preparation of DOS derivatives4 has become an important field
of synthetic research.
Several researchers have used methyl glycoside 1 as a source
for 3,4-dideoxy ribose (2) for inclusion in conjugates. Racemic
trans-glycoside 1 has been synthesized by the epoxidation of
Synthesis of Deoxy Sugar Esters: A
Chemoenzymatic Stereoselective Approach
Affording Deoxy Sugar Derivatives Also in the
Form of Aldehyde
Ly Villo,*,† Kady Danilas,† Andrus Metsala,† Malle Kreen,†
Imre Vallikivi,‡ Sirje Vija,§ To˜nis Pehk,§ Luciano Saso,| and
Omar Parve†
Department of Chemistry, Tallinn UniVersity of Technology,
Ehitajate tee 5, 19086 Tallinn, Estonia, Institute of Technology,
UniVersity of Tartu, Nooruse 1, 50411 Tartu, Estonia,
Department of Chemical Physics, National Institute of
Chemical Physics and Biophysics, Akadeemia tee 23,
12618 Tallinn, Estonia, and Department of Human Physiology
and Pharmacology, UniVersity of Rome ”La Sapienza”,
P.le Aldo Moro 5, 00185 Rome, Italy
2,3-dihydropyran in methanol5 and used in the synthesis of
polycyclic ethers: (a) upon a Friedel-Crafts cyclization of 2-O-
benzyl ethers,6 (b) by means of a cation-mediated cyclization
of the thioglycoside derived from glycoside 1 to afford a
ketooxetane,7 (c) for the preparation of 2,7-dioxabicyclo[4.4.0]-
decane and 2,8-dioxabicyclo[5.4.0]undecane.8
Derivatives of 2 have been synthesized with high enantio-
meric purity starting from L-glutamic acid or D- or L-arabi-
nose.1,12 The synthesis of (2S,3S)-2-methoxytetrahydropyran-
3-ol9 (1) by bromohydroxylation of 2,3-dihydropyran followed
by treatment with LiOH in methanol has been described.10 In
this synthesis, the enantiomers of bromohemiacetal 5 were
resolved by lipase-catalyzed acetylation.11 3,4-Dideoxy ribose
in the form of a glycoside has been included in several
conjugates to be used as a chiral auxiliary in an asymmetric
modification of the parent structure.12-14
ReceiVed December 22, 2006
For the synthesis of sugar esters, several enzymatic processes
have been developed.15 For the synthesis of hydroxy carboxylic
acid esters using routine acylation techniques, the alcoholic
hydroxyl groups of the acid have to be protected prior to
acylation.16 For a chemoselective esterification of unprotected
hydroxy carboxylic (phenolic) acids the Mitsunobu reaction has
been used.17
A chemoenzymatic synthesis of deoxy sugar esters is
described. The synthesis is based on the O-alkylation of
carboxylic acid with 2-bromo-5-acetoxypentanal. The method
allows treatment of hydroxy carboxylic acids without protec-
tion of alcoholic hydroxyl groups. Several stereoisomeric
deoxy sugar esters were resolved (up to ee or de > 98%)
using a lipase-catalyzed acetylation of hemiacetals that in
certain cases afforded deoxy sugar derivatives in the form
of aldehydes. The stereochemistry of the reactions was
determined by the NMR spectra of mandelic acid derivatives.
The aim of the present work was to develop a synthetic
approach for the preparation of stereochemically pure 3,4-
(4) Kirschning, A.; Jesberger, M.; Scho¨ning, K.-U. Synthesis 2001, 507-
540.
(5) Sweet, F.; Brown, R. K. Can. J. Chem. 1966, 44, 1571-1576.
(6) Fearnley, S. P. R.; Tidwell, M. W. Org. Lett. 2002, 4, 3797-3798.
(7) Craig, D.; Munasinghe, V. R. N.; Tierney, J. P.; White, A. J. P.;
Williams, D. J.; Williamson, C. Tetrahedron 1999, 55, 15025-15044.
(8) Simart, F.; Brunel, Y.; Robin, S.; Rousseau, G. Tetrahedron 1998,
54, 13557-13566.
(9) Numeration for compounds named as pyran rings starts from oxygen,
and for sugars, from C1.
(10) Villo, L.; Metsala, A.; Parve, O.; Pehk, T. Tetrahedron Lett. 2002,
43, 3203-3207.
(11) Vallikivi, I.; Lille, U¨ .; Lookene, A.; Metsala, A.; Sikk, P.; To˜ugu,
V.; Vija, H.; Villo, L.; Parve, O. J. Mol. Cat. B: Enzym. 2003, 22, 279-
298.
Deoxy sugars (DOS) play a significant role in many active
compounds of medicines such as antibiotics, antiviral drugs,1
glycosylation inhibitors,2 etc. Some of the DOS derivatives have
been used as chiral auxiliaries in organic synthesis.3 Considering
the above, the development of diverse strategies for the
(12) Charette, A. B.; Benslimane, A. F.; Mellon, C. Tetrahedron Lett.
1995, 36, 8557-8560.
† Department of Chemistry, Tallinn University of Technology.
‡ Institute of Technology, University of Tartu.
(13) Charette, A. B.; Mellon, C.; Motamedi, M. Tetrahedron Lett. 1995,
36, 8561-8564.
§ Department of Chemical Physics, National Institute of Chemical Physics
and Biophysics.
(14) Sugai, T.; Ikeda, H.; Ohta, H. Tetrahedron 1996, 52, 8123-8134.
(15) (a) Wu, Q.; Lu, D.; Xiao, Y.; Yao, S.; Lin, X. Chem. Lett. 2004,
33, 94-95. (b) Raku, T.; Tokiwa, Y. Macromol. Biosci. 2003, 3, 151-
156. (c) Kou, X.; Xu, J. Ann. N.Y. Acad. Sci. 1998, 864, 352-358.
(16) Parve, O.; Aidnik, M.; Lille, U¨ .; Martin, I.; Vallikivi, I.; Vares, L.;
Pehk, T. Tetrahedron: Asymmetry 1998, 9, 885-896.
(17) Appendino, G.; Minassi, A.; Daddario, N.; Bianchi, F.; Tron, G. C.
Org. Lett. 2002, 4, 3839-3841.
| Department of Human Physiology and Pharmacology, University of Rome
”La Sapienza”.
(1) Chong, Y.; Chu, C. K. Carbohydr. Res. 2002, 337, 397-402.
(2) Woynarowska, B.; Skrincosky, D. M.; Haag, A.; Sharma, M.; Matta,
K.; Bernacki, R. J. J. Biol. Chem. 1994, 9, 269(36), 22797-803.
(3) Mash, E. A.; Arterburn, J. B.; Fryling, J. A.; Mitchell, S. H. J. Org.
Chem. 1991, 56, 1088-1093.
10.1021/jo062640b CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/29/2007
J. Org. Chem. 2007, 72, 5813-5816
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