A short and highly efficient synthesis of l-ristosamine and l-epi-daunosamine glycosides

Article abstract of DOI:10.1021/ol102891t

A highly efficient synthesis of l-ristosamine and l-epi-daunosamine glycosides via BF₃·OEt₂ promoted tandem hydroamination/glycosylation of 3,4-di-O-acetyl-6-deoxy-l-glucal and l-galactal has been developed. The new method proceeds i

Full text of DOI:10.1021/ol102891t

ORGANIC
LETTERS
2011
Vol. 13, No. 4
652–655
A Short and Highly Efficient Synthesis
of L-Ristosamine and L-epi-Daunosamine
Glycosides
Feiqing Ding, Ronny William, Fei Wang, Jimei Ma, Li Ji, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371
xuewei@ntu.edu.sg
Received November 30, 2010
ABSTRACT
A highly efficient synthesis of L-ristosamine and L-epi-daunosamine glycosides via BF3 OEt2 promoted tandem hydroamination/glycosylation of
3
3,4-di-O-acetyl-6-deoxy-L-glucal and L-galactal has been developed. The new method proceeds in a completely stereocontrolled manner within
a short reaction time. Preparation of a library of L-ristosamine and L-epi-daunosamine glycosides with potential biochemical applications,
by varying each component, exemplified the generality of the reaction.
Partially deoxygenated unbranched amino sugars are
important components of several classes of effective phar-
maceutical compounds with demonstrated antibiotic and
anticancer activity.1 Among those commonly encountered
are the 3-amino-2,3,6-trideoxyhexoses, e.g., L-daunosamine,
L-epi-daunosamine, L-ristosamine, L-acosamine, L-vancos-
amine, and nocardicylins (Figure 1).2 It has been well
established that the sugar moieties are essential for the
biological activity of these antibiotics. L-Daunosamine and
related analogues constitute carbohydrate moieties of the
anthracycline family of antitumor antibiotics.3 L-Ristos-
amine is part of the carbohydrate appended to the risto-
mycins, members of the vancomycin antibiotic family that
cause platelet aggregation and which are used to diagnose
variants of von Willebrand disease.4 On account of their
biological importance and commercial nonavailability,
development of an expedient stereoselective approach to
synthesize 3-amino-2,3,6-trideoxysugars and their un-
branched sugars has attracted considerable interest in the
synthetic community.5
(1) (a) Reusser, F. J. Antibiot. 1979, 32, 1186. (b) Arcamone, F.
Doxorubicin-Anticancer Antibiotics; Academic Press: New York, 1981.
(c) Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35. (d) Arcamone,
F.; Penco, S.; Vigevani, A.; Redaelli, S.; Franchi, G.; DiMarco, A.;
Casazza, A. M.; Dasdia, T.; Formelli, F.; Necco, A.; Soranzo, C. J. Med.
Chem. 1975, 18, 703.
Synthesis of aminoglycosides, in particular 2-deoxyamino
glycosides and their derivatives, remains a remarkable
(3) Portugal, J.; Cashman, D. J.; Trent, J. O.; Ferrer-Miralles, N.;
Przewloka, T.; Fokt, I.; Priebe, W.; Chaires, J. B. J. Med. Chem. 2005,
48, 8209.
(2) (a) Johnson, D. A.; Liu, H.-W. Comp. Nat. Prod. Chem. 1999, 3,
311. (b) Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35.
(c) Tanaka, Y.; Graefe, U.; Yazawa, K.; Mikami, Y. J. Antibiot. 1998,
€
51, 589. (d) Johnson, A. W.; Smith, R. M.; Guthrie, R. D. J. Chem. Soc.,
Perkin Trans. 1 1972, 2153. (e) Hauser, F. M.; Ellenberger, S. R. Chem.
Rev. 1986, 86, 35.
(4) (a) Sweeney, J. D.; Hoernig, L. A.; Fitzpatrick, J. E. Am. J.
Hematol. 1989, 32, 190. (b) Zhou, L.; Schmaier, A. H. Am. J. Clin.
Pathol. 2005, 123, 172.
r
10.1021/ol102891t
Published on Web 01/18/2011
2011 American Chemical Society

Figure 2. Our synthetic strategy.
diastereomeric 3-amino-2,3,6-trideoxysugars.5l In another
multistep synthesis, the sequence of asymmetric dihydroxy-
lation and a regio-reversed Wacker oxidation via the applica-
tion of silicon-tethered vinyl addition under tin-free thiyl
radical conditions accomplished the synthesis of L-daunos-
amine derivatives.5e
Figure 1. Natural products containing 3-amino-2,3,6-trideoxy-
sugars.
challenge due to the absence of neighboring participating
groups at C-2 which usually dictate the stereochemical
outcome at the anomeric position. Consequently, such
reactions always result in a mixture of anomers. A wide
variety of approachestoracemic and asymmetricsyntheses
of daunosamine, ristosamine, and their unbranched ana-
logs have been reported from both sugar and nonsugar
precursors.5 Recently, Lowary and co-workers developed
an alternative method which involves a photoinduced
acylnitrene aziridination reaction, and subsequent hydro-
genolytic aziridine ring-opening furnishes 2,3,6-trideoxy-
3-aminohexopyranoses.5h Riera et al. utilized reagent-
controlled stereoselective epoxidation and organometallic
addition in a stereodivergent approach to synthesize four
However, most of the reported approaches suffer from
drawbacks such as an excessive number of synthetic steps,
low yields, poor stereoselectivity, and long reaction times.
In continuation of our efforts to develop a reliable method
to prepare aminosugars with potential biological activity,6
we wish to report a direct and stereospecific synthesis of
3-amino-2,3,6-trideoxyhexoses that include L-ristosamine
and L-epi-daunosamine glycosides. We envisaged a rapid
assembly of 3-amino-2,3,6-trideoxyhexoses via a three-
component reaction of 3,4-di-O-acetyl-6-deoxy-L-glucal
with two (N- and O-, or S-containing) nucleophiles in a
one-pot manner. Our synthetic strategyinvolves regio- and
stereoselective tandem hydroamination/glycosylation on
the protected glycal scaffold (Figure 2). To demonstrate
the versatility of the present method, it was applied for
facile synthesis of L-ristosamine and L-epi-daunosamine
glycosides in a three-step reaction sequences.
(5) For recent syntheses of 3-amino-2,3,6-trideoxyhexoses, see:
(a) Matsushima., Y.; Kino., J. Eur. J. Org. Chem. 2010, 2206. (b) Shi,
W.; Coleman, R. S.; Lowary, T. L. Org. Biomol. Chem. 2009, 7, 3709.
(c) Fan, E.; Shi, W.; Lowary, T. L. J. Org. Chem. 2007, 72, 2917. (d) Doi,
K.; Shibata, K.; Kinbara, A.; Takahashi, T. Chem. Lett. 2007, 36, 1372.
(e) Friestad, G. K.; Jiang, T.; Mathies, A. K. Org. Lett. 2007, 9, 777.
(f) Matsushima, Y.; Kino, J. Tetrahedron Lett. 2006, 47, 8777.
(g) Hayman, C. M.; Larsen, D. S.; Simpson, J.; Bailey, K. B.; Gill,
G. S. Org. Biomol. Chem. 2006, 4, 2794. (h) Matthew, T. M.; Peng, T.;
Christopher, M. H.; Robert, S. C.; Lowary, T. L. J. Org. Chem. 2006, 71,
8059. (i) Parker, K. A.; Chang, W. Org. Lett. 2005, 7, 1785. (j) Parker,
K. A.; Chang, W. Org. Lett. 2003, 5, 3891. (k) Trost, B. M.; Jiang, C. H.;
Hammer, K. Synthesis 2005, 3335. (l) Ginesta, X.; Pasto, M.; Pericas,
M. A.; Riera, A. Org. Lett. 2003, 5, 3001. (m) Brimble, M. A.; Davey,
R. M.; McLeod, M. D.; Murphy, M. Aust. J. Chem. 2003, 56, 787.
(n) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749.
(o) Liberek, B.; Dabrowska, A.; Frankowski, R.; Matuszewska, M.;
Smiatacz, Z. Carbohydr. Res. 2002, 337, 1803. (p) Saotome, C.; Ono, M.;
Akita, H. Tetrahedron: Asymmetry 2000, 11, 4137. (q) Davey, R. M.;
Brimble, M. A.; Mcleod, M. D. Tetrahedron Lett. 2000, 41, 5141.
(r) Effenberger, F.; Roos, J. Tetrahedron: Asymmetry 2000, 11, 1085.
(s) Davies, S. G.; Smyth, G. D.; Chippindale, A. M. J. Chem.
Soc., Perkin Trans. 1 1999, 3089. (t) Szechner, B.; Achmatowicz, O.;
Badowska-Roslonek, K. Pol. J. Chem. 1999, 73, 1133. (u) Nicolaou,
K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes, R.; Winssinger,
N.; Natarajan, S.; Koumbis, A. E. Chem.;Eur. J. 1999, 5, 2648.
(v) Daley, L.; Roger, P.; Monneret, C. J. Carbohydr. Chem. 1997, 16,
25. (w) Colinas, P. A.; Bravo, R. D. Org. Lett. 2003, 5, 4509. (x) Colinas,
In our initial study, a mixture of 3,4-di-O-acetyl-6-deoxy-
L-glucal (1a), benzyl alcohol (2a), and benzyl carbamate
(3a) in DCE was subjected to treatment with 2.2 equiv of
BF3 OEt2 at room temperature under a nitrogen atmo-
3
sphere for 20 min, to afford 4a in 87% yield with exclusive
stereospecificity (Table 1, entry 1). The exclusive forma-
tion of pure diastereomers allowed easy purification of the
desired product by SiO2 flash column chromatography.
Chemical structure determination and stereochemical
characterization of 4a was achieved by extensive and
detailed 1D and 2D NMR studies.7 The JH1-H2a of
3.2 Hz for anomeric proton H-1 signal at δ 4.93 in 1H NMR
is diagnostic for R-linked glycosides. The stereochemistry
at the C-3 position is assigned by NOESY experiment.
The correlation for N-H/H-5 and no correlation for
H-1/N-H or H-1/H-3 indicate that the newly introduced
sulfonamido group and glycosyl acceptor are in a cis
diaxial configuration, adopting 1C4 conformation in solu-
tion. With this gratifying preliminary result, our attention
was directed toinvestigating the substrate scope by varying
the nucleophiles. A diverse set of primary, secondary,
tertiary alcohols (2b-2p) and thiol (2q) worked well as
nucleophiles to provide the desired N-benzyloxycarbonyl-
L-ristosamine glycosides with exclusive stereoselectivity
ꢀ
P. A.; Nicolas, A. N.; Bravo, R. D. J. Carbohydr. Chem. 2008, 27, 141.
(y) Sibi, M.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864. Sibi et al.
provide an extensive list of references to earlier syntheses.
(6) (a) Lorpitthaya, R.; Xie, Z. Z.; Sophy, K. B.; Kuo, J. L.; Liu,
X.-W. Chem.;Eur. J. 2010, 16, 588. (b) Gorityala, B. K.; Lorpitthaya,
R.; Bai, Y.; Liu, X.-W. Tetrahedron 2009, 65, 5844. (c) Yang, R. L.;
Pasunooti, K. K.; Li, F.; Liu, X.-W.; Liu, C.-F. J. Am. Chem. Soc.
2009, 131, 13592. (d) Ding, F. Q.; William, R.; Gorityala, B. K.; Ma,
J. M.; Wang, S. M.; Liu, X.-W. Tetrahedron Lett. 2010, 51, 3146.
(e) Lorpitthaya, R.; Xie, Z. H.; Sophy, K. B.; Kuo, J. L.; Liu, X.-W.
Chem.;Eur. J. 2010, 16, 588. (f) Lorpitthaya, R.; Xie, Z. Z.; Kuo, J. L.;
Liu, X.-W. Chem.;Eur. J. 2008, 14, 1561. (g) Lorpitthaya, R.; Sophy,
K. B.; Kuo, J. L.; Liu, X.-W. Org. Biomol. Chem. 2009, 7, 1284.
(7) See Supporting Information, pp S32-S36.
Org. Lett., Vol. 13, No. 4, 2011
653

Table 1. Substrate Scope Studies for BF3 OEt2-Promoted Three-Component R-Selective Tandem Hydroamination/Glycosylation
3
Reactiona
a See Supporting Information for a detailed experimental procedure. b All products were characterized by 1H NMR, 13C NMR, IR, and HRMS.
c Isolated yield.
in good yield as shown in Table 1. Accordingly, facile
syntheses of 3-amino-2,3,6-trideoxyhexoses 4b-4q were
achieved in moderate to good yields (55-86%) (Table 1,
entries 2-13). To further exploit this protocol, L-menthol
glucoside 4rwaspreparedin54% yield (Table1, entry 14).8
To our delight, in all cases, the desired aminosugars were
obtained as pure diastereomers with an R configuration at
the C-1 position. The stereochemical outcome can pre-
sumably be viewedasa resultofstereospecificamination at
the C-3 position followed by possible hydrogen bonding
between the nitrogen and the incoming O-nucleophile
(ROH). Additionally, the anomeric effect also favors the
formation of the thermodynamically morestableR anome-
ric product.9
were carried out with NsNH2, TsNH2, or MsNH2, the
corresponding aminosugars were isolated in high yields
with exclusive stereoselectivities (Table 2, entries 1-3, 4 rd,
4rf, 4rg, and 4s). In comparison to sulfonamides, reaction
with ethyl carbamate (3j) gave the corresponding 3-amino-
2,3,6-trideoxyhexoses 4t in slightly lower yields (Table 2,
entry 4). In contrast, reaction of trimethylsilyl azide
(TMSN3) with 3,4-di-O-acetyl-6-deoxy-L-glucal (1a)
turned out to be unsuccessful.
As a final step in the sequence, N-benzyloxycarbonyl-
L-ristosamine glycosides were converted into the desired
free L-ristosamine glycosides. For example, one-pot depro-
tection of the Cbz and acetyl groups resulted in L-ristos-
amine derivatives (5a) and (5b) in 82% and 87% yield,
respectively (Scheme 1). Overall, the development of this
novel one-pot method is of particular significance for the
synthesis of L-ristosamine glycosides 5a and 5b, as it is highly
superior to previously described routes that normally are
comprised of 9 to 11 linear steps.5h,10 X-ray crystallography
Having established the scope for the O-nucleophile, we
set out to demonstrate the generality of the reaction by
using various N-nucleophiles. It is noteworthy that the
reaction proceeded remarkably well with aromatic and
aliphatic sulfonamides. For example, when the reactions
(8) Noguchi, K.; Nakagawa, H.; Yoshiyama, M.; Shimura, S.;
Kirimura, K.; Usami, S. J. Ferment. Bioeng. 1998, 85, 436.
(9) (a) Bussolo, V. D.; Caselli, M.; Romano, M. R.; Pineschi, M.;
Crotti, P. J. Org. Chem. 2004, 69, 7383. (b) Bussolo, V. D.; Romano,
M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2005, 7, 1299.
(10) (a)Sztaricskai,F.;Hornyak,U.;Konaromi, I.;Gyula,B. G.;Pelyvis,
I. F. Bioorg. Med. Chem. Lett. 1992, 3, 235. (b) Kovacs, I.; Herczegh, P.;
Sztaricskai, F. Tetrahedron 1991, 47, 7837. (c) Sztaricskai, F.; Pelyvas, I.;
Szilagyi, L.; Bognar, R. Carbohydr. Res. 1978, 65, 193. (d) Claudio, F. C.;
Grasselli, P.; Fantoni, G. P. J. Org. Chem. 1983, 48, 909.
654
Org. Lett., Vol. 13, No. 4, 2011

Table 2. Scope of the Nitrogenic Nucleophilesa
Figure 3. X-ray structure of L-ristosamine derivative 5b; red (O);
blue (N); Cl- is omitted for clarity.
Scheme 2. Synthesis of L-epi-Daunosamine Derivative (5c)
a See Supporting Information for a detailed experimental procedure.
b All products were characterized by IR, HRMS, 1H NMR, and 13C
NMR. c Isolated yield.
Scheme 1. Synthesis of L-Ristosamine Glycosides 5a and 5b
regioselection. The spectroscopic data (1H and 13C
NMR, IR) and optical rotation of 5c were identical
to those reported in the literature.5e,12
In summary, a stereocontrolled one-pot BF3 OEt2-pro-
3
moted hydroamination/glycosylation on glycal scaffolds
to synthesize 3-amino-2,3,6-trideoxyhexoses has been
developed that circumvents the problem of lack of stereo-
selectivity, and thus laborious isolation of pure diastereo-
meric products, associated with previously reported
strategies. Other attractive features of this multicompo-
nent reaction are a simple and practical experimental
procedure and its adaptability for the synthesis of a diverse
set of aminosugars. The synthetic utility of this novel
method has been further illustrated in a concise and highly
expedient synthesis of L-ristosamine and L-epi-daunos-
amine glycosides. Thus, the present methodology represents
an attractive entry to aminosugars, and its further applica-
tion is underway and will be reported in due course.
analysis of L-ristosamine derivative 5b further confirmed
the structure and stereochemical outcome of the tandem
hydroamination/glycosylation (Figure 3).
To prepare another diastereomeric 3-amino-2,3,6-tri-
deoxyhexose, L-epi-daunosamine, the starting 3,4-di-
O-acetyl-6-deoxy-L-galactal (1b) was synthesized from
L-fucose according to a literature reported procedure.11
Intermediary carbamate protected L-epi-daunosamine
(4u) was obtained in 79% yield via a three-component
reaction involving benzyl carbamate (CbzNH2) (3a), cyclo-
hexanol (2e), and 3,4-di-O-acetyl-6-deoxy-L-galactal
(Scheme 2). Similarly, removal of the acetyl group by
treating 4u with NaOMe in methanol, followed by
direct removal of the Cbz group through treatment
with Pd/C under H2, provided cyclohexyl L-epi-daunos-
amine (5c) in 83% yield with exclusive stereo- and
Acknowledgment. We gratefully acknowledge Nanyang
Technological University (RG50/08) and the Ministry of
Education, Singapore (MOE 2009-T2-1-030) for the
financial support of this research. We thank Prof. Koichi
Narasaka for invaluable discussion and Dr Yongxin Li for
X-ray analyses.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Shull, B. K.; Wu, Z.; Koreeda, M. J. Carbohydr. Chem. 1996,
15, 955.
(12) Other efficient syntheses of daunosamine and its derivatives
from commercially available achiral or noncarbohydrate precursors
range from five to nine steps with 7-34% overall yield.
Org. Lett., Vol. 13, No. 4, 2011
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