1-Deoxy-D-xylulose: Synthesis based on molybdate-catalyzed rearrangement of a branched-chain aldotetrose

Article abstract of DOI:10.1021/ol016265f

equation presented 1-Deoxy-D-xylulose has been prepared in seven steps and ～21% overall yield from 2,3-O-isopropylidene-D-erythrono-1,4-lactone. The key reaction involves transformation of a branched-chain aldotetrose to the 1-deoxy-2-ketopentose catalyze

Full text of DOI:10.1021/ol016265f

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3819-3822
1-Deoxy-D-xylulose: Synthesis Based on
Molybdate-Catalyzed Rearrangement of
a Branched-Chain Aldotetrose
,§
Shikai Zhao,† Ladislav Petrus,‡ and Anthony S. Serianni*
Omicron Biochemicals, Inc., 1347 North Ironwood DriVe,
South Bend, Indiana 46615-3566, Institute of Chemistry, SloVak Academy of Science,
SK-842 38 BratislaVa, SloVak Republic, and Department of Chemistry and
Biochemistry, UniVersity of Notre Dame, Notre Dame, Indiana 46556-5670
serianni.1@nd.edu
Received June 12, 2001 (Revised Manuscript Received October 4, 2001)
ABSTRACT
1-Deoxy-D-xylulose has been prepared in seven steps and ∼21% overall yield from 2,3-O-isopropylidene-D-erythrono-1,4-lactone. The key
reaction involves transformation of a branched-chain aldotetrose to the 1-deoxy-2-ketopentose catalyzed by molybdic acid. Other branched-
chain aldotetroses containing bulkier substituents at C2 also engage in the conversion, suggesting routes to protected 2-ketoses and r-ketoacids/
esters. This synthetic route mimics reactions of the non-mevalonate isoprenoid pathway in plants and bacteria.
In most eukaryotic organisms and archaebacteria, the
mevalonate pathway is responsible for the biosynthesis of
isoprenoid compounds wherein acetyl CoA serves as the
metabolic precursor. Recent studies, however, suggest that
1-deoxy-D-xylulose 5-phosphate 1 serves as a precursor in
the biosynthesis of isoprenoids in bacteria, green algae, and
plants, as well as in the biosynthesis of vitamins B6 and B1.1-5
Interest in elucidating these new pathways has stimulated
recent reports on the preparation of 1-deoxy-D-xylulose 2
and its 5-phosphate 1.6-11 Here we describe a chemical route
to 2 (Scheme 1) involving a unique carbon skeleton re-
arrangement that mimics one of the putative metabolic
reactions of these pathways.
Earlier work had demonstrated a unique C2-epimerization
reaction of aldoses catalyzed by molybdate in which C1 and
C2 are transposed stereospecifically, thereby leading to facile
interconversion of [1-13C]aldoses with their [2-13C]C2-
epimers.12 Using 13C and 2H isotopes as structural probes, a
reaction mechanism was proposed that implicated dimolyb-
date-acyclic aldose complexes as productive species in the
reaction. Subsequent NMR13 and crystallographic14 studies
of molybdate complexed with acyclic alditols confirmed the
structure of this species. It was observed recently that the
† Omicron Biochemicals, Inc.
‡ Slovak Academy of Science.
§ University of Notre Dame (Tel: 219-631-7807).
(1) Rohmer, M.; Seemann, M.; Horbach, S.; Bringer-Meyer, S.; Sahm,
H. J. Am. Chem. Soc. 1996, 118, 2564-2566.
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Chem. 1995, 14, 171-175.
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Chem. 1995, 73, 1329-1337.
(9) Giner, J.-L. Tetrahedron Lett. 1998, 39, 2479-2482.
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(11) Shabat, D.; List, B.; Lerner, R. A.; Barbas, C. F., III Tetrahedron
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Soc. 1982, 104, 6764-6769.
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(14) Ma, L.; Liu, S.; Zubieta, J. Polyhedron 1989, 1571.
(2) Sagner, S.; Latzel, C.; Eisenreich, W.; Bacher, A.; Zenk, M. H. Chem.
Commun. 1998, 221-222.
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10.1021/ol016265f CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/09/2001

Scheme 1a
a (a) NaBH4, pH 4-7, 0-5 °C, 90 min; (b) CH2O/CH3OH, K2CO3, 80-85 °C, 48 h; (c) MeOH/acetone, HCl/ether, 40 °C, 72 h; (d)
TsCl/pyridine, 0-25 °C, 12 h; (e) LAH/CHCl3/ether, 30 °C, 20 h; (f) Dowex 50 (H+), 80 °C, 60 min; (g) MoO3/H2O/pH 4.2, 70 °C, 30
min.
aldehydic proton of an acyclic aldose could be replaced by
a CH2OH group, thereby promoting interconversion between
a C2 branched-chain aldose and a 2-ketose.15 It thus became
evident that the synthesis of 2 might be effected through a
similar transformation.
detectable byproducts. Purification of this mixture was
achieved by chromatography on Dowex 50WX8-400 ion-
exchange resin in the Ca2+ form17 (2 elutes first, followed
by 918) (Figure 2). This route could be shortened appreciably
To explore this possibility, 2,3-O-isopropylidene-D-eryth-
rono-1,4-lactone 3 (commercially available from Aldrich)
was reduced with NaBH4 in H2O to give the reducing sugar
4 in 85% yield and 4 was alkylated with CH2O under mildly
basic conditions to give the protected branched-chain aldo-
tetrose 5 in 65% yield. Methyl glycosidation of 5 gave the
â-furanoside 6 in 65% yield, and tosylation followed by
reduction with LAH and deprotection gave 2-C-(methyl)-D-
erythrose 916 in 23% overall yield from 3 (Scheme 1, Figure
1). The key transformation of 9 into the desired 1-deoxy-
Figure 2. The 13C{1H} NMR spectrum (75 MHz) of the product
ketose, 1-deoxy-D-xylulose 2, after purification, showing the
presence of R- and â-furanoses and acyclic keto forms. The acyclic
keto form predominates (signal assignments shown). Specific
chemical shift values are given in ref 18.
if 9 could be prepared via direct methylation of an appropri-
ate precursor rather than through the traditional but cumber-
some protection/deprotection strategy applied here.
The remarkable transformation of 9 into 2 is believed to
involve the formation of dimolybdate complexes I and II
Figure 1. The 13C{1H} NMR spectrum (75 MHz) of the starting
branched-chain aldotetrose, 2-C-(methyl)-D-erythrose 9, showing
the presence of R- and â-furanose forms. Signal assignments are
indicated; specific chemical shift values are given in ref 16.
(15) Hricoviniova-Bilikova, Z.; Hricovini, M.; Petrusova, M.; Serianni,
A. S.; Petrus, L. Carbohydr. Res. 1999, 319, 38-46.
(16) The 13C{1H}NMR spectrum of 9 in H2O/2H2O solvent showed the
presence of R- and â-furanoses in nearly equal abundance (Figure 1) and
having the following chemical shifts (in ppm relative to δC1 of R-D-
mannopyranose (95.2 ppm)): C1 (103.9, 101.7); C2 (79.5, 77.4); C3, C4
(75.5, 75.2, 72.8, 71.4); CH3 (22.8, 19.5).
2-ketopentose 2 is catalyzed by molybdic acid in aqueous
solution at 70 °C and pH 4.2 and yields an equilibrium
mixture containing ∼95% 2 and ∼5% 9 and no other NMR-
(17) Angyal, S. J.; Bethell, G. S.; Beveridge, R. Carbohydr. Res. 1979,
73, 9-18.
3820
Org. Lett., Vol. 3, No. 24, 2001

having structures shown in Scheme 2. Similar complexes
were originally proposed in molybdate-catalyzed C2-epimer-
facilitated by attack of OH- or water during the reaction
instead of internal transfer of O1 as shown in Figure 3. In
the present case, the thermodynamic equilibrium favors the
2-ketopentose despite its preferred acyclic form,19 rather than
the cyclic branched-chain aldotetrose.
We examined the ability of the proposed dimolybdate
complexes to accommodate alkyl groups other than CH3 at
C2 of 9. The CH2OH and CH2OBn substituents in 10 and
11, respectively, were accepted, yielding D-xylulose 12 and
1-O-benzyl-D-xylulose 13, respectively (Scheme 3). In both
Scheme 2
Scheme 3
ization of aldoses in which C1 and C2 are transposed via
C2-C3 bond cleavage,12 and more recently in the molybdate-
catalyzed conversion of 2-C-(hydroxymethyl)aldopentoses
to 2-ketohexoses.15 An inspection of these proposed com-
plexes reveals that the aldehydic hydrogen in aldose-
dimolybdate complexes can be replaced by CH3 without
introducing unfavorable steric crowding in this region of the
complexes (see Scheme 2), thus explaining the facile
interconversion of 9 and 2 via analogous C2-C3 bond
cleavage and transposition.
As observed previously,12 the stereochemistry of the
reaction is controlled by the structures of I and II, but the
underlying driving force governing C-C bond cleavage
remains elusive. A putative transition state (Figure 3) for
cases, the equilibria highly favored the 2-ketopentoses. The
observed reactivity of 11 suggests a high tolerance of
relatively large functional groups at C2 of the aldotetrose
core. While COOH(R) substituents were not investigated,
these reactions are expected to yield R-ketoacid(ester)
products, thus potentially providing a convenient route to
these biologically important compounds.
The route shown in Scheme 1 can be adapted for selective
or multiple 13C-labeling of 2 at sites in addition to C1. 13C-
Labeled D-erythrono-1,4-lactones are obtained from the
oxidation of labeled D-erythroses, which are available in
various 13C-isotopomeric forms.20-22 Thus, for example, [2,5-
13C2]-2 is prepared from D-[2,4-13C2]erythrose 14, which is
obtained via glycol scission21,22 from D-[4,6-13C2]glucose 15
as shown in Scheme 4.
The uniqueness of the epimerization reaction described
herein assumes further significance when the close cor-
respondence is noted between the Mo-catalyzed intercon-
version of 9 and 2 and the proposed metabolism of 1 via the
(18) The 13C{1H} NMR spectrum of purified 2 in H2O/2H2O solvent
showed the presence of R- and â-furanose and acyclic keto forms, with the
latter considerably more abundant than the former (Figure 2). The following
chemical shifts (in ppm relative to δC1 of R-mannopyranose (95.2 ppm))
were observed for the keto (k) and furanose (f) forms: C2k (214.5); C2f
(107.6, 104.2); C3, C4, C5 (82.7f, 82.3f, 78.7k, 77.6f, 76.5f, 73.0k, 71.0f,
63.7k); C1 (27.3k, 25.2f, 22.3f).
Figure 3.
the reaction starting from complexed 9 (see Scheme 2)
involves partial breaking of the C1-O1 and C2-C3 bonds
and partial formation of C2-O1 and C1-C3 bonds. The
dimolybdate bridge controls the stereochemistry at C1 and
C3, which become the chiral C3 and C4 atoms in the product
2. The original C2 of 9 becomes the C2 carbonyl of 2 in its
hydrated (gem-diol) state. Diol formation at C2 may be
(19) Hoeksema, H.; Baczynskyj, L. J. Antibiot. 1976, 29, 688-691.
(20) Serianni, A. S.; Clark, E. L.; Barker, R. Carbohydr. Res. 1979, 72,
79-91.
(21) Serianni, A. S.; Bondo, P. B. J. Biomol. Struct. Dyn. 1994, 11,
1133-1148.
(22) Serianni, A. S.; Vuorinen, T.; Bondo, P. B. J. Carbohydr. Chem.
1990, 9, 513-541.
Org. Lett., Vol. 3, No. 24, 2001
3821

scribed herein mimics this biological transformation. In the
metabolic pathway, no evidence exists implicating the
involvement of molybdenum in the pinacol rearrangement.
However, the ease with which Mo-catalyzed epimerization
occurs may hint at a heretofore unrecognized role for
molybdenum in other biological epimerizations via a mech-
anism similar to that shown in Scheme 2. This is an intriguing
possibility that remains to be explored.
Scheme 4
Acknowledgment. This work was supported by a grant
from Omicron Biochemicals, Inc. of South Bend, IN.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2, 8-11,
and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
non-mevalonate isoprenoid pathway. It has been suggested
that 1 is converted in vivo to 2-C-(methyl)-D-erythritol 4P
via tandem pinacol rearrangement/reduction during its
metabolism.1-5 The molybdate-catalyzed rearrangement de-
OL016265F
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Org. Lett., Vol. 3, No. 24, 2001