Diastereoselective synthesis of all eight L-hexoses from L-ascorbic acid

Article abstract of DOI:10.1021/jo0521192

A novel versatile method for the synthesis of all eight diastereomerically pure L-hexoses was developed. L-Ascorbic acid was converted to two diastereomers A. These α-hydroxy esters were transformed into four γ-alkoxy- α,β-unsaturated esters C via the int

Full text of DOI:10.1021/jo0521192

Diastereoselective Synthesis of All Eight L-Hexoses from
L-Ascorbic Acid
Ludmila Ermolenko and N. Andre´ Sasaki*
Institut de Chimie des Substances Naturelles, CNRS,
1 AVenue de la Terrasse, 91198 Gif-sur-YVette, France
andre.sasaki@icsn.cnrs-gif.fr
ReceiVed October 10, 2005
A novel versatile method for the synthesis of all eight diastereomerically pure L-hexoses was developed.
L-Ascorbic acid was converted to two diastereomers A. These R-hydroxy esters were transformed into
four γ-alkoxy-R,â-unsaturated esters C via the intermediates B and subsequent Wittig olefination reactions.
Each one of compounds C was subjected to dihydroxylation to provide a set of two diols D. Anti/syn-
differentiation in diol formation was manipulated by using (DHQD)2PHAL and (DHQ)2PHAL as chiral
ligands. Further two-step reaction sequence affords all eight diastereopure L-hexoses.
Introduction
saponin from a marine octocoral has been reported.8 L-Hexoses
have also demonstrated potential as noncaloric sweeteners,9
laxatives,10 and selectively toxic insecticides.11
The rare L-hexoses are key components of numerous biologi-
cally important oligosaccharides, glycopeptides, steroid glyco-
sides, antibiotics, and other biologically active natural products.
L-Altrose, for instance, is a constituent of extracellular polysac-
charide from ButuriVibrio fibrisolVents strain CF3.1 L-Gulose
constitutes the disaccharide subunit of bleomycin A3, the major
component of a family of glycopeptide antibiotics.2 L-Idose is
a constituent of heparin and heparane sulfates that are found
on the cell surfaces and the extracellular matrix of all eukaryotes
where they play pivotal role in a large number of biological
events.3-6 L-Mannose has been found in the sugars units of
steroid glycosides.7 Recently, isolation of the first R-L-galactosyl
Although replacing an L-amino acid with its D-isomer in a
bioactive peptide is quite relevant in order to alter its physi-
ological consequences, this sort of enantiomer-exchange has
hardly been practiced in the domain of glycoconjugates.
Given the importance of L-hexoses in the field of glycobi-
ology and limited natural sources, the need to develop efficient
methodologies for their synthesis continues to exist. Among the
methods known in the literature ranging from classical modi-
fication of readily available D-sugars to the recent organocata-
lytic aldol synthesis and iterative dihydroxylation of dienes,12
there are only two versatile strategies that can provide all eight
hexoses. These are the Masamune-Sharpless synthesis employ-
ing asymmetric epoxidation as a key step13 and the Ogasawara
procedure starting from furfural via levoglucosenone by oxida-
tive ring expansion.14
(1) Stack, R. J. FEMS Microbiol. Lett. 1987, 48, 83-87.
(2) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1997, 62, 6261-
6267.
(3) van Boeckel, C. A. A.; Beetz, T.; Vos, A. J. M.; de Jong, A. J. M.;
van Aelst, S. F.; van den Bosch, R. H.; Mertens, J. M. R.; van der Vlugt,
F. A. J. Carbohydr. Chem. 1985, 4, 293-321.
(4) Prabhu, A.; Venot, A.; Boons, G.-J. Org. Lett. 2003, 26, 4975-4978.
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Y.-S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.; Hung, S.-C.
Chem. Eur. J. 2004, 10, 399-415.
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Herbert, J.-M.; Petitou, M.; Sinay, P. Biorg. Med. Chem. 1999, 7, 1567-
1580.
(7) Kubelka, W. Phytochemistry 1974, 13, 1805-1808.
(8) Guttie´rrez, M.; Capson, T.; Guzma´n, H. M.; Quin˜oa´, E.; Riguera, R.
Tetrahedron Lett. 2004, 45, 7833-7836.
(9) (a) Shallenberger, R. S.; Acree, T. E.; Lee, C. Y. Nature 1961, 221,
555-556. (b) Levin, G. V. U.S. Patent 4262032, 1981.
(10) Tarka Jr., S. M.; Shively, C. A.; Apgar, J. L.; Koch, K. L. U.S.
Patent 5219573, 1989.
(11) Levin, G. V.; Zehner, L. R. U.S. Patent 5166193, 1992.
10.1021/jo0521192 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/09/2005
J. Org. Chem. 2006, 71, 693-703
693

Ermolenko and Sasaki
SCHEME 1. General Strategy for the Synthesis of
L-Hexoses
The key compound of the series, ethyl (2R,3S)-3,4-O-
isopropylidene-2,3,4-trihydroxybutanoate 1, was prepared from
L-ascorbic acid in two steps by the known procedure.16 Inversion
of configuration at C-2 in 1 by the convenient chloroacetate
modification of the Mitsunobu reaction17 provided ethyl (2S,3S)-
3,4-O-isopropylidene-2,3,4-trihydroxybutanoate 2 in 65% yield
after the selective chloroacetate alcoholysis in mild basic
conditions (Scheme 2). For pursuing the synthesis, the free
hydroxyl group in 1 and 2 must be protected. To this end, we
chose benzyl group that facilitated easy removal under neutral
conditions. Benzylation of a substrate possessing both base-
sensitive ester and acid-labile acetal functionalities is rather
challenging task. Benzylation of a hydroxy group by treatment
of 1 and 2 with benzyl trichloroacetimidate in the presence of
catalytic amount of triflic acid18 was attempted only to recover
starting material after 24 h under standard conditions. Under
more acidic conditions, the isopropylidene group was partially
removed. Eventually, benzylation of 1 with benzyl bromide in
the presence of silver oxide19 in dichloromethane was proved
to be efficient for affording the O-benzyl ether 3 in 85% yield
after 3 h. As for the hydroxyester 2, the same O-benzylation
conditions gave 4 only in 70% yield after 72 h. Better result
was obtained when the reaction was performed in boiling
acetonitrile in the presence of catalytic amount of Bu4NI.20 The
O-benzyl ester 4 was isolated in 80% yield after 12 h. Since a
direct reduction of these esters to the corresponding aldehydes
gave mixtures, the two-step procedure was applied. The
reduction of 3 and 4 with LiBH4 in ether21 furnished the alcohols
5 and 6 in 95% yield. Subsequent Swern oxidation of these
alcohols afforded the pure aldehydes 7 and 8 that can be directly
used in the following olefination step.
Olefination of R-alkoxy-substituted aldehydes and ketones
has been shown to be sensitive to the reagent, solvent, occasional
additives, and reaction temperature. The reaction of semistabi-
lized phosphoranes Ph3PdCHCOOR (R ) Me or Et) with
R-alkoxy aldehydes have been reported to give the R,â-
unsaturated esters in E/Z ratios varied from 10:1 (CH2Cl2, rt)22
to 1:10 (MeOH, 0 °C).23 In accordance with these results, the
reaction of aldehyde 7 with Ph3PdCO2Et in CH2Cl2 provided
the R,â-unsaturated ester 9 with an E/Z ratio of 10:1 in 80%
yield (Scheme 2). However, under the same conditions, aldehyde
8 gave the corresponding enoate 10 in E/Z ratio of 2:1. In
benzene, the reaction became nonselective (E/Z ) 1:1). To
resolve this problem, we turned our attention to the stabilized
phosphonates that, in general, exhibit a strong (E)-selectivity
with R-alkoxy aldehydes.24 Indeed, the coupling of triethyl
phosphonoacetate with aldehydes 7 and 8 in benzene at room
temperature resulted in the unsaturated esters 9 and 10 in high
Results and Discussion
In our preliminary communication, we have reported a novel
stereodivergent approach to L-hexoses using L-ascorbic acid as
a single starting material by exploiting the inherent chirality at
the C-5 stereocenter of final products.15 As illulstrated in Scheme
1, our strategy to synthesize all eight diastereopure L-hexoses
comprises the following major steps: (i) preparation of two
chiral aldehydes B, one of which involving Mitsunobu inversion,
from R-hydroxy ester A that is in turn readily available from
L-ascorbic acid; (ii) transformation of aldehydes B into four R,â-
unsaturated esters C with the specified (E) or (Z) configuration
via the Wittig olefination reactions; (iii) stereoselective dihy-
droxylation of each one of R,â-unsaturated esters C followed
by partial reduction of resulting eight polyol esters D; (iv)
cyclization of thus obtained aldehydes E to provide L-hexopy-
ranoses F.
As a result of our efforts in developing this methodology into
a truly practical method, we describe herein the synthesis of all
eight diastereoisomers of L-hexoses by employing Sharpless
asymmetric dihydroxylation as a key step.
(12) (a) Humoller, F. L.; Frush, H. L.; Isbell, H. S.; Sowden, J. C.;
Whistler, R. L.; BeMiller, J. N.; Shafizaden, F. In Methods in Carbohydrate
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Evans, M. E.; Parrish, F. W.; Blanc-Muesser, M.; DeFaye, J.; Horton, D.;
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Pitzer, K. K.; Thorpe, A. J. Chem. ReV. 1996, 96, 1195-1220 and references
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Tetrahedron Lett. 2001, 42, 1321-1324. (e) Hung, S.-C.; Wang, C.-C.;
Thopate, S. R. Tetrahedron Lett. 2000, 41, 3119-3122. (f) Harris, J. M.;
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Res. 2000, 328, 17-36. (g) Adinolfi, M.; Barone, G.; De Lorenzo, F.;
Iadonisi, A. Synlett 1999, 3, 336-338. (h) Hajko´, J.; Lipta´k, A.; Pozsgay,
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1988, 53, 2598-2602.
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K. B.; Walker, F. J. Tetrahedron 1990, 46, 245-264.
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3578-3582.
694 J. Org. Chem., Vol. 71, No. 2, 2006

DiastereoselectiVe Synthesis of L-Hexoses from L-Ascorbic Acid
SCHEME 2. Synthesis of r,â-Unsaturated Esters 9-12a
a Key: (a) ClCH2COOH, Ph3P, DIAD, THF, 12 h, then Et3N-EtOH, 65% in two steps; (b) BnBr, Ag2O, CH2Cl2, rt, 3 h, 85%; (c) BnBr, Ag2O, CH3CN,
reflux, 12 h, 80%; (d) LiBH4, Et2O, 0 °C, 2 h, 95%; (e) (COCl)2, DMSO, CH2Cl2, -70 °C, 20 min, Et3N, -78 °C, 1 h, 95%; (f) (C2H5O)2POCH2CO2Et,
NaH, benzene, rt, 2h; (g) (CF3CH2O)2POCH2CO2Me, 18-crown-6, KN(TMS)2, THF, -78 °C.
yield and selectivity (E/Z ) 98:2). For the preparation of (Z)
unsaturated esters, the Still modification25 of the Horner-
Emmons procedure was applied to the aldehydes 7 and 8
resulting in esters 11 and 12, respectively, with excellent (Z)
selectivity (>99:1). It should be noted that all the (E)- and
(Z)-isomers obtained in this series are easily separable by column
chromatography on silica gel. With all four R,â-unsaturated
esters (9-12) in hand, the dihydroxylation of these substrates
was addressed to set the remaining two stereogenic centers on
the hexose precursors.
The stereochemical outcome of the osmium-catalyzed dihy-
droxylation of γ-alkoxy-R,â-unsaturated esters follows the
Kishi-Stork empirical rule that predicts 1,2-anti relationship
between the resident and newly formed stereogenic centers in
case of (E)-γ-alkoxy enoates, and 1,2-syn product for the
(Z)-γ-alkoxy conjugate esters.26 The (E)-γ-alkoxy-R,â-unsatur-
ated esters typically show strong facial preference, though
(Z)-enoates often exhibit irregular magnitude of diastereofacial
selectivity that can vary from very low (1:1) to very high
(25:1).27 With regard to dihydroxylation of our R,â-unsaturated
esters, a low selectivity for some diol products and inacces-
sibility of others could be the issue.28
dihydroxylation of γ-alkoxy-R,â-unsaturated esters. However,
improvements in selectivity have remained moderate, even under
stoichiometric conditions.27f,29 It is assumed that the use of a
more efficient second-generation chiral ligands can override the
inherent facial selectivity of (E)-γ-alkoxy-R,â-unsaturated ester
by its own induction efficacy. This makes the otherwise minor
diastereomer available in acceptable yield. The catalytic asym-
metric dihydroxylation using the latest techniques has been
successfully applied to a number of (E)-γ-alkoxy-R,â-unsatur-
ated esters and R,â-unsaturated lactones. However, to the best
of our knowledge, no data is available for the corresponding
(Z)-enoates, and no systematic application of asymmetric
dihydroxylation to the synthesis of sugars, particularly to
hexoses, has been reported. We expected the Sharpless asym-
metric dihydroxylation would provide a powerful tool to
overcome the inherent facial selectivity of our substrates and
to gain access, from the same R,â-unsaturated ester, to both
stereoisomers of diol in acceptable yields regardless the con-
figuration of double bond and γ-stereogenic center. Previously
reported results on the double diastereoselection in asymmetric
dihydroxylation of the R,â-unsaturated esters30 prompted
(27) (a) Saito, S.; Morikawa, Y.; Moriwake, T. J. Org. Chem. 1990, 55,
5424-5426. (b) Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S.; Bennet,
F.; Taylor, I. D. J. Chem. Soc., Perkin Trans. 1 1986, 815-821. (c)
Izquierdo, I.; Plaza, M. T.; Robles, R.; Rodriguez, C. Tetrahedron:
Asymmetry 1996, 7, 3593-3604. (d) DeNinno, M. P.; Danishefsky, S. J.;
Schulte, G. J. Am. Chem. Soc. 1988, 110, 3925-3929. (e) Evans, D. A.;
Kaldor, S. W. J. Org. Chem. 1990, 55, 1698-1670. (f) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron 1988, 44, 6897-6902.
(e) Jorgensen, M.; Iversen, E. H.; Madsen, R. J. Org. Chem. 2001, 68,
4625-4629.
Ever since the introduction of asymmetric dihydroxylation,
the double-asymmetric induction principle has been applied to
(24) (a) Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V., S.; Masamune,
S.; Sharpless, K., B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982,
47, 1373-1378. (b) Minami, N.; Ko, S., S.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 1109-1111. (c) Trost, B. M.; Lynch, J.; Renaut, P.; Steinman,
D. H. J. Am. Chem. Soc. 1986, 108, 284-291. (d) Larsen, R. O.; Aksnes,
G. Phosphorus Sulfur 1983, 16, 339-344.
(25) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(26) (a) Christ, W. C.; Cha, J. K.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3947-3950. (b) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24, 3951-
3954. (c) Cha, J. K.; Christ, W. C.; Kishi, Y. Tetrahedron 1984, 40, 2247-
2255.
(28) In our preliminary studies on OsO4/NMO dihydroxylation of
TBDPS-protected analogues of 9, 10, 11, and 12, the diols were produced
in ratios 90:10, 85:15, 30:70, and 40:60, respectively.
(29) Brimacombe, J. S.; McDonald, G.; Abdur Rahman, M. Carbohydr.
Res. 1990, 205, 422-427.
J. Org. Chem, Vol. 71, No. 2, 2006 695

Ermolenko and Sasaki
SCHEME 3. Synthesis of l-Galactose19, L-Idose 21, L-Glucose 29, and L-Altrose 31a
a Key: (a) OsO4, (DHQD)2PHAL, K3Fe(CN)6, MeSO2NH2, t-BuOH/H2O, 90%; (b) OsO4, (DHQ)2PHAL, K3Fe(CN)6, MeSO2NH2, t-BuOH/H2O, 90%;
(c) DMP, acetone; (d) DIBAL, toluene; (e) 80% acetic acid; (f) Ac2O, Et3N, DMAP, CH2Cl2; (g) H2, Pd/C, EtOAc.
us to opt for the phthalazine ligands, (DHQD)2PHAL and
(DHQ)2PHAL, as the ligands of choice. In view of wide variety
of steric and electronic factors involved in the reaction, each
major diol product obtained during our studies was converted
into corresponding sugar pentaacetate to confirm unequivocally
its stereochemistry by comparing its 13C NMR spectrum with
the known data of the D-series.31 Selectivities of dihydroxylation
were determined by HPLC using pure diols as references.
L-Galactose, L-Idose, L-Glucose, and L-Altrose. Syntheses
of these four hexoses were achieved by asymmetric dihydroxyl-
ation of (E)-unsaturated esters 9 and 10 using the “reinforced
AD-mix” reagent formulations (6% OsO4, 10% of the corre-
sponding ligand, 3 equiv of K3Fe(CN)6, 3 equiv of K2CO3, 1
equiv of MeSO2NH2). When (E)-unsaturated ester 9 was
dihydroxylated in the presence of the â-directing (DHQD)2PHAL
ligand, the easily separable diols 13 (â-face attack product) and
14 (R-face attack product) were obtained in 99:1 ratio and in
90% yield (Scheme 3). As in the case of esters 1 and 2, an
appropriate protection of the free hydroxyls of 13 was needed
for the next reduction step. From our earlier experience in the
synthesis of 2-amino sugars32 and L-sugars,15 the selective
monoprotection of one of the two newly formed hydroxy groups
of diol esters was expected to be difficult in some cases.
To keep results consistent along with all the series, we chose
the isopropylidene protecting group which is stable to DIBAL
reduction conditions. Accordingly, the diol 13 was converted
into its acetonide 15 (2,2-dimethoxypropane, 3% of p-TsOH)
in 95% yield after 6 h. The totally protected hydroxy ester 15
was reduced with DIBAL in toluene at -78 °C to give the
aldehyde 17 in excellent yield (95%).20 Although no over-
reduction to the alcohol was observed, quenching of the reaction
with methanol resulted in 30% of the corresponding dimethyl-
acetal. Since both of these compounds were useful for our
synthetic purpose, thus obtained crude product was subjected
to cyclization without further purification. Hydrolysis of the
product with Amberlite IR 120 in 1/1 dioxane-water followed
by acetylation afforded the fully protected L-galactose 19 in 60%
yield (three steps) as a mixture of R- and â-anomers in 22:78
ratio. Hydrogenolysis of the benzyl group in 19 followed by
acetylation gave pentaacetate of L-galactose 20 in 95% yield
(two steps). The 13C NMR spectrum of 20 was proved identical
(30) (a) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568-
7570. (b) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7570-7571. (c) Morikawa, K.; Sharpless K., B. Tetrahedron Lett.
1993, 34, 5575-5578. (d) Ziegler, F. E.; Wang, Y. J. Org. Chem. 1998,
63, 7920-7930. (e) Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993,
58, 7096-7099. (f) Abdur Rahman, M.; Adams, J. P.; Boyes, A. L.; Kelly
M. J.; Mansfield, D. J.; Procopiou, P. A.; Roberts, S. M.; Slee, D. H.;
Sidebottom, P. J.; Sik, V.; Watson, N. S. J. Chem. Soc., Chem. Commun.
1993, 1841-1843.
(31) Bock, K.; Thogersen, H. Annu. Rep. NMR Spectrosc. 1982, 13,
1-57.
(32) Ermolenko, L.; Sasaki, N. A.; Potier, P. J. Chem. Soc., Perkin Trans.
1 2000, 2465-2473.
696 J. Org. Chem., Vol. 71, No. 2, 2006

DiastereoselectiVe Synthesis of L-Hexoses from L-Ascorbic Acid
SCHEME 4. Synthesis of l-Gulose 38, L-Talose 40, L-Allose 48, and L-Mannose 50a
a Key: (a) OsO4, (DHQD)2PHAL, K3Fe(CN)6, MeSO2NH2, t-BuOH/H2O, 90%; (b) OsO4, (DHQ)2PHAL, K3Fe(CN)6, MeSO2NH2, t-BuOH/H2O, 90%;
(c) DMP, acetone; (d) DIBAL, toluene; (e) 80% acetic acid; (f) Ac2O, Et3N, DMAP, CH2Cl2; (g) H2, Pd/C, EtOAc.
to those published for the corresponding pentaacetates of
D-galactose.31
Thus, dihydroxylation of (E)-ester 10 in the presence of
(DHQD)2PHAL ligand afforded diols in 55:1 ratio in favor of
the â-diol 23 with gluco-configuration in 72% yield. Reward-
ingly, the use of R-directing (DHQ)2PHAL ligand gave pre-
dominantly the R-diol 24 with altro-configuration that was
obtained virtually as a single isomer in 88% yield. Thus, the
catalytic asymmetric dihydroxylation of our (E)-R,â-unsaturated
esters 9 and 10 proceeded under the control of a chiral ligand
and provided all four corresponding L-hexoses in high selectivity
and in good overall yield.
It was noted that 2,3-O-isopropylidene protection of the diol
23 proceeded rapidly and in 90% yield as in case of the diol
13. On the other hand, the diol 24 reacted sluggishly (exactly
the same as for the diol 14). The reduction of the fully protected
hydroxy ester 25 and 26 was carried out at -78 °C with DIBAL
in toluene to give the aldehydes 27 and 28, respectively, in 95%
yield in both cases. Acetonide deprotection of the aldehyde 27
in the presence of Amberlite IR 120 followed by acetylation
afforded fully protected L-glucose 29 in 70% yield (two steps)
as a mixture of R- and â-anomers in approximately 42:58 ratio.
Pentaacetate of L-glucose 30 was obtained by hydrogenolysis
of the benzyl group of 29 followed by acetylation in 95% yield
(two steps). The same reaction sequence was applied to the
aldehyde 28 to furnish pentaacetate of L-altrose 31 as a mixture
(71:29) of R- and â-anomers. The 13C NMR spectra of thus
obtained pentaacetates match to the corresponding data known
in the literature on the fingerprint level.31
The example of the galacto-isomer 13 was rather trivial since
both the diastereofacial selectivity of the substrate 9 and the
directing effect of the chiral ligand were matching. On the
contrary, the ido-isomer 14 was not expected to be available in
reasonable yield by ligand-free dihydroxylation of 9 (see the
note aboVe). However, to our delight, under the influence of
the R-directing (DHQ)2PHAL ligand the direction of dihydroxyl-
ation was changed drastically to give diols 14 (R-face attack)
and 13 (â-face attack) in 95:5 ratio and in 90% yield (Scheme
3). Conversion of the diol ester 14 into its acetonide 16
proceeded sluggishly (48 h, compared to 6 h required for 13),
but in 96% yield. The aldehyde 18 was obtained in 95% yield
by reducing with DIBAL. Deprotection of both of the acetonide
groups of aldehyde 18 in 1/1 dioxane-water in the presence of
Amberlite IR 120 followed by acetylation led to the 1,2,3,6-
O-teraacetyl-4-O-benzyl-L-idose 21 in 60% yield as a mixture
of R- and â-anomers in ca. 4:6 ratio. Pentaacetate of L-idose
22 was obtained by hydrogenolysis of the benzyl ester 21
followed by acetylation in 95% yield (2 steps). The 13C NMR
spectrum of 22 was identical to that published for the pentaac-
etates of D-idose.31
L-Glucose and L-altrose are the epimers at C-4 of L-galactose
and L-idose, respectively. The preparation of these hexoses was
attained with high diastereoselectivity from the (E)-unsaturated
ester 10 in the same synthetic sequence as described above.
J. Org. Chem, Vol. 71, No. 2, 2006 697

Ermolenko and Sasaki
L-Gulose, L-Talose, L-Allose, and L-Mannose. The structure
of these four hexoses can be easily related to cis-dihydroxylation
of the (Z)-enoates 11 and 12 (see Scheme 4). Unfortunately,
little is known with certitude about the diastereofacial selectivity
of this transformation, and its magnitude could not be predicted
a priori as was mentioned above. Among a limited number of
reports on osmylation of (Z)-conjugated carbonyl substrates, the
1,2-syn stereochemistry of dihydroxylation was found in ac-
cordance with the Kishi-Stork rule in most cases. Nevertheless,
several authors have reported the 1,2-anti addition that presum-
ably involves other factors. Taking into account that the
Sharpless AD of (Z) olefins is less selective than that of (E)
olefins, the catalytic asymmetric dihydroxylation of our (Z)-
enoates 11 and 12 has been expected to be the most intriguing
of the series. In the event, the dihydroxylation of unsaturated
(Z)-ester 11 in the presence of (DHQD)2PHAL ligand afforded
the mixture of the diol esters 32 and 33 in 91:9 ratio, while the
dihydroxylation with R-directing ligand (DHQ)2PHAL pro-
ceeded less selective to give the diol 33 with a 84:16 diaste-
reoselectivity.
Dihydroxylation of (Z)-unsaturated ester 12 followed the same
direction regardless of the C-4 stereocenter. Thus, in the
presence of (DHQD)2PHAL ligand, the dihydroxylation of 12
furnished in a 87:13 ratio the diols 42 and 43. Similarly, the
use of (DHQ)2PHAL provided the mixture of products in ratio
94:6 in favor of the diol 43. These results clearly demonstrated
that the asymmetric dihydroxylation of our R,â-unsaturated
esters 9-12 proceeded under the total control of the chiral ligand
used, regardless of the chirality of C-4 stereogenic center and
double-bond configuration. As in the previous cases, the
stereochemistry of these products was unequivocally proved by
13C NMR spectroscopy of the corresponding pentaacetates of
pyranoses that were obtained by the same reaction sequence
described above. The acetonide protection of the diols 32, 33,
42, and 43 proceeded in good yields but in different rates as
for the diols 13, 14, 23, and 24. The reduction of these fully
protected esters provided corresponding aldehydes without over-
reduction in high yield. Cyclization of gulo-aldehyde 36 with
80% acetic acid (24 h, rt) followed by acetylation afforded
1,2,3,6-O-tetraacetyl-4-O-benzyl-â-L-gulose 38 in 95% yield.
Under the same conditions, the cyclization of talo-aldehyde 37
provided 1,2,3,6-O-tetraacetyl-4-O-benzyl-L-talose 40 in 75%
yield as a mixture of R- and â-anomers in 5:1 ratio.
and chiral ligand in subsequent dihydroxylation step is the key
feature for the versatility of our new method.
Experimental Section
General Procedure for Preparation of Diols 13, 14, 23, 24,
32, 33, 42, and 43. To a well-stirred mixture of (DHQD)2PHAL
or (DHQ)2PHAL (156 mg, 0.2 mmol), K3Fe(CN)6 (1.974 g, 6
mmol), K2CO3 (828 mg, 6 mmol), and CH3SO2NH2 (190 mg, 2
mmol) in 1:1 t-BuOH-H2O (24 mL) at 0 °C was added OsO4 (1.2
mL of 0.1 M t-BuOH solution, 0.12 mmol). After 15 min, R,â-
unsaturated ester (640 mg, 2 mmol) in t-BuOH (1 mL) was added
over 15 min, and the mixture was stirred for another 36 h at 4 °C.
Solid sodium sulfite (6 g) was added, and the mixture was stirred
for 30 min at 4 °C and allowed to warm to room temperature.
EtOAc was added, and the layers were separated. The aqueous layer
was further extracted with EtOAc. The combined organic phases
were washed successively with 2 M NaOH, H2O, and brine and
then dried, concentrated, and chromatographed with heptane-EtOAc
(2:1) to afford a diol.
Ethyl (2S,3S,4S,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-galacto-diol) 13 was prepared from
9 in the presence of (DHQD)2PHAL in 90% yield by the general
procedure. 13 (colorless oil): [R]D -15.9 (c 1.0); IR (CHCl3) cm-1
3446, 2983, 2935, 1731, 1497, 1454, 1369, 1269, 1240, 1212, 1113,
1058, 1028, 857; 1H NMR 7.35 (m, 5H), 4.78, 4.68 (2d, J ) 11.0
Hz, 2H), 4.48 (dd, J ) 6.0, 1.5 Hz, 1H), 4.42 (m, 1H), 4.26 (m,
2H), 4.04 (m, 2H), 3.89 (dd, J ) 8.5, 7.6 Hz, 1H), 3.67 (dd, J )
8.9, 5.1 Hz, 1H), 3.29 (d, J ) 6.0 Hz, 1H), 2.87 (d, J ) 7.3 Hz,
1H), 1.45 (s, 3H), 1.38 (s, 3H); 1.29 (t, J ) 7.2 Hz, 3H); 13C NMR
173.6, 138.0, 127.9, 128.5, 128.1, 109.2, 77.8, 76.8, 74.6, 72.2,
70.5, 65.9, 62.1, 26.3, 25.3, 14.2; MS (ESI) m/z 377 [M + Na]+;
HRMS calcd for C18H26O7Na [M + Na]+ 377.1576, found
377.1572.
Ethyl (2R,3R,4S,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-ido-diol) 14 was prepared from 9 in
the presence of (DHQ)2PHAL in 90% yield by the general
procedure. 14 (colorless oil): [R]D -18.4 (c 1.3); IR (CHCl3) cm-1
3547, 3024, 2988, 2938, 2907, 1735, 1686, 1654, 1560, 1456, 1383,
1
1373, 1227, 1205, 1156, 1118, 1071, 1028, 883, 854; H NMR
7.36 (m, 5H), 4.85, 4.62 (2d, J ) 11.0 Hz, 2H), 4.42 (dd, J )
12.8, 6.4 Hz, 1H), 4.30 (dd, J ) 5.0, 3.0 Hz, 1H), 4.22-4.02 (m,
3H), 3.85 (dd, J ) 7.9, 7.6 Hz, 1H), 3.70 (dd, J ) 5.6, 4.4 Hz,
1H), 3.50 (d, J ) 5.1 Hz, 1H), 2.95 (d, J ) 8.4 Hz, 1H), 1.46 (s,
3H), 1.39 (s, 3H), 1.23 (t, J ) 7.4 Hz, 3H); 13C NMR 172.9, 137.9,
128.5, 128.3, 128.0, 109.6, 78.5, 76.3, 74.2, 71.6, 71.2, 65.9, 62.0,
26.5, 25.5, 14.1; MS (ESI) m/z 377 [M + Na]+; HRMS calcd for
C18H26O7Na [M + Na]+ 377.1576, found 377.1569.
Ethyl (2S,3S,4R,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-gluco-diol) 23 was prepared from 10
in the presence of (DHQD)2PHAL in 70% yield by the general
procedure. 23 (colorless oil): [R]D -15.0 (c 2.30); IR (CHCl3) cm-1
3531, 3027, 3015, 2990, 2938, 2892, 1733, 1603, 1497, 1455, 1383,
Deprotection of acetonide groups for allo-aldehyde 46 was
accomplished in the presence of Amberlite IR 120. After
subsequent acetylation, 1,2,3,6-O-tetraacetyl-4-O-benzyl-L-allose
48 was obtained as a mixture of R- and â-anomers in 1:2 ratio.
The anomeric sugar derivatives 48a and 48b were easily
separated by column chromatography and each of them was
subjected to hydrogenolysis followed by acetylation to provide
the pentaacetates of L-allose 49a and 49b, respectively, in good
yield. Under the same conditions, 1,2,3,6-O-tetraacetyl-4-O-
benzyl-L-mannose 50 was obtained as a mixture of R- and
â-anomers in 3:1 ratio. The fully protected sugars 50a and 50b
were easily separated by column chromatography and converted
into the corresponding pentaacetates of L-mannose 51a and 51b.
1
1373, 1248, 1228, 1205, 1158, 1122, 1074, 1028, 915, 854; H
NMR 7.34 (m, 5H), 4.80, 4.68 (2d, J ) 11.0 Hz, 2H), 4.35 (m,
2H), 4.22-3.92 (m, 5H), 3.82 (dd, J ) 5.6, 4.3 Hz, 1H), 3.40 (d,
J ) 5.9 Hz, 1H), 3.20 (d, J ) 8.8 Hz, 1H), 1.44 (s, 3H), 1.37 (s,
3H), 1.24 (t, J ) 7.0 Hz, 3H); 13C NMR 173.2, 137.8, 128.5, 128.1,
128.0, 109.0, 78.3, 76.9, 74.3, 72.3, 71.0, 66.3, 62.0, 26.6, 25.2,
14.1; MS (ESI) m/z 377 [M + Na]+; HRMS calcd for C18H26O7Na
[M + Na]+ 377.1576, found 377.1568.
Ethyl (2R,3R,4R,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-altro-diol) 24 was prepared from 10
in the presence of (DHQ)2PHAL in 88% yield by the general
procedure. 24 (colorless oil): [R]D -7.5 (c 1.20); IR (CHCl3) cm-1
3458, 2990, 2986, 2936, 1736, 1498, 1455, 1382, 1372, 1238, 1217,
1140, 1118, 1066, 962, 859, 754, 699; 1H NMR 7.40 (m, 5H), 4.79,
4.72 (2d, J ) 11.1 Hz, 2H), 4.42 (d, J ) 6.3 Hz, 1H), 4.28 (q, J )
7.2 Hz, 2H), 4.11 (dd, J ) 8.2, 6.5 Hz, 1H), 3.95 (m, 2H), 3.75
(dd, J ) 8.6, 6.3 Hz, 1H), 3.52 (d, J ) 6.6 Hz, 1H), 3.35 (d, J )
Conclusion
We have developed a novel methodology for the highly
selective synthesis of the diastereometrically pure L-hexoses.
According to our strategy, any one of eight L-hexoses can be
prepared in good overall yield from L-ascorbic acid. Appropriate
selection of reagents in the Horner-Wittig-Emmons olefination
698 J. Org. Chem., Vol. 71, No. 2, 2006

DiastereoselectiVe Synthesis of L-Hexoses from L-Ascorbic Acid
6.4 Hz, 1H), 1.45 (s, 3H), 1.37 (s, 3H), 1.28 (t, J ) 7.2 Hz, 3H);
13C NMR 173.5, 138.0, 128.6, 128.1, 128.0, 109.4, 77.8, 77.6, 74.7,
74.0, 70.5, 66.3, 62.1, 26.5, 25.3, 14.2; MS (ESI) m/z 377 [M +
Na]+; HRMS calcd for C18H26O7Na [M + Na]+ 377.1576, found
377.1608.
completion in 6 h to afford the acetonide in 95% yield. 15 (colorless
oil): [R]D +15.0 (c 2.5); IR (CHCl3) cm-1 2986, 2936, 1744, 1454,
1
1383, 1370, 1350, 1254, 1211, 1161, 1083, 1054, 904, 862; H
NMR 7.33 (m, 5H), 4.83 (s, 2H), 4.62 (d, J ) 6.8 Hz, 1H), 4.37
(dd, J ) 6.8, 4.0 Hz, 1H), 4.25-4.10 (m, 3H), 4.02 (dd, J ) 8.5,
6.4 Hz, 1H), 3.78 (dd, J ) 8.3, 7.4 Hz, 1H), 3.68 (dd, J ) 6.4, 4.0
Hz, 1H), 1.46 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H), 1.26 (t, J ) 7.4
Hz, 3H); 13C NMR 171.0, 138.3, 128.3, 127.9, 127.6, 111.0, 109.3,
79.9, 79.0, 77.3, 75.9, 74.7, 66.0, 61.4, 26.8, 26.3, 25.7, 25.6, 14.1;
m/z 417 [M + Na]+; HRMS calcd for C21H30O7Na [M + Na]+
417.1889, found 417.1873.
Methyl (2S,3R,4S,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-gulo-diol) 32 was prepared from 11
in the presence of (DHQD)2PHAL in 70% yield by the general
procedure. 32 (colorless oil): [R]D -9.0 (c 1.3); IR (CHCl3) cm-1
3547, 3023, 2990, 2955, 2937, 1734, 1497, 1455, 1440, 1382, 1372,
1
1230, 1156, 1109, 1076, 1028, 986, 849; H NMR 7.37 (m, 5H),
4.85, 4.62 (2d, J ) 11.2 Hz, 2H), 4.42 (dd, J ) 13.1, 6.4 Hz, 1H),
4.22 (dd, J ) 8.5, 6.5 Hz, 1H), 4.05 (dd, J ) 8.3, 6.5 Hz, 1H),
3.65 (dd, J ) 6.3, 2.4 Hz, 1H), 3.73 (s, 3H), 3.38 (d, J ) 8.5 Hz,
1H), 3.05 (d, J ) 9.0 Hz, 1H), 1.44 (s, 3H), 1.38 (s, 3H); 13C NMR
173.4, 137.9, 128.6, 128.4, 128.1, 109.8, 78.7, 76.8, 74.2, 72.4,
72.1, 66.0, 52.6, 26.6, 25.7; MS (ESI) m/z 363 [M + Na]+; HRMS
calcd for C17H24O7Na [M + Na]+ 363.1420, found 363.1408.
Methyl (2R,3S,4S,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-talo-diol) 33 was prepared from 11
in the presence of (DHQ)2PHAL in 76% yield by the general
procedure. 33 (colorless oil): [R]D -26.9 (c 1.1); IR (CHCl3) cm-1
3522, 3031, 3015, 2991, 2955, 2935, 1734, 1496, 1455, 1442, 1382,
1372, 1228, 1203, 1157, 1071, 983, 917, 898, 853; 1H NMR 7.32
(m, 5H), 4.75, 4.55 (2d, J ) 10.7 Hz, 2H), 4.42-4.30 (m, 2H),
4.11-4.05 (m, 2H), 3.85 (dd, J ) 8.6, 7.6 Hz, 1H), 3.75 (dd, J )
8.6, 5.9 Hz, 1H), 3.58 (d, J ) 4.8 Hz, 1H), 3.55 (s, 3H), 3.35 (d,
J ) 6.1 Hz, 1H), 1.45 (s, 3H), 1.37 (s, 3H); 13C NMR 172.7, 138.0,
128.5, 128.4, 127.9, 109.1, 77.6, 77.5, 74.0, 73.4, 72.1, 66.3, 52.4,
26.4, 25.3; MS (ESI) m/z 363 [M + Na]+; HRMS calcd for
C17H24O7Na [M + Na]+ 363.1420, found 363.1413.
Ethyl (2R,3S,4R,5S)-2,3;5,6-di(O-isopropylidene)-4-O-benzyl-
2,3,4,5,6-pentahydroxyhexanoate (L-ido-acetonide) 16 was ob-
tained from 14 for 48 h in 96% yield. 16 (colorless oil): [R]D -48.3
(c 1.10); IR (CHCl3) cm-1 3020, 3011, 2991, 2939, 1750, 1602,
1497, 1455, 1383, 1373, 1350, 1301, 1249, 1213, 1205, 1159, 1103,
1
1028, 980, 901, 857; H NMR 7.37 (m, 5H), 4.95, 4.75 (2d, J )
11.8 Hz, 2H), 4.54 (d, J ) 7.4 Hz, 1H), 4.42 (dd, J ) 14.0, 7.0
Hz, 1H), 4.20 (m, 3H), 4.08 (dd, J ) 8.1, 6.6 Hz, 1H), 3.78 (t, J
) 8.1 Hz, 1H), 3.65 (dd, J ) 7.4, 3.0 Hz, 1H), 1.48 (s, 3H), 1.46
(s, 3H), 1.42 (s, 3H), 1.39 (s, 3H), 1.26 (t, J ) 7.4 Hz, 3H); 13C
NMR 170.7, 138.3, 128.4, 128.2, 127.8, 111.6, 109.5, 78.8, 77.6,
76.9, 75.3, 74.0, 66.3, 61.5, 26.7 (two carbons), 26.0, 25.7, 14.2;
MS (ESI) m/z 417 [M + Na]+; HRMS calcd for C21H30O7Na [M
+ Na]+ 417.1889, found 417.1906.
Ethyl (2S,3R,4S,5S)-2,3;5,6-di(O-isopropylidene)-4-O-benzyl-
2,3,4,5,6-pentahydroxyhexanoate (L-gluco-acetonide) 25 was
obtained from 23 for 6 h in 95% yield. 25 (colorless oil): [R]D
+9.2 (c 1.44); IR (CHCl3) cm-1 3032, 2991, 2939, 2905, 1752,
1586, 1497, 1455,1383, 1373, 1352, 1244, 1226, 1203, 1159, 1075,
1053, 1028, 988, 908, 857, 824; 1H NMR 7.35 (m, 5H), 4.88, 4.72
(2d, J ) 11.8 Hz, 2H), 4.50 (d, J ) 7.4 Hz, 1H), 4.30 (m, 2H),
4.21 (q, J ) 7.4 Hz, 2H), 4.02 (m, 2H), 3.80 (dd, J ) 4.4, 3.7 Hz,
1H), 1.45 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H), 1.28 (t, J ) 7.0 Hz,
3H); 13C NMR 170.5, 138.1, 128.4, 127.9, 127.8, 111.2, 108.7,
79.8, 77.5, 77.0, 75.2, 75.0, 66.0, 61.4, 26.6 (two carbons), 26.1,
25.3, 14.2; MS (ESI) m/z 417 [M + Na]+; HRMS calcd for
C21H30O7Na 417.1889, found 417.1859.
Methyl (2S,3R,4R,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-allo-diol) 42 was prepared from 12
in the presence of (DHQD)2PHAL in 90% yield by the general
procedure. 42 (colorless oil): [R]D -6.1 (c 1.2); IR (CHCl3) cm-1
:
3523, 3025, 3015, 2989, 2937, 1729, 1454, 1440, 1383, 1374,
1349, 1226, 1200, 1137, 1098, 1067, 1028, 909, 856, 799; 1H NMR
7.32 (m, 5H), 4.75, 4.55 (2d, J ) 11.0 Hz, 2H), 4.45 (m, 2H), 4.10
(m, 1H), 3.95 (m, 2H), 3.80 (m, 1H), 3.55 (s, 3H), 3.40 (d, J ) 5.5
Hz, 1H), 3.05 (d, J ) 6.4 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H); 13C
NMR 172.7, 137.9, 128.4, 128.2, 127.9, 109.5, 77.3, 76.5, 74.0,
73.7, 71.9, 65.9, 52.5, 26.5, 25.1; MS (ESI) m/z 363 [M + Na]+;
HRMS calcd for C17H24O7Na [M + Na]+ 363.1420, found
363.1432.
Ethyl (2R,3S,4S,5S)-2,3;5,6-di(O-isopropylidene)-4-O-benzyl-
2,3,4,5,6-pentahydroxyhexanoate (L-altro-acetonide) 26 was
obtained from 24 for 24 h in 78% yield. 26 (colorless oil): [R]D
-41.9 (c 1.70); IR (CHCl3) cm-1 2988, 2937, 1756, 1497, 1455,
1
1381, 1259, 1211, 1164, 1140, 1078, 925, 856, 809, 738, 699; H
NMR 7.34 (m, 5H), 4.85, 4.70 (2d, J ) 11.7 Hz, 2H), 4.64 (d, J )
6.8 Hz, 1H), 4.48 (dd, J ) 7.4, 2.9 Hz, 1H), 4.20 (m, 3H), 4.05
(dd, J ) 8.8, 5.9 Hz, 1H), 3.85 (m, 2H), 1.50 (s, 3H), 1.44 (s, 3H),
1.41(s, 3H), 1.32 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR 171.2,
137.9, 128.3, 127.8, 127.7, 111.1, 109.1 79.8, 78.5, 74.9, 74.7, 74.5,
66.7, 61.3, 26.7, 26.5, 25.2, 25.1, 14.0; MS (ESI) m/z 417 [M +
Na]+; HRMS calcd for C21H30O7Na [M + Na]+ 417.1889, found
417.1862.
Methyl (2S,3S,4R,5S)-2,3;5,6-di(O-isopropylidene)-4-O-ben-
zyl-2,3,4,5,6-pentahydroxyhexanoate (L-gulo-acetonide) 34 was
obtained from 32 for 48 h in 94% yield. 34 (colorless oil): [R]D
-30.4 (c 1.20); IR (CHCl3) cm-1 3030, 3018, 2990, 2937, 1727,
1497, 1454, 1439, 1382, 1373, 1245, 1229, 1083, 1072, 983, 887,
851; 1H NMR 7.34 (m, 5H), 4.95 (d, J ) 12.1 Hz, 1H), 4.70 (d, J
) 7.4 Hz, 1H), 4.52-4.34 (m, 3H), 4.05 (dd, J ) 8.1, 6.4 Hz,
1H), 3.82 (t, J ) 8.1 Hz, 1H), 3.73 (dd, J ) 6.4, 3.7 Hz, 1H), 3.46
(s, 3H), 1.63 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H); 13C
NMR 170.4, 138.7, 128.1, 127.1, 126.8, 110.9, 109.5, 78.1, 77.1
(two carbons), 75.3, 72.6, 66.1, 51.9, 26.6, 26.5, 25.7, 25.5; MS
(ESI) m/z 403 [M + Na]+; HRMS calcd for C20H28O7Na [M +
Na]+ 403.1733, found 403.1719.
Methyl (2R,3S,4R,5S)-4-O-benzyl-5,6-O-isopropylidene-2,3,4,5,6-
pentahydroxyhexanoate (L-manno-diol) 43 was prepared from
12 in the presence of (DHQ)2PHAL in 65% yield by the general
procedure. 43 (colorless oil): [R]D -15.3 (c 1.6); IR (CHCl3) cm-1
3546, 3024, 3015, 2991, 2957, 2934, 2892, 1737, 1497, 1455, 1440,
1383, 1373, 1224, 1158, 1074, 1028, 977, 909, 878, 850; 1H NMR
7.34 (m, 5H), 4.80, 4.65 (2d, J ) 11.0 Hz, 2H), 4.27 (m, 2H), 4.10
(dd, J ) 8.4, 6.4 Hz, 1H), 3.98-3.82 (m, 3H), 3.74 (s, 3H), 3.02
(d, J ) 7.6 Hz, 1H), 2.82 (d, J 8.9 Hz, 1H), 1.42 (s, 3H), 1.25 (s,
3H); 13C NMR 173.6, 137.7, 128.5, 128.2, 128.1, 108.7, 78.0, 76.9,
74.7, 72.4, 72.2, 66.0, 52.5, 26.6, 25.1; MS (ESI) m/z 379 [M +
K]+, 363 [M + Na]+; HRMS calcd for C17H24O7Na [M + Na]+
363.1420, found 363.1424.
General Procedure for the Preparation of Acetonides 15, 16,
25, 26, 34, 35, 44, and 45. To a solution of the diol in acetone (1
mmol/mL) were added 2,2-dimethoxypropane (2 mmol) and p-TSA
(6 mg, 3% mol). The reaction mixture was stirred at room
temperature for the time indicated in each case. Upon completion
of the reaction, triethylamine was added to neutralize the reaction
mixture, acetone was evaporated, and the residue was purified by
flash chromatography in heptane-EtOAc (4:1) to afford the
corresponding acetonide.
Methyl (2R,3R,4R,5S)-2,3;5,6-di(O-isopropylidene)-4-O-ben-
zyl-2,3,4,5,6-pentahydroxyhexanoate (L-talo-acetonide) 35 was
obtained from 33 for 14 h in 90% yield. 35 (colorless oil): [R]D
-29.4 (c 1.60); IR (CHCl3) cm-1 3027, 3017, 2990, 2953, 2938,
2858, 1750, 1497, 1455, 1438, 1382, 1372, 1228, 1203, 1183, 1159,
Ethyl (2S,3R,4R,5S)-2,3;5,6-di(O-isopropylidene)-4-O-benzyl-
2,3,4,5,6-pentahydroxyhexanoate (L-galacto-acetonide) 15 was
prepared from 13 by the general procedure. The reaction came to
J. Org. Chem, Vol. 71, No. 2, 2006 699

Ermolenko and Sasaki
1
1131, 1092, 1072, 1030, 966, 911, 869; H NMR 7.35 (m, 5H),
3H), 1.44 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H); 13C NMR 200.6, 138.0,
128.4, 128.1, 127.8, 111.6, 109.4, 81.1, 77.5, 76.8, 76.4, 74.0, 66.2,
26.6, 26.5, 26.2, 25.6; MS (ESI) m/z 373 [M + Na]+; HRMS calcd
for C19H26O6Na [M + Na]+ 373.1627, found 373.1599.
5.00 (d, J ) 11.0 Hz, 1H), 4.69 (d, J ) 5.9 Hz, 1H), 4.44 (d, J )
11.0 Hz, 1H), 4.28 (m, 2H), 4.05 (dd, J ) 8.8, 5.9 Hz, 1H), 3.82
(dd, J ) 8.8, 7.8 Hz, 1H), 3.65 (dd, J ) 7.8, 6.8 Hz, 1H), 3.49 (s,
3H), 1.59 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13C
NMR 170.1, 138.5, 128.3, 127.6, 127.5, 111.0, 108.9, 79.0, 78.1,
76.1, 73.6, 66.8, 51.9, 27.0, 26.6, 25.8, 25.6; MS (ESI) m/z 403
[M + Na]+; HRMS calcd for C20H28O7Na [M + Na]+ 403.1733,
found 403.1718.
Methyl (2S,3S,4S,5S)-2,3;5,6-di(O-isopropylidene)-4-O-ben-
zyl-2,3,4,5,6-pentahydroxyhexanoate (L-allo-acetonide) 44 was
obtained from 42 for 6 h in 95% yield. 44 (colorless oil): [R]D
-13.6 (c 2.0); IR (CHCl3) cm-1 3067, 3029, 3012, 2989, 2939,
2891, 1750, 1497, 1455, 1382, 1374, 1348, 1226, 1205, 1160, 1138,
1089, 1030, 969, 918, 856; 1H NMR 7.33 (m, 5H), 4.75, 4.65 (2d,
J ) 11.1 Hz, 2H), 4.68 (d, J ) 6.8 Hz, 1H), 4.47 (dd, J ) 6.6, 4.7
Hz, 1H), 4.35 (dd, J ) 12.6, 6.2 Hz, 1H), 4.04 (dd, J ) 8.3, 6.4
Hz, 1H), 3.92 (m, 2H), 3.45 (s, 3H), 1.69 (s, 3H), 1.41 (s, 3H),
1.39 (s, 3H), 1.36 (s, 3H); 13C NMR 170.8, 138.1, 128.3, 128.1,
127.7, 110.6, 109.5, 79.2, 77.1, 75.6, 75.0, 74.9, 66.4, 52.0, 27.0,
26.8, 25.6, 25.3; MS (ESI) m/z 403 [M + Na]+; HRMS calcd for
C20H28O7Na [M + Na]+ 403.1733, found 403.1724.
(2S,3R,4S,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-gluco-aldehyde) 27 was prepared from
25 by the general procedure and purified by flash chromatography
(heptane-EtOAc 1:1), yield 90%. 27 (colorless oil): [R]D -4.7 (c
1.1); IR (CHCl3) cm-1 3028, 3012, 2989, 2937, 2899, 1732, 1455,
1
1383, 1373, 1243, 1229, 1159, 1072, 908, 857; H NMR 9.76 (d,
J ) 1.4 Hz, 1H), 7.39 (m, 5H), 4.84, 4.72 (2d, J ) 11.7 Hz, 2H),
4.32 (dd, J ) 7.4, 1.4 Hz, 1H), 4.20-4.15 (m, 2H), 4.08 (dd, J )
8.5, 6.3 Hz, 1H), 3.95 (dd, J ) 8.5, 6.8 Hz, 1H), 3.65 (dd, J ) 5.3,
4.2 Hz, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H);
13C NMR 200.7, 137.5, 128.1, 128.0, 127.5, 110.9, 108.6, 80.4,
77.8, 76.3, 74.6, 65.8, 26.2, 26.1, 26.0, 24.9; MS (ESI) m/z 373
[M + Na]+; HRMS calcd for C19H26O6Na [M + Na]+ 373.1627,
found 373.1604.
(2R,3S,4S,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-altro-aldehyde) 28 was prepared from
26 in 78% yield by the general procedure and purified by flash
chromatography (heptane-EtOAc 2:1). 28 (colorless oil): [R]D
-22.9 (c 0.9); IR (CHCl3) cm-1 2990, 2938, 1735, 1497, 1455,
Methyl (2R,3R,4S,5S)-2,3;5,6-di(O-isopropylidene)-4-O-ben-
zyl-2,3,4,5,6-pentahydroxyhexanoate (L-manno-acetonide) 45
was obtained from 43 for 24 h in 77% yield. 45 (colorless oil):
[R]D +8.5 (c 1.3); IR (CHCl3) cm-1 3030, 2991, 2938, 2905, 1731,
1
1383, 1374, 1247, 1220, 1210, 1161, 1076, 912, 860; H NMR
9.73 (d, J ) 2.0 Hz, 1H), 7.34 (m, 5H); 4.85, 4.72 (2d, J ) 11.0
Hz, 2H), 4.47 (dd, J ) 7.3, 2.0 Hz, 1H), 4.33 (dd, J ) 7.3, 3.5 Hz,
1H), 4.15 (dd, J ) 12.7, 6.3 Hz, 1H), 4.05 (dd, J ) 8.1, 6.3 Hz,
1H), 3.85 (m, 2H), 1.52 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.34 (s,
3H); 13C NMR 200.6, 137.8, 128.5, 128.1, 128.0, 111.3, 109.5,
81.0, 78.3, 77.7, 75.0, 74.8, 66.7, 26.8, 26.7, 25.8, 25.2; MS (ESI)
m/z 373 [M + Na]+; HRMS calcd for C19H26O6Na [M + Na]+
373.1627, found 373.1616.
(2S,3S,4R,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-gulo-aldehyde) 36 was prepared from
34 by general procedure in 94% yield and purified by flash
chromatography (heptane-EtOAc 1:1). 36 (colorless oil): [R]D
-60.3 (c 1.3); IR (CHCl3) cm-1 3029, 2990, 2937, 2875, 1724,
1498, 1455, 1383, 1373, 1247, 1221, 1205, 1160, 1132, 1087, 988,
896, 845; 1H NMR 9.52 (d, J ) 2 Hz, 1H), 7.34 (m, 5H), 4.95 (d,
J ) 11.5 Hz, 1H), 4.45 (m, 2H), 4.34 (dd, J ) 8.0, 2.0 Hz, 1H),
4.25 (d, J ) 11.5 Hz, 1H), 4.09 (dd, J ) 8.1, 6.2 Hz, 1H), 3.77(t,
J ) 8.1 Hz, 1H), 3.44 (dd, J ) 7.2, 2.3 Hz, 1H), 1.59 (s, 3H), 1.43
(s, 3H), 1.36 (s, 6H); 13C NMR 201.7, 138.3, 128.2, 127.3, 127.2,
111.4, 109.6, 80.7, 80.3, 77.3, 76.9, 72.2, 66.2, 26.7, 26.6, 25.8,
25.1; MS (ESI) m/z 373 [M + Na]+; HRMS calcd for C19H26O6Na
[M + Na]+ 373.1627, found 373.1604.
(2R,3R,4R,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-talo-aldehyde) 37 was prepared from 35
by the general procedure in 90% yield and purified by flash
chromatography (heptane-EtOAc 2:1). 37 (colorless oil): [R]D
-54.0 (c 1.50); IR (CHCl3) cm-1 3026, 2990, 2938, 2891, 1730,
1455, 1382, 1374, 1243, 1228, 1158, 1088, 1070, 1028, 911, 866;
1H NMR 9.68 (s, 1H), 7.33 (m, 5H), 4.70-4.60 (m, 3H), 4.52 (dd,
J ) 7.0, 4.3 Hz, 1H), 4.20 (ddd, J ) 12.0, 7.8, 4.3 Hz, 1H), 4.00
(dd, J ) 7.8, 6.6 Hz, 1H), 3.85-3.75 (m, 2H), 1.64 (s, 3H), 1.42
(s, 3H), 1.40 (s, 3H), 1.39 (s, 3H); 13C NMR 197.5, 137.5, 128.5,
128.0, 110.0, 109.7, 81.6, 81.2, 77.4, 76.2, 74.0, 66.0, 27.2, 26.3,
25.8, 25.4; MS (ESI) m/z 373 [M + Na]+; HRMS calcd for
C19H26O6Na [M + Na]+ 373.1627, found 373.1624.
1
1455, 1440,1383, 1373, 1223, 1208, 1159, 1069, 851; H NMR
7.32 (m, 5H), 4.90, 4.45 (2d, J ) 11.7 Hz, 2H), 4.72 (d, J ) 7.4
Hz, 1H), 4.52 (dd, J ) 7.4, 3.3 Hz, 1H), 4.27 (m, 1H), 4.10-3.96
(m, 3H), 3.47 (s, 3H), 1.57 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H); 13
C
NMR 170.1, 138.5, 128.2, 127.2, 126.8, 110.6, 108.4, 79.1, 77.4,
76.4, 75.3, 73.2, 66.1, 51.9, 26.4 (two carbons), 25.5, 25.1; MS
(ESI) m/z 403 [M + Na]+; HRMS calcd for C20H28O7Na [M +
Na]+ 403.1733, found 403.1723.
General Procedure for the Reduction of Esters in Aldehydes.
To a solution of ester in toluene (1 mmol/ 7 mL) at -78 °C was
added DIBAL (1.5 mmol, 1 mL of 1.5 M solution in toluene). The
reaction mixture was stirred for 1 h at -78 °C and quenched with
1 mL of methanol, and the solution was slowly warmed to room
temperature. A sodium potassium tartrate saturated solution (0.2
mL), 0.4 mL of brine, and EtOAc (20 mL) were added with MgSO4
(1 g), and the mixture was stirred for 1 h. The solids were removed
by filtration, filtrate and washings were concentrated, and the residue
was purified by flash chromatography (heptane-EtOAc 2:1) to
afford the corresponding aldehyde.
(2S,3R,4R,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-galacto-aldehyde) 17 was prepared from
15 by the general procedure in 95% yield and subjected to
cyclization without further purification. The analytical simple was
obtained by flash chromatography (heptane-EtOAc 2:1). 17
(colorless oil): [R]D -14.1 (c 2.0); IR (CHCl3) cm-1 2986, 2935,
1735, 1497, 1454, 1383, 1370, 1252, 1210, 1157, 1064, 905, 860;
1H NMR 9.70 (d, J ) 1.2 Hz, 1H), 7.36 (m, 5H), 4.86, 4.81 (2d,
J ) 11.4 Hz, 2H), 4.55 (dd, J ) 6.8, 1.2 Hz, 1H), 4.20-4.15 (m,
2H), 4.05 (dd, J ) 8.3, 6.4 Hz, 1H), 3.78 (dd, J ) 6.0, 4.5, Hz,
1H), 1.47 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H); 13C
NMR 200.1, 138.0, 128.4, 128.15, 127.8, 111.0, 109.4, 81.6, 79.0,
77.9, 77.6, 74.7, 66.1, 26.6, 26.4, 25.8, 25.7; MS (ESI) m/z 373
[M + Na]+; HRMS calcd for C19H26O6Na [M + Na]+ 373.1627,
found 373.1611.
(2S,3S,4S,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-allo-aldehyde) 46 was prepared from 44
by general procedure in 70% yield and purified by flash chroma-
tography (heptane-EtOAc 2:1). 46 (colorless oil): [R]D -4.8 (c
1.3); IR (CHCl3) cm-1 3025, 3020, 2990, 2937, 2890, 1728, 1602,
1497, 1454, 1383, 1374, 1348, 1264, 1245, 1161, 1137, 1074, 1027,
(2R,3S,4R,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-ido-aldehyde) 18 was prepared from 16
by general procedure in 95% yield and subjected to cyclization
without further purification. 18 (colorless oil): [R]D -18.7 (c 2.0);
IR (CHCl3) cm-1 3410, 2986, 2935, 1731, 1454, 1371, 1247, 1216,
1
1
1128, 1067, 1027, 855; H NMR 9.70 (d, J ) 1.5 Hz, 1H), 7.36
985, 909, 856; H NMR 9.61 (d, J ) 2.3 Hz, 1H), 7.31 (m, 5H),
(m, 5H), 4.89, 4.72 (2d, J ) 11.7 Hz, 2H), 4.42-4.32 (m, 2H),
4.15 (dd, J ) 7.4, 3.7 Hz, 2H), 4.04 (dd, J ) 8.2, 6.4 Hz, 1H),
3.78 (t, J ) 8.0, Hz, 1H), 3.58 (dd, J ) 6.4, 3.7 Hz, 1H), 1.48 (s,
4.73 (s, 2H), 4.60 (dd, J ) 7.2, 3.7 Hz, 1H), 4.52 (dd, J ) 7.2, 2.3
Hz, 1H), 4.20 (dd, J ) 12.5, 6.6 Hz, 1H), 4.00 (dd, J ) 8.1, 6.6
Hz, 1H), 3.85 (dd, J ) 6.9, 3.7 Hz, 1H), 3.78 (dd, J ) 8.1, 5.9 Hz,
700 J. Org. Chem., Vol. 71, No. 2, 2006

DiastereoselectiVe Synthesis of L-Hexoses from L-Ascorbic Acid
1H), 1.65 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H); 13C
NMR 198.5, 137.5, 128.5, 128.1, 128.0, 110.3, 109.7, 80.9 (two
carbons), 77.7, 75.2, 74.7, 66.7, 27.3, 26.7, 25.1, 24.9; MS (ESI)
m/z 373 [M + Na]+; HRMS calcd for C19H26O6Na [M + Na]+
373.1627, found 373.1616.
3.4 Hz, 1H (â-anomer), 4.35 (m, 1H (R-anomer), 4.22-4.10 [m,
2H (R-anomer) and 3H (â-anomer)], 2.17, 2.13, 2.05, 2.05, 2.03,
2.01, 2.00 [7s, 15H (R-anomer) and 15H (â-anomer)]; 13C NMR
(â-anomer) 92.1, 71.7, 70.8, 67.9, 66.9, 61.1 (lit.30 91.8, 71.5, 70.6,
67.8, 66.8, 61.0); (R-anomer) 89.7, 68.8, 67.4, 67.4, 66.4, 61.3 (lit.30
89.5, 68.5, 67.2, 67.2, 66.2, 61.0); MS (ESI) m/z 413 [M + Na]+;
HRMS calcd for C16H22O11Na [M + Na]+ 413.1060, found
413.1063.
(2R,3R,4S,5S)-2,3;5,6-Di(O-isopropylidene)-4-O-benzyl-2,3,4,5,6-
pentahydroxyhexanal (L-manno-aldehyde) 47 was prepared from
45 by general procedure in 70% yield and purified by flash
chromatography (heptane-EtOAc 2:1). 47 (colorless oil): [R]D
+23.5 (c 1.2); IR (CHCl3) cm-1: 3019, 2990, 2937, 1724, 1497,
1455, 1383, 1374, 1224, 1208, 1158, 1146, 1079, 1059, 905, 847;
1H NMR 9.52 (d, J ) 1.9 Hz, 1H), 7.31 (m, 5H), 4.93 (d, J ) 11.3
Hz, 1H), 4.57 (dd, J ) 8.1, 5.8 Hz, 1H), 4.38 (dd, J ) 8.1, 6.2 Hz,
1H), 4.31 (ddd, J ) 10.0, 7.2, 3.0 Hz, 1H), 4.25 (d, J ) 11.3 Hz,
1H), 3.83 (dd, J ) 2.8 Hz, 1H), 1.54 (s, 3H), 1.40 (s, 3H), 1.35 (s,
6H); 13C NMR 201.8, 138.1, 128.4, 128.3, 127.5, 127.2, 111.1,
108.2, 81.9, 80.2, 77.4, 75.2, 72.8, 65.7, 26.5, 26.4, 25.2, 24.9;
MS (ESI) m/z 373 [M + Na]+; HRMS calcd for C19H26O6Na [M
+ Na]+ 373.1627, found 373. 1603.
General Procedure for the Cyclization of Aldehydes to Fully
Protected Sugars. (A) Aldehyde (1 mmol) was dissolved in 80%
acetic acid (15 mL). The reaction mixture was stirred at the
temperature and for the time indicated in each case. Upon
completion of the reaction, the mixture was evaporated with toluene.
To a solution of the residue in CH2Cl2 (5 mL) were successively
added triethylamine (10 mmol), Ac2O (8 mmol), and DMAP (100
mg), and the reaction mixture was stirred until the reaction was
complete. The solvent was evaporated, and the residue was
dissolved in EtOAc, washed successively with water, 1 M HCl,
saturated aq NaHCO3, and brine, dried over Na2SO4, and concen-
trated. The residue was purified by flash chromatography (heptane-
EtOAc 1:1) to afford the corresponding fully protected sugar.
(B) A solution of aldehyde (1 mmol) in the mixture of dioxane-
water 1:1 (25 mL) was stirred in the presence of Amberlite IR 120
(H+) for 12 h. After removal of the resin, the solvents were
evaporated with toluene and the residue was acetylated as above
giving the fully protected sugar.
1,2,3,6-O-Tetraacetyl-4-O-benzyl-L-idopyranose 21 was pre-
pared from 18 by general procedure B in 60% yield (R-/â-anomers
40:60). 21 (colorless oil): IR (CHCl3) cm-1 2937, 1737, 1497, 1454,
1
1433, 1369, 1212, 1169, 1134, 1044, 1013, 960, 908; H NMR
7.35 (m, 5H), 6.05 (d, J ) 2.1 Hz, 1H), 5.37 (dd, J ) 9.4, 3.4 Hz,
1H), 5.25 (dd, J ) 3.4, 2.1 Hz, 1H), 4.70, 4.60 (2d, J ) 11.1 Hz,
2H), 4.32 (d, J ) 3.8 Hz, 2H), 3.97(ddd, J ) 10.0, 3.6, 3.2 Hz,
1H), 3.88 (t, J ) 9.6 Hz, 1H), 2.17, 2.14, 2.08, 2.01 (4s, 12H); 13
C
NMR 170.6, 169.8, 169.7, 168.3, 137.3, 128.6, 128.1, 127.8, 90.7,
75.1, 72.5, 71.7, 71.5, 68.8, 62.8, 20.9, 20.8, 20.8, 20.8; MS (ESI)
m/z 461 [M + Na]+; HRMS calcd for C21H26O10Na [M + Na]+
461.1424, found 461.1418.
L-Idopyranose pentaacetate 22 was obtained from 21 by
hydrogenolysis followed by acetylation in 95% yield (R-/â-anomers
40:60). 22 (colorless oil): IR (CHCl3) cm-1 2977, 1738, 1433, 1369,
1208, 1166, 1124, 1093, 1044, 961, 898, 755; 1H NMR 6.09 (d, J
) 2.3 Hz, 1H, R-anomer), 6.06 (d, J ) 1.7 Hz, 1H, â-anomer),
5.25 (t, J ) 4.9 Hz, 1H, R-anomer), 5.07 (dd, J ) 3.7, 3.0 Hz, 1H,
â-anomer), 5.02 (dd, J ) 4.9, 2.6 Hz, 1H, R-anomer), 4.93 [m, 1H
(R-anomer and 1H (â-anomer)], 4.88 (m, 1H, â-anomer), 4.48 (ddd,
J ) 8.7, 6.4, 2.3 Hz, 1H, â-anomer), 4.39 (m, 1H, R-anomer), 4.26
(dd, J ) 6.9, 6.1 Hz, 2H, R-anomer), 4.20 (dd, J ) 6.4, 1.0 Hz,
2H, â-anomer), 2.14, 2.13, 2.12, 2.12, 2.11, 2.07, 2.07 [7 s, 15H
(R-anomer and 15H (â-anomer)]; 13C NMR (R-anomer) 90.7, 66.2,
66.2, 66.3, 66.3, 61.8 (lit.30 90.4, 65.9, 65.9, 66.2, 66.2, 61.8); (â-
anomer) 89.9, 72.0, 67.2, 66.7, 66.2, 62.2; MS (ESI) m/z 413 [M
+ Na]+; HRMS calcd for C16H22O11Na [M + Na]+ 413.1060, found
413.1075.
1,2,3,6-O-Tetraacetyl-4-O-benzyl-L-glucopyranose 29 was pre-
pared from 27 by general procedure B in 70% yield (R-/â-anomers
42:58). 29 (colorless oil): IR (CHCl3) cm-1 3029, 3013, 1753, 1431,
1371, 1227, 1207, 1156, 1064, 1015, 974; 1H NMR 7.33, 7.28 (2m,
5H, R- and â-anomers), 6.25 (d, J ) 3.6 Hz, 1H, R-anomer), 5.70
(d, J ) 8.3 Hz, 1H, â-anomer), 5.56 (dd, J ) 10.4, 9.2 Hz, 1H,
R-anomer), 5.30 (m, 1H, â-anomer), 5.05 (m, 2H, R- and â-ano-
mers), 4.58 (m, 4H, R- and â-anomers), 4.38-4.20 (m, 4H, R- and
â-anomers), 4.02 (m, 1H, â-anomer), 3.74 (m, 3H, R- and
â-anomers), 2.15, 2.10, 2.07, 2.06, 2.03, 2.01, 2.01, 1.98 (8s, 24
H); 13C NMR 170.5, 170.0, 169.9, 169.7, 169.0, 168.9, 137.0, 128.6,
128.6, 128.2, 128.2, 128.1, 128.0, 91.6, 89.2, 75.3, 75.1, 75.0, 74.9,
74.8, 73.8, 71.9, 71.0, 70.8, 69.6, 62.3, 62.2, 20.9, 20.9, 20.8, 20.8,
20.8, 20.8, 20.6, 20.5; MS (ESI) m/z 461 [M + Na]+; HRMS calcd
for C21H26O10Na [M + Na]+ 461.1424, found 461.1431.
General Procedure for the Hydrogenolysis of Fully Protected
4-O-Benzyl-L-hexoses. A stirred solution of 4-O-benzyl-L-hexose
(1 mmol) in EtOAc (25 mL) was hydrogenated in the presence of
10% Pd/C at atmospheric pressure for 12 h. After removal of the
catalyst by filtration through Celite, the solvent was evaporated.
The residue was acetylated as above and purified by column
chromatography to give the pentaacetate of the corresponding sugar.
1,2,3,6-O-Tetraacetyl-4-O-benzyl-L-galactopyranose 19 was
prepared from 17 by general procedure A in 60% yield (R-/â-
anomers 22:78). 19 (colorless oil): IR (CHCl3) cm-1 2938, 1744,
1
1431, 1368, 1214, 1123, 1062, 1043, 903; H NMR 7.34 [m, 5H
(R-anomer) and 5H (â-anomer)], 6.36 (d, J ) 3.8 Hz, 1H,
R-anomer), 5.67 (d, J ) 8.1 Hz, 1H, â-anomer), 5.52 (dd, J ) 7.2,
3.8 Hz, 1H, R-anomer), 5.49 (dd, J ) 10.3, 8.3 Hz, 1H, â-anomer),
5.29 (dd, J ) 10.9, 2.9 Hz, 1H, R-anomer), 5.01 (dd, J ) 10.3, 3.0
Hz, 1H, â-anomer), 4.76, 4.56 (2d, J ) 11.5 Hz, 2H, â-anomer),
4.73, 4.53 (2d, J ) 11.2 Hz, 2H, R-anomer), 4.26-4.15 [m, 2H
(R-anomer) and 1H (â-anomer)], 4.14-4.04 [m, 2H (R-anomer)
and 1H (â-anomer)], 3.97 (m, 1H, â-anomer), 3.86 (m, 1H,
â-anomer), 2.13, 2.09, 2.06, 2.04, 2.04, 2.01, 2.00 [7s, 15H (R-
anomer) and 15H (â-anomer)]; 13C NMR 170.5, 170.4, 170.3, 170.3,
169.7, 169.4, 169.2, 169.0, 92.2, 90.1, 75.3, 75.1, 74.3, 73.7, 73.2,
73.1, 70.4, 70.3, 68.6, 67.0, 62.2, 62.1, 20.9, 20.9, 20.9, 20.8, 20.8,
20.7, 20.6; MS (ESI) m/z 461 [M + Na]+; HRMS calcd for
C21H26O10Na [M + Na]+ 461.1424, found 461.1445.
L-Galactopyranose pentaacetate 20 was obtained from 19 by
hydrogenolysis followed by acetylation in 95% yield (R-/â-anomers
22:78). 20 (colorless oil): IR (CHCl3) cm-1 2982, 1742, 1433, 1368,
1207, 1170, 1125, 1062, 1042, 953, 929, 899, 754; 1H NMR 6.38
(d, J ) 1.9 Hz, 1H, R-anomer), 5.72 (d, J ) 8.3 Hz, 1H, â-anomer),
5.51 (m, 1H, R-anomer), 5.43 (d, J ) 3.4 Hz, 1H, â-anomer), 5.37-
5.28 [m, 2H (R-anomer) and 1H (â-anomer)], 5.10 (dd, J ) 10.0,
L-Glucopyranose pentaacetate 30 was prepared from 29 by
hydrogenolysis followed by acetylation in 95% yield (R-/â-anomers
49:51). 30 (colorless oil): IR (CHCl3) cm-1 3032, 2962, 1756, 1430,
1
1368, 1241, 1207, 1153, 1079, 1040, 1012, 939, 909; NMR H
6.32 (d, J ) 3.6 Hz, 1H, R-anomer), 5.71 (d, J ) 8.3 Hz, 1H,
â-anomer), 5.48 (t, J ) 10.0 Hz, 1H), 5.25 (t, J ) 9.4 Hz, 1H),
5.18-5.05 (m, 4H), 4.35-4.25 (m, 2H), 4.15-4.05 (m, 3H), 3.85
(ddd, J ) 10.0, 4.5, 2.3 Hz, 1H), 2.19, 2.12, 2.10, 2.09, 2.05, 2.04,
2.03, 2.02, 2.02 (9s, 30H); 13C NMR (â-anomer) 91.7, 72.8, 72.7,
70.2, 67.9, 61.4 (lit.30 91.8, 72.8, 72.8, 70.5, 68.1, 61.7); (R-anomer)
89.1, 69.8, 69.8, 69.2, 67.7, 61.4 (lit30 89.2, 70.0, 70.0, 69.4, 68.1,
61.1); MS (ESI) m/z 413 [M + Na]+; HRMS calcd for C16H22O11Na
[M + Na]+ 413.1060, found 413.1044.
L-Altropyranose pentaacetate 31 was obtained from 28 by
general procedure B and subsequent hydrogenolysis followed by
acetylation in 60% yield (4 steps), (R-/â-anomers 71:29). 31
(colorless oil): IR (CHCl3) cm-1 3029, 3013, 1753, 1431, 1371,
1227, 1207, 1156, 1064, 1015, 974; 1H NMR 6.16 (d, J ) 2.0 Hz,
J. Org. Chem, Vol. 71, No. 2, 2006 701

Ermolenko and Sasaki
1H, R-anomer), 6.0 (br s, 1H, â-anomer), 5.44 (dd, J ) 5.6, 3.2
Hz, 1H, R-anomer), 5.32 (t, J ) 3.4 Hz, 1H, â-anomer), 5.24-
5.18 [m, 2H (R-anomer) and 1H (â-anomer)], 4.98 (dd, J ) 3.7,
1.4 Hz, 1H (â-anomer), 4.42-4.25 [m, 1H (R-anomer) and 2H (â-
anomer)], 4.22-4.10 [m, 2H (R-anomer) and 1H (â-anomer)], 2.17,
2.15, 2.14, 2.14, 2.11, 2.10, 2.05, 2.03 [8s, 15H (R-anomer) and
15H (â-anomer)]; 13C NMR (R-anomer) 90.5, 68.4, 66.6, 66.6, 64.6,
62.3 (lit.30 90.2, 68.2, 66.4, 66.4, 64.6, 62.1); (â-anomer) 90.1, 72.2,
67.3, 65.5, 62.7; MS (ESI) m/z 413 [M + Na]+; HRMS calcd for
C16H22O11Na [M + Na]+ 413.1060, found 413.1044.
1,2,3,6-O-Tetraacetyl-4-O-benzyl-â-L-gulopyranose 38 was
obtained from 36 by general procedure A (for 24 h at room
temperature) in 85% yield. 38 (colorless oil): [R]D + 58.5 (c 2.2);
IR (CHCl3) cm-1 3029, 3012, 2976, 1744, 1455, 1430, 1369, 1213,
1151, 1065, 1052, 922, 745, 701; 1H NMR 7.28 (m, 5H), 6.00 (d,
J ) 7.0 Hz, 1H), 5.65 (dd, J ) 3.7, 3.0 Hz, 1H), 5.25 (dd, J ) 6.8,
3.0 Hz, 1H), 4.82, 4.55 (2d, J ) 11.7 Hz, 2H), 4.25-4.10 (m, 3H),
3.52 (d, J ) 3.7 Hz, 1H), 2.14, 2.12, 2.05, 1.99 (4s, 12H); 13C
NMR 170.5, 169.6, 169.5, 169.3, 136.7, 128.6, 128.5, 128.4, 89.9,
72.8, 72.3, 72.3, 67.6, 67.0, 62.6, 21.0, 20.9, 20.8, 20.7; MS (ESI)
m/z 461 [M + Na]+; HRMS calcd for C20H26O8Na [M + Na]+
461.1424, found 461.1443.
21.1, 21.0, 20.9, 20.6; MS (ESI) m/z 461 [M + Na]+; HRMS calcd
for C21H26O10Na [M + Na]+ 461.1424, found 461.1442.
48b (â-anomer): [R]D -40.5 (c 1.0); IR (CHCl3) cm-1 3031,
2925, 1746, 1454, 1372, 1226, 1207, 1074, 1019, 951, 907; NMR
1H 7.32 (m, 5H), 6.01 (d, J ) 8.7 Hz, 1H), 5.91 (t, J ) 2.8 Hz,
1H), 4.87 (dd, J ) 8.7, 2.8 Hz, 1H), 4.61, 4.34 (2d, J ) 11.3 Hz,
2H), 4.32-4.20 (m, 2H), 4.10 (m, 1H), 3.62 (dd, J ) 9.8, 2.8 Hz,
1H), 2.16, 2.10, 2.04, 1.96 (4s, 12H); 13C NMR 171.4, 170.9, 170.3,
170.0, 137.4, 129.4, 129.2, 129.1, 90.8, 72.9, 72.2, 72.0, 69.6, 67.3,
63.5, 21.8, 21.6, 21.6, 21.4; MS (ESI) m/z 461 [M + Na]+; HRMS
calcd for C21H26O10Na [M + Na]+ 461.1424, found 461.1434.
r-L-Allopyranose pentaacetate 49a was obtained from 48a by
hydrogenolysis followed by acetylation in 90% yield. 49a (colorless
oil): [R]D -69.7 (c 1.1); IR (CHCl3) cm-1 3020, 3014, 1748, 1431,
1371, 1218, 1206, 1127, 1047, 1014, 969, 950, 908; 1H NMR 6.23
(d, J ) 4.2 Hz, 1H), 5.66 (t, J ) 3.0 Hz, 1H), 5.12 (dd, J ) 4.1,
3.6 Hz, 1H), 5.04 (dd, J ) 10.2, 3.0 Hz, 1H), 4.35 (m, 1H), 4.30
(dd, J ) 12.2, 4.1 Hz, 1H), 4.14 (dd, J ) 12.2, 1.9 Hz, 1H), 2.17,
2.16, 2.09, 2.02 (4s, 15H); 13C NMR 170.7, 170.1, 169.3, 169.1,
169.0, 88.5, 67.0, 65.9, 65.9, 65.2, 61.7, 20.9, 20.8, 20.7, 20.5, 20.4;
MS (ESI) m/z 413 [M + Na]+; HRMS calcd for C16H22O11Na [M
+ Na]+ 413.1060, found 413.1073.
â-L-Gulopyranose pentaacetate 39 was prepared from 38 by
hydrogenolysis followed by acetylation in 95% yield. 39 (colorless
oil): [R]D + 2.9 (c 1.9); IR (CHCl3) cm-1: 3030, 3010, 2970, 1755,
1430, 1371, 1229, 1205, 1151, 1131, 1072, 941, 918, 893; 1H NMR
6.00 (d, J ) 8.6 Hz, 1H), 5.42 (dd, J ) 3.7, 3.5 Hz, 1H), 5.12 (dd,
J ) 8.6, 3.5 Hz, 1H), 5.01 (dd, J ) 4.0, 1.5 Hz, 1H), 4.20-4.10
(m, 2H), 2.16, 2.15, 2.13, 2.10, 2.00 (5s, 15H); 13C NMR 89.9,
71.4, 67.6, 67.4, 67.3, 61.5 (lit.30 89.7, 71.1, 67.3, 67.1, 67.1, 61.3);
MS (ESI) m/z 413 [M + Na]+; HRMS calcd for C16H22O11Na [M
+ Na]+ 413.1060, found 413.1075.
â-L-Allopyranose pentaacetate 49b was prepared from 48b by
the same procedure and in the same yield. 49b (colorless oil): [R]D
+12.1 (c 1.2); IR (CHCl3) cm-1: 3029, 2960, 1753, 1431, 1370,
1218, 1205, 1170, 1046, 1020, 951, 914; 1H NMR 6.02 (d, J ) 8.7
Hz, 1H), 5.70 (t, J ) 3.0 Hz, 1H), 5.00 (m, 2H), 4.30-4.10 (m,
3H), 2.17, 2.13, 2.08, 2.02, 2.01 (5s, 15H); 13C NMR 90.1, 71.1,
68.2, 68.1, 65.7, 61.9 (lit.30 90.1, 71.2, 68.2, 68.2, 65.8, 61.9); MS
(ESI) m/z 413 [M + Na]+; HRMS calcd for C16H22O11Na [M +
Na]+ 413.1060, found 413.1053
1,2,3,6-O-Tetraacetyl-4-O-benzyl-L-mannopyranose 50 was
obtained from 47 by procedure B as a mixture of R- and â-anomers
(3:1) easily separated by flash chromatography (heptane-EtOAc
3:1). R-anomer 50a (colorless oil): [R]D -57.5 (c 1.5); IR (CHCl3)
cm-1: 3030, 3013, 1751, 1455, 1371, 1226, 1205, 1153, 1083,
1026, 973, 908; 1H NMR 7.35 (m, 5H), 6.05 (d, J ) 2.1 Hz, 1H),
5.37 (dd, J ) 9.4, 3.4 Hz, 1H), 5.25 (dd, J ) 3.4, 2.1 Hz, 1H),
4.70, 4.60 (2d, J ) 11.1 Hz, 2H), 4.32 (d, J ) 3.8 Hz, 2H), 3.97
(ddd, J ) 10.0, 3.6, 3.2 Hz, 1H), 3.88 (t, J ) 9.6 Hz, 1H), 2.17,
2.14, 2.08, 2.01 (4s, 12H); 13C NMR 170.6, 169.8, 169.7, 168.3,
137.3, 128.6, 128.1, 127.8, 90.7, 75.1, 72.5, 71.7, 71.5, 68.8, 62.8,
20.9, 20.8, 20.8, 20.8; MS (ESI) m/z 461 [M + Na]+; HRMS calcd
for C21H26O10Na [M + Na]+ 461.1424, found 461.1438.
1,2,3,6-O-Tetraacetyl-4-O-benzyl-L-talopyranose 40 was ob-
tained from 37 by general procedure A (for 4 h at room temperature)
in 75% yield (R-/â-anomers 5:1). 40 (colorless oil): IR (CHCl3)
cm-1 3031, 3020, 3010, 2928, 1747, 1497, 1455, 1371, 1228, 1206,
1
1147, 1105, 1051, 1027, 975; 953; 914; 867; H NMR 7.34 (m,
5H, R- and â-anomers), [6.15 (d, J ) 2.0 Hz, R-anomer), 5.85 (d,
J ) 2.2 Hz, â-anomer), 1H], [5.35 (m, R-anomer), 5.30 (m,
â-anomer), 1H], [5.18 (m, R- anomer), 5.13 (m, â-anomer), 1H],
[4.75 (d, J ) 11.4 Hz, R-anomer), 4.72 (d, J ) 11.4 Hz, â-anomer),
1H], [4.60 (d, J ) 11.4 Hz, R-anomer), 4.57 (d, J ) 11.4 Hz,
â-anomer), 1H], 4.50-4.15 (m, R- and â-anomers, 3H), 3.95-3.80
(m, R- and â-anomers, 1H), 2.13, 2.12, 2.10, 2.08, 2.07, 2.06, 2.03,
2.0 (8s, 12H); 13C NMR 170.6, 170.2, 169.8, 168.7, 168.3, 137.8,
128.6, 128.1, 91.6, 90.3, 74.5, 74.1, 73.8, 72.4, 71.8, 71.2, 69.7,
68.3, 66.9, 62.8, 62.4, 20.9; MS (ESI) m/z 461 [M + Na]+; HRMS
calcd for C21H26O10Na [M + Na]+ 461.1424, found 461.1429.
r-L-Talopyranose pentaacetate 41 was prepared from 40 by
hydrogenolysis followed by acetylation in 85% yield. 41 (colorless
oil): [R]D -40.0 (c 1.0); IR (CHCl3) cm-1 3030, 2994, 2928, 2855,
1755, 1648, 1454, 1430, 1372, 1234, 1203, 1145, 1099, 1049, 1019,
â-Anomer 50b (colorless oil): [R]D +25.8 (c 0.5); IR (CHCl3)
1
cm-1 3031, 1751, 1368, 1228, 1205, 1087, 1036, 911; NMR H
7.33 (m, 5H), 5.85 (d, J ) 1.1 Hz, 1H), 5.48 (dd, J ) 3.2, 1.1 Hz,
1H), 5.13 (dd, J ) 9.4, 3.2 Hz, 1H), 4.67, 4.57 (2d, J ) 11.1 Hz,
2H), 4.37 (dd, J ) 12.0, 2.3 Hz, 1H), 4.30 (dd, J ) 12.3, 4.9 Hz,
1H), 3.83 (t, J ) 9.4 Hz, 1H), 3.74 (ddd, J ) 9.4, 4.9, 2.3 Hz, 1H),
2.21, 2.09, 2.08, 1.99 (4s, 12H); 13C NMR 170.7, 170.2, 169.7,
168.4, 137.4, 128.6, 128.2, 127.8, 90.4, 75.1, 74.3, 73.4, 72.5, 68.7,
62.9, 20.9, 20.8, 20.8, 20.7; MS (ESI) m/z 461 [M + Na]+; HRMS
calcd for C21H26O10Na [M + Na]+ 461.1424, found 461.1431.
r-L-Mannopyranose pentaacetate 51a was prepared from 50a
by hydrogenolysis followed by acetylation in 95% yield. 51a
(colorless oil): [R]D -54.9 (c 1.1); IR (CHCl3) cm-1 3031, 2959,
1753, 1431, 1371, 1226, 1207, 1152, 1088, 1054, 1025, 975, 909;
1H NMR 6.09 (d, J ) 1.9 Hz, 1H), 5.35 (m, 2H), 5.25 (dd, J )
2.5, 1.9 Hz, 1H), 4.35 (dd, J ) 12.4, 4.9 Hz, 1H), 4.05 (m, 2H),
2.18, 2.18, 2.10, 2.06, 2.01 (5s, 15H); 13C NMR 170.6, 169.9, 169.7,
169.5, 168.0, 90.5, 70.6, 68.7, 68.3, 65.5, 62.1, 20.8, 20.7, 20.7,
20.6, 20.6 (lit.30 90.4, 70.5, 68.6, 68.2, 65.4, 62.0); MS (ESI) m/z
413 [M + Na]+; HRMS calcd for C16H22O11Na [M + Na]+
413.1060, found 413.1049.
1
1001, 962, 909, 869; NMR H 6.17 (d, J ) 1.7 Hz, 1H), 5.40-
5.25 (m, 2H), 5.05 (m, 1H), 4.25 (m, 1H), 4.15 (m, 2H), 2.16 (s,
6H), 2.15, 2.05, 2.01 (3 s, 9H); 13C NMR 91.5, 68.9, 66.4, 65.4,
65.2, 61.5 (lit.30 91.4, 68.8, 66.3, 65.3, 65.2, 61.5); MS (ESI) m/z
413 [M + Na]+; HRMS calcd for C16H22O11Na [M + Na]+
413.1060, found 413.1048.
1,2,3,6-O-Tetraacetyl-4-O-benzyl-L-allopyranose 48 was ob-
tained from 46 by general procedure B in 85% yield as a mixture
of R- and â-anomers in 1:2 ratio, which were separated by flash
chromatography (heptane-EtOAc 3:1).
48a (R-anomer): [R]D -95.2 (c 1.1); IR (CHCl3) cm-1 3030,
3008, 2957, 1744, 1454, 1372, 1226, 1207, 1132, 1061, 1016, 966,
910; NMR 1H 7.33 (m, 5H), 6.20 (d, J ) 4.1 Hz, 1H), 5.87 (t, J )
3.0 Hz, 1H), 5.03 (dd, J ) 4.0, 3.6 Hz, 1H), 4.63, 4.37 (2d, J )
11.3 Hz, 2H), 4.22 (m, 3H), 3.65 (dd, J ) 9.8, 3.0 Hz, 1H), 2.17,
2.14, 2.03, 1.97 (4s, 12H); 13C NMR 170.7, 170.5, 169.7, 169.3,
136.7, 128.7, 128.5, 128.4, 88.6, 71.0, 70.7, 67.1, 66.6, 65.4, 62.6,
â-L-Mannopyranose pentaacetate 51b was obtained from 50b
by the same procedure and in the same yield. 51b (colorless oil):
[R]D +23.3 (c 1.1); IR (CHCl3) cm-1: 3031, 1754, 1602, 1460,
1430, 1369, 1226, 1207, 1169, 1090, 1057, 970, 909, 859; 1H NMR
702 J. Org. Chem., Vol. 71, No. 2, 2006

DiastereoselectiVe Synthesis of L-Hexoses from L-Ascorbic Acid
5.85 (d, J ) 1.0 Hz, 1H), 5.49 (dd, J ) 3.2, 1.0 Hz, 1H), 5.29 (t,
J ) 10.0 Hz, 1H), 5.16 (dd, J ) 10.0, 3.2 Hz, 1H), 4.32 (dd, J )
12.3, 5.1 Hz, 1H), 4.14 (dd, J ) 12.3, 2.5 Hz, 1H), 3.83 (ddd, J )
10.0, 5.2, 2.5 Hz, 1H), 2.22, 2.11, 2.10, 2.06, 2.01 (5s, 15H); 13C
NMR 170.6, 170.2, 169.8, 169.6, 168.4, 90.4, 73.2, 70.6, 68.2, 65.4,
62.1, 20.8, 20.8, 20.8, 20.7, 20.5; MS (ESI) m/z 413 [M + Na]+;
HRMS calcd for C16H22O11Na [M + Na]+ 413.1060, found
413.1057.
him for stimulating discussions and encouragement for pursuing
this work. L.E. acknowledges a postdoctoral fellowship from
ICSN.
Supporting Information Available: General conditions,
experimental procedures, and spectroscopic data for compounds
1
2-12 and copies of H and 13C spectra for compounds 9-51.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This paper is dedicated to Professor
Pierre Potier on the occasion of his 71st birthday. We thank
JO0521192
J. Org. Chem, Vol. 71, No. 2, 2006 703