Novel synthesis of L-ribose from D-mannono-1,4-lactone.

Article abstract of DOI:10.1021/ol026141i

[reaction: see text] D-Mannono-1,4-lactone was efficiently converted into L-ribose in eight steps. A key step of this synthesis is the cyclization of a gamma-hydroxyalkoxamate under Mitsunobu conditions. It is noteworthy that the O-alkylation product was

Full text of DOI:10.1021/ol026141i

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2401-2403
Novel Synthesis of L-Ribose from
D-Mannono-1,4-lactone
Hideyo Takahashi, Yoshinori Iwai, Yuko Hitomi, and Shiro Ikegami*
Faculty of Pharmaceutical Sciences, Teikyo UniVersity, Sagamiko,
Kanagawa 199-0195, Japan
shi-ike@pharm.teikyo-u.ac.jp
Received May 7, 2002
ABSTRACT
D-Mannono-1,4-lactone was efficiently converted into L-ribose in eight steps. A key step of this synthesis is the cyclization of a
γ-hydroxyalkoxamate under Mitsunobu conditions. It is noteworthy that the O-alkylation product was obtained in 94% yield and that none of
the N-alkylation product was detected in this cyclization.
Since Miller reported several efficient biomimetic â-lactam
syntheses based on the intramolecular N-alkylation of â-hy-
droxyalkoxamates under Mitsunobu conditions,1 a consider-
able number of studies have been conducted on this type of
intramolecular cyclization.2 Recently, we reported the intra-
molecular O-/N-alkylation of δ-hydroxyalkoxamates derived
from D-glycono-1,5-lactones.3 In contrast to â-hydroxy-
alkoxamates, we found that the cyclization of δ-hydroxy-
alkoxamates resulted mainly in O-alkylation rather than
N-alkylation. Taking advantage of the structural relationship
between D-glucose and L-idose, D-galactose and L-altrose,
and D-mannose and L-gulose, we utilized the O-alkylated
products, which had the inverted stereochemistry at C5, as
precursors for the corresponding L-sugars and developed a
novel, practical synthesis of the rare L-pyranoses (Scheme
1).
These successful results prompted us to investigate the
intramolecular O-/N-alkylation of the γ-hydroxyalkoxamate
derived from D-mannono-1,4-lactone in the hope of develop-
ing a practical synthesis of L-ribofuranose. In the past decade,
the number of reports of L-nucleosides4 has increased drama-
tically due to their potent biological activity as antiviral
agents.5 Thus, an efficient method of producing the rare
sugar, L-ribofuranose, would be extremely beneficial.6 Herein
we describe the novel and practical conversion of D-man-
nono-1,4-lactone into L-ribose. The key feature of the se-
quence is O-alkylation of γ-hydroxyalkoxamates with inver-
sion of the stereochemistry at C4 under Mitsunobu conditions.
As shown in Scheme 2, the readily available 2,3,5,6-di-
O-isopropylidene-D-mannono-1,4-lactone7 5 was first con-
verted into the γ-hydroxyalkoxamate 6. Treatment of 5 with
O-benzylhydroxyamine (1.4 equiv) in CH2Cl2 for 30 min,
(1) (a) Mattingly, P. G.; Kerwin, J. F., Jr.; Miller, M. J. J. Am. Chem.
Soc. 1979, 101, 3983-3985. (b) Morrison, M. A.; Miller, M. J. J. Org.
Chem. 1983, 48, 4421-4423. (c) Miller, M. J.; Mattingly, P. G. Tetrahedron
1983, 39, 2563-2570. (d) Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991,
32, 3305-3308.
(2) For a discussion of O-/N-alkylation selectivity in Mitsunobu reactions
of various amides and carbamates, see: (a) Miller, M. J.; Mattingly, P. G.;
Morrison, M. A.; Kerwin, J. F. Jr. J. Am. Chem. Soc. 1980, 102, 7026-
7032. (b) Bose, A. K.; Sahu, D. P.; Manhas, M. S. J. Org. Chem. 1981, 46,
1229-1230. (c) Krook, M. A.; Miller, M. J. J. Org. Chem. 1985, 50, 1126-
1128. (d) Gale´otti, N.; Montagne, C.; Poncet, J.; Jouin, P. Tetrahedron Lett.
1992, 33, 2807-2810. (e)Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992,
33, 6267-6270. (f) Koppel, I.; Koppel, J.; Koppel, I.; Leito, I.; Pihl, V.;
Wallin, A.; Grehn, L.; Ragnarsson, U. J. Chem. Soc., Perkin Trans. 2 1993,
655-658.
(4) L-RNA: (a) Ashley, G. W. J. Am. Chem. Soc. 1992, 114, 9731-
9736. L-DNA: (b) Damha, M. J.; Giannaris, P. A.; Marfey, P. Biochemistry
1994, 33, 7877-7885. (c) Hashimoto, Y.; Iwanami, N.; Fujimori, S.; Shudo,
K. J. Am. Chem. Soc. 1993, 115, 9883-9887. (d) Fujimori, S.; Shudo, K.;
Hashimoto, Y. J. Am. Chem. Soc. 1990, 112, 7436-7438.
(5) Mansuri, M. M.: Farina, V.; Starrett, J. E. Jr.; Benigni, D. A.;
Brankovan, V.: Martin, J. C. Bioorg. Med. Chem. Lett. 1991, 1, 65-68
(6) For other syntheses of L-ribose, see: (a) Shi, Z.-D.; Yang, B.-H.;
Wu, Y.-L. Tetrahedron Lett. 2001, 42, 7651-7653. (b) Sivets, G. G.;
Klennitskaya, T. V.; Zhernosek, D. V.; Mikhailopulo, I. A. Synthesis 2002,
253-259. (c) Jung, M. E.; Xu, Y. Tetrahedron Lett. 1997, 38, 4199-4202.
(3) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am. Chem. Soc.
2000, 122, 2995-3000.
10.1021/ol026141i CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/18/2002

Scheme 1. Synthesis of L-Pyranoses from
Scheme 2. Synthesis of L-Ribose from D-Mannono-1,4-lactone
D-Glycono-1,5-lactones
was treated with NaIO4 to provide 10 in 87% yield. Of the
methods examined for the reduction of the aldehyde moiety
of 10, hydrogenolysis using PtO2 as a catalyst gave the best
results. Finally, acidic hydrolysis to deprotect the isopropyl-
idene group afforded L-ribose in 83% yield from 10. Thus,
the conversion of D-mannono-1,4-lactone to L-ribose was
accomplished efficiently in 50% overall yield.
Having obtained these successful results, we next turned
our attention to the ratio of O-/N-alkylated products in the
reaction of γ-hydroxyalkoxamates under Mitsunobu condi-
tions. In a previous paper, we reported that the significant
difference in the ratios of O-/N-alkylation was dependent
on the stereochemistry of the D-sugars: the δ-hydroxyalkox-
amates (2a, 2b) derived from D-glucono-1,5-lactone 1a and
D-galactono-1,5-lactone 1b provided a mixture of O-/N-
alkylated products, whereas the δ-hydroxyalkoxamate 2c
derived from D-mannono-1,5-lactone 1c afforded the O-
cyclized compound 3c as the sole product. As for the
γ-hydroxyalkoxamate 6, we observed complete specificity
for the O-alkylated product 7 as shown in the above
synthesis. Next, we carried out studies on the selectivity of
the O-/N-alkylation using different protective groups in order
to determine if the configuration of the γ-hydroxyalkoxa-
mates was important (Scheme 3).
followed by addition of Me3Al (1.1 equiv) at room temper-
ature, afforded the corresponding γ-hydroxybenzyloxamate
6 in 88% yield.8 We next examined the cyclization of 6 under
Mitsunobu conditions9 (3.0 equiv of TPP and 3.0 equiv of
DEAD10). Fortunately, 7 was obtained as the sole product
in 94% yield. It is noteworthy that none of the N-alkylated
product was detected. Treatment of the O-cyclized oxime
compound 7 with p-TsOH monohydrate (1.0 equiv) in
acetone at room temperature gave L-gulono-1,4-lactone 8 in
89% yield. Compound 8 crystallized, and the inversion of
stereochemistry at C4 was shown by X-ray crystallography.
The carbonyl moiety of 8 was reduced by excess DIBAL to
provide 96% of 2,3,5,6-di-O-isopropylidene-L-gulofuranose
9. Compound 9 was partially hydrolyzed to the diol, which
(7) (a) Standring, D. N.; Bridges, E. G.; Placidi, L.; Faraj, A.; Loi, A.
G.; Pierra, C.; Dukhan, D.; Gosselin, G.; Imbach, J.-L.; Hernandez, B.;
Juodawlkis, A.; Tennant, B.; Korba, B.; Cretton-Scott, E.; Schinazi, R. F.;
Myers, M.; Bryant, M. L.; Sommadossi, J.-P. AntiViral Chem. Chemother.
2001, 12, 119-129. (b) Anderson, K. S. AntiViral Chem. Chemother. 2001,
12, 13-17. (c) Gumina, G.; Song, G.-Y.; Chu, C. K. FEMS Mirobiol. Lett.
2001, 202, 9-15. (d) Chen, S.-H. Front. Biotechnol. Pharm. 2001, 2, 307-
328. (e) Graciet, J.-C. G.; Schinazi, R. F. AdV. AntiViral Drug Des. 1999,
3, 1-68.
The γ-hydroxyalkoxamate 11 derived from 2,3-di-O-
methoxymethyl-D-mannono-1,4-lactone was easily converted
into the O-alkylated product 12. Similarly, the reaction of
the γ-hydroxyalkoxamate 13 derived from 2,3-di-O-benzyl-
D-mannono-1,4-lactone proceeded to give the O-alkylated
product 14. It is interesting to note that no N-alkylated
(8) We found that the later addition of Me3Al resulted in more enormous
acceleration of the reaction than the use of the preceding formation of Me3-
Al-alkoxyamine complex to be considered as an active species. For earlier
studies on amidation, see: Basha, A.; Lipton, M.; Weinreb, S. M.
Tetrahedron Lett. 1977, 4171-4174.
(9) Review: Mitsunobu, O. Synthesis 1981, 1-28.
(10) To execute the reaction completely, excess amount of Mitsunobu
reagent is used.
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Org. Lett., Vol. 4, No. 14, 2002

Scheme 3. Effect of Protective Groups on the Ratio of
O-/N-Alkylation
Scheme 4. Solvent Effect on Selectivity of O-/N-Alkylation
product was detected in either case. These results indicated
that the steric requirement of the protective groups at C2
and C3 did not affect the selectivity of the O-/N-alkylation.
We next investigated the effect of solvent on this cyclization
(Scheme 4).
The reactions proceeded smoothly in all solvents (THF,
toluene, CH2Cl2, DMSO) and provided the O-alkylated
product 7 in good yields: the N-alkylated product was never
observed. It must be recalled here that the δ-hydroxyalkox-
amate 2c derived from the D-mannono-1,5-lactone 1c gave
similar results: none of the N-alkylated product was detected
in that case. One explanation for this result may be that the
axially oriented substituent at C2 in mannose causes the
O-alkylation under Mitsunobu conditions to be much more
favorable.
transformation of D-sugars to other L-sugars based on similar
concepts and controlling the ratios of O-/N-alkylation are in
progress.
Acknowledgment. We thank Dr. Moto Shiro, Rigaku
Corp., Matsubara, Akishima, Tokyo, for providing X-ray
crystallographic data. We are grateful to Misses J. Shimode
and M. Kitsukawa for spectroscopic measurements. The
generous financial support for this research from the Ministry
of Education, Science, Sports and Culture of Japan, The
Fujisawa Foundation, and Hayashi Memorial Foundation for
Female Natural Scientists is gratefully acknowledged.
Supporting Information Available: Representative ex-
perimental procedures and characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
In conclusion, we have established a novel and efficient
method for the conversion of D-mannono-1,4-lactone into
L-ribose. This is the first application of the Mitsunobu-type
cyclization for the synthesis of an L-furanose. Work on the
OL026141I
Org. Lett., Vol. 4, No. 14, 2002
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