) Yamada, Y.; Kagimoto, S.; Kubota, A.; Yasuda, K.; Masuda, K.;
Someya, Y.; Ihara, Y.; Li, Q.; Imura, H.; Seino, S. Biochem. Biophys.
Res. Commun. 1993, 195, 844.
(22) For a previous observation of a related cyclic carbamate see:
Fellows, L. E.; Bell, E. A.; Lynn, D. G.; Pilkiewicz, F.; Miura, I.;
Nakanishi, K. J. Chem. Soc., Chem. Commun. 1979, 977.
J. Org. Chem, Vol. 70, No. 21, 2005 8529

Gouin and Murphy
SCHEME 5
TABLE 1. Binding of Iminosugar Derivatives at Somatostatin Receptors
sst
sst4
sst5
sst5
sst5
(nonspecific)
Ki (µM)
(% inhibition at
(% inhibition at
(% inhibition at
(% inhibition at
compd
1.0 × 10-6 M)
1.0 × 10-6 M)
1.0 × 10-5 M)
1.0 × 10-4 M)
2
21
26
21
46
48
<5
<5
22
26
78
78
(1H, dd, J2,3 8 Hz, J3,4 8 Hz, H-3), 4.03 (1H, dd, J3,4 8 Hz, J4,5
11 Hz, H-4), 3.70 (1H, t, J5,6 11 Hz, J6,6′ 11 Hz, H-6), 3.38 (1H,
dt, J4,5 11 Hz, J5,6 11 Hz, J5,6′ 4 Hz, H-5), 2.96 (1H, m, H-1′),
1.52, 1.49, 1.46, 1.33 (12H, s, each CH3). 13C NMR (CDCl3, 75
MHz): δ (ppm) 156.0 (s, CdO), 136.0 (s, aromatic C), 128.7,
128.3, 128.2 (each d, each aromatic CH), 110.0, 99.6 (each s),
75.5, 72.0, 71.9 (each d), 67.7, 63.0 (each t), 50.2, 42.7 (each
d), 29.0, 26.8, 24.2, 19.2 (each q). ES-HRMS: found 378.1917
[M + H]+; C20H28NO6 requires 378.1933.
2.4. Summary and Conclusions. A synthesis of
somatostatin mimetics based on the DMJ has been
developed which facilitated strategic grafting of phar-
macophoric tryptophan and lysine side chains to the
nitrogen atom of the piperidine ring and to the primary
hydroxyl group of DMJ, respectively. The synthetic
compounds showed preferential affinity for sst4 receptors
when compared to sst5 receptors. It may be possible to
enhance affinity for somatostatin receptors by introduc-
ing other pharmacophoric groups at other hydroxyl
groups of the DMJ scaffold, as has been shown by
Hirschmann and co-workers for pyranoside scaffolds.
Development of strategies for regioselective synthesis of
such compounds from DMJ and other iminosugars is
underway. It seems interesting that 2 has significant
binding to sst4 receptors even though it is lacking in
benzyl groups of 1 and the spatial relationships between
the indole and pentylamino group would also be different
from 1.
N-Benzyloxycarbonyl-6-O-tert-butyldimethylsilyl-1,5-
dideoxy-1,5-imino-2,3-O-isopropylidene-D-mannitol 6. To
acetonide 4 (317 mg, 0.94 mmol) were added anhydrous DMF
(3 mL) and imidazole (256 mg, 3.8 mmol) and to this mixture
was added, dropwise, a solution of TBSCl (283 mg, 1.9 mmol)
in DMF (1.5 mL). After 2 min of stirring under nitrogen at
room temperature, the mixture was diluted with water (50 mL)
and extracted with diethyl ether (3 × 50 mL). The organic layer
was then dried (MgSO4) and filtered, and the solvent removed
under diminished pressure. Chromatography (EtOAc-cyclo-
hexane, 1:4 as eluant) gave 6 as a colorless oil (339 mg, 80%);
1
[R]D -71 (c ) 0.6, CH2Cl2). H NMR (DMSO-d6, 500 MHz, 90
°C): δ (ppm) 7.35 (5H, s, aromatic H), 5.10 (2H, s, CH2OCO),
5.04 (1H, d, JOH,4 6 Hz, OH), 4.29 (1H, ddd, J1,2 7 Hz, J1′,2
4
3. Experimental Section
Hz, J2,3 7 Hz, H-2), 4.07 (1H, dd, J1,1′ 13 Hz, J1,2 7 Hz, H-1),
4.01 (1H, t, J2,3 7 Hz, J3,4 7 Hz, H-3), 3.92-3.81 (3H, m,
H-4,6,6′), 3.59 (1H, dt, J4,5 3.5 Hz, J5,6 7 Hz, H-5), 2.93 (1H,
dd, J1,1′ 13 Hz, J1′,2 4 Hz, H-1′), 1.41 (3H, s, CH3), 1.30 (3H, s,
CH3), 0.86 (9H, s, (CH3)3CSi), -0.01 (6H, 2s, (CH3)2Si). 13C
NMR (DMSO-d6, 75 MHz, 90 °C): δ (ppm) 154.8 (s, CdO),
136.8 (s, aromatic C), 128.2-127.2 (each d, each aromatic CH),
108.5 (s), 77.7, 70.5, 66.5 (each d), 66.3, 60.7 (each t), 58.0,
42.4 (each d), 27.2, 27.1, 25.6, 24.8, 24.7 (each q), 17.7 (s), -5.6
(q). ES-HRMS: found 452.2478 [M + H]+; C23H38NO6Si
requires 452.2468.
N-Benzyloxycarbonyl-1,5-dideoxy-1,5-imino-2,3-O-iso-
propylidene-D-mannitol 4. The benzyloxycarbonyl deriva-
tive 3 (387 mg, 1.3 mmol) was dissolved in acetone (10 mL)
and PPTS monohydrate (10 mg, 0.05 mmol) was added. The
mixture was stirred at room temperature for 14 h and the
solvent was then removed under diminished pressure. Chro-
matography of the residue (EtOAc-cyclohexane, 3:1 as eluant)
gave, in order of elution, 5 (5 mg) as a white solid and 4 (307
mg, 70%) as a colorless oil. Analytical data for 4: [R]D -55 (c
) 0.4, DMSO-d6). 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 7.37
(5H, s, aromatic H), 5.27 (1H, d, J4,OH 4 Hz, OH), 5.07 (2H, m,
N-Benzyloxycarbonyl-6-O-tert-butyldimethylsilyl-1,5-
dideoxy-1,5-imino-2,3-O-isopropylidene-4-methoxymethyl-
D-mannitol 7. To acetonide 6 (305 mg, 0.068 mmol) were
added anhydrous CH2Cl2 (9 mL), DIPEA (942 µL, 5.4 mmol),
and molecular sieves (300 mg) and the mixture was stirred
for 30 min under nitrogen at room temperature. Then MOMCl
(411 µL, 5.4 mmol) was added and stirring continued for 19 h.
The solvent was then removed under diminished pressure and
chromatography (EtOAc-cyclohexane, 4:96 to 3:97 gradient
elution) of the residue gave 7 as a colorless oil (299 mg, 89%);
CH2OCO), 4.75 (1H, br s, OH), 4.27 (1H, ddd, J2,3 4 Hz, J1,2
6
Hz, J1′,2 8 Hz, H-2), 4.07 (1H, br s, H-1), 3.97 (1H, t, J2,3 4 Hz,
J3,4 4 Hz, H-3), 3.87 (1H, br s, H-4), 3.60-3.67 (2H, m, H-6,6′),
3.48 (1H, br s, H-5), 2.93 (1H, br s, H-1′), 1.39 (3H, s, CH3),
1.26 (3H, s, CH3). 13C NMR (DMSO-d6, 75 MHz): δ (ppm)
160.5, 160.0 (each s, each CdO), 142.3 (s, aromatic C), 133.8,
133.2, 132.9 (each d, each aromatic CH), 113.9 (s), 83.1, 76.0,
75.7, 71.9 (d), 71.7 (t), 64.4 (t), 63.9, 63.6, 63.5 (each d), 47.9,
47.5 (each t), 27.2, 27.1 (each q). ES-HRMS: found 338.1604
[M + H]+; C17H24NO6 requires 338.1619. Analytical data for
N-benzyloxycarbonyl-1,5-dideoxy-2,3:4,6-di-O-isopropylidene-
1
[R]D +70 (c ) 0.5, DMSO). H NMR (DMSO-d6, 500 MHz): δ
(ppm) 7.36 (5H, m, aromatic H), 5.20-5.00 (2H, s, CH2OCO),
4.80 (1H, s, CHH′OMe), 4.60 (1H, s, CHH′OMe), 4.33 (1H, m,
H-2), 4.17 (1H, t, J2,3 7 Hz, J3,4 7 Hz, H-3), 4.01 (2H, m, H-1,
4), 3.90-3.70 (3H, m, H-4,6,6′), 3.27 (3H, m, CH2OCH3), 3.01
1
1,5-imino-D-mannitol 5: [R]D -78 (c ) 0.8, CH2Cl2). H NMR
(CDCl3, 300 MHz): δ (ppm) 7.36 (5H, s, aromatic H), 5.20-
5.07 (2H, CH2OCO), 4.37-4.22 (3H, m, H-1, H-2, H-6′), 4.15
8530 J. Org. Chem., Vol. 70, No. 21, 2005

Synthesis of Somatostatin Mimetics
(1H, m, H-1′), 1.41 (3H, s, CH3), 1.28 (3H, s, CH3), 0.83 (9H, s,
(CH3)3CSi), -0.03 (6H, s, (CH3)2Si). 13C NMR (DMSO-d6, 75
MHz): δ (ppm) 154.8, 154.4 (each s, CdO), 136.5 (s, aromatic
C), 128.2-127.4 (each d, each aromatic CH), 108.7 (s), 95.3
(t), 75.8 (d), 70.8, 70.3, 70.0 (each d), 66.4, 66.3, 60.4, 59.8 (each
t), 56.1 (d), 55.2 (q), 42.4 (d), 27.2, 27.1, 25.6, 24.8, 24.7 (each
q), 17.6 (s), -5.7 (q). ES-HRMS: found 496.2750 [M + H]+,
C25H42NO7Si requires 496.2731.
OCH3), 3.26 (4H, m, CH2N3, CH2CH2O), 2.97 (1H, m, H-1′),
1.50-1.23 (12H, m, CH2, CH3). 13C NMR (DMSO-d6, 75
MHz): δ (ppm) 154.9, 154.6 (each s, each CdO), 136.6 (s,
aromatic C), 128.3, 127.8, 127.4 (each d, each aromatic CH),
108.8 (s), 95.4 (t), 75.6, 71.4 (each d), 70.0 (2s, d and t), 68.0,
66.4 (each t), 55.2 (q), 54.4 (d), 50.5, 40.1, 28.4, 27.9 (each t),
26.9, 24.8 (each q), 22.8 (t). ES-HRMS: found 493.2659 [M +
H]+; C24H37N4O7 requires 493.2662.
6-O-tert-Butyldimethylsilyl-1,5-dideoxy-1,5-imino-2,3-
O-isopropylidene-4-methoxymethyl-D-mannitol 8. Ac-
etonide 7 (23 mg, 0.046 mmol) was added to THF (2.5 mL)
containing 10% Pd-C (5 mg) and the mixture was stirred for
4 h under an atmosphere of hydrogen at room temperature.
Filtration and removal of solvent under diminished pressure
afforded 8 as a colorless oil (17 mg, quantitative); [R]D -34 (c
6-O-(5′-azidopentyl)-1,5-dideoxy-1,5-imino-2,3-O-iso-
propylidene-4-methoxymethyl-D-mannitol 17. Azide 16
(48 mg, 9.7 mmol) was dissolved in 50% KOH and ethanol (1:
1, 2 mL) and the mixture heated at reflux for 15 h. Water was
then added (20 mL) and the compound was extracted with CH2-
Cl2 (20 mL). The organic layer was dried (MgSO4) and filtered,
and solvent removed under diminished pressure to give 17 as
a colorless oil (34 mg, 98%). 1H NMR (CDCl3, 300 MHz): δ
(ppm) 4.92 (1H, d, J 6 Hz, CHH′OMe), 4.66 (1H, d, J 7 Hz,
1
) 0.5, DMSO). H NMR (DMSO-d6, 500 MHz): δ (ppm) 4.79
(1H, d, J 6 Hz, CHH′OMe), 4.60 (1H, d, J 6 Hz, CHH′OMe),
4.06 (1H, m, H-2), 3.97 (1H, dd, J2,3 5 Hz, J3,4 7 Hz, H-3), 3.68
(2H, m, H-6,6′), 3.54 (1H, dd, J3,4 7 Hz, J4,5 3 Hz, H-4), 3.30
(3H, m, CH2OCH3), 3.17 (1H, d, J1,1′ 14 Hz, H-1), 2.84 (1H, d,
J1,1′ 14 Hz, H-1′), 2.33 (1H, br s, H-5), 1.41 (3H, s, CH3), 1.28
(3H, s, CH3), 0.87 (9H, s, (CH3)3CSi), 0.03 (6H, s, (CH3)2Si).
13C NMR (DMSO-d6, 75 MHz): δ (ppm) 107.8 (s), 95.3 (t), 79.4,
74.1, 73.8, 62.1, 58.0 (each d), 55.0 (q), 42.4 (d), 27.7, 26.4, 25.5
(each q), 17.7 (s), -5.7 (q). ES-HRMS: found 362.2374 [M +
H]+; C17H36NO5Si requires 362.2363.
CHH′OMe), 4.16 (1H, m, H-2), 4.02 (1H, dd, J2,3 5 Hz, J3,4
Hz, H-3), 3.63-3.37 (9H, m, H-1,4,6,6′, CH2CH2O, CH2OCH3),
3.29 (2H, t, J 7 Hz, CH2N3), 2.96 (1H, dd, J1,1′ 15 Hz, J1′,2
7
2
Hz, H-1′), 2.49 (1H, ddd, J 3 Hz, J 5 Hz, J 10 Hz, H-5), 1.80
(1H, s, NH), 1.66-1.37 (12H, overlapping signals, CH2 and
CH3). 13C NMR (CDCl3, 50 MHz): δ (ppm) 109.2 (s), 96.4 (t),
80.5, 75.8, 74.4 (each d), 71.1, 70.5 (each t), 57.8 (d), 56.1 (q),
51.5 (t), 45.9 (d), 29.3, 28.8 (each t), 28.2, 26.7 (each q), 23.5
(t). ES-HRMS: found 359.2311 [M + H]+, C16H31N4O5 requires
359.2294.
N-benzyloxycarbonyl-1,5-dideoxy-1,5-imino-2,3-O-iso-
propylidene-4-methoxymethyl-D-mannitol 9. Acetonide 7
(25 mg, 0.05 mmol) was added to anhydrous THF (1 mL) to
which had been pre-added a stock solution (0.2 mL) of HF-
pyridine:pyridine:THF (2:4:10). The resulting mixture was
stirred for 50 h under nitrogen at room-temperature. Then
saturated aqueous NaHCO3 (2.5 mL) was added and the
resulting mixture was stirred again for 10 min. The mixture
was then diluted with EtOAc (5 mL), the organic layer
separated, dried (MgSO4), and filtered, and the solvent re-
moved under diminished pressure. Chromatography (EtOAc-
cyclohexane, 3:7 to 1:1) gave 9 as a colorless oil (14 mg, 75%);
6-O-(5′-Azidopentyl)-1,5-dideoxy-1-(N-phenylsulfonylin-
dol-3-yl)ethyl-1,5-imino-2,3-O-isopropylidene-4-methoxy-
methyl-D-mannitol 20. Triflic anhydride (332 µmol) was
added dropwise to a stirring solution of alcohol 18 (52 µL, 332
µmol) and 2,6-di-tert-butyl-4-methylpyridine (68 mg, 332 µmol)
in anhydrous CH2Cl2 (2 mL) at 0 °C. The mixture was stirred
at room temperature for 20 min and was then poured into
water (20 mL) and extracted with CH2Cl2 (20 mL). The organic
layer was dried (MgSO4) and concentrated under vacuum to
a volume ca. 10 mL. The concentration of the triflate 19 in
solution was ca. 33 mM. This solution (3.5 mL, 118 µmol) was
added to a flask containing 17 (22 mg, 61 µmol) and NaH (13
mg, 325 µmol, 60% dispersion) in CH2Cl2 (0.75 mL) at 0 °C,
which had been pre-stirred for 30 min, and the resulting
mixture was stirred under nitrogen at room temperature for
16 h. Water (20 mL) was poured into the solution which was
then extracted with CH2Cl2 (20 mL). The organic layer was
dried (MgSO4) and concentrated in a vacuum. Chromatography
(EtOAc-cyclohexane, 1:3) gave 20 as a colorless oil (20 mg,
1
[R]D -25 (c ) 0.7, DMSO). H NMR (DMSO-d6, 500 MHz): δ
(ppm) 7.37-7.35 (5H, m, aromatic H), 5.09 (2H, s, CH2OCO),
4.78 (1H, m, OH), 4.75 (1H, s, CHH′OMe), 4.65 (1H, s,
CHH′OMe), 4.30 (1H, m, H-2), 4.15 (1H, t, J2,3 7 Hz, J3,4 7 Hz,
H-3), 4.00 (2H, m, H-1,4), 3.79-3.60 (4H, m, H-1,5,6,6′), 3.30
(3H, m, CH2OCH3), 3.01 (1H, m, H-1′), 1.42 (3H, s, CH3), 1.29
(3H, s, CH3). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) 154.9,
154.6 (each s, CdO), 136.6 (s, aromatic C), 128.3, 127.7, 127.3
(each d, each aromatic CH), 108.7 (s), 95.3 (t), 76.0, 71.0, 70.2,
69.8 (each d), 66.9, 66.2 (each t), 58.7, 58.3, 56.4 (each d), 55.2
(q), 41.5, 40.0 (each d), 28.9, 27.0, 25.0 (each q). ES-HRMS:
found 382.1886 [M + H]+; C19H28NO7 requires 382.1881.
1
47%); [R]D -18 (c ) 0.5, CDCl3). H NMR (CDCl3, 300 MHz):
δ (ppm) 7.97 (1H, d, J 8 Hz, aromatic H), 7.86 (2H, d, J 7 Hz,
aromatic H), 7.54-7.20 (7H, m, aromatic H), 4.81 (1H, d, J 6
Hz, CHH′OMe), 4.72 (1H, d, J 7 Hz, CHH′OMe), 4.32 (1H, m,
H-2), 4.19 (1H, dd, J2,3 5 Hz, J3,4 6 Hz, H-3), 3.91 (1H, t, J2,3
5
6-O-(5′-Azidopentyl)-N-benzyloxycarbonyl-1,5-dideoxy-
1,5-imino-2,3-O-isopropylidene-4-methoxymethyl-D-man-
nitol 16. To a stirred solution of 5-azido-1-pentanol (23 mg,
178 µmol) and 2,6-di-tert-butyl-4-methylpyridine (37 mg, 180
µmol) in anhydrous CH2Cl2 (1 mL) at 0 °C was added,
dropwise, triflic anhydride (29 µL, 180 µmol). The mixture was
stirred at room temperature for 15 min, then poured into water
(12 mL) and extracted with CH2Cl2 (3 × 12 mL). The organic
phases were combined and dried (MgSO4) and solvent removed
under diminished pressure to a volume approximating 25 mL.
The concentration of the triflate solution was then ca. 8 mM.
Some of this solution (6.5 mL, 52.5 µmol) was added to 9 (20
mg, 52.5 µmol) and the reaction mixture concentrated under
diminished pressure and then placed under high vacuum for
2 h. This procedure was repeated (×3) and the residue kept
under high vacuum for 12 h. Chromatography (EtOAc-
cyclohexane, 1:4) gave 16 as a colorless oil (20 mg, 77%); [R]D
Hz, J3,4 5 Hz, H-4), 3.56 (1H, dd, J5,6 5 Hz, J6,6′ 10 Hz, H-6),
3.53 (1H, dd, J5,6′ 5 Hz, J6,6′ 10 Hz, H-6′), 3.41 (3H, s, CH2-
OCH3), 3.37 (2H, t, J 6 Hz, CH2CH2O), 3.18 (2H, t, J 7 Hz,
CH2N3), 3.05-2.92 (6H, m, H-1, H-5, NCH2CH2), 1.60-1.33
(12H, m, CH2 and CH3). 13C NMR (CDCl3, 50 MHz): δ (ppm)
138.5, 135.2, 133.5, 131.2, 129.1, 126.6, 124.6, 123.2, 123.0,
121.3, 119.4, 113.7 (aromatic C and CH), 109.1 (s), 96.4 (t, CH2-
OMe), 76.6, 73.7, 72.8 (each d), 70.9, 69.3 (each t), 61.9 (d),
55.8 (q), 53.7, 51.3, 50.0, 29.1, 28.6 (each t), 27.4, 25.5 (each
q), 23.4, 22.8 (each t). ES-HRMS: found 642.2973 [M + H]+;
C32H44N5O7S requires 642.2961.
1,5-Dideoxy-6-O-(5′-iminopentyl)-N-[(indol-3-yl)ethyl]-
1,5-imino-2,3-O-isopropylidene-4-methoxymethyl-D-man-
nitol 21. Azide 20 (25 mg, 39 µmol) was dissolved in a mixture
of 5 M NaOH (850 µL) and EtOH (5 mL) and the mixture
heated at reflux for 2 h. The ethanol was removed under
diminished pressure, water (20 mL) was added, and the
product was then extracted into CH2Cl2 (2 × 20 mL). The
combined organic layers were washed with water (20 mL),
dried (MgSO4) and filtered, and solvent removed to give the
intermediate as a colorless oil (14 mg, 70%); [R]D -15 (c ) 0.3,
1
-36 (c 0.3, DMSO). H NMR (DMSO-d6, 500 MHz): δ (ppm)
7.37-7.29 (5H, m, aromatic H), 5.09 (2H, m, CH2OCO), 4.76
(1H, d, J 7 Hz, CHH′OMe), 4.61 (1H, d, J 7 Hz, CHH′OMe),
4.32 (1H, m, J2,3 7 Hz, H-2), 4.15 (1H, t, J2,3 7 Hz, J3,4 7 Hz,
H-3), 3.95 and 3.60 (5H, each m, H-1,4,5,6), 3.29 (3H, s, CH2-
J. Org. Chem, Vol. 70, No. 21, 2005 8531

Gouin and Murphy
CH2Cl2). 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.95 (1H, s, NH),
7.60 (1H, d, J 8 Hz, aromatic H), 7.35 (1H, d, J 9 Hz, aromatic
H), 7.18 (1H, t, J 7 Hz, J 7 Hz, aromatic H), 7.10 (1H, t, J 8
Hz, J 8 Hz, aromatic H), 7.04 (1H, d, J 2 Hz, indole H), 4.82
(1H, d, J 6 Hz, CHH′OMe), 4.72 (1H, d, J 6 Hz, CHH′OMe),
4.35 (1H, m, H-2), 4.20 (1H, t, J2,3 5 Hz, J3,4 6 Hz, H-3), 3.93
(1H, t, J3,4 6 Hz, J4,5 5 Hz, H-4), 3.64 (1H, dd, J5,6 5 Hz, J6,6′ 10
Hz, H-6), 3.58 (1H, dd, J5,6′ 5 Hz, J6,6′ 10 Hz, H-6′), 3.40 (5H,
m, CH2CH2O and CH2OCH3), 3.20-2.88 (6H, m, H-1,1′ and
NCH2CH2), 2.73 (1H, dd, J1,1′ 10 Hz, J1,2 5 Hz, H-5), 1.60-
1.33 (12H, m, CH2 and CH3). 13C NMR (CDCl3, 75 MHz): δ
(ppm) 136.5, 129.3, 122.2, 121.7, 119.4, 119.0, 114.9, 111.29
(each aromatic C and CH), 109.3 (s), 96.4 (t), 78.0, 74.1, 73.2
(each d), 71.1, 69.5 (each t), 62.0 (d), 56.1 (q), 55.1 (t), 51.5 (d),
50.5, 29.9, 29.4, 28.9 (each t), 27.7, 25.9 (each q), 23.7, 23.1
(each t). ES-HRMS: found 502.3036 [M + H]+ C26H40N5O5
requires 502.3029. This intermediate (2.2 mg, 4.4 µmol) was
dissolved in MeOH (2 mL) and 10% Pd-C was added. The
resulting mixture was stirred at room temperature for 45 min
under an atmosphere of hydrogen. The mixture was then
filtered through Celite and the solvent removed under dimin-
ished pressure to provide 21 as a colorless oil; [R]D -10 (c )
pressure. The residue was freeze-dried (x2) giving the com-
pound as a hygroscopic white solid (1.3 mg, quant); [R]D -36
(c ) 0.3, DMSO). 1H NMR (D2O, 300 MHz): δ (ppm) 7.72 (1H,
d, J 8 Hz, aromatic H), 7.55 (1H, d, J 8 Hz, aromatic H), 7.37
(1H, s, aromatic H), 7.30 (1H, t, J 8 Hz, aromatic H), 7.22 (1H,
t, J 8 Hz, aromatic H), 4.30 (1H, s, H-5), 3.90-3.73 (6H, m,
H-6,6′, CH2O and CH2Ar), 3.50-3.25 (7H, m, H-1,1′,2,3,4 and
CH2N), 2.78 (2H, m, CH2), 1.46 (2H, m, CH2), 1.13 (4H, m,
2CH2). 13C NMR (D2O, 75 MHz): δ (ppm) 139.3, 129.0, 127.0,
125.1, 122.4, 121.0, 114.9, 110.5, 74.7, 73.7, 68.5, 68.2, 65.6,
57.4, 55.8, 42.0, 30.4, 29.2, 24.9, 21.9. ES-HRMS: found
392.2563 [M + H]+; C21H34N3O4 requires 392.2549.
Biological Evaluation. The assays were carried out at
Cerep26 as previously described.23 Compounds were evaluated
for their ability to inhibit somatostatin binding to sst receptors
from AtT-20 cells (nonselective assay), to human recombinant
sst424 receptors (CHO cells), and to human recombinant sst525
receptors (HEK-293 cells). The IC50 values (concentration
causing a half-maximal inhibition of control-specific binding)
and Hill coefficients (nH) were determined by nonlinear regres-
sion analysis of competition curves using Hill equation curve
fitting. The inhibition constants (Ki) were calculated from the
Cheng Prusoff equation (Ki ) IC50/(1 + (L/KD), where L is the
concentration of radioligand in the assay, and KD is the affinity
of the radioligand for the receptor).
1
0.2, CH2Cl2). H NMR (CDCl3, 300 MHz): δ (ppm) 8.15 (1H,
s, NH), 7.60 (1H, d, J 8 Hz, aromatic H), 7.35 (1H, d, J 8 Hz,
aromatic H), 7.18 (1H, t, J 8 Hz, aromatic H), 7.10 (1H, t, J 8
Hz, aromatic H), 7.06 (1H, s, aromatic H), 4.82 (1H, d, J J 6
Hz, CHH′OMe), 4.72 (1H, d, J 6 Hz, CHH′OMe), 4.35 (1H, m,
Acknowledgment. The authors thank Geraldine
Fitzpatrick for NMR spectra and Dr. Dilip Rai for high
resolution mass spectrometry measurements. Funding
was provided by the European Commission through a
Marie Curie IntraEuropean Fellowship (proposal No.
514958) to S.G.G. P.V.M. thanks the Science Foundation
Ireland and the Program for Research in Third-Level
Institutions (PRTLI), administered by the HEA (of
Ireland) for funding.
H-2), 4.19 (1H, t, J2,3 6 Hz, J3,4 6 Hz, H-3), 3.93 (1H, t, J3,4
6
Hz, J4,5 6 Hz, H-4), 3.64 (1H, dd, J5,6 5 Hz, J6,6′ 10 Hz, H-6),
3.58 (1H, dd, J5,6′ 5 Hz, J6,6′ 10 Hz, H-6′), 3.36 (5H, m,
CH2CH2O and CH2OCH3), 3.11-2.88 (6H, m, H-1,1′ and
NCH2CH2), 2.74 (1H, dd, J4,5 6 Hz, J5,6 5 Hz, H-5), 2.63 (1H,
t), 1.60-1.33 (12H, m, CH2 and CH3), 13C NMR (CDCl3, 75
MHz): δ (ppm) 136.5, 127.9 (each s, aromatic C), 122.1, 122.0,
121.8, 119.0, 114.8 (each d, aromatic CH), 111.2 (s, aromatic
C), 109.3 (s), 96.4 (t), 74.1, 73.2, 71.4 (each d), 69.3 (t), 62.0
(d), 56.0, 55.0 (each q), 50.5 (t), 42.4, 29.8, 27.7 (each t), 25.9,
23.8 (each q), 23.1 (t). ES-HRMS: found 476.3136 [M + H]+;
C26H42N3O5 requires 476.3124.
Supporting Information Available: General experimen-
tal conditions, analytical data for 14, and 1H and 13C NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1,5-Dideoxy-N-(indol-3-yl)ethyl-6-O-(5′-iminopentyl)-
1,5-imino-D-mannitol 2. Indole 21 (1.2 mg, 2.53 µmol) was
dissolved in MeOH (250 µL) and a solution of 30% HCl (25
µL) was added. The mixture was stirred at room temperature
for 2 h and the solvent was then removed under diminished
JO051454N
(26) See http://www.cerep.fr.
8532 J. Org. Chem., Vol. 70, No. 21, 2005