New stereodivergent approach to 3-amino-2,3,6-trideoxysugars. Enantioselective synthesis of daunosamine, ristosamine, acosamine, and epi-daunosamine

Article abstract of DOI:10.1021/ol034843h

(Matrix presented) An enantioselective preparation of the four diastereomeric 3-amino-2,3,6-trideoxy-hexoses, key components of anthracycline antibiotics, has been developed. Sharpless catalytic asymmetric epoxidation of the (2E)-2,5-hexadien-1-ol, regios

Full text of DOI:10.1021/ol034843h

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3001-3004
New Stereodivergent Approach to
3-Amino-2,3,6-trideoxysugars.
Enantioselective Synthesis of
Daunosamine, Ristosamine, Acosamine,
and Epi-daunosamine
Xavier Ginesta, Mireia Pasto´, Miquel A. Perica`s, and Antoni Riera*
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Departament de Qu´ımica
Orga`nica/Parc Cient´ıfic de Barcelona, UniVersitat de Barcelona, C/Josep Samitier 1-5,
08028 Barcelona, Spain
ariera@pcb.ub.es
Received May 15, 2003
ABSTRACT
An enantioselective preparation of the four diastereomeric 3-amino-2,3,6-trideoxy-hexoses, key components of anthracycline antibiotics, has
been developed. Sharpless catalytic asymmetric epoxidation of the (2E)-2,5-hexadien-1-ol, regioselective ring opening with azide, followed by
convenient functional group transformations, afforded the key aldehydes cis- or trans-6 in any configuration. The diastereoselective addition
of methylmetal reagents to these aldehydes followed by ozonolysis gives access in a completely stereocontrolled manner to the four isomeric
trideoxyaminosugars.
Anthracycline antibiotics have received much attention
because of their bioactivity against a wide range of human
tumors.1 A large number of these clinically important
antibiotics, for example, daunomycin (I), adriamycin (II),
or epirubicin (III), consist of a tetracyclic chromophore and
one amino sugar residue (Figure 1). Clinical studies revealed
that the relative stereochemistry of the functional groups in
the glycosidic component strongly influences the bioactivity
of the drug. It has been reported that changing L-daunosamine
(1) to the 4-epimer, L-acosamine (4), as in adriamycin, nearly
suppresses the undesired toxic side effects while maintaining
similar antitumor activity.2 Therefore, the synthetic com-
munity has dedicated numerous efforts toward efficient,
stereoselective, and stereocontrolled syntheses of the not
readily available four diastereomeric 3-amino-2,3,6-trideoxy-
L-hexoses (1-4) (Figure 2). A wide variety of approaches
that range from classical sugar chemistry,3 synthesis from
other chiral pool molecules,4 catalytic asymmetric synthesis,5
use of chiral auxiliaries,6 and enzymatic methods7 have been
reported.
(1) (a) Arcamone, F.; Franceschi, G.; Minghetti, A.; Penco, S.; Redaelli,
S. J. Med. Chem. 1974, 17, 335-337. (b) Arcamone, F.; Franceschi, G.;
Orezzi, P.; Cassinelli, G.; Barbieri, W.; Mondelli, R. J. Am. Chem. Soc.
1964, 86, 5334-5335. (c) Arcamone, F.; Cassinelli, G.; Orezzi, P.;
Franceschi, G.; Mondelli, R. J. Am. Chem. Soc. 1964, 86, 5335-5336.
(2) Arcamone, F.; Penco, S.; Vigevani, A.; Redaelli, S.; Franchi, G.; Di
Marco, A.; Casazza, A. M.; Dasdia, T.; Formelli, F.; Necco, A.; Soranzo,
C. J. Med. Chem. 1975, 18, 703-707.
Figure 1. Anthracycline antibiotics with antitumoral activity.
10.1021/ol034843h CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/19/2003

Scheme 1. Retrosynthetic Analysis of
3-Amino-2,3,6-trideoxyhexoses 1-4
Figure 2. Structures of some natural 3-amino-2,3,6-trideoxysugars.
In a project devoted to the synthesis of different structural
types of amino acids and dipeptide isosteres,8 we have
explored the diastereoselective addition of methylmetal
reagents to N-Boc-2,2,4-trimethyloxazolidine-5-formalde-
hydes and we have succeeded in generating either the syn-
or the anti-3-amino-1,2-diols products in highly diastereo-
selective way by simple modification of the organometallic
reagent.9 As an application of this general methodology for
the aminodiol fragment, we envisaged the preparation of the
four stereoisomeric 3-amino-2,3,6-trideoxyhexoses 1-4.
Our retrosynthetic analysis involves ozonolysis of oxazo-
lidine alcohols 5, stereoselectively prepared by addition of
a methylmetal reagent to oxazolidine aldehydes cis-6 or
trans-6 (Scheme 1). These oxazolidine aldehydes would be
in turn obtained from the common intermediate N-Boc-
aminodiol 7 prepared by regioselective ring opening of the
enantiomerically enriched epoxy alcohol 8 with an ammonia
equivalent.
Sharpless epoxidation was performed as described11 using
L-(+)-DET to afford epoxy alcohol 8 in 84% yield and 93%
ee.12
Enantiomerically enriched 8 was subjected to nucleophilic
epoxide ring-opening by azide. Using trimethylsilyl azide
under Sharpless conditions13 produced a completely regio-
selective reaction, although the ring-opening could be
performed somewhat more conveniently using titanium
diazidodiisopropoxide.14 The corresponding azido alcohol
was then treated with a variety of reducing agents such as
SnCl2, Lindlar catalyst, or LiAlH4, but after protection with
Boc2O, very low yields of N-Boc-3-amino-5-hexen-1,2-diol
(7) were obtained. Gratifyingly, conversion of the azide into
the N-Boc-amine15 could be performed efficiently by treat-
ment with PPh3 or PBu3 and reaction of the iminophospho-
rane with Boc2O, affording the protected aminodiol 7 in 50%
overall yield (three steps) (Sheme 2).
The synthesis started with the preparation of the known
allyl alcohol 9 from propargyl alcohol.10 The catalytic
(3) (a) Renneberg, B.; Li, Y.-M.; Laatsch, H.; Fiebig, H.-H. Carbohydr.
Res. 2000, 329, 861-872. (b) Herczegh, P.; Zsely, M.; Kovacs, I.; Batta,
G.; Sztaricskai, F. J. Tetrahedron Lett. 1990, 31, 1195-1198. (c) Gurjar,
M. K.; Pawar, S. M. Tetrahedron Lett. 1987, 28, 1327-1328.
(4) (a) Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T.
Tetrahedron 1990, 46, 4823-4846. (b) Konradi, A. W.; Pedersen, S. F. J.
Org. Chem. 1990, 55, 4506-4508. (c) Kita, Y.; Itoh, F.; Tamura, O.; Ke,
Y. Y.; Miki, T.; Tamura, Y. Chem. Pharm. Bull. 1989, 37, 1446-1451.
(d) Hirama, M.; Shigemoto, T.; Ito, S. J. Org. Chem. 1987, 52, 3342-
3346. (e) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1986, 51,
4245-4249.
Scheme 2
(5) Wade, P. A.; D’Ambrosio, S. G.; Rao, J. A.; Shah-Patel, S.; Cole,
D. T.; Murray, J. K., Jr.; Carroll, P. J. J. Org. Chem. 1997, 62, 3671-
3677.
(6) (a) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864-
5872. (b) Po, S.-Y.; Uang, B.-J. Tetrahedron: Asymmetry 1994, 5, 1869-
1872. (c) Warm, A.; Vogel, P. J. Org. Chem. 1986, 51, 5348-5353.
(7) Effenberger, F.; Roos, J. Tetrahedron: Asymmetry 2000, 11, 1085-
1095.
(8) Selected references: (a) Ginesta, X.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 2002, 43, 779-782. (b) Medina, E.; Moyano, A.; Perica`s,
M. A.; Riera, A. HelV. Chim. Acta 2000, 83, 972-988. (c) Pasto´, M.;
Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1998, 39, 1233-
1236. (d) Pasto´, M.; Castejo´n, P.; Moyano, A.; Perica`s, M. A.; Riera, A. J.
Org. Chem. 1996, 61, 6033-7. (e) Poch, M.; Alco´n, M.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1993, 34, 7781-7784.
(9) While it was found that lithium dimethyl cuprate in ether solution
adds into these aldehydes with high syn diastereoselectivity, an excellent
diastereomeric ratio in favor of the anti isomer was obtained with MeLi or
MeMgBr in the presence of TiCl4. Pasto´, M.; Ginesta, X.; Perica`s, M. A.;
Riera, A. Unpublished results.
3002
Org. Lett., Vol. 5, No. 17, 2003

Aldehyde cis-6 was prepared from N-Boc-3-amino-5-
hexen-1,2-diol 7 through the following sequence: protection
of the primary hydroxyl group, formation of the oxazolidine
ring, deprotection, and oxidation. Thus, treatment of 7 with
tert-butyldiphenylsilyl chloride/imidazole in DMF afforded
chemoselectively the tert-butyldiphenylsilyl ether 10 in
excellent yield. Subsequent treatment with excess 2,2-
dimethoxypropane (DMP) in the presence of a catalytic
amount of p-toluenesulfonic acid16 in benzene at reflux
provided the silyloxymethyloxazolidine 11 also in high yield.
The primary hydroxyl group was then selectively deprotected
by treatment with tetrabutylammonium fluoride in THF and
oxidized under Swern conditions17 to afford the target
aldehyde cis-6 almost quantitatively (Scheme 2).
ing the Sharpless epoxidation with D-(-)-DET. Ozonolysis
of cis-anti-5 afforded the protected L-Ristosamine derivative
14 as a 9:1 epimeric mixture that could be fully characterized
(Scheme 3).
Scheme 3
The results of the diastereoselective addition of methyl-
metal reagents to aldehyde cis-6 are shown in Table 1. As
Table 1. Methyl Addition to Aldehyde cis-6
Aminosugars with a trans configuration between the
3-amino and the 4-hydroxyl would be available starting from
aldehyde trans-6. The simplest solution involves a base-
catalyzed epimerization of the corresponding cis isomer8c,20
(Scheme 4).
reagent
solvent, T, time
yield
syn/antia
Scheme 4
Me2CuLi
MeLi/TiCl4
Et2O, -20°C, 5 h
Et2O, -30°C, 3 h
81%
73%
93/7
4/96
a Determined by GC.
expected from our previous work,9 addition of lithium
dimethylcuprate in diethyl ether afforded the syn diastere-
omer in excellent diastereoselectivity, whereas MeLi in the
presence of TiCl4 provided almost exclusively the anti
isomer.
Reductive ozonolysis18 of cis-syn-5 afforded a mixture of
hemiacetals corresponding to a protected form of D-Daun-
osamine. To facilitate the characterization of the product, it
was deprotected with HCl/MeOH and treated with Ac2O to
afford the known derivative 1319 as an (8:2) acetalic mixture.
Obviously, the corresponding enantiomer with L-configura-
tion would be obtained with the same sequence but perform-
Treatment of cis-6 with potassium carbonate in methanol
overnight afforded a 5/1 mixture of trans-/cis-6 that was
submitted to the addition of methylmetal reagents (Table 2).
Table 2. Methyl Addition to Aldehyde trans-6
(10) Raifeld, Y. E. (American Cyanamid Co.). Can. Patent CA 2,068,226,
1992; Chem. Abstr. 1993, 119, 117737.
reagent
solvent, T, time
yield
syn/anti
(11) (a) Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron:
Asymmetry 1999, 10, 4639-4651. (b) Gao, Y.; Klunder, J. M.; Hanson, R.
M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765-5780.
Me2CuLi
MeLi/TiCl4
Et2O, -20°C, 5 h
Et2O, -30°C, 3 h
72%
81%
89/11
6/94
1
(12) Determined by H NMR of the corresponding Mosher ester.
(13) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557-1560.
(14) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem. 1988, 53,
5185-5187.
(15) Afonso, C. A. M. Tetrahedron Lett. 1995, 36, 8857-8858
(16) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361-2364.
(17) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(18) Allen, N. E.; Boyd, D. B.; Campbell, J. B.; Deeter, J. B.; Elzey, T.
K.; Foster, B. J.; Hatfield, L. D.; Hobbs, J. N., Jr.; Hornback, W. J.; et al.
Tetrahedron 1989, 45, 1905-1928.
(19) Jurczak, J.; Kozak, J.; Golebiowski, A. Tetrahedron 1992, 48, 4231-
4238.
As expected according to our previous study,9 the reaction
with lithium dimethyl cuprate afforded the trans-syn-5 in
good yield and selectivity. On the other hand, the reaction
with MeLi/TiCl4 afforded trans-anti-5 as the major com-
pound. In both cases, the major isomer was purified by
(20) Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han, F. S.
J. Med. Chem. 1987, 30, 976-982.
Org. Lett., Vol. 5, No. 17, 2003
3003

chromatography and submitted to reductive ozonolysis. The
trans stereochemistry of the oxazolidine prevented the
cyclization of the hydroxy aldehydes, which were conse-
quently submitted to acid hydrolysis in methanol, leading
to the corresponding aminosugars. To facilitate characteriza-
tion, the crude products were acylated with acetic anhydride.
Thus, the sequence of ozonolysis, hydrolysis, and acylation
of trans-syn-5 afforded, in good overall yield, 15, a known21
derivative of L-Epi-daunosamine 2. Likewise, the same
sequence starting with trans-anti-5 led to diacetyl derivative
of D-Acosamine 1622 (Scheme 5).
used in the Sharpless epoxidation, the configuration at C-4
by the epimerization (or not) of the oxazolidinecarbaldehyde
intermediate, and the configuration at C-5 by the organo-
metallic reagent used in the methyl addition (Figure 3).
Figure 3. General approach to aminosugars with control of the
configuration of the stereogenic centers.
Scheme 5
Acknowledgment. We thank DGI-MCYT (BQU2002-
02459) and CIRIT (2001SGR-00050) for financial support.
X.G. thanks University of Barcelona for a fellowship.
Supporting Information Available: Experimental details
for the synthesis of 13-16 and full characterization of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034843H
In summary, we have developed a new enantioselective
entry to 3-amino-2,3,6-trideoxysugars with complete control
of the stereochemistry of the three contiguous stereogenic
centers. The configuration at C-3 is controlled by the tartrate
(21) (a) Dyong, I.; Wiemann, R. Chem. Ber. 1980, 113, 1592-602. (b)
Wade, P. A.; D’Ambrosio, S. G.; Rao, J. A.; Sharmila, S.-P.; Cole, D. T.;
Murray J. K.; Carroll, P. J. J. Org. Chem. 1997, 62, 3671-3677
(22) Socha, D.; Jurczak, M.; Chmielewski, M. Tetrahedron 1997, 53,
739-746.
3004
Org. Lett., Vol. 5, No. 17, 2003