Iodomethyl group as a hydroxymethyl synthetic equivalent: Application to the syntheses of D-manno-hept-2-ulose and L-fructose derivatives

Article abstract of DOI:10.1021/jo0342166

The one-carbon elongation of aldoses to ketoses using iodomethyllithium as the key reagent in the homologation step is exemplified by the preparation of two carbohydrates of chemical and biological interests: D-manno-hept-2-ulose from D-mannose and L-fructose from L-arabinose.

Full text of DOI:10.1021/jo0342166

SCHEME 1
Iodomethyl Group as a Hydroxymethyl
Synthetic Equivalent: Application to the
Syntheses of D-manno-Hept-2-ulose and
L-Fructose Derivatives
Bernard Bessie`res and Christophe Morin*
Universite´ Joseph Fourier, UMR CNRS 5616, Chimie
Recherche (LEDSS), BP 53, 38041 Grenoble Cedex 9, France
christophe.morin@ujf-grenoble.fr
Received February 19, 2003
an hexose, such as the addition of benzyloxymethylmag-
nesium chloride to mannonolactone 2, has been pro-
posed.12 This procedure gave 1 in 28% overall yield, with
38% recovery of 2, this yield being based on reacted
lactone. Therefore, we considered that a more reactive
species was necessary for this homologation reaction.
When reacted with diiodomethane/samarium, esters
are converted to cyclopropanols13 but the addition of an
iodomethyl group to the carbonyl group can be ac-
complished by reaction with iodomethyllithium.14 Due to
its thermal instability, ICH2Li is generated at low tem-
perature from diiodomethane/MeLi, lithium/iodine ex-
change taking preference over metalation; this can be
effected in the presence of the lactone partner;14 no
addition of methyllithium on the carbonyl group is
observed.15
Abstract: The one-carbon elongation of aldoses to ketoses
using iodomethyllithium as the key reagent in the homolo-
gation step is exemplified by the preparation of two carbo-
hydrates of chemical and biological interests: D-manno-hept-
2-ulose from D-mannose and L-fructose from L-arabinose.
The elongation of carbohydrates from the reducing end
allows a net aldose to ketose homologation;1 we now show
this transformation to be feasible using the iodomethyl
group as a hydroxymethyl equivalent (Scheme 1); this is
exemplified by the preparation of two ketoses, D-manno-
hept-2-ulose and L-fructose, which have been selected for
their chemical and biological interests.
D-manno-Hept-2-ulose, 1. The effects of this seven-
carbon ketose2 on insulin secretion have been known for
a long time,3 and 1 has been shown to be a high-affinity
inhibitor of glucokinase in pancreatic â-cells4 and tumor
cells;5 it has been proposed that 1 is transported across
the plasma membrane at the specific intervention of
GLUT-2, an isoform of the human carbohydrate transport
proteins.6 manno-Hept-2-ulose, which is no longer com-
mercially available, can be isolated from certain varieties
of avocado7 or after isomerization of D-glycero-D-galacto-
heptose.8 Condensation of 1,3-dihydroxypropanone with
an erythrose derivative9 and of nitroethanol with arabi-
nose derivatives10 have also yielded 1 as well as a
molybdic acid induced rearrangement of 2-C-hydroxy-
methyl-D-glucose.11 Since these procedures require sepa-
ration of epimers, the addition of a 1-carbon synthon to
Thus, after reacting the readily available mannofura-
nonolactone 216 with iodomethyllithium at low temper-
ature, 3 was isolated in 92% yield (Scheme 2); this yield
compares favorably with those observed for other lac-
tones14 and can be explained by internal coordination of
the organometallic species by the oxygens of the acetals
of 3, which all lie on the same side of the furanose ring.
As shown by an nOe effect between H-3 and the hydroxyl
group, 3 exists mostly in solution as the R-anomer
(>95%), which is also the form that could be crystallized
(Philouze, C., unpublished results). Attempts to get 4
using reagents which are known to convert hindered
halides to hydroxyl groups, such as superoxide anion,17
hydrated alumina,18 or TEMPO-mediated free-radical
substitution followed by reduction19 were ineffective;
however, 412 could be obtained after treatment with
potassium hydroxide. Noteworthy is the outcome ob-
served when iodide 3 was treated with a strong base
(DBU) in aprotic solvent, pyranone 5 (73%) being the only
(1) For a review about elongation of carbohydrates: Gyo¨rgydea`k,
Z.; Pelyva`s, I. F. Monosaccharide sugars. Chemical synthesis by chain
elongation, degradation and epimerization; Academic Press: San Diego,
1997.
(2) For a review: Stankovic, L.; Bilik, V. Chem. Listy. 1986, 80, 520.
(3) For a review: Simon, E.; Frenkel, G.; Kraicer, P. F. Isr. J. Med.
Sci. 1972, 8, 743.
(11) Hricoviniova, Z.; Hricovini, M.; Petrus, L. Chem. Papers 1998,
52, 692.
(4) Xu, L. Z.; Harrison, R. W.; Gidh-Jain, M.; Pilkis, S. J. Biochem-
istry 1995, 34, 6083.
(12) Kampf, A.; Dimant, E. Carbohydr. Res. 1974, 32, 380.
(13) Imamoto, T.; Hatajima, T.; Takiyama, N.; Takeyama, T.;
Kamiya, R.; Yoshizawa, T. J. Chem. Soc., Perkin Trans. 1 1991, 3127.
(14) Bessieres, B.; Morin, C. Synlett 2000, 1691.
(15) (a) Wallace, R. H.; Battle, W. Synth. Commun. 1995, 61, 100.
(b) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1995,
60, 6696. (c) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org.
Chem. 1999, 64, 2843.
(5) Board, M.; Colquhoun, A.; Newsholme, E. A. Cancer Res. 1995,
55, 3278.
(6) (a) Ferrer, J.; Gomis, R.; Fernandez Alvarez, J.; Casamijtana,
R.; Vilardell, E. Diabetes 1993, 42, 1273. (b) Malaisse, W. J. Diabeto-
logia 2001, 44, 393.
(7) (a) La Forge, F. B. J. Biol. Chem. 1916, 28, 516. (b) Nordal, A.;
Benson, A. A. J. Am. Chem. Soc. 1954, 76, 5054. (c) Richtmyer, N. K.
Methods Carbohydr. Chem. 1963, 1, 173.
(16) (a) Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 319. (b)
Garegg, P. J.; Samuelsson, B. Carbohydr. Res. 1978, 67, 267.
(17) Corey, E. J.; Nicolaou, K. C.; Shibasaki, M.; Machida, Y.; Shiner,
C. S. Tetrahedron Lett. 1975, 37, 3183.
(18) Gray, B. D.; Miller, J. A. J. Chem. Soc., Chem. Commun. 1987,
1136.
(19) Barrett, A. G. M.; Melcher, L. M.; Bezuidenhoudt, B. C. B.
Carbohydr. Res. 1992, 232, 259.
(8) (a) Montgomery, E. M.; Hudson, C. S. J. Am. Chem. Soc. 1939,
61, 1654. (b) Kucar, S.; Linek, K.; Novotna, Z. Chem. Zvesti 1981, 35,
695.
(9) Schaffer, R.; Isbell, H. S. J. Org. Chem. 1962, 27, 3268.
(10) (a) Sowden, J. C.; Strobach, D. R. J. Am. Chem. Soc. 1958, 80,
2532. (b) Sowden, J. C. J. Am. Chem. Soc. 1950, 72, 3325.
10.1021/jo0342166 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/18/2003
4100
J. Org. Chem. 2003, 68, 4100-4103

SCHEME 2
To get L-fructose we considered the addition of iodom-
ethyllithium to a suitably protected arabinonolactone,
since we have shown during the synthesis of 1 that an
iodomethyl group could be considered as a hydroxymethyl
equivalent. Our approach (Scheme 3) begins with the
readily available acetal 8,31 which was first oxidized to 9
by bromine,32 in the presence of barium carbonate as a
buffer,33 then benzylated to give lactone 10.34 When
reacted with iodomethyllithium, 10 gave the expected
iodohydrin 11.
Displacement of the neopentylic iodide by hydroxyde
proceeded in better yield (77%) than for the manno-
heptulose series, and 12 thus formed was next converted
to acetal 13.35 Completion of the synthesis involved
removal of the benzyl group (to give alcohol 1421) and
then hydrolysis to 7.
Besides this scheme providing a preparation of L-
fructose, we believe its main advantage lies in an access
to 14 and related chiral auxiliaries, and in particular to
15 (whose enantiomer, 6, is known under the trademark
Epoxone) as, by making them available under the L-form,
this should expand their uses in asymmetric reactions.36
Experimental Section
Toluene was distilled over sodium and stored over 4 Å
molecular sieves, diiodomethane was distilled and stored over
copper turnings, acetone was distilled over calcium sulfate, and
acetonitrile was distilled over calcium hydride and stored over
4 Å molecular sieves. 1H spectra are referenced from tetram-
ethylsilane or from the residual peak of CHCl3 (δH ) 7.24 ppm)
and are reported as follows: chemical shift (ppm), multiplicity,
integration, coupling constants (Hz) and assignments. Chemical
shifts for 13C spectra are referenced from CDCl3 resonance
(δC ) 77.0 ppm).
product (this can be explained by displacement of the
iodide by the alkoxide at position-5 arising from the open-
chain form of the carbohydrate). Deprotection of the
acetals of 4 was then effected conventionally12 which gave
D-manno-hept-2-ulose 1 in 40% overall yield from 2. This
compares favorably with literature procedures and thus
sets up a practical preparation.
L-Fructose, 7. Ketone 6 is a chiral auxiliary which has
found important synthetic applications in asymmetric
epoxidation20,21 and enantioselective oxidation of vic-
diols.22 Other fructose-derived acetals have been shown
to be effective in enantioselective cyclopropanations23 or
Diels-Alder cycloadditions.24 However, the high price of
L-fructose, 7, the non-natural enantiomer, brings some
limitations to the applicability of these otherwise efficient
procedures.
1-Deoxy-3,4:6,7-di-O-isopropylidene-1-iodo-D-manno-hept-
2-ulose (3). Under argon, to a solution of lactone 216 (6.80 g,
26.5 mmol) and diiodomethane (10.71 g, 40.0 mmol) in dry
toluene (180 mL) cooled to -70 °C was added dropwise a solution
of methyllithium in diethyl ether (19.7 mL of a 1.6 M solution;
31.5 mmol). The solution was maintained at -70 °C for 20 min
and quenched with a saturated solution of ammonium chloride
in water (50 mL). The organic layer was decanted, and the
aqueous layer was extracted with chloroform (3 × 50 mL); the
combined organic layers were dried over sodium sulfate and the
solvents evaporated under reduced pressure to give 3 (9.79 g,
24.5 mmol, 92%) as a pale yellow solid which can be used in the
next step without purification. An analytical sample was ob-
tained by recrystallization from ethyl acetate/n-hexane: mp
Syntheses of L-fructose and derivatives have been
elaborated from L-carbohydrates and they include elon-
gation of arabinonic acid,25 arabinose,26 or glyceralde-
hyde,27 inversion of the 4-OH of sorbose,21,28 or enzymatic
methods such as isomerization of mannose29 or bacterial
oxidation of mannitol.30
1
(AcOEt/n-hexane) 87 °C; H NMR (CDCl3, 300 MHz) δ 1.33 (s,
3H, CH3), 1.38 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.49 (s, 3H, CH3),
2.72 (s, 1H, OH), 3.45 and 3.54 (AB q, 2H, J ) 11 Hz, H-1), 4.02-
4.11 (m, 3H, H-5, H-7 and H-7′), 4.32-4.40 (m, 1H, H-6), 4.62
(d, 1H, J3,4 ) 6 Hz, H-3), 4.95 (dd, 1H, J4,5 ) 4 Hz, J3,4 ) 6 Hz,
H-4); 13C NMR (CDCl3, 75.5 MHz) δ 12.2 (C-1), 24.8 (CH3), 25.7
(20) Review: Frohn, M.; Shi, Y. Synthesis 2000, 1979.
(21) (a) Wang, Z.-X.; TU, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224. (b) Burke, A.; Dillon, P.; Martin, K.;
Hanks, T. W. J. Chem. Educ. 2000, 77, 271.
(29) Mayo, J. W.; Anderson, R. L. Carbohydr. Res. 1968, 8, 344.
(30) Dhawale, M. R.; Szarek, W. A.; Hay, G. W.; Kropinski, A. M.
B. Carbohydr. Res. 1986, 155, 262.
(22) Adam, W.; Saha-Mo¨ller, C. R.; Zhao, C.-G. J. Org. Chem. 1999,
64, 7492.
(31) Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95.
(32) Williams, D. R.; Klinger, F. D.; Allen, A. A.; Lichtenthaler, F.
W. Tetrahedron Lett. 1988, 29, 5087
(23) Kang, J.; Lim, G. J.; Yoon, S. K.; Kim, M. Y. J. Org. Chem.
1995, 60, 564.
(24) Enholm, E. J.; Jiang, S. J. Org. Chem. 2000, 65, 4756.
(25) Wolfrom, M. L.; Thompson, A. J. Am. Chem. Soc. 1946, 68, 791.
(26) Matsumoto, T.; Enomoto, T.; Kurosaki, T. J. Chem. Soc., Chem.
Commun. 1992, 610.
(27) Alajarin, R.; Garcia-Junceda, E.; Wong, C.-H. J. Org. Chem.
1995, 60, 4294.
(28) (a) Chen, C. C.; Whistler, R. L. Carbohydr. Res. 1988, 175, 265.
(b) Gizaw, Y.; BeMiller, J. N. Carbohydr. Res. 1995, 266, 81. (c) Bach,
T.; Ho¨fer, F. J. Org. Chem. 2001, 66, 3427.
(33) Estevez, J. C.; Fairbanks, A. J.; Fleet, G. W. J. Tetrahedron
1998, 54, 13591.
(34) For another, but less efficient approach to 10, see; Saburi, M.;
Ishii, Y.; Kaji, N.; Aoi, T.; Sasaki, I.; Yoshikawa, S.; Uchida, Y. Chem.
Lett. 1989, 563.
(35) Kang, J.; Lim, G. J.; Yoon, S. K.; Kim, M. Y. J. Org. Chem.
1995, 60, 564.
(36) For recent developments, see (a) Tian, H.; She, X.; Shi, Y. Org.
Lett. 2001, 3, 1929. (b) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc.
2002, 124, 8792.
J. Org. Chem, Vol. 68, No. 10, 2003 4101

SCHEME 3
(CH3), 26.2 (CH3), 27.3 (CH3) 66.7 (C-7), 76.5, 80.4, 81.1, 83.6
(C-3, C-4, C-5, C-6), 102.6 (C-2), 109.2 (C(CH3)2), 113.2 (C(CH3)2);
mixture was stirred in the dark for 3 h, and the reaction was
quenched by addition of a saturated aqueous solution of sodium
thiosulfate. The mixture was extracted with ethyl acetate (3 ×
20 mL), the organic phase was dried over sodium sulfate, and
the solvents were evaporated under vacuum to yield lactone 9
(695 mg, 3.7 mmol, 74%), which was used in the next step
without further purification.
[R]25 -8 (5 min) f -11 (24 h) (c 1, CHCl3). Anal. Calcd for
D
C
13H21IO6: C, 39.01; H, 5.29; I, 31.71. Found: C, 38.84; H, 5.52;
I, 31.57.
3,4:6,7-Di-O-isopropylidene-D-manno-hept-2-ulose (4). A
1 M aqueous solution of NaOH (50 mL, 1.9 equiv) was added to
a solution of iodide 3 (10.3 g, 25.7 mmol, 1 equiv) in a mixture
of acetonitrile (150 mL)/water (50 mL), and the resulting solution
was stirred for 35 min. The aqueous phase was extracted with
3 × 50 mL of AcOEt. The resulting organic phase was dried over
magnesium sulfate and concentrated under vacuum to afford
5.20 g of an oil which was chromatographed over silica gel
(eluant: n-hexane/ethyl acetate, from 6/4 to 4/6) to afford 3.55
g (12.2 mmol, 48%) of diol 4 as a white solid:
An analytical sample was purified by rapid chromatography
over silica gel (too long a chromatography results in opening of
the lactone to the acid-alcohol), eluting with ethyl acetate/n-
hexane (2/1) and recrystallized from petroleum ether.
The 1H and 13C NMR spectra are in accordance with the ones
reported in the literature:37 mp (petroleum ether) 92 °C (lit.37
mp 95 °C); [R]25 -70 (c 1.8, MeOH) (lit.37 [R]22 -9.8 (c 1.8,
D
D
MeOH), lit.38 [R]D -1 (c 3, CHCl3)).
mp 85 °C (toluene/pentane) (lit.12 mp 88 °C); 1H NMR (300
MHz, CDCl3) δ 1.33 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.45 (s, 3H,
CH3), 1.47 (s, 3H, CH3), 1.97 (m, 1H, CH2OH), 3.15 (s, 1H, 2-OH),
3.70-3.83 (m, 2H, 1-H), 3.98-4.10 (AB part of an ABX system,
2-O-Benzyl-3,4-O-isopropylidene-L-arabinono-1,5-lac-
tone (10). Under argon, to a solution of lactone 9 (1.750 g, 9.3
mmol) in dry acetonitrile (40 mL) was added freshly prepared
silver(I) oxide39 (9.264 g, 40.0 mmol) followed by benzyl bromide
(8.545 g, 50.0 mmol), and the resulting suspension was stirred
in the dark overnight. The mixture was filtered over a pad of
Celite, which was rinsed with methylene chloride, and the
solvents were removed under vacuum. The oil thus obtained was
purified by chromatography over silica gel (methylene chloride/
methanol, 9/1) and the product recrystallized in n-hexane to give
benzyl ether 10 as a white solid (1.500 g, 5.4 mmol, 58%): mp
76-77 °C (n-hexane). The 1H NMR is in accordance with the
one reported in the literature:34 13C NMR (75.5 MHz, CDCl3) δ
24.0 (CH3), 25.9 (CH3), 67.4 (C-5), 72.6 (CH2Ph), 71.2, 74.9, 75.6,
(C-2, C-3, C-4) 110.4 (C(CH3)2), 128.2. 128.3, 128.5 (CH Ar), 136.1
2H, JAB ) 9 Hz, H-7 and H-7′), 4.13 (dd, 1H, J4,5 ) 4 Hz, J5,6
)
8 Hz, H-5), 4.35-4.41 (m, 1H, H-6), 4.60 (d, 1H, J3,4 ) 6 Hz,
H-3), 4.92 (dd, 1H, J4,5 ) 4 Hz, J5,6 ) 6 Hz, H-4). 13C NMR (75.5
MHz, CDCl3) δ 24.3 (CH3), 25.1 (CH3), 25.7 (CH3), 26.8 (CH3),
64.4 (C-1), 66.6 (C-7), 73.1 (C-6), 79.5 (C-5), 80.3 (C-4), 85.0 (C-
3), 104.7 (C-2), 109.1 (C(CH3)2), 112.9 (C(CH3)2); [R]25 +25 (5
D
min.) f +17 (24 h) (c 1, CHCl3) (lit.12 [R]D +20.4 (c 1, CHCl3)).
1-Deoxy-3,4:6,7-di-O-isopropylidene-2-keto-D-manno-hep-
topyranose (5). DBU (75µL, 0.5 mmol) was added to a solution
of iodide 3 (200 mg, 0.5 mmol, 1 equiv) in dry THF (5 mL), and
the reaction mixture was stirred for 3 h. Water (2 mL) was
added, the reaction mixture was extracted with methylene
chloride, the organic phase was dried over sodium sulfate, and
the solvents were evaporated under vacuum to afford 164 mg of
an oil which was chromatographed over silica gel (eluant:
n-hexane/ethyl acetate, 3/1) to afford 100 mg (0,37 mmol, 73%)
(C ipso Ar), 167.7 (CdO); [R]23 +123 (c 1, CHCl3).
D
3-O-Benzyl-1-deoxy-1-iodo-4,5-O-isopropylidene-L-fruc-
topyranose (11). Under argon, to a solution of lactone 10 (1.50
g, 5.4 mmol) and diiodomethane (2.169 g, 8.1 mmol) in dry
toluene (60 mL) cooled to -70 °C was added dropwise methyl-
lithium (4.3 mL of a 1.6 M solution in diethyl ether, 6.9 mmol)
at a rate such as to maintain the internal temperature between
-70 and -60 °C. The solution was kept at -70 °C for 20 min
and quenched with an aqueous saturated solution of ammonium
chloride (20 mL). The organic layer was decanted, the aqueous
layer was extracted with chloroform (2 × 50 mL), the combined
organic phases were dried over sodium sulfate, and the solvents
1
of heptose 5 as white solid: mp 58 °C (pentane); H NMR (300
MHz, CDCl3) δ 1.35 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.41 (s, 3H,
CH3), 1.46 (s, 3H, CH3), 3,51 (dd, 1H, J ) 2, 8 Hz, H-5), 3.96-
4.10 (m, 3H, H-1 and H-7′), 3.96-4.37 (m, 3H, H-1, H-3 and H-7),
4.64 (dd, 1H, J ) 2, 7 Hz, H-4); 13C NMR (75.5 MHz, CDCl3) δ
25.5 (CH3), 26.1 (CH3), 27.1 (CH3), 27.4 (CH3), 67.3 (C-1) 73.8
(C-7), 74.3(C-3 or C-6), 76.3 (C-4), 77.8 (C-3 or C-6), 77.9 (C-5),
110.0 (C(CH3)2), 112.3 (C(CH3)2), 204.4 (CdO); [R]25 -41 (c 1,
D
CHCl3).
(37) Han, S.-Y.; Jouille´, M. M.; Fokin, V. V.; Petasis, N. Tetrahedron:
Asymmetry 1994, 5, 2535.
(38) Morenglie, S. Acta Chem. Scand. 1972, 26, 2518.
(39) Ag2O was prepared as reported in: Vogel’s textbook of practical
organic chemistry, 4th ed.; Longman: London, 1978; p 344.
3,4-O-Isopropylidene-L-arabinono-1,5-lactone (9). Bro-
mine (1.998 g, 12.5 mmol) was added dropwise to a mixture of
lactol 8 (950 mg, 5.0 mmol) and barium carbonate (1.184 g, 6.0
mmol) in water (10 mL) and dioxane (5 mL). The reaction
4102 J. Org. Chem., Vol. 68, No. 10, 2003

were evaporated under reduced pressure. The crude oil was
purified by flash chromatography over silica gel (n-hexane/ethyl
acetate, 9/1) to give 11 as an oil (1.47 g, 3.5 mmol, 65%).
Spectral data for the major anomer: 1H NMR (300 MHz,
CDCl3) δ 1.29 (s, 3H, CH3), 1.43 (s, 3H, CH3), 3.14 (s, 1H, OH),
were evaporated under reduced pressure, and the solution was
extracted with methylene chloride (3 × 15 mL). The organic layer
was dried over sodium sulfate and the solvent removed in vacuo.
The crude product was purified by flash chromatography over
silica gel (toluene/ethyl acetate, 100/5) to give 13 (130 mg, 0.37
mmol, 74%) as an oil.
3.23 and 3.47 (AB q, 2H, JAB ) 10 Hz, H-1), 3.60 (d, 1H, J3,4
)
The 1H spectrum is in accordance with the one reported in
the literature:35 13C NMR (75.5 MHz, CDCl3) δ 26.0 (CH3), 26.2
(CH3), 26.9 (CH3), 28.1 (CH3), 60.2 (C-6), 71.9 (CH2), 73.0 (CH2),
73.8, 76.0, 77.8 (C-3, C-4, C-5), 104.4 (C-2), 109.0 (C(CH3)2), 112.1
7 Hz, H-3), 3.87 (A part of ABM, 1H, J6,6′ ) 12 Hz, H-6), 3.98-
4.03 (m, 1H, H-6′), 4.10 (dd, 1H, J5,6 ) 2 Hz, J4,5 ) 6 Hz, H-5),
4.28 (t, 1H, J4,5 ) 6 Hz, H-4), 4.61 and 4.85 (AB q, 2H, JAB ) 11
Hz, CH2Ph), 7.23-7.27 (m, 5H, Ar); 13C NMR (75.5 MHz, CDCl3)
δ 14.9 (C-1), 26.1 (CH3), 28.0 (CH3), 60.3 (C-6), 73.2 (CH2Ph),
73.5 76.7, 77.2 (C-3, C-4, C-5), 94.5 (C-2), 109.2 (C(CH3)2), 128.1,
(C(CH3)2), 127.5, 127.7, 128.2 (CH Ar), 138.2 (C ipso Ar); [R]23
D
22.5
+87 (c 2, CHCl3) (lit.35 [R]D
-89.6 (c 2.22, CHCl3) for the
128.4 (CH Ar), 137.4 (C ipso Ar); [R]25 +35.5 (5 min) δ + 32.6
D
D-isomer).
(24 h) (c 1, CHCl3). Anal. Calcd for C16H21IO5: C, 45.73; H, 5.04.
Found: C, 45.63; H, 5.27.
1,2:4,5-Di-O-isopropylidene-â-L-fructopyranose (14). To
a solution of benzyl ether 13 (55 mg, 0.16 mmol) in ethanol (2.5
mL) was added 5% Pd/C (20 mg). The flask was placed under
an hydrogen atmosphere and the mixture stirred overnight. The
flask was flushed with argon and filtered over Celite and the
solvent removed in vacuo to afford pure alcohol 14 (40 mg, 0.15
mmol, 98%) as a white solid.
3-O-Benzyl-4,5-O-isopropylidene-L-fructopyranose (12).
To a solution of 11 (840 mg, 2 mmol) in acetonitrile (15 mL)
was added an aqueous solution of KOH (4 mL of a 1 M solution,
4 mmol), and the mixture was stirred for 1 h. The pH was
adjusted to 8 by addition of 1 N HCl, the acetonitrile evaporated,
and the aqueous mixture extracted with ethyl acetate (3 × 10
mL). The organic phase was dried over sodium sulfate and the
solvent evaporated to give diol 12 (480 mg, 1.5 mmol, 75%) as a
white solid which was used in the next step without purification.
An analytical sample was obtained by recrystallization from
n-hexane/dichloromethane (8/3): mp 101 °C (n-hexane/dichlo-
romethane); 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H, CH3), 1.50
(s, 3H, CH3), 1.98 (X part of ABX, 1H, OH-1), 3.50 and 3.64 (AB
part of ABX, 2H, J1,1′ ) 11 Hz, H-1, H-1′), 3.51 (s, 1H, OH-2),
3.59 (d, 1H, J3,4 ) 6 Hz, H-3), 3.94 and 4.14 (AB part of ABX,
2H, J6,6′ ) 13 Hz, H-6, H-6′), 4.24-4.27 (m, 1H, H-5), 4.47 (t,
1H, J ) 6 Hz, H-4), 4.67 and 4.90 (AB q, 2H, JAB ) 12 Hz, CH2-
Ph), 7.34-7.36 (m, 5H, Ar). 13C NMR (75.5 MHz, CDCl3) δ 26.0
(CH3), 27.8 (CH3), 59.9 (C-6), 65.9 (C-1), 73.1 (CH2Ph), 73.3, 76.0,
76.2 (C-3, C-4, C-5), 96.1 (C-2), 109.06 (C (CH3)2), 127.9, 128.2,
The spectral data are in accordance with those reported in
the literature:21 mp 117 °C (hexane/dichloromethane) (lit.21 mp
118 °C); [R]23 +143 (c 1, CHCl3) ([R]D -144.2 (c 1, CHCl3) for
D
the D-isomer).21
L-Fructose (7). A solution of 1,2:4,5-di-O-isopropylidene-â-
L-fructopyranose 14 (26 mg, 0.1 mmol) in ethanol (1.5 mL) was
acidified to pH ) 1 by addition of 2 N sulfuric acid and heated
at 40 °C overnight. The solution was cooled to room temperature
and the pH adjusted to 7-8 by addition of 2 N sodium hydroxide.
After addition of ethanol and filtration of the salts, the solvents
were evaporated and the residue chromatographed over silica
gel using a mixture of AcOEt/MeOH/H2O (40/10/7) as the eluent
to give L-fructose 7 (13 mg, 0.072 mmol) in 72% yield.
The NMR data are identical with those recorded for D-
fructose: [R]23D +87 (c 0.21, H2O) (lit.28a [R]23D +88 (c 1.5, H2O),
lit.28b [R]23 +94.4 (c 1.8, H2O), lit.27 [R]23 +87.2 (c 2.1, H2O),
128.3 (CH Ar), 137.4 (C ipso Ar); [R]25 +56.4 (5 min) f 38.8
D
D
D
(24 h) (c 1, CHCl3). Anal. Calcd for C16H22O6: C, 61.92; H, 7.15.
Found: C, 61.90; H, 7.38.
lit.29 [R]23 +91 (c 2.5, H2O), lit.30 [R]23 +86 (c 1, H2O), lit.25
D
D
[R]23 +93 (c 9.5, H2O),).
D
3-O-Benzyl-1,2:4,5-di-O-isopropylidene-â-L-fructopyra-
nose (13). To a solution of diol 12 (155 mg, 0.50 mmol) in dry
acetone (5 mL) were added 2,2-dimethoxypropane (185 µL, 1.49
mmol) and HClO4 (22 µL, 0.25 mmol of a 70% aqueous solution),
and the resulting dark red solution was stirred for 4 h and then
poured into concentrated ammonium hydroxide. The volatiles
Acknowledgment. C. Philouze is thanked for ra-
diocrystallographic analysis of 3.
JO0342166
J. Org. Chem, Vol. 68, No. 10, 2003 4103