Expedient and versatile formation of novel amino-deoxy-ketoheptuloses

Article abstract of DOI:10.1021/ol4021699

Novel monoketoheptuloses have been synthesized employing an amination step in a pre- and/or post-C1 chain elongation using a Petasis reagent by starting from aldohexoses or aldohexosamines. A series of gluco and manno configured 1-/3-deoxy-1-/3-amino-keto

Full text of DOI:10.1021/ol4021699

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Expedient and Versatile Formation of
Novel Amino-deoxy-ketoheptuloses
Yevgeniy Leshch, Anna Jacobsen, Julian Thimm, and Joachim Thiem*
University of Hamburg, Faculty of Sciences, Department of Chemistry,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
thiem@chemie.uni-hamburg.de
Received July 31, 2013
ABSTRACT
Novel monoketoheptuloses have been synthesized employing an amination step in a pre- and/or post-C1 chain elongation using a Petasis reagent
by starting from aldohexoses or aldohexosamines. A series of gluco and manno configured 1-/3-deoxy-1-/3-amino-ketohept-2-uloses could be
obtained.
Deoxy sugars and deoxy aminosugars are ubiquitously
present in plants, fungi, and bacteria. Further, they con-
stitute structurally relevant parts of the LPS lipopolysac-
charides as well as EPS extracellular polysaccharides and
are found as secondary metabolites displaying antibiotic
activity. Their biosynthesis is mainly by transamination,
and under physiological conditions ionized amines are
responsible for their pharmacokinetic properties by induc-
ing inter- and intramolecular electrostatic interactions.
The ability of aminosugars to display bacteriocidal activity
has been synthetically exploited and resulted in potent
amino glycose antibiotics and antiviral agents.1,2 Amino
glycosides are preferably used to combat infections due to
Gram-negative bacteria, such as e.g. Pseudomonas, Acine-
tobacter, and Enterobacter species.3,4 Their mode of action
is concentration dependent and primarily based on impair-
ing bacterial protein synthesis through binding to prokar-
yotic ribosomes. However, new bacteriocidal derivatives
are desired due to growing resistance effects by aminogly-
coside modifying enzymes (AME, ∼60 known) expressed
by resistant bacteria.5
of potent bacteriocidal and antiviral aminoglycoside
targets. Recently, we reported on efficient syntheses
of rare ketoheptuloses and regioisomeric fluorinated
19F- ketoheptuloses.6À8 The use of methylene exoglycals
allows for versatile access to regiospecific positions and
facile introduction of various functionalities.
Our focus was on the synthesis of 1- and 3-amino-D-
gluco/manno-hept-2-uloses, since primary and secondary
mono- and diamino functions are common structural
themes in aminoglycosides such as kanamycin, tobramy-
cin, and gentamicin.4
Starting from D-glucose the exocyclic glycal 1 was
accessible in seven steps (Scheme 1).6À8 Subsequent Sharp-
less bishydroxylation9À12 to give 2, and azide insertion to
3,13 led after hydrogenolysis to the desired 1-amino-keto-
hept-2-ulose 4.
(6) Waschke, D.; Thimm, J.; Thiem Org. Lett. 2011, 13, 3628–3631.
(7) Leshch, Y.; Waschke, D.; Thimm, J.; Thiem, J. Synthesis 2011,
3871–3877.
(8) Waschke, D.; Thimm, J.; Leshch, Y.; Thiem, J.; Louchami, K.;
Malaisse W. Seven Carbon (C-7) Sugars Derivatives and Their Use.
WO 2012016935 (A1) February. 09, 2012.
(9) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970.
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Rev. 1994, 94, 2483–2547.
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766–768.
The present work describes syntheses of novel amino
deoxy-ketoheptuloses to be considered as a novel class
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r
10.1021/ol4021699
XXXX American Chemical Society

Scheme 1. N-Insertion Post-C1 Elongation from Aldohexoses:
Synthesis of 1-Deoxy-1-amino-D-gluco-hept-2-ulose 4
Scheme 2. N-Insertion prior to C1 Elongation from Aldohexoses:
Synthesis of 3-Deoxy-3-amino-D-manno-heptulose Derivative 10
It was shown that stereoselective β-addition to 1-C-
nitro-glycals allows for syntheses of 3-azido-keto-heptu-
loses. However access to 1-C-nitro-glycals, handling, and
overall reaction efficiency were disadvantageous.14
Synthesis of 3-amino-ketoheptuloses was initially
performed by N-insertion prior to C1 elongation, using
azide 5, which was obtained in six steps from methyl
R-D-glucopyranoside.15À19 Its reduction and protection
by 2-trimethylsilylethanesulfonyl (SES)20 afforded 6.
By using pyridine as both solvent and base21 the yield of
this step could be increased to 55%. Hydrolysis of 6 with
NBS in aqueous acetone to give 7, followed by oxidation
with acetic anhydride and DMSO,22 afforded lactone 8.
Apparently, due to interactions between the titanium
reagent and the amine function,23 the methylenation
of 8 using Petasis reagent gave 9 in low yields. Further
bishydroxylation of 9 afforded the amino derivative 10
(Scheme 2). The syntheses of 3-amino-3-deoxy-D-gluco/
manno-hept-2-uloses were therefore attempted in a corre-
sponding fashion by introducing the azido functionality at
a later stage starting from the tribenzyl orthoesters 11 and
12, which can be obtained in five steps from D-mannose or
D-glucose, respectively (Scheme 3).
Petasis reagent gave the 3-O-acetylated exocyclic glycals 17
ꢀ
and 18, respectively. After deacetylation under Zemplen
conditions25,26 and subsequent bishydroxylation 4,5,7-tri-
O-benzyl-manno-hept-2-ulopyranose 19 and 4,5,7-tri-O-
benzyl-gluco-hept-2-ulopyranose 20 were obtained. Then
19 and 20 were transformed into the 1,2-isopropylidene
derivatives 21 and 22. These were then transferred into
their corresponding 3-azido derivatives, using nucleophilic
substitution with triflic anhydride and tetrabutylammo-
nium azide. The configuration at C-3 was inverted during
this step to give the azido derivatives 23 and 24. In the case
of the manno derivative 21 substitution gave the gluco
component 23 and the byproduct 25 due to elimination.
Correspondingly, the gluco derivative 22 was converted
into the 3-azido manno derivative 24, which by selective
hydrogenation in pyridine gave the manno amine 26.
However, deacetylation of exocyclic glucal 17 followed
by mesylation to 27 and subsequent substitution by azide
led to the unexpected rearrangement product 2,6-anhydro-
1-azido-4,5,7-tri-O-benzyl-1,3-dideoxy-D-arabino-hept-
2-enitol 28 (Scheme 4). Hydrolysis of 28 in trifluoroacetic
acid and water27 afforded 1-azido-4,5,7-tri-O-benzyl-1,3-
dideoxy-R-D-arabino-hept-2-ulopyranose 29, which could
be easily hydrogenated to give amine 30, the 1-amino
derivative of the natural product Kamusol found in fungus
Aspergillus sulphureus.28,29
Ring opening of the orthoesters 11 and 12 in acetic acid
and water24 afforded the hemiacetals 13 and 14. Further,
oxidationtothe lactones15and 16and methylenation with
(14) Baumberger, F.; Beer, D.; Christen, M.; Prewo, R.; Vasella, A.
Helv. Chim. Acta 1986, 69, 1191–1204.
(15) Demchenko, A. V.; Pornsuriyasak, P.; de Meo, C. J. Chem.
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Naughton, A. B. J. J. Org. Chem. 1990, 55, 5700–5710.
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(17) Popelova, A.; Kefurt, K.; Hlavackova, M.; Moravcova, J.
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Carbohydr. Res. 2005, 340, 161–166.
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van Boom, J. H. Tetrahedron Lett. 2001, 42, 8693–8696.
(19) Girard, C.; Miramon, M.-L.; de Solminihac, T.; Herscovici J.
Carbohydr. Res. 2002, 337, 1796–1774.
(20) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett.
1986, 27, 2099–2102.
(21) Parker, K. A.; Mindt, T. L. Org. Lett. 2002, 4, 4265–4268.
(22) Zhang, F.; Vasella, A. Carbohydr. Res. 2007, 342, 2546–2556.
(23) Lensink, C. J. Organomet. Chem. 1998, 553, 387–392.
(24) Yamazaki, F.; Sato, S.; Nukada, T.; Ito, Y.; Ogawa, T. Carbo-
hydr. Res. 1990, 201 (1), 31–50.
Sharpless dihydroxylation of 28gave 1-azido-4,5,7-tri-O-
benzyl-1-deoxy-R-D-gluco-hept-2-ulopyranose 31. Only the
(27) Suda, M.; Fukushima, A. Tetrahedron Lett. 1981, 22, 759–762.
(28) Kamal, A.; Haider, Y.; Arkhtar, R.; Qureshi, A. A. Pakistan J.
Sci. Ind. Res 1971, 14, 63–67.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Syntheses of 3-Amino-3-deoxy-D-gluco/manno-hept-2-uloses
deoxy-R-D-gluco-hept-2-ulopyranose hydrochloride 32 in
90% yield.
Scheme 4. Synthesis and Functionalization of 1-Azido-4,5,7-tri-
O-benzyl-1-deoxy-R-D-gluco-2-ulopyranose 31
Since sulfonamide protection for the 3-amino-D-manno-
hept-2-ulose series was unsuitable due to complexation with
Petasis reagent, a suitable protecting group for the 2-amino
group had to be found starting from the 2-amino-2-deoxy-
hexoses (Scheme 2). The phthalimido protection was chosen.
However, this was considered risky since the two carbonyl
groups could well be methylenated. The 3-phthalimido
exocyclic enol ether 35 was nevertheless obtained from
the known protected D-glucosamine derivative 3330 by
oxidation31 to lactone 34 and subsequent olefination
(Scheme 5). Following Upjohn dihydroxylation12,32,33 the
diol 36 was isolated in 79% yield. The R-configuration was
confirmed by NOESY experiments. In the final step, 36 was
deprotected and hydrogenated to give the desired amino
compound 37. In addition acetylation of amine 38, which
was formed from 35 by cleavage of phthalimide, led to the
N-acetyl derivate 39. This compound was dihydroxylated
to give 3-acetamido-4,5,7-tri-O-benzyl-3-deoxy-R-D-gluco-
hept-2-ulopyranose 40 in 88% yield. Again, according
to NOESY experiments only the R-anomer was isolated.
Finally, hydrogenation of 40 afforded 3-N-acetyl-D-gluco-
heptulose 41 in 97% yield (Scheme 6).
In summary, a variety of versatile synthetic routes to
complex amino-deoxy-D-heptuloses and their intermediates
ꢀ
´
a, A.; Cristobal-Lumbroso, G. J. Org. Chem.
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R-anomer of 31 was isolated as confirmed by NOESY
experiments. Subsequent hydrogenation gave 1-amino-1-
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Alternative Synthesis of 3-Amino-3-deoxy-D-gluco-
hept-2-ulose 37
Scheme 6. Synthesis of 3-N-Acetyl-D-gluco-heptulose 41
amino glycoside targets which will be reported in due
course.
have been established. Starting from monosaccharides, a C-1
extension via heptenitols allows for regiospecific transforma-
tions. The introduction of amine was achieved by the
conversion of the hydroxyl group into a suitable leaving
group followed by nucleophilic attack by azide. Unexpect-
edly, nucleophilic substitution of 27 led to the rearrangement
product 28, which was easily converted into the 1-amino
derivative of kamusol. Additionally, Sharpless dihydroxyla-
tion of 28 with subsequent hydrogenolysis gave the 1-amino
derivative of D-gluco-heptulose.
Acknowledgment. This work was supported by the
European Community FP7-NMP Grant Agreement
No. 228933. Dedicated to Professor Chi-Huey Wong,
President of Academia Sinica, on the occasion of his 65th
anniversary.
Supporting Information Available. Experimental pro-
cedures for preparation of all novel compounds with full
spectroscopic data. This material is free of charge via the
Internet at http://pubs.acs.org.
In conclusion, these versatile synthetic approaches
allow access to a variety of amino-deoxy-ketoheptuloses.
These represent useful structures for formation of novel
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX