Synthesis of iminosugar derivatives presenting naphthyl and alkyl amine interacting groups and binding to somatostatin receptors

Article abstract of DOI:10.1039/c4md00074a

The synthesis of 1-deoxynojirimycin (DNJ) derivatives presenting a 2-naphthylmethyl and an alkyl amino side chain from l-sorbose is described. The synthetic derivatives were tested for their ability to inhibit the binding of somatostatin-14 to human recombinant somatostatin receptors (hSSTRs). One DNJ derivative showed selective binding for hSSTR5 over hSSTR4. The presence of benzyl groups and acetates on the oxygen atoms of the iminosugar scaffold led to increased affinity for both hSSTR5 and hSSTR4. Ligand-lipophilicity efficiencies (LLEs) are calculated for the iminosugar derivatives. The LLE values are significantly higher for iminosugar derivatives where hydroxyl groups are not protected, as compared to where they are benzylated. This indicates that leaving hydroxyl groups free or avoiding the use of multiple benzyl groups could be important for drug discovery research based on sugar scaffolds. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4md00074a

MedChemComm
View Article Online
View Journal | View Issue
CONCISE ARTICLE
Synthesis of iminosugar derivatives presenting
naphthyl and alkyl amine interacting groups and
binding to somatostatin receptors†
Cite this: Med. Chem. Commun., 2014,
5, 1150
a
b
*
Stephen Barron and Paul V. Murphy
The synthesis of 1-deoxynojirimycin (DNJ) derivatives presenting a 2-naphthylmethyl and an alkyl amino
side chain from L-sorbose is described. The synthetic derivatives were tested for their ability to inhibit the
binding of somatostatin-14 to human recombinant somatostatin receptors (hSSTRs). One DNJ derivative
showed selective binding for hSSTR5 over hSSTR4. The presence of benzyl groups and acetates on the
oxygen atoms of the iminosugar scaffold led to increased affinity for both hSSTR5 and hSSTR4. Ligand-
lipophilicity efficiencies (LLEs) are calculated for the iminosugar derivatives. The LLE values are
significantly higher for iminosugar derivatives where hydroxyl groups are not protected, as compared to
where they are benzylated. This indicates that leaving hydroxyl groups free or avoiding the use of
multiple benzyl groups could be important for drug discovery research based on sugar scaffolds.
Received 21st February 2014
Accepted 20th March 2014
DOI: 10.1039/c4md00074a
www.rsc.org/medchemcomm
graed via the iminosugar C-6 alcohol group whereas the
tryptophan side chain was graed to the scaffold via the ring
Introduction
nitrogen. The iminosugar 4, which is the tri-o-benzylated
derivative of 5, is analogous to pyranoside derivatives such as 3,
the latter being introduced by Hirschmann and collaborators.10
Here, we present the synthesis and biological evaluation of
DNJ derivatives 6–8 where the iminosugar presents the
2-naphthylmethyl group and an alkyl amine group. The naph-
thalene residue is introduced as a replacement for the indole
residue and in this compound there is only a one carbon spacer
between the naphthalene group and the piperidine nitrogen.
The use of naphthalene as an isostere for indole on sugar based
peptidomimetics was studied previously by Hirschmann and
Carbohydrate scaffolds have been of interest in medicinal
chemistry.1 Each functional group inherent on the scaffold
provides a specic location where groups involved in interac-
tions can be placed. As a consequence various carbohydrate
scaffolds have been investigated, and these include sugar
amino acids2 as well as other monosaccharides3 and disaccha-
rides.4 Research has included solid phase syntheses of libraries
centred on the carbohydrate scaffold.5 These carbohydrate
frameworks and their derivatives have found application in
peptidomimetic and glycomimetic and other research.6,7 Imi-
nosugars, which are analogues of the monosaccharides where
the ring oxygen atom of a saccharide is replaced by a nitrogen
atom, have also been investigated in this regard. The use of
iminosugars, such as 1-deoxynojirimycin 2 (DNJ, Fig. 1), gives
additional features compared to their oxygen containing coun-
terparts, in that the ring nitrogen atom would be protonated at
physiological pH and attachment of interacting groups to the
ring nitrogen are possible. The latter possibility has been
investigated,8 including by the synthesis of the somatostatin
mimetic 5, which showed activity for the human somatostatin
receptor (hSSTR) 4 but not for hSSTR5.9 This dipeptide mimetic
presented both lysine and tryptophan side chains which are
found in somatostatin. In 5, lysine's butylamino side chain is
aSchool of Chemistry and Chemical Biology, University College Dublin, Beleld, Dublin
4, Ireland
bSchool of Chemistry, National University of Ireland Galway, University Road, Galway,
Ireland. E-mail: paul.v.murphy@nuigalway.ie
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4md00074a
Fig. 1 Structures of somatostatin 1, 1-deoxynojirimycin 2, and sugar
based somatostatin mimetics 3–8.
1150 | Med. Chem. Commun., 2014, 5, 1150–1158
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
co-workers.11 A naphthalene group provides a p-cloud for
intermolecular interactions similar to those expected for the
indole residue and would be expected to increase lipophilicity.
The pentylamine chain, which mimics that of the lysine side
chain, is attached directly to the piperidine ring with the
methylene and oxygen spacer between the ring and pentyla-
mino group in 5 being deleted in 6–8. As well as the compound
with free OH groups 6, the tri-o-benzylated and tri-o-acetylated
derivatives 7 and 8 are described.
Results and discussion
Firstly, molecular modelling was used to estimate low energy
conformations for 6, and to compare these with 5. In the low
energy structure for 5,8 which had been generated by a confor-
mational search using Macromodel, the tryptophan and lysine
side chains had previously been shown to have overlap with
those in sandostatin, whose solution structure has been deter-
mined,12 and which acts on SSTRs. Macromodel13 was again
employed and a conformational search, using the OPLS-AA
force eld, on 6 yielded the low energy conformer shown in
Fig. 2. In this conformer the naphthyl group and alkyl group are
stacked. This is similar to that of the low energy structure for 5
where the indole and alkyl group also showed stacking.
However, in the case of 6 the distance between the amino group
and the aromatic group is reduced compared to that in 5. An
observation from the calculated structures was that while a
hydrogen bond was possible in 5 between the iminosugar 4-OH
group and the iminosugar oxygen atom at C-6, this possibility
was removed for 6. As a consequence the pharmacophoric
naphthalene and alkyl amino chain, while keeping a stacked
orientation, adopted a different orientation with respect to the
piperidine ring in 6 than in 5.
Meanwhile, the synthesis of the target compounds was
commenced from 9 (Scheme 1) which is readily prepared from
L-sorbose. In previous work the oxidation of 9 to its aldehyde
was carried out using the Swern oxidation. Here the hypervalent
iodine oxidant IBX14 was found to deliver a more facile and
higher yielding oxidation (>77%, Scheme 1). The use of elevated
temperatures (stirring at 80 ꢀC in EtOAc), is necessary due to the
poor solubility of IBX. This can be problematic when sensitive
substrates or products are involved, but this was not the case
here. The next step was a Wittig reaction. The precursor 10 to
the required Wittig reagent was obtained by the reaction of
Scheme 1
benzyl alcohol and 1,4-dibromobutane in the presence of
sodium hydroxide (65%) and subsequent treatment of the
product with triphenylphosphine (74%) to give 10.15 The reac-
tion of 10 with NaHMDS gave the required Wittig reagent and
its reaction with the aldehyde obtained from oxidation of L-
sorbose in THF gave an alkene intermediate (46%). Catalytic
hydrogenation of this alkene gave 11 (91%). Next, the regiose-
lective deprotection of the acetonide derived from the primary
alcohol of sorbose was performed using 60% aq. acetic acid at
80 ꢀC to generate a diol (73%). This diol was converted to a cyclic
sulte by reaction with thionyl chloride and pyridine in CH2Cl2.
Subsequent reaction of this cyclic sulte with sodium azide gave
the primary azide 12 (73% over two steps). The remaining ace-
tonide protecting group was then removed from 12 by its reac-
tion with the Dowex 50WX8 resin in acetonitrile and water; the
mixture was heated at reux and gave the desired deprotected
sorbose derivative 13 (62%). Compound 13 adopted an acyclic
structure, similar to that observed previously for related sorbose
derivatives.16 Evidence for this structural assignment for 13 was
supported by a signal at d 208.6 in the 13C-NMR spectrum,
which corresponds to the ketone C]O group. The next step
involved a one pot catalytic hydrogenation of the azide to give
the primary amine. This amine then reacted in situ with the
ketone group of the open chain form of the sorbose derivative to
generate an imine. The piperidine 14 (80%) is formed from this
imine aer further in situ catalytic hydrogen addition.17,18 The
next problem to be addressed was the introduction of both the
amine functionality in the alkyl chain of 14 and the 2-naph-
thylmethyl group onto the piperidine ring nitrogen atom. It was
decided to postpone introduction of the 2-naphthylmethyl
group until later in the synthesis. This was because the 2-
naphthylmethyl group, used as a protecting group for alcohols,
Fig. 2 Space filling models of low energy structures of 5 (left) and 6
(right). Structures were obtained by a conformational search using
Macromodel.
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1150–1158 | 1151

View Article Online
MedChemComm
Concise Article
is susceptible to both acid catalysed hydrolysis and catalytic azide was accomplished under hydrogen in the presence of
hydrogenolysis. Hence, the orthogonal protection of the imi- palladium on carbon in MeOH, giving the target compound 6
nosugar hydroxyl groups and piperidine nitrogen were rst (37%). The catalytic hydrogenation of 15 directly gave 7 (94%).
carried out. The carbamate 15 was thus formed by reaction of 14 Finally, tri-o-benzylation of 16 using sodium hydride and benzyl
with di-tert-butyl dicarbonate and DIPEA in CH2Cl2 (86%). bromide in DMF, followed by catalytic hydrogenation of the
The free alcohol groups of 15 were then acetylated using product gave 8 (28% over two steps).
acetic anhydride, pyridine and a catalytic amount of DMAP to
With 6–8 in hand, they were tested‡ for their ability to inhibit
give 16 (94%).
the binding of radiolabelled somatostatin-14 to human
Next the de-o-benzylation of 16 was carried out by treating it recombinant SSTR4 (ref. 19) and SSTR5 (ref. 20) in vitro and the
with a mixture of palladium on carbon as well as palladium results are summarized in Table 1. Included in the table are Ki
hydroxide on carbon in EtOAc under hydrogen (90%). In our data for 4 and 5, which were previously determined. Somato-
hands, this unusual catalyst mixture was needed as the use of statin displayed Ki values of <2.0 nM for these receptors.
either palladium or palladium hydroxide on carbon individually Compound 6 showed binding hSSTR5 (Ki ¼ 36 mM) but there
were not effective. Subsequently, the alcohol product was was no evidence for binding to hSSTR4. The presence of benzyl
mesylated and the crude mesylate exposed to sodium azide in groups on the scaffold gave a ligand 8, which showed improved
DMF to furnish the primary azide 17 in 84% yield. With the affinity for hSSTR5 (Ki ¼ 2 mM) and also for hSSTR4 (Ki ¼ 1.9
amine that would ultimately be introduced now masked as an mM). The presence of acetate groups in 7 also led to affinity
azide, it was time to approach the attachment of the 2-naph- increases for both receptors compared with 6, although 7 was
thylmethyl group. The t-BOC group was rst cleaved using for- less potent towards hSSTR4 (Ki ¼ 5.4 mM) and hSSTR5 (Ki ¼ 7.7
mic acid and the resulting free piperidine nitrogen atom was mM) than 8. The activity displayed for 6, which showed selective
then coupled with 2-(bromomethyl) naphthalene using DIPEA binding for hSSTR5 is contrary to that found for 5, the latter
as a base, in DMF to give 18 (83%, two steps, Scheme 2). The de- showing selective binding towards hSSTR4. The precise reason
o-acetylation of 18 was initially attempted with sodium meth- for this nding is not clear. This could be due to the spacing
oxide in methanol. However, the 2-naphthyl group was found to between the p-cloud and alkyl amino chain being altered as
be cleaved during treatment of the subsequent mixture with the indicated by the modeling. Alternatively the change in orien-
Amberlite acidic ion exchange resin. Acidication with an acidic tation the iminosugar scaffold in 6 when compared with 5 with
ion exchange resin is oen used aer reaction with methoxide respect to the pharmacophoric groups as discussed above could
in methanol. This problem was overcome by reacting 18 in also lead to the different biological properties between 5 and 6,
MeOH in the presence of Ambersep 900 OH resin, which led to particularly if the scaffold also had interactions. Compound 8
the isolation of 19 (86%) without the need for treatment with showed a slight improvement over 4 for both receptor subtypes,
the acidic ion exchange resin. Aerwards, the reduction of the indicating again interaction of at least one of the benzyl groups
in SSTR binding sites.
The achievement of high potency (low value for Ki) for
molecules is highly desirable in medicinal chemistry. Lip-
ophilicity (log P) is also important as it inuences a com-
pound's water solubility, its ability to move through cell
membranes, its clearance, its selectivity, and whether it has
non-specic toxicity. In addition to the Ki values, the log P
values of compounds 4–8 have been calculated21 and are lis-
ted in Table 1. For orally available drugs, a log P between 2
and 3 has been stated as optimal, with a value <5 being
considered as necessary.22 Compound 6 is estimated to be
more lipophilic than 5 and less so than 4, 7 and 8. Compound
6 was water soluble despite the presence of the more lipo-
philic naphthalene group. The ligand-lipophilicity efficiency
LLE,23 dened as pKi ꢁ log P, allows both potency and lip-
ophilicity to be considered in a single parameter. Drug
candidates normally have an LLE value >6. The calculated
LLE values for 4–8 are shown in Table 1. The data suggests
that the tri-o-benzylated 4 and 8 would not be drug-like. On
the other hand, there may be some promise in commencing a
medicinal chemistry programme based on 5 or 6 (or another
related compound) where some OH groups on the scaffold
are kept free.
Scheme 2
‡ This assay was conducted at Cerep (http:www.cerep.com).
1152 | Med. Chem. Commun., 2014, 5, 1150–1158
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
Table 1 Binding of 4–8 at Somatostatin receptorsa
Compd
Ki [mM] (hSSTR4)
Ki [mM] (hSSTR5)
log P
LLEb (hSSTR4)
LLEb (hSSTR5)
4
5
6
7
8
4.4
3.2
Not active
5.4
1.9
5
7.58
0.48
1.57
2.89
8.67
ꢁ2.22
5.01
—
2.37
ꢁ2.94
ꢁ2.27
—
2.89
2.22
ꢁ2.97
Not active
34
7.7
2.0
a
Calculator plugins were used for log P prediction and calculation, Marvin 6.2, 2014, ChemAxon (http://www.chemaxon.com). Log P for each
b
compound was estimated using the physicochemical property prediction, which is based on published methods.21 LLE ¼ Ligand-Lipophilicity
Efficiency ¼ pKi ꢁ log P.
Aldrich. All hydrogenation reactions were carried out at
ambient pressure.
Conclusions
A synthetic route from L-sorbose to ligands for somatostatin
receptors based on the 1-deoxynojirimycin scaffold is described.
This route facilitated the introduction of an acid sensitive
2-naphthylmethyl pharmacophoric group on the piperidine
ring nitrogen atom as well as the lysine alkyl amino side chain.
The iminosugars generated herein showed activity for somato-
statin receptors, with selectivity for hSSTR5 over hSSTR4 being
observed for one compound. Somatostatin regulates, through
binding to its receptors a number of processes including the
release of growth hormone and other pituitary hormones.24 This
research provides a basis for further development of iminosu-
gar derivatives that can potentially modulate the function of
somatostatin and its receptors. Attaining ligands for the
different hSSTR sub-types has been of interest.25 Improvement
of potency of iminosugar derivatives while keeping lipophilicity
in the desired range would be important. Achieving success in
this regard will depend on improving the synthetic chemistry to
enable a more facile synthesis of iminosugar derivatives in
order that potency and other physicochemical properties can be
optimised.26
2,3:4,6-Di-o-isopropylidene-(2R,3S,4S,5S)-2-(5-(benzyloxy)-
pentyl)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol 11
To alcohol 9 (ref. 27) (8.4 g, 32.3 mmol) in EtOAc (200 mL) was
added IBX (27.1 g, 96.8 mmol). This suspension was stirred at
ꢀ
80 C while being le open to air for 4 h and was then ltered
through a sintered glass funnel. The solid residue was washed
with EtOAc and the solvent was removed under reduced pres-
sure to give the aldehyde intermediate (6.4 g, 77%, Rf: 0.1,
EtOAc–petroleum ether, 1 : 1), which was used in the next step
without further purication. To a suspension of 10 (14.5 g,
29 mmol) in dry THF (50 mL) at ꢁ78 ꢀC under a N2 atmosphere,
was added dropwise 1 M sodium bis(trimethylsilyl)amide in
THF (30 mL, 30 mmol). The reaction mixture was stirred at
ꢁ78 ꢀC for 30 min, 0 ꢀC for 30 min and at room temperature for
a further 30 min. The mixture was cooled again to ꢁ78 ꢀC and a
solution of the aldehyde intermediate (4.95 g, 19 mmol) in dry
THF (20 mL) was added. The reaction mixture was allowed to
attain room temperature, while stirring, over 15 h and then
quenched with satd aq. NH4Cl at 0 ꢀC. The layers were separated
and the aq. layer was extracted with EtOAc (ꢂ3). The combined
organic layers were washed with water (ꢂ3) and brine, dried
over sodium sulfate, ltered and the solvent was removed under
reduced pressure. Flash chromatography of the residue (EtOAc–
Experimental
General experimental conditions
Optical rotations were determined at the sodium D line at 20 ꢀC petroleum ether, 1 : 4; Rf, 0.2) gave the intermediate alkene as a
using Schmidt and Haensch UniPol L1000. NMR spectra were pale yellow oil (3.53 g, 46%); 1H NMR (500 MHz, CDCl3): d 7.35–
recorded with a 500 MHz spectrometer. Chemical shis are 7.30 (m, 4H, Ar H), 7.29–7.24 (m, 1H, Ar H), 5.65–5.57 (over-
reported relative to internal Me4Si in CDCl3 (d 0.0) or HOD for lapping signals, 2H, 2 ꢂ alkene CH), 4.49 (s, 2H, CH2Ph), 4.33
D2O (d 4.80) or CD2HOD (d 3.31) for 1H and Me4Si in CDCl3 (s, 1H, H-3), 4.25 (d, J ¼ 1.76 Hz, 1H, H-4), 4.11–4.01 (m, 3H, H-5
1
(d 0.0) or CDCl3 (d 77.0) or CD3OD (d 49.05) for 13C. H NMR and CH2), 3.51 (t, J ¼ 6.8 Hz, 2H, CH2), 2.65–2.56 (m, 1H, CHH),
signals were assigned with the aid of COSY and 13C NMR signals 2.53–2.44 (m, 1H, CHH), 1.81–1.68 (m, 2H, CH2), 1.49, 1.42, 1.37
were assigned with the aid of DEPT, gHSQCAD and/or and 1.34 (each s, 12H, 4 ꢂ CH3); 13C (125 MHz, CDCl3): d 138.7
gHMBCAD. Coupling constants are reported in hertz (Hz). The (Ar C), 134.9, 128.3, 127.6, 127.4 (2 ꢂ CH), 113.6 (C-2), 111.2
IR spectra were recorded using thin lm with a PerkinElmer (C(CH3)), 97.4 (C(CH3)), 89.1 (C-3), 74.0 (C-4), 72.8 (CH2Ph), 72.2
Spectrum 100 FT-IR spectrometer with an ATR attachment. (C-5), 70.1 (CH2OBn), 60.2 (CH2), 29.8 (CH2), 28.8, 27.1, 26.2
High resolution mass measurements were obtained using a (each CH3), 24.9 (CH2), 18.7 (CH3); ESI-HRMS: found 427.2097
Waters LCT Premier XE. Silica gel (pore size 60 A, particle size required 427.2097 [M + Na]+. To this intermediate alkene (1.83
˚
40–60 mm, 230–400 mesh particle size) was purchased from g, 4.52 mmol), 10% Pd–C (400 mg) was added, under N2, in
Sigma-Aldrich. Dichloromethane, MeOH, THF and DMF reac- EtOAc (150 mL). The reaction mixture was stirred under H2 for
tion solvents were obtained from a Pure Solv™ solvent puri- 16 h. The solution was then ltered through celite which was
cation system. Acetonitrile (Chromasolv for HPLC grade, washed with EtOAc. The solvent was removed under reduced
>99.9%) and anhydrous pyridine were obtained from Sigma- pressure and ash chromatography of the residue
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1150–1158 | 1153

View Article Online
MedChemComm
Concise Article
(EtOAc–petroleum ether, 1 : 2, Rf: 0.47) gave the title compound Hz, 1H, OH), 1.96–1.84 (m, 2H, CH2), 1.69–1.61 (m, 2H, CH2),
1
(1.67 g, 91%) as a clear oil; H NMR (500 MHz, CDCl3): d 7.36– 1.61–1.50 (m, 2H, CH2), 1.48 (s, 3H, CH3), 1.47–1.39 (m, 2H,
7.31 (m, 4H, Ar H), 7.30–7.24 (m, 1H, Ar H), 4.50 (s, 2H, CH2Ph), CH2), 1.33 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3): d 138.6
4.24 (overlapping signals, 2H, H-3 and H-4), 4.08–3.99 (over- (Ar–C), 128.3, 127.6, 127.5 (each Ar CH), 115.3 (C-2), 111.1
lapping signals, 3H, CH2 and H-5), 3.48 (t, J ¼ 6.7 Hz, 2H, CH2), (C(CH3)2), 87.1 (C-3), 78.4 (C-5), 76.0 (C-4), 72.9 (CH2Ph), 70.3
2.00–1.90 (m, 2H, CH2), 1.70–1.50 (overlapping signals, 4H, 2 ꢂ (CH2), 49.5 (CH2), 38.0 (CH2), 29.6 (CH2), 27.4, 26.6 (each CH3),
CH2), 1.47 (s, 3H, CH3), 1.46–1.39 (overlapping signals, 5H, CH2 26.3 (CH2), 23.7 (CH2); ESI-HRMS: found 374.1710 required
and CH3), 1.36 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (125 374.1692 [M + Na]+; IR (lm) cmꢁ1: 3450, 2935, 2861, 2111, 1455,
MHz, CDCl3): d 138.7 (Ar C), 128.3, 127.6, 127.4 (each Ar CH), 1372, 1215, 1077, 989.
115.7 (C-2), 110.7 (C(CH3)2), 97.2 (C(CH3)2), 86.2 (C-3), 73.7 (C-
4), 72.8 (CH2Ph), 71.7 (C-5), 70.4 (CH2), 60.4 (CH2), 37.8 (CH2),
29.7 (CH2), 28.9, 27.5, 26.7 (each CH3), 26.4 (CH2), 24.0 (CH2),
18.7 (CH3); ESI-HRMS: found 429.2252 required 429.2253 [M +
Na]+.
(2R,3R,4R,5S)-2-(5-(Benzyloxy)pentyl)piperidine-3,4,5-triol 14
Dowex 50WX8100 (H+) resin (6 g) was added to a solution of 12
(1.29 g, 3.29 mmol) in CH3CN–H2O (1 : 4, 60 mL) and the
mixture was stirred while heating at reux for 3 h. Aer cooling
to room temperature, the reaction mixture was ltered and the
solvent was removed under reduced pressure. Flash chroma-
tography of the residue (EtOAc–petroleum ether, 1 : 1, Rf: 0.15)
gave the intermediate sorbose derivative 13 (713 mg, 62%) as a
clear oil; 1H NMR (500 MHz, CD3OD): d 7.37–7.30 (m, 4H, Ar H),
7.30–7.26 (m, 1H, Ar H), 4.49 (s, 2H, CH2Ph), 4.24 (s, 1H, H-3),
4.13 (br s, 1H, OH), 4.05 (dt, 1H, J ¼ 5.8 Hz, J ¼ 2.7 Hz, H-5), 4.01
(s, 1H, H-4), 3.51–3.39 (overlapping signals, 5H, OH and 2 ꢂ
CH2), 2.85–2.75 (m, 1H, OH), 2.65 (ddd, 1H, J ¼ 17.3 Hz, J ¼ 8.3
Hz, J ¼ 6.4 Hz, CHH), 2.51 (ddd, 1H, J ¼ 17.3 Hz, J ¼ 8.2 Hz, J ¼
6.6 Hz, CHH), 1.75–1.60 (overlapping signal, 4H, 2 ꢂ CH2),
1.45–1.38 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3): d 208.6
(C]O), 138.5 (Ar C), 128.4, 127.6 (2s) (each Ar CH), 79.4 (C-3),
72.9 (CH2Ph), 72.0 (C-5), 70.1 (C-4), 70.0 (CH2), 52.9 (CH2), 37.7
(CH2), 29.4 (CH2), 25.7 (CH2), 23.1 (CH2); ESI-HRMS: found
350.1718 required 350.1716 [M ꢁ H]ꢁ. To a solution of this
intermediate (267 mg, 0.76 mmol) in MeOH (30 mL) was added
20% Pd(OH)2–C (90 mg) and the suspension was stirred under
H2 for 12 h. The reaction mixture was ltered through celite and
the solvent was removed under reduced pressure. Flash chro-
matography of the residue (CH2Cl2–MeOH, 9 : 1 to 7 : 3, Rf: 0.38
(7 : 3)) gave the title piperidine (187 mg, 0.605 mmol, 80%) as a
white solid; 1H-NMR (500 MHz, CD3OD): d 7.36–7.31 (m, 4H, Ar
H), 7.30–7.25 (m, 1H, Ar H), 4.49 (s, 2H, CH2Ph), 3.57 (ddd, J ¼
11.0 Hz, J ¼ 9.5 Hz, J ¼ 4.9 Hz, 1H, H-5), 3.50 (t, J ¼ 6.4 Hz, 2H,
CH2), 3.28–3.16 (overlapping signals, 3H, H-6a, H-3 and H-4),
2.76–2.70 (m, 1H, H-2), 2.67 (t, J ¼ 11.7 Hz, 1H, H-6b), 2.01–1.95
(m, 1H, CHH–CHN), 1.69–1.60 (m, 2H, CH2), 1.58–1.36 (over-
lapping signals, 5H, CHH–CHN & 2 ꢂ CH2); 13C NMR (125 MHz,
CD3OD): d 139.9 (Ar–C), 129.4, 128.9, 128.7 (each Ar CH), 79.2
(C-4), 74.4 (C-3), 73.9 (CH2Ph), 71.3 (CH2), 70.1 (C-5), 61.0 (C-2),
49.3 (CH2), 31.6 (CH2), 30.5 (CH2), 27.3 (CH2), 26.1 (CH2); ESI-
HRMS: found 308.1865 required 308.1862 [M ꢁ H]ꢁ.
2,3-O-Isopropylidene-(2R,3S,4S,5S)-5-(azidomethyl)-2-(5-
(benzyloxy)pentyl)tetrahydrofuran-2,3,4-triol 12
A solution of 11 (1 g, 2.5 mmol) in 60% acetic acid–water (100
mL) was stirred at 60 ꢀC for 1 h. The solvent was removed under
reduced pressure and ash chromatography (EtOAc–petroleum
ether, 2 : 1, Rf: 0.35) of the residue gave the intermediate diol as
a white solid (659 mg, 73%); 1H NMR (500 MHz, CDCl3): d 7.37–
7.32 (m, 4H, Ar H), 7.31–7.26 (m, 1H, Ar H), 4.50 (s, 2H, CH2Ph),
4.28 (d, J ¼ 2.9 Hz, 1H, H-5), 4.23 (s, 1H, H-3), 4.17 (dd, J ¼ 5.9
Hz, J ¼ 2.8 Hz, 1H, H-4), 4.09–4.04 (overlapping signals, 2H,
CH(H)O– and OH), 4.02–3.96 (m, 1H, C(H)HO–), 3.52–3.44 (m,
2H, CH2), 2.67 (dd, J ¼ 8.1 Hz, J ¼ 4.6 Hz, 1H, OH), 2.01–1.87 (m,
2H, CH2), 1.68–1.59 (overlapping signals, 3H, CH2 and CHH),
1.57–1.48 (overlapping signals, 2H, CH2), 1.47 (s, 3H, CH3),
1.46–1.38 (m, 1H, CH2), 1.33 (s, 3H, CH3); 13C-NMR (125 MHz,
CDCl3): d 138.5 (Ar C), 128.4, 127.7, 127.6 (each Ar CH), 115.3
(C-2), 110.8 (C(CH3)2), 87.5 (C-3), 78.6 (C-4), 77.9 (C-5), 72.9
(CH2Ph), 70.4 (CH2O), 61.6 (CH2OH), 37.6 (CH2), 29.4 (CH2),
27.5 (CH3), 26.6 (CH3), 26.3 (CH2), 23.8 (CH2); ESI-HRMS: found
365.1964 required 365.1964 [M ꢁ H]ꢁ, IR (lm) cmꢁ1: 3401,
2936, 2862, 1641, 1454, 1372, 1215. To a mixture of this diol (628
mg, 1.71 mmol) and pyridine (0.32 mL, 4 mmol) in dry CH2Cl2
(30 mL) at 0 ꢀC, under N2, was added dropwise a solution of
SOCl2 (238 mg, 0.15 mL, 2 mmol) in dry CH2Cl2 (7 mL). Aer
stirring for 1 h, the reaction mixture was washed with water (ꢂ3)
and brine. The organic layer was dried (Na2SO4), ltered, and
ꢀ
the solvent was removed at 30 C under reduced pressure. The
residue was dissolved in dry DMF (40 mL) and sodium azide
(333 mg, 5.1 mmol) was added. The reaction mixture was stirred
at 105 ꢀC under N2 for 16 h. Aer being allowed to cool to room
temperature the mixture was diluted with water and then
extracted with EtOAc (ꢂ3). The combined organic layers were
then washed with water (ꢂ3) and brine, dried (Na2SO4), ltered
and the solvent was removed under reduced pressure. Flash
chromatography of the residue (EtOAc–petroleum ether, 1 : 1,
(2R,3R,4R,5R)-tert-Butyl 2-(5-(benzyloxy)pentyl)-3,4,5-
trihydroxypiperidine-1-carboxylate 15
Rf: 0.53) gave the title compound (490 mg, 73%) as a white solid; To a solution of 14 (92 mg, 0.297 mmol) and DIPEA (0.26 mL,
1H NMR (500 MHz, CDCl3): d 7.37–7.32 (m, 4H, Ar H), 7.30–7.26 1.485 mmol) in dry DMF (2.5 mL), was added Boc2O (195 mg,
(m, 1H, Ar H), 4.49 (s, 2H, CH2Ph), 4.32 (td, J ¼ 5.6 Hz, J ¼ 2.8 0.893 mmol), under N2. The reaction mixture was stirred at 40
Hz, 1H, H-5), 4.22 (s, 1H, H-3), 4.19 (t, J ¼ 3.2 Hz, 1H, H-4), 3.63 ꢀC overnight, then diluted with water, and extracted with EtOAc
(dd, J ¼ 12.8 Hz, J ¼ 6.3 Hz, 1H, CHH), 3.52 (dd, J ¼ 12.8 Hz, J ¼ (ꢂ3). The combined organic layers were washed with brine,
5.2 Hz, 1H, CHH), 3.48 (t, J ¼ 6.6 Hz, 2H, CH2), 2.34 (d, J ¼ 4.7 dried (Na2SO4), ltered and the solvent was removed under
1154 | Med. Chem. Commun., 2014, 5, 1150–1158
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
reduced pressure. Flash chromatography (EtOAc, Rf: 0.32) of the 1.85–1.76 (m, 1H, CHHCHN), 1.62–1.51 (overlapping signals,
residue gave title compound (104 mg, 0.254 mmol, 86%) as a 3H, CHHCHN and CH2), 1.45 (s, 9H, tert-Bu CH3), 1.41–1.27
1
white solid; H NMR (500 MHz, CDCl3): d 7.37–7.31 (m, 4H, Ar (overlapping signals, 4H, 2 ꢂ CH2); 13C-NMR (125 MHz, CDCl3):
H), 7.30–7.26 (m, 1H, Ar H), 4.49 (s, 2H, CH2Ph), 4.21 (dd, J ¼ 9.5 d 169.7, 169.6, 168.6 (each C]O), 155.6 (carbamate C]O), 80.0
Hz, J ¼ 4.8 Hz, 1H, H-2), 4.02 (d, J ¼ 14.4 Hz, 1H, H-6a), 3.88 (s, (tert-Bu C), 69.7 (C-3), 68.2 (C-4), 67.5 (C-5), 62.5 (CH2), 53.2 (C-
1H, H-4), 3.76 (s, 1H, H-5), 3.64 (s, 1H, H-3), 3.58 (s, 1H, OH), 2), 37.9 (CH2), 32.5 (CH2), 28.7 (CH2), 28.3 (3 ꢂ tert-Bu CH3),
3.52 (s, 1H, OH), 3.46 (t, J ¼ 6.6 Hz, 2H, CH2), 3.28 (d, J ¼ 14.4 25.5, 25.0 (each CH2), 20.9 (3 ꢂ CH3); ESI-HRMS: found
Hz, 1H, H-6b), 2.55 (s, 1H, OH), 1.92–1.82 (m, 1H, CH2), 1.65– 468.2196 required 468.2210 [M + Na]+; IR (lm) cmꢁ1: 3474,
1.52 (overlapping signals, 3H, CHH & CH2), 1.48–1.28 (over- 2933, 1740, 1693, 1418, 1367, 1219, 1163, 1043. To this alcohol
lapping signals, 13H, 2 ꢂ CH2 & 3 ꢂ tert butyl CH3); 13C NMR (175 mg, 0.393 mmol) in anhydrous CH2Cl2 (12 mL), under N2,
ꢀ
(125 MHz, CDCl3): d 157.3 (C]O), 138.5 (Ar–C), 128.4, 127.7, at 0 C, was added triethylamine (163 mL, 1.18 mmol) followed
127.5 (each Ar CH), 80.2 (tert-Bu C), 72.9 (CH2Ph), 71.9 (C-3), by methanesulfonyl chloride (43 mL, 0.56 mmol). The reaction
70.5 (CH2), 70.0 (2s, C-3 and C-4), 57.9 (C-2), 40.5 (C-6), 29.6 was stirred at 0 ꢀC and then room temperature for 1 h and then
(CH2), 29.1 (CH2), 28.4 (CH3), 26.4 (CH2), 26.0 (CH2); ESI-HRMS: diluted with CH2Cl2. The mixture was washed with water (ꢂ3),
found 432.2364 required 432.2362 [M + Na]+.
dried (Na2SO4), ltered, and the solvent was removed under
reduced pressure. The residue, which was the mesylate, was
then dissolved in dry DMF (15 mL) to which sodium azide
(77 mg, 1.18 mmol) was added. The reaction was stirred while
heating at 105 ꢀC for 15 h. The reaction mixture was diluted with
water and then extracted with CH2Cl2. The combined organic
layers were washed with water (ꢂ3) and brine, dried (Na2SO4),
ltered and the solvent was removed under reduced pressure.
Flash chromatography (EtOAc–petroleum ether, 1 : 3, Rf: 0.15)
of the residue gave the title compound (155 mg, 84%) as a white
solid; 1H NMR (500 MHz, CDCl3): d 4.97 (s, 1H, H-4), 4.70
(overlapping signals, 2H, H-3, H-5), 4.36 (m, 1H, H-2), 4.24 (d,
J ¼ 14.5 Hz, 1H, H-6a), 3.27 (t, J ¼ 6.9 Hz, 2H, CH2N3), 3.17 (d,
J ¼ 15.1 Hz, 1H, H-6b), 2.10 (s, 3H, CH3), 2.07 (overlapping
signals, 6H, 2 ꢂ CH3), 1.84–1.74 (m, 1H, CHHCHN), 1.63–1.54
(overlapping signals, 3H, CHHCHN and CH2), 1.45 (s, 9H, tert-
Bu CH3), 1.42–1.28 (overlapping signals, 4H, 2 ꢂ CH2); 13C NMR
(125 MHz, CDCl3): d 169.7, 169.6, 168.6 (each acetate C]O),
155.5 (carbamate C]O), 80.0 (tert-Bu C), 69.6 (CH), 68.2 (CH),
67.5 (CH), 53.3 (CH), 51.3 (CH2), 37.9 (CH2), 28.8 (CH2), 28.6
(CH2), 28.3 (3 ꢂ tert-Bu CH3), 26.2 (CH2), 25.5 (CH2), 20.9 (CH3);
ESI-HRMS: found 493.2264 required 493.2274 [M + Na]+; IR
(lm) cmꢁ1: 2926, 2096, 1742, 1697, 1576, 1524, 1415, 1369,
1230, 1017.
(2R,3R,4R,5S)-2-(5-(Benzyloxy)pentyl)-1-(tert-butoxycarbonyl)-
piperidine-3,4,5-triyl triacetate 16
DMAP (3 mg, 0.0274 mmol) was added to a stirring solution of 15
(112 mg, 0.274 mmol) in acetic anhydride–pyridine (1 : 1, 10 mL),
under N2. Aer stirring for 4 h at room temperature, the reaction
was diluted with EtOAc, followed by water. The layers were
separated and the aq. layer was extracted with EtOAc (ꢂ2). The
combined organic layers were washed with water (ꢂ3) and brine,
dried (Na2SO4), ltered and the solvent was removed under
reduced pressure. Flash chromatography of the residue (EtOAc–
petroleum ether, 1 : 2, Rf: 0.34) gave the title compound (138 mg,
94%) as a white solid; 1H-NMR (500 MHz, CDCl3): d 7.35–7.31 (m,
4H, Ar H), 7.30–7.25 (m, 1H, Ar H), 4.96 (m, 1H, H-4), 4.70
(overlapping signals, 2H, H-3 and H-5), 4.49 (s, 2H, CH2Ph), 4.35
(m, 1H, H-2), 4.23 (d, 1H, J ¼ 14.9 Hz, H-6a), 3.46 (t, J ¼ 6.5 Hz,
2H, CH2), 3.16 (d, J ¼ 15.1 Hz, 1H, H-6b), 2.08 (s, 3H, acetate
CH3), 2.06 (2s, 6H, 2 ꢂ acetate CH3), 1.83–1.73 (m, 1H, CHHCHN)
1.65–1.51 (overlapping signals, 3H, CHHCHN and CH2), 1.44 (s,
9H, tert butyl CH3), 1.42–1.27 (overlapping signals, 4H, 2 ꢂ CH2);
13C NMR (125 MHz, CDCl3): d 169.7, 169.6, 168.6 (each acetate
C]O), 155.5 (carbamate C]O), 138.6 (Ar–C), 128.3, 127.6, 127.5
(each Ar CH), 79.8 (tert butyl C), 72.9 (CH2Ph), 70.3 (CH2), 69.7
(C-3), 68.2 (C-4), 67.5 (C-5), 53.5 (C-2), 37.8 (C-6), 29.7 (CH2), 28.7
(CH2), 28.3 (tert butyl CH3), 25.8 (2s, 2 ꢂ CH2), 20.9 (acetate CH3);
ESI-HRMS: found 534.2701 required 534.2703 [M ꢁ H]ꢁ; IR (lm)
cmꢁ1: 2983, 1737, 1698, 1372, 1235, 1044.
(2R,3R,4R,5S)-2-(5-Azidopentyl)-1-(naphthalen-2-ylmethyl)-
piperidine-3,4,5-triyl triacetate 18
Compound 17 (41 mg, 0.09 mmol) was dissolved in formic acid
(4 mL). Aer stirring at room temperature for 1 h, the solvent
was removed under reduced pressure. The residue was dis-
solved in DMF (5 mL) aer which 2-(bromomethyl) naphthalene
(2R,3R,4R,5S)-2-(5-azidopentyl)-1-(tert-butoxycarbonyl)-
piperidine-3,4,5-triyl triacetate 17
To a solution of 16 (233 mg, 0.435 mmol) in EtOAc (20 mL) was (97 mg, 0.44 mmol) and DIPEA (93 mg, 0.72 mmol) were added.
added 10% Pd–C (77 mg) and 20% Pd(OH)2–C (77 mg). This The solution was stirred at 50 ꢀC overnight and then the solvent
solution was placed under H2 and stirred overnight. The reac- was removed under reduced pressure. The residue was diluted
tion mixture was ltered through celite and the solvent was with CH2Cl2 and washed with water (ꢂ3) and brine, dried
removed under reduced pressure. Flash chromatography of the (Na2SO4), ltered and the solvent was removed under reduced
residue (EtOAc–petroleum ether, 1 : 1 to 2 : 1, Rf: 0.1 (1 : 1)) gave pressure. Flash chromatography of the residue (EtOAc–petro-
the alcohol intermediate (175 mg, 90%) as a white solid; 1H leum ether, 1 : 2 to 1 : 1, Rf: 0.48) gave the title compound as a
1
NMR (500 MHz, CDCl3): d 4.96 (s, 1H, H-4), 4.70 (overlapping white solid (37 mg, 83%); H NMR (500 MHz, CDCl3): d 7.84–
signals, 2H, H-3 and H-5), 4.37 (d, J ¼ 3.8 Hz, 1H, H-2), 4.24 (d, J 7.79 (m, 3H, Ar H), 7.72 (s, 1H, Ar H), 7.50–7.43 (m, 3H, Ar H),
¼ 14.9 Hz, 1H, H-6a), 3.63 (t, J ¼ 6.4 Hz, 2H, CH2), 3.18 (d, J ¼ 5.15 (t, 1H, J ¼ 9.5 Hz, H-3), 5.10–5.02 (overlapping signals, 2H,
14.9 Hz, 1H, H-6b), 2.10, 2.08, 2.05 (3s, 9H, each acetate CH3), H-4 and H-5), 4.11 (d, 1H, J ¼ 13.6 Hz, CHHNaph), 3.48 (d, 1H, J
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1150–1158 | 1155

View Article Online
MedChemComm
Concise Article
¼ 13.6 Hz, CHHNaph), 3.21 (t, 2H, J ¼ 6.9 Hz, CH2N3), 3.05–3.00 28.0, 24.1 (each CH2); ESI-HRMS: found 359.2339 required
(m, 1H, H-6a), 2.66 (dt, 1H, J ¼ 10.0 Hz, J ¼ 4.0 Hz, H-2), 2.20– 359.2335 [M + Na]+.
2.14 (m, 1H, H-6b), 2.07, 2.01, 1.90 (each s, each CH3), 1.78–1.67
(m, 1H, CHHCHN), 1.61–1.47 (overlapping signals, 5H,
CHHCHN, 2 ꢂ CH2), 1.37–1.27 (m, 2H, CH2); 13C NMR (125
MHz, CDCl3): d 170.4, 170.0, 169.8 (each acetate C]O), 135.6,
133.3, 132.9, 128.4, 127.7, 127.1, 126.2 (2s), 125.8 (Ar C and CH),
75.4 (C-4), 71.1 (C-3), 68.5 (C-5), 62.7 (C-2), 54.6 (CH2Naph), 52.5
(C-6), 51.3 (CH2N3), 28.7 (CH2), 27.5 (CH2), 27.0 (CH2), 22.9
(CH2), 20.8 (3s, 3 ꢂ CH3) ESI-HRMS: found 511.2558 required
511.2557 [M + H]; IR (lm) cmꢁ1: 2945, 2094, 1745, 1601, 1509,
1434, 1367, 1220, 1030, 819.
(2R,3R,4R,5S)-2-(5-Aminopentyl)-1-(naphthalen-2-ylmethyl)-
piperidine-3,4,5-triyl triacetate 7
To a solution of 18 (9 mg, 0.018 mmol) in EtOAc–MeOH (1 : 1, 2
mL) was added 10% Pd–C (3 mg). The suspension was stirred
under H2 atmosphere for 30 min, aer which the mixture was
ltered through celite and the solvent was removed under
reduced pressure. Flash chromatography of the residue (EtOAc–
MeOH–satd aq. NH4OH, 8 : 2 : 0.1, Rf: 0.14) furnished the title
1
compound as a white solid (8 mg, 0.017 mmol, 94%); H NMR
(500 MHz, CD3OD): d 7.85–7.81 (m, 3H, Ar H), 7.78 (s, 1H, Ar H),
7.51–7.43 (m, 3H, Ar H), 5.11 (t, J ¼ 9.5 Hz, 1H, H-3), 5.04 (t, J ¼
9.4 Hz, 1H, H-4), 4.95 (td, J ¼ 9.9 Hz, J ¼ 4.9 Hz, 1H, H-5), 4.19 (d, J
(2R,3R,4R,5S)-2-(5-Azidopentyl)-1-(naphthalen-2-ylmethyl)-
piperidine-3,4,5-triol 19
Piperidine 18 (37 mg, 0.072 mmol) was dissolved in MeOH ¼ 13.5 Hz, 1H, CHHNaph), 3.48 (d, J ¼ 13.6 Hz, 1H, CHHNaph),
(6 mL) and Ambersep 900 OH resin (150 mg) was added. The 3.02 (dd, J ¼ 11.9 Hz, J ¼ 4.9 Hz, 1H, H-6a), 2.70–2.65 (m, 1H, H-
mixture was shaken at room temperature for 15 h. The resin was 2), 2.60 (t, J ¼ 7.3 Hz, 2H, CH2NH2), 2.18 (dd, J ¼ 11.7 Hz, J ¼ 10.8
then removed by ltration and the solvent was removed under Hz, 1H, H-6b), 2.06 (s, 3H, CH3), 1.98 (s, 3H, CH3), 1.88 (s, 3H,
reduced pressure. Flash chromatography of the residue (EtOAc, CH3), 1.86–1.76 (m, 1H, CHHCH), 1.62–1.50 (overlapping signals,
Rf: 0.13) gave the title compound as a white solid (24 mg, 86%); 3H, CHHCH and CH2), 1.49–1.42 (m, 2H, CH2), 1.36–1.22 (m, 2H,
1H NMR (500 MHz, CD3OD): d 7.84–7.80 (m, 3H, Ar H), 7.76 CH2); 13C NMR (125 MHz, CD3OD): d 171.9, 171.8, 171.7 (each
(s, 1H, Ar H), 7.49 (dd, J ¼ 8.3 Hz, J ¼ 1.5 Hz, 1H, Ar H), 7.47–7.42 C]O), 137.4, 134.9, 134.4, 129.3, 128.8, 128.7, 128.4, 127.5, 127.2,
(m, 2H, Ar H), 4.20 (d, 1H, J ¼ 13.3 Hz, CHHNaph), 3.43 (ddd, 126.8 (Ar C and CH), 76.8 (C-4), 72.5 (C-3), 70.2 (C-5), 64.3 (C-2),
1H, J ¼ 10.3 Hz, J ¼ 9.3 Hz, J ¼ 4.8 Hz, H-5), 3.34 (t, 1H, J ¼ 9.2 56.0 (CH2Naph), 53.7 (C-6), 42.3 (CH2NH2), 33.1, 28.5, 28.1, 24.1
Hz, H-3, partially obscured by NMR solvent peak), 3.27 (d, 1H, J (each CH2), 20.8, 20.7, 20.6 (each CH3); ESI-HRMS: found
¼ 13.4 Hz, CHHNaph), 3.23 (t, 2H, J ¼ 6.9 Hz, CH2N3), 3.14 (t, 485.2642 required 485.2652 [M + H]+.
1H, J ¼ 9.0 Hz, H-4), 2.88 (dd, 1H, J ¼ 11.5 Hz, J ¼ 4.8 Hz, H-6a),
2.23 (dt, 1H, J ¼ 9.5 Hz, J ¼ 3.7 Hz, H-2), 1.97–1.83 (overlapping
5-((2R,3R,4R,5S)-3,4,5-Tris(benzyloxy)-1-(naphthalen-2-
signals, 3H, H-6b and CH2), 1.63–1.49 (overlapping signals, 4H,
2 ꢂ CH2), 1.42–1.32 (m, 2H, CH2); 13C NMR (125 MHz, CD3OD):
d 138.0, 135.0, 134.3, 129.1, 128.7 (2s), 128.5, 128.0, 127.1, 126.7
(Ar C and CH), 80.8 (C-4), 73.7 (C-3), 70.8 (C-5), 67.2 (C-2), 58.1
(C-6), 57.7 (CH2Naph), 52.5, 30.0, 28.8, 28.4, 24.1 (each CH2);
ESI-HRMS: found 385.2241 required 385.2240 [M + H]+.
ylmethyl)piperidin-2-yl)pentan-1-amine 8
Sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol) was
added slowly to a stirring solution of 19 (11 mg, 0.03 mmol) in
dry DMF (1.5 mL) at 0 ꢀC under N2. Aer stirring for 5 min,
benzyl bromide (14 mL, 0.12 mmol), was added dropwise. The
ꢀ
mixture was stirred, rst at 0 C and then allowing it to attain
room temperature, for 16 h and was then poured on to ice. The
ice was allowed to melt and the mixture was then extracted with
EtOAc (ꢂ3). The combined organic layers were washed with
(2R,3R,4R,5S)-2-(5-Aminopentyl)-1-(naphthalen-2-ylmethyl)-
piperidine-3,4,5-triol 6
To a solution of azide 19 (13 mg, 0.03 mmol) in MeOH (1 mL) water (ꢂ3) and brine, dried (Na2SO4), ltered and the solvent
was added 10% Pd–C (4 mg). Aer stirring under H2 for 20 min, was removed under reduced pressure. Flash chromatography of
the mixture was ltered through celite. The solvent was the residue (EtOAc–petroleum ether, 1 : 7, Rf: 0.19) gave the
removed under reduced pressure and ash chromatography of benzylated intermediate as a white solid (12 mg, 0.018 mmol,
the residue (CHCl3–MeOH–satd aq. NH4OH, 8 : 3:0.4, Rf: 0.14) 60%); 1H NMR (CDCl3, 500 MHz): d 7.86–7.83 (m, 1H, Ar H), 7.79
gave the title compound (4 mg, 37%) as a white solid; 1H NMR (d, J ¼ 8.3 Hz, 2H, Ar H), 7.65 (s, 1H, Ar H), 7.51–7.45 (m, 2H, Ar
(500 MHz, CD3OD): d 7.84–7.78 (m, 3H, Ar H), 7.76 (s, 1H, Ar H), H), 7.40 (dd, J ¼ 8.4 Hz, J ¼ 1.5 Hz, 1H, Ar H), 7.37–7.27 (m, 10H,
7.51–7.41 (m, 3H, Ar H), 4.20 (d, J ¼ 13.4 Hz, 1H, CHHNaph), Ar H), 7.16–7.08 (m, 5H, Ar H), 4.98 (overlapping signals, 2H, 2
3.43 (ddd, J ¼ 10.5 Hz, J ¼ 9.2 Hz, J ¼ 4.8 Hz, 1H, H-5), 3.34 (t, J ¼ ꢂ CHHPh), 4.82 (d, J ¼ 11.0 Hz, 1H, CHHPh), 4.65 (d, J ¼ 10.9
9.2 Hz, 1H, H-3 partially obscured by NMR solvent peak), 3.28 Hz, 1H, CHHPh), 4.51 (d, J ¼ 11.7 Hz, 1H, CHHPh), 4.43 (d, J ¼
(d, J ¼ 13.4 Hz, 1H, CHHNaph), 3.15 (t, 1H, J ¼ 9.0 Hz, H-4), 2.88 11.7 Hz, 1H, CHHPh), 4.08 (d, J ¼ 13.5 Hz, 1H, CHHNaph), 3.60–
(dd, 1H, J ¼ 11.5 Hz, J ¼ 4.8 Hz, H-6a), 2.82 (t, J ¼ 6.6 Hz, 2H, 3.52 (overlapping signals, 2H, H-5, H-4), 3.48 (t, J ¼ 9.0 Hz, 1H,
CH2NH2), 2.25 (dt, 1H, J ¼ 9.4 Hz, J ¼ 3.7 Hz, H-2), 1.99–1.86 H-3), 3.29 (d, J ¼ 13.5 Hz, 1H, CHHNaph), 3.19 (t, J ¼ 7.0 Hz, 2H,
(overlapping signals, 3H, H-6b and CH2), 1.68–1.50 (overlapping CH2N3), 2.97 (dd, J ¼ 11.8 Hz, J ¼ 4.2 Hz, 1H, H-6a), 2.43 (dt, J ¼
signals, 4H, 2 ꢂ CH2), 1.45–1.33 (m, 2H, CH2); 13C NMR (125 9.3 Hz, J ¼ 3.9 Hz, 1H, H-2), 1.95 (dd, J ¼ 11.6 Hz, J ¼ 10.1 Hz,
MHz, CD3OD): d 138.0, 134.9, 134.3, 129.1, 128.7, 128.4, 127.9, 1H, H-6b), 1.88–1.76 (m, 2H, CH2), 1.55–1.46 (overlapping
127.2, 126.7 (Ar C and CH), 80.8 (C-4), 73.7 (C-3), 70.8 (C-5), 67.0 signals, 3H, CHH and CH2), 1.42–1.33 (m, 1H, CHH), 1.32–1.23
(C-2), 58.0 (C-6), 57.6 (CH2Naph), 41.1 (CH2NH2), 29.7, 28.7, (m, 2H, CH2); 13C NMR (CDCl3, 125 MHz): d 138.9, 138.5, 138.3,
1156 | Med. Chem. Commun., 2014, 5, 1150–1158
This journal is © The Royal Society of Chemistry 2014

View Article Online
Concise Article
MedChemComm
136.6, 133.4, 132.8, 128.4 (2s), 128.2, 128.1, 128.0, 127.9, 127.7
(3s), 127.5, 127.0, 126.5, 126.0, 125.6 (Ar C and CH), 87.6 (C-4),
79.9 (C-3), 78.0 (C-5), 75.4, 75.3, 72.5 (each CH2Ph), 64.7 (C-2),
55.6 (CH2Naph), 53.9 (C-6), 51.4 (CH2N3), 28.9, 27.8, 27.2, 23.4
(each CH2); ESI-HRMS: found 655.3641 required 655.3648 [M +
H]+. To this intermediate (11 mg, 0.017 mmol) in EtOAc–MeOH
(2 : 1, 1.5 mL) was added 10% Pd–C (5 mg). The reaction
mixture was stirred under H2 for 30 min. The mixture was
ltered through celite and the solvent was removed under
reduced pressure. Flash chromatography of the residue (EtOAc–
MeOH–satd aq. NH4OH, 8 : 2 : 0.1, Rf: 0.17) furnished the title
R. Dulina, B. W. Huang, M. Kamau, C. W. Wang,
E. Baizman, A. Branstrom, N. Bristol, R. Goldman,
K. H. Han, C. Longley, S. Midha and H. R. Axelrod, J. Med.
Chem., 1999, 42, 3193.
5 (a) T. Wunberg, C. Kallus, T. Opatz, S. Henke, W. Schmidt
and H. Kunz, Angew. Chem., Int. Ed., 1998, 37, 2503; (b)
M. J. Soa, R. Hunter, T. Y. Chan, A. Vaughan, R. Dulina,
H. Wang and D. Gange, J. Org. Chem., 1998, 63, 2802.
6 D. B. Werz and P. H. Seeberger, Chem.–Eur. J., 2005, 11, 3194.
7 C. H. Wong, M. Hendrix, D. D. Manning, C. Rosenbohm and
W. A. Greenberg, J. Am. Chem. Soc., 1998, 120, 8319.
8 (a) Y. Le Merrer, L. Poitout, J. C. Depezay, I. Dosbaa,
S. Geoffroy and M. J. Foglietti, Bioorg. Med. Chem., 1997, 5,
519–533; (b) F. Chery, L. Cronin, J. L. O'Brien and
P. V. Murphy, Tetrahedron, 2004, 60, 6597; (c) S. G. Gouin
and P. V. Murphy, J. Org. Chem., 2005, 70, 8527.
1
compound (5 mg, 47%); H NMR (CD3OD, 500 MHz): d 7.87–
7.84 (m, 1H, Ar H), 7.81 (d, J ¼ 8.5 Hz, 2H, Ar H), 7.68 (s, 1H, Ar
H), 7.52–7.45 (m, 2H, Ar H), 7.41 (dd, J ¼ 8.5 Hz, J ¼ 1.5 Hz, 1H,
Ar H), 7.35–7.24 (m, 10H, Ar H), 7.09 (dd, J ¼ 7.7 Hz, J ¼ 1.8 Hz,
2H, Ar H), 7.06–7.01 (m, 3H, Ar H), 4.94 (2d, J ¼ 11.1 Hz, 2H, 2ꢂ
CHHPh), 4.77 (d, J ¼ 11.0 Hz, 1H, CHHPh), 4.67 (d, J ¼ 11.1 Hz,
1H, CHHPh), 4.47 (d, J ¼ 11.9 Hz, 1H, CHHPh), 4.40 (d, J ¼ 11.9
9 V. Chagnault, J. Lalot and P. V. Murphy, ChemMedChem,
2008, 3, 1071.
Hz, 1H, CHHPh), 4.13 (d, J ¼ 13.3 Hz, 1H, CHHNaph), 3.54–3.43 10 R. Hirschmann, K. C. Nicolaou, S. Pietranico, E. M. Leahy,
(overlapping signals, 3H, H-3,4,5), 3.26 (d, J ¼ 13.3 Hz, 1H,
CHHNaph), 2.92 (dd, J ¼ 11.8 Hz, J ¼ 4.2 Hz, 1H, H-6a), 2.58 (t, J
¼ 7.3 Hz, 2H, CH2NH2), 2.36 (dt, J ¼ 9.0 Hz, J ¼ 3.8 Hz, 1H, H-2),
1.91–1.78 (overlapping signals, 3H, H-6b, CH2), 1.57–1.48 (m,
1H, CHH), 1.47–1.36 (overlapping signals, 3H, CHH and CH2),
J. Salvino, B. Arison, M. A. Cichy, P. Grant Spoors,
W. C. Shakespeare, P. A. Sprengeler, P. Hamley,
A. B. Smith, T. Reisine, K. Raynor, L. Maechler,
C. Donaldson, W. Vale, R. M. Freidinger, M. R. Cascieri
and C. D. Strader, J. Am. Chem. Soc., 1993, 115, 12550.
1.30–1.18 (m, 2H, CH2); 13C-NMR (CD3OD, 125 MHz): d 140.3, 11 A. R. Angeles, I. Neagu, E. T. Birzin, E. R. Thornton,
140.0, 139.7, 138.0, 135.0, 134.4, 129.4 (2s), 129.2 (2s), 129.1, A. B. Smith, III and R. Hirschmann, Org. Lett., 2005, 7, 1121.
129.0 (2s), 128.8 (2s), 128.7, 128.6, 128.3, 127.7, 127.1, 126.8 (Ar 12 G. Melacini, Q. Zhu and M. Goodman, Biochemistry, 1997,
C and CH), 88.8 (C-4), 81.3 (C-3), 79.2 (C-5), 76.4, 76.2, 73.5 (each 36, 1233.
CH2Ph), 66.4 (C-2), 57.0 (CH2Naph), 55.1 (C-6), 42.3 (CH2NH2), 13 F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp,
33.1, 29.0, 28.4, 24.9 (each CH2); ESI-HRMS: found 629.3755
required 629.3743 [M + H]+.
M. Lipton, C. Caueld, G. Chang, T. Hendrickson and
W. C. Still, J. Comput. Chem., 1990, 11, 440.
14 M. Frigerio and M. Santagostino, Tetrahedron Lett., 1994, 35,
8019.
Acknowledgements
15 (a) R. M. Versteegen, D. J. M. van Beek, R. P. Sijbesma,
D. Vlassopoulos, G. Fytas and E. W. Meijer, J. Am. Chem.
Soc., 2005, 127, 13862; (b) J. E. Baldwin, T. D. W. Claridge,
A. J. Culshaw, F. A. Heupel, V. Lee, D. R. Spring and
R. C. Whitehead, Chem.–Eur. J., 1999, 5, 3154; (c)
M. J. Gresser, P. A. Keller and S. M. Wales, Tetrahedron
Lett., 2009, 50, 4899.
Material presented herein was supported by Science Founda-
tion Ireland (Grant no. 07/IN.1/B966) and the Irish Research
Council through an Enterprise Partnership award part-funded
by Eli Lilly (Kinsale, Ireland).
Notes and references
16 C. O'Brien and P. V. Murphy, J. Carbohydr. Chem., 2011, 30,
626.
1 (a) I. Velter, B. La Ferla and F. Nicotra, J. Carbohydr. Chem.,
2006, 25, 97; (b) W. Meutermans, G. T. Le and B. Becker, 17 For synthesis of 1-DNJ from L-sorbose see: D. Beaupere,
ChemMedChem, 2006, 1, 1164; (c) P. V. Murphy and
J. L. Dunne, Curr. Org. Synth., 2006, 3, 403.
B. Stasik, R. Uzan and G. Demailly, Carbohydr. Res., 1989,
191, 163.
2 (a) E. Graf von Roedern, E. Lohof, G. Hessler, M. Hoffmann 18 For reviews on iminosugar synthesis see (a) B. La Ferla,
and H. Kessler, J. Am. Chem. Soc., 1996, 118, 10156; (b)
Y. Bleriot, M. I. Simone, M. R. Wormald, R. A. Dwek,
D. J. Watkin and G. W. J. Fleet, Tetrahedron: Asymmetry,
2006, 17, 2276.
L. Cipolla and F. Nicotra, Curr. Top. Med. Chem., 2003, 3,
485; (b) K. Afarinkia and A. Bahar, Tetrahedron: Asymmetry,
2005, 16, 1239; (c) P. Compain, V. Chagnault and
O. R. Martin, Tetrahedron: Asymmetry, 2009, 20, 672.
3 R. Hirschmann, J. Hynes Jr, M. A. Cichy-Knight, R. D. van 19 L. Rohrer, F. Raulf, C. Bruns, R. Buettner, F. Hofstaedter and
¨
R. Schule, Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 4196.
Rijn, P. A. Sprengeler, P. G. Spoors, W. C. Shakespeare,
S. Pietranico-Cole, J. Barbosa, J. Liu, W. Yao, S. Rohrer and 20 Y. Yamada, S. Kagimoto, A. Kubota, K. Yasuda, K. Masuda,
A. B. Smith, J. Med. Chem., 1998, 41, 1382.
4 M. J. Soa, N. Allanson, N. T. Hatzenbuhler, R. Jain,
Y. Someya, Y. Ihara, Q. Li, H. Imura and S. Seino, Biochem.
Biophys. Res. Commun., 1993, 195, 844.
R. Kakarla, N. Kogan, R. Liang, D. S. Liu, D. J. Silva, 21 Calculator Plugins were used for log P prediction and
H. M. Wang, D. Gange, J. Anderson, A. Chen, F. Chi,
calculation, Marvin 6.2, 2014, ChemAxon (http://
This journal is © The Royal Society of Chemistry 2014
Med. Chem. Commun., 2014, 5, 1150–1158 | 1157

View Article Online
MedChemComm
Concise Article
www.chemaxon.com). log P for each compound was 24 R. Hirschmann, Angew. Chem., Int. Ed., 1991, 30, 1278.
estimated using the physicochemical property prediction, 25 G. Abbenante, B. Becker, S. Blanc, C. Clark, G. Condie,
which is based on a publication by: V. N. Viswanadhan, A.
K. Ghose, G. R. Revankar, R. K. Robins, J. Chem. Inf.
Comput. Sci., 1989, 29, 163.
G. Fraser, M. Grathwohl, J. Halliday, S. Henderson, A. Lam,
L. Liu, M. Mann, C. Muldoon, A. Pearson, R. Premraj,
T. Ramsdale, T. Rossetti, K. Schafer, G. Le Thanh,
G. Tometzki, F. Vari, G. Verquin, J. Waanders, M. West,
N. Wimmer, A. Yau, J. Zuegg and W. Meutermans, J. Med.
Chem., 2010, 53, 5576.
22 C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney,
Adv. Drug Delivery Rev., 1997, 23, 3.
23 (a) A. R. Leach, M. M. Hann, J. N. Burrows and E. J. Griffen,
Mol. BioSyst., 2006, 2, 429; (b) P. D. Leeson and 26 E. Danieli, J. Lalot and P. V. Murphy, Tetrahedron, 2007, 63,
B. Springthorpe, Nat. Rev. Drug Discovery, 2007, 6,
6827.
881.
27 K. P. R. Kartha, Tetrahedron Lett., 1986, 27, 3415.
1158 | Med. Chem. Commun., 2014, 5, 1150–1158
This journal is © The Royal Society of Chemistry 2014