Convenient syntheses of orthogonally protected aminocyclopentitols from aldopentoses

Article abstract of DOI:10.1016/j.tetlet.2014.12.008

Orthogonally protected aminocyclopentitols were synthesized from commercially available aldopentoses using a convenient three-step procedure that does not require protection of the free anomeric hydroxyl group of the starting carbohydrate. The synthesized compounds are important building blocks with potential use in medicinal chemistry and drug discovery.

Full text of DOI:10.1016/j.tetlet.2014.12.008

Accepted Manuscript
Convenient syntheses of orthogonally protected aminocyclopentitols from al-
dopentoses
Urban Košak, Marina Hrast, Damijan Knez, Nenad Maraš, Martin Črnugelj,
Stanislav Gobec
PII:
S0040-4039(14)02062-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.008
TETL 45532
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 September 2014
14 November 2014
2 December 2014
Please cite this article as: Košak, U., Hrast, M., Knez, D., Maraš, N., Črnugelj, M., Gobec, S., Convenient syntheses
of orthogonally protected aminocyclopentitols from aldopentoses, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.12.008
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Convenient syntheses of orthogonally
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Urban Košak, Martina Hrast, Damijan Knez, Nenad Maraš, Martin Črnugelj, Stanislav Gobec

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Convenient syntheses of orthogonally protected aminocyclopentitols from
aldopentoses
Urban Košaka, Marina Hrasta, Damijan Kneza, Nenad Marašb, Martin Črnugeljb, Stanislav Gobeca
aFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
bAPI Development, Lek Pharmaceuticals d.d, Sandoz Development Center Slovenia, Kolodvorska 27, 1234 Mengeš, Slovenia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Orthogonally protected aminocyclopentitols were synthesized from commercially available
aldopentoses using a convenient three-step procedure that does not require protection of the free
anomeric hydroxyl group of the starting carbohydrate. The synthesized compounds are
important building blocks with potential use in medicinal chemistry and drug discovery.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aminocyclopentitols
Aldopentoses
Orthogonal protection
Carbocycles
Aminocyclopentitols are structural motifs that are present in
a number of pharmacologically important natural products and
drugs. Neplanocin A1 and aristeromycin2 are naturally
occurring carbocyclic analogues of adenosine that demonstrate
antiviral and antitumor activities. Allosamidin,3 mannostatins
A and B,4 and trehazolin5 are natural glycosidase inhibitors that
have received significant attention as lead compounds in drug
discovery for diseases such as diabetes and cancer, and for
viral and bacterial infections, and Gaucher's disease.4 The
aminocyclopentitol structure is also present in peramivir,6
which is a selective influenza neuraminidase inhibitor, and in
ticagrelor,7 which is a reversible P2Y12 receptor antagonist for
the prevention of thrombosis (Figure 1).
deprotection steps were uninviting, as the protection step is
either an oxidation of the free anomeric hydroxyl group of D-(–
)-ribose to lactone 3 using hazardous bromine in aqueous
NaHCO3,9 or an oxidation with the expensive RhH(PPh3)4-
benzalacetone system.10 Additionally, the deprotection step
involves reduction of lactone 4 to hemiacetal 5 with the highly
flammable diisobutylaluminium hydride (DIBAL-H).11-13
Considering
the
pharmacological
importance
of
aminocyclopentitols, convenient methods for the synthesis of
these compounds are highly desirable. In this context, we
focused on orthogonally protected aminocyclopentitol
1
(Scheme 1). The synthesis of this compound from protected D-
(+)-ribono-1,4-lactone 2 was first reported by Marco-Contelles
et al.8 We wanted to prepare compound 1 from the
commercially available and inexpensive D-(–)-ribose, by
combining procedures available in the literature into our initial
synthetic plan (Scheme 1).
However, after careful analysis of this plan, a number of
potential problems were identified. The synthesis required the
protection of the free anomeric hydroxyl group of D-(–)-ribose
Figure 1. Examples of biologically important natural aminocyclopentitols
in the form of a lactone 2. The reagents for the protection and
———
and aminocyclopentitol-based drugs.
 Corresponding author. Tel.: +364(1)4769585; fax: +386(1)4258031; e-mail: stanislav.gobec@ffa.uni-lj.si

2
Tetrahedron Letters
Scheme 1. Synthetic plan for the preparation of compound 1 from D-(–)-
ribose based on the steps published in the literature. Reagents and
conditions: i. (a) Br2, NaHCO3, H2O, 0 °C, 110 min, (b) NaHSO3, 0 °C; ii.
benzalacetone, RhH(PPh3)4 (cat.), anhydrous DMF, 40 °C, under argon,
1.5 h, 99%; iii. anhydrous acetone, 2,2-dimethoxypropane, conc. H2SO4
(cat.), r.t., 50 min, 73% from D-(–)-ribose, (b) Ag2CO3, r.t.; iv. (a) PPh3,
NBS, CH2Cl2, 10–25 °C, 2.5 h, (b) BaCO3, reflux, 15 min, 80%; v. (a)
DIBAL-H, anhydrous PhMe or anhydrous THF, –80 °C, 30 min, under
argon, (b) MeOH, r.t., 30 min, 95%; vi. BnONH3 Cl-, pyridine, CH2Cl2,
H2O, reflux, 18 h; 95%; vii. (a) (n-Bu)3SnH, AIBN (cat.), PhMe, reflux,
under argon, 6 h, (b) Et2O, 15% KF aq, overnight, 75%.
+
Scheme 2. Reagents and conditions: i. (a) acetone, conc. H2SO4 (cat.), r.t.,
18 h, (b) PPh3, NBS, DMF, 0 °C to r.t., 20 h, 28% for 5 from D-(–)-ribose,
38% for 12 from L-(+)-ribose, 18% for 13 from D-(–)-lyxose; ii.
+
BnONH3 Cl-, pyridine, CH2Cl2, H2O, reflux, 18 h, 93% for 7 from 5, 82%
In our attempts to make the synthesis of compound 1 more
convenient, we eliminated the initial protection of the free
anomeric hydroxyl group of D-(–)-ribose. We converted the
starting aldopentose into bromide 5 in two steps, without
purification of the intermediate 6. The first stage was the
conversion of D-(–)-ribose into its 2,3-O-isopropylidene
derivative 6.16 The crude acetonide 6 was then treated with
for 14 from 12, 93% for 15 from 13; iii. (a) (n-Bu)3SnH, ABCN (cat.),
PhMe, reflux, argon, 6 h, (b) Et2O, 20% KF aq, 12 h, 77% for 1 from 7,
71% for 8 from 14, 68% for 9 from 15.
Table 1.
Orthogonally protected aminocyclopentitols 1, 8 and 9 obtained from
aldopentoses.
PPh3
and
N-bromosuccinimide
(NBS)
in
N,N-
Final orthogonally
Overall yield
Starting aldopentose
protected
dimethylformamide (DMF) to give the bromide 5 in 28% yield
from D-(–)-ribose, after purification by flash column
chromatography. The bromide was converted into the oxime 7
using a literature procedure,15 in 93% yield. For the free-radical
carbocyclization of compound 7 into orthogonally protected
aminocyclopentitol 1, the radical initiator 2,2-azobis(2-
methylpropionitrile) (AIBN) as used in the literature
procedure,8 was replaced with the less hazardous 1,1-
azobis(cyclohexanecarbonitrile) (ABCN). The yield of this
carbocyclization step was 77% (Scheme 2). The overall yield
for the preparation of compound 1 from D-(–)-ribose using this
three-step procedure was 20% (Table 1), while the calculated
overall yield of the six-step procedure reported in the literature
was 40% (Scheme 1).
(%)b
aminocyclopentitol
20
22
11
We were thus able to make the synthesis of compound 1
more convenient by reducing the number of steps from six to
three, and by avoiding reactions that required the use of some
hazardous reagents. To confirm the general applicability of our
procedure, we converted L-(+)-ribose into compound 8, in 22%
overall yield, and D-(–)-lyxose into compound 9, in 11% yield,
bIsolated yield of pure product
As the configurations at C1, C2 and C3 of compounds 1, 8
and 9 are the same as in the corresponding starting
aldopentose, we were able to determine the configuration at C4
of these compounds using NOESY spectroscopy. In
compounds 1 and 8, where the hydroxyl group and the
benzylhydroxylamino group are in the trans configuration,
proton H1 correlates more intensely with one of the protons
H5, while proton H4 correlates more intensely with the other
H5 proton (Figure 2). In compound 9, where the hydroxyl
group and the benzylhydroxylamino group are in cis
thus
obtaining
two
additional
stereoisomeric
aminocyclopentitols (Scheme 2, Table 1).

3
10. Isaac, I.; Stasik, I.; Beaupère, D.; Uzan, R. Tetrahedron Lett.
1995, 36, 383.
configuration, proton H1 and proton H4 correlate more
intensely with the same H5proton (Figure 2).
11. Ingall, A. H.; Moore, P. R.; Roberts, S. M. J. Chem. Soc.,
Chem. Commun. 1994, 83.
12. Wilcox, C. S.; Thomasco, L. M.; J. Org. Chem. 1985, 50, 546.
13. Lalot, J.; Stasik, I.; Demailly, G.; Beaupère, D. Carbohydr. Res.
2002, 337, 1411.
14. Jäger, V.; Häfele, B. Synthesis 1987, 801.
15. Marco-Contelles, J.; Ruiz, P.; Martinez, L.; Martinez-Grau, A.
Tetrahedron 1993, 49, 6669.
16. Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R.
Synthesis 1990, 1031.
Figure 2. NOESY correlations of 1, 8 and 9.
To conclude, we have successfully synthesized
orthogonally protected aminocyclopentitols from commercially
available aldopentoses using
a
convenient three-step
procedure. The aminocyclopentitols thus prepared are building
blocks with potential use in medicinal chemistry and drug
discovery.
Acknowledgment
We thank Lek Pharmaceuticals d.d. and the Ministry of Higher
Education, Science and Technology of the Republic of Slovenia
for financial support.
Supplementary data
Supplementary data associated with this article (general
methods, experimental procedures, compound characterization,
and 1H NMR and 13C NMR spectra of all synthesized
compounds) can be found in the online version, at (insert link
here).
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