Taming carbohydrate complexity: A facile, high-yield route to chiral 2,3-dihydroxybutanoic acids and 4-hydroxytetrahydrofuran-2-ones with very high optical purity from pentose sugars

Full text of DOI:10.1021/jo991069w

J . Org. Chem. 1999, 64, 7633-7634
7633
Ta m in g Ca r boh yd r a te Com p lexity:
A F a cile, High -Yield Rou te to Ch ir a l
,3-Dih yd r oxybu ta n oic Acid s a n d
Ch a r t 1
2
4
-Hyd r oxytetr a h yd r ofu r a n -2-on es w ith
Ver y High Op tica l P u r ity fr om
P en tose Su ga r s
Rawle I. Hollingsworth*
Department of Chemistry, Michigan State University,
East Lansing, Michigan 48824
Received J uly 2, 1999
(S)-3,4-Dihydroxybutanoic acid and its γ-lactone ((S)-
4
-hydroxytetrahydrofuran-2-one) are important four-
carbon synthons obtainable from some substituted D-
hexose sugars and from L-malic acid. Until now there has
been no easy route to the R-isomers because of the rarity
both of suitably substituted L-hexose sugars and D-malic
acid. Here we describe a method for preparing both
enantiomeric forms of the free acids and their corre-
sponding γ-lactones from pentose sugars.
The S-isomers of 3,4-dihydroxybutanoic acid (1, Chart
1
) and the corresponding γ-lactone 2 have recently been
1
used in the preparation of a chiral membrane probe, pH-
sensitive liposomes,2 drug intermediates,
3-5
advanced
6
two-dimensional supramolecular systems, and azetidi-
nones. These same molecules or close derivatives from
tion of the enol so formed. The diketone is cleaved by
7
15
peroxide anion to yield the products.
(
S)-malic acid (hydroxybutanedioic acid) 3 have been used
The preparation of 1 and 2 from malic acid often
involves the reduction of the acid to the corresponding
butanetriol (4) followed by conversion to (S)-4-hydroxy-
methyl-2,2-dimethyl-1,3-dioxolane (5). The lone alcohol
function is often oxidized to the level of an acid or
aldehyde. The triol 4 and derivatives are readily obtain-
able from 1 by a simple reduction (with half as many
equivalents compared to the malic acid case). Treatment
of 1 with 2,2-dimethoxypropane and methanol with a
trace of acid easily affords the 4-carboxymethyl-1,3-
dioxolane 6 without the expense of the reduction and
oxidation steps required if malic acid were used. Com-
pounds 1 and 2 therefore allow access to a wide spectrum
of optically pure three- and four-carbon synthons with
very well-established uses.
Because the abundant naturally occurring hexoses
have the D-configuration, it has not been possible to use
this chemistry to access the complimentary range of
compounds that can be afforded by the (R)-lactone. Two
of the pentose sugars, arabinose (7) and xylose (8), occur
abundantly as both the D- and the L-forms. L-Arabinose
is especially abundant and is a predominant component
of the complex carbohydrates found in sugar beet pulp
and some wood pulp residues. Substitution of the 3-posi-
tion of L-arabinose with a good leaving group such as an
acetal ring residue should make it susceptible to alkaline
peroxide oxidation to yield the (R)-dihydroxybutyric acid
to prepare a variety of chiral substructures and phar-
maceutical intermediates.8
-14
Compounds 1 and 2 were
obtained by the selective oxidative cleavage of 4-linked
hexopyranose sources such as lactose, starch, cellulose,
cellobiose, maltose, and maltodextrins. In the prepara-
tion of 1 and 2 by this method, the chiral centers are
derived from the 5-position of a hexose that always has
the D-configuration. The mechanism of the reaction
involves the isomerization of the reducing aldose sugar
to a ketose, which readily affords a 2,3-diketone by
â-elimination of the 4-alkoxy function and tautomeriza-
1
*
Phone: 517-353-0613. Fax: 517-353-9334. E-mail: rih@argus.cem.
msu.edu.
(
1) Huang, G.; Hollingsworth, R. I. Tetrahedron 1998, 54, 1355-
1
1
1
9
1
360.
(
2) Song J .; Hollingsworth, R. I. J . Am. Chem. Soc.1999, 121, 1851-
861.
(
3) Wang, G.; Hollingsworth, R. I. J . Org. Chem. 1999, 64, 1036-
038.
(4) Huang, G.; Hollingsworth, R. I. Tetrahedron Asymmetry 1999,
, 4113-4115.
(
5) Wang, G.; Hollingsworth, R. I. Tetrahedron Assym. 1999, 10,
895-1901.
(
(
6) Wang, G.; Hollingsworth, R. I. Langmuir 1999, 15, 3062-3069.
7) Wu, G.; Wong, Y.; Chen, X.; Ding, Z. J . Org. Chem. 1999, 64,
3
714-3718.
8) Corey, E. J .; Niwa, H.; Knolle, J . J . Am. Chem Soc. 1978, 100,
942-1943.
9) Uchikawa, O.; Okukado, N.; Sakata, T.; Arase, K.; Terada, K.
Bull. Chem. Soc. J pn. 1988, 61, 2025-2029.
10) Hayashi, H.; Nakanishi, K.; Brandon, C.; Marmur, J . J . Am.
Chem. Soc. 1973, 95, 8749-8757.
11) Danklmaier, J .; Honig, H. Liebigs. Ann. Chem. 1988, 1149-
153.
12) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5419-5422.
13) Shieh, H. M.; Prestwich, G. D. Tetrahedron Lett. 1982, 23,
643-4646.
14) Mori, K.; Takigawa, T.; Matsuo T. Tetrahedron Lett. 1988, 29,
423-5426.
(
1
(
(
(Scheme 1) through the formation of an R-dicarbonyl
(
intermediate. This is assuming that conditions can be
found in which the myriad of possible competing reac-
tions such as oxidation of the aldehyde group or aldol
condensations do not compete. Acetals afford a quick
1
(
(
4
5
(
(15) Hollingsworth, R. Biotechnol. Annu. Rev. 1996, 2, 281-291.
1
0.1021/jo991069w CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/14/1999

7
634 J . Org. Chem., Vol. 64, No. 20, 1999
Notes
Sch em e 1
straightforward way of selectively functionalizating hy-
droxyl groups, even in complicated molecular systems
with several hydroxyl groups. The 3,4-O-isopropylidene
acetal 9 can be prepared simply and in very high yield
Exp er im en ta l Section
Typ ica l P r oced u r es for Oxid a tion . 3,4-O-Isopropylidene-
L-arabinose (30 g) was treated with 2700 mL of 0.36% sodium
hydroxide and 27 g of 30% hydrogen peroxide. The mixture was
heated at 65 °C for 10 h, neutralized, extracted with 1 volume
of ethyl acetate, concentrated to a syrup, acidified to pH 1 with
(
>90%) from L-arabinose.16 The oxidation of pentose
acetals (or indeed any sugar acetals) to yield these
products has never been described. Oxidation of 9 with
hydrogen peroxide and sodium hydroxide under the
6
M sulfuric acid, and concentrated at 40 °C until no more
solvent was removed. The syrup was extracted with 1.5 L of ethyl
acetate. The ethyl acetate layer was concentrated to yield 15.5
g (96%) of (R)-3-hydroxy-γ-butyrolactone. The product was >90%
pure by gas chromatography and could be purified by silica
chromatography using 9:1 chloroform:methanol. Chiral GC
1
conditions described before readily yielded (R)-3,4-dihy-
droxybutanoic acid in >85% yield and 99.5% ee. Oxida-
tion of the acetal of the D-sugar gave the corresponding
(
S)-lactone in the same yield and optical purity. The 3,5-
analysis on a cyclodextrin phase (Supelco Betadex) showed
1
6
O-isopropylidene acetals of xylose also gave good con-
version to the corresponding enantiomeric acids. The
oxidation could be extended to the less attractive 2,3-
acetal of D-ribose,16 which also gave (S)-3,4-dihydroxybu-
tanoic acid, but in much lower yield. 3-O-Galactosyl
D-arabinose is also commercially available and is a good
1
>
2
99.8% of the R-isomer: H NMR (300 MHz, D-chloroform) δ
.28 (1H, dd, J ) 18.0 + 0.2 Hz), 2.73 (1H, dd, J ) 18.0 + 5.8
Hz), 4.13 (1H, dd, J ) 9.8 + 0.2 Hz), 4.31 (1H, dd, J ) 9.8 + 4.5
Hz, 4.48, (1H, m); 13C NMR (75 MHz) 177.1, 76.8, 67.8, 37.7,
[R]
D
+87.4 (c ) 3.1, ethanol), lit.19 [R]
+86°.
D
In an alternative procedure, the oxidation was carried out on
60 g of 3,4-O-isopropylidenearabinose, and the volumes of the
liquid were considerably reduced, but the desired concentration
of hydrogen peroxide and sodium hydroxide maintained by
pumping in the solutions. The acetal was dissolved in 800 mL
of water. Sodium hydroxide (40 g) dissolved in 300 mL of water
and hydrogen peroxide (60 g) dissolved in 300 mL of water, were
added to the heated solution (56 °C) over a 6 h period. Heating
was continued for a further 3 h after the addition was completed.
The product was isolated as the lactone as described above. The
yield and purity were similar.
3
-linked pentose source to which this oxidation can be
applied to yield (S)-3,4-dihydroxybutanoic acid.
Despite their availability and chiral richness, carbo-
hydrates are still grossly underutilized as raw materials
for fine chemistry. The oxidation of carbohydrates to yield
1
,15,17
(S)-3,4-dihydroxybutanoic acid and derivatives
is an
important step forward in renewable resource chemistry.
Here we provide for an expansion of renewable raw
material resources and a broader stereochemistry palette
which should considerably further our advancement
toward a carbohydrate-based chiral chemistry. This
method is superior in yield and far more simple than the
other carbohydrate route that utilizes D- and L-ascorbic
acid in a complex seven-step process that involves me-
sylation, halogenation, and a hydrogenation step.18
Ack n ow led gm en t. This work was supported by
Synthon Corp. and the State of Michigan Research
Excellence Fund.
J O991069W
(
(
16) Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95-101.
17) Hollingsworth, R. Process for the preparation of 3,4-dihydroxy-
(18) Tanaka, A.; Yamashita, K. Synthesis 1987, 6, 570-574.
(19) Masse, C. E.; Yang, M.; Soloman, J .; Panek, J . S. J . Am. Chem.
Soc. 1998, 120, 4123-4134.
butanoic acid and salts thereof. U.S. patent 5,292,939, 1994.