Carbon-branched carbohydrate chirons: practical access to both enantiomers of 2-C-methyl-ribono-1,4-lactone and 2-C-methyl-arabinonolactone

Article abstract of DOI:10.1016/j.tetasy.2008.10.013

Readily crystallized 2-C-methyl-d-ribono-1,4-lactone is formed in a one-pot procedure from d-glucose without any protecting groups by treatment with dimethylamine to give an Amadori ketose and then with aqueous calcium hydroxide in yields of approximately 25%; 2-C-methyl-l-ribono-1,4-lactone is similarly produced from l-glucose. 3,4-O-Isopropylidene-2-C-methyl-d-arabinono-1,5-lactone and 2-C-methyl-d-arabinono-1,4-lactone were prepared in a combined 60% yield by the Kiliani reaction of sodium cyanide with a protected 1-deoxy-d-ribulose derived from d-erythronolactone; the enantiomeric arabinonolactones are similarly available from l-erythronolactone.

Full text of DOI:10.1016/j.tetasy.2008.10.013

Tetrahedron: Asymmetry 19 (2008) 2417–2424
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Carbon-branched carbohydrate chirons: practical access to both enantiomers
of 2-C-methyl-ribono-1,4-lactone and 2-C-methyl-arabinonolactone
Kathrine V. Booth a, Filipa P. da Cruz a, David J. Hotchkiss a, Sarah F. Jenkinson a, Nigel A. Jones a,
Alexander C. Weymouth-Wilson b, Robert Clarkson b, Thomas Heinz c, George W. J. Fleet a,
*
a Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
b Dextra Laboratories Ltd, The Science and Technology Centre, Whiteknights Road, Reading, RG6 6BZ, UK
c Chemical and Analytical Development, Novartis Pharma AG, Postfach CH-4002, Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Readily crystallized 2-C-methyl-D-ribono-1,4-lactone is formed in a one-pot procedure from D-glucose
Received 24 September 2008
Accepted 10 October 2008
Available online 5 November 2008
without any protecting groups by treatment with dimethylamine to give an Amadori ketose and then
with aqueous calcium hydroxide in yields of approximately 25%; 2-C-methyl- -ribono-1,4-lactone is sim-
ilarly produced from -glucose. 3,4-O-Isopropylidene-2-C-methyl- -arabinono-1,5-lactone and 2-C-
methyl- -arabinono-1,4-lactone were prepared in a combined 60% yield by the Kiliani reaction of sodium
cyanide with a protected 1-deoxy-
onolactones are similarly available from
L
L
D
D
D-ribulose derived from
D-erythronolactone; the enantiomeric arabin-
L-erythronolactone.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
preparation of 6L and 7L. The arabinonolactones 6 and 7 have been
used in syntheses of 20-C-methyl nucleosides8 and carbon-
branched ketoses.5
Monosaccharides provide the most diverse family of constitu-
ents of the chiral pool for the synthesis of highly functionalized
homochiral targets, all of which have linear carbon chains.1 The
lack of availability of C-branched carbohydrate starting materials
has meant that there are only a few examples of their use as chir-
2. Results and discussion
2.1. Synthesis of 2-C-methyl-
methyl- -ribono-1,4-lactone 3L from
1L by the treatment of Amadori ketoses with calcium hydroxide
D-ribono-1,4-lactone 3 and 2-C-
ons.2 2-C-Methyl-
D-ribono-1,4-lactone 3, obtained in low yield by
L
D
-glucose 1 and -glucose
L
calcium oxide treatment of fructose in water, has been used in
the synthesis of branched 20-3 and 40-4 C-nucleosides, 4-C-methyl-
pentuloses,5 and branched imino sugars.6 Even so, the difficulty of
this preparation means that most studies of bioactive 20-C-methyl
nucleosides have been made by lengthy sequences from un-
branched sugars.7
D-Glucose 1 on heating with calcium oxide in water for 1 h gave
2-C-methyl ribono-1,4-lactone 3 in approximately 0.5% yield; over
50 other products were also identified.9 Base treatment of mono-
saccharides induces a wide range of reversible aldol, epimerization
and dehydration reactions as well as Lobry de Bruyn rearrange-
ments.10 The most readily isolated compounds are saccharinic
acids which are crystallized relatively easily; furthermore, their
carboxylate salts are inert to further base catalyzed reactions.11
Fructose 8 with calcium hydroxide under carefully controlled con-
ditions of temperature and time allowed the isolation of 3 in a
yield of around 10% in about 8–10 weeks;12 if the reaction mixture
is heated to avoid the long period of standing at room temperature
the yield obtained by this method is much lower.
A pathway for the isomerization of fructose 8 is shown in
Scheme 2.13 Fructose can form either of two ene diols 9 or 10, both
of which may be stabilized by calcium ions. The loss of the proton
at the C-3 OH of 9 and the OH at C-1 would give the enol 12;
alternatively, dehydration by loss of the C-2 hydroxyl proton could
form the Favorskii intermediate 13. Either the enol 12 or the
This paper illustrates the convenient synthesis of two epimeric
saccharinic acid lactones
3 and 7. A practical synthesis of
2-C-methyl- -ribonolactone 3 from glucose 1 involves an initial
D
Amadori reaction with dimethylamine to give the aminofructose
2 followed by treatment with calcium oxide in water; direct
crystallization of 3 allows the isolation of large amounts of product
without any chromatography (Scheme 1). L-Glucose 1L may be
converted to the enantiomer 3L. The protected 2-C-methyl-arabin-
ono-1,5- 6 and unprotected 2-C-methyl-arabinono-1,4- 7 lactones
can be obtained from
protected deoxyribulose 5 followed by treatment with sodium
cyanide; -erythronolactone 4L is equally available to allow the
D-erythronolactone 4 by conversion to the
L
* Corresponding author.
E-mail address: george.fleet@chem.ox.ac.uk (G. W. J. Fleet).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.013

2418
K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
OHC
HO
HO
Me2NH2C
HO
OH
OH
O
OH
O
O
O
O
HOH2C
(ii)
(iii)
OH
Me
(iv)
O
O
(i)
HOH2C
O
O
O
+
OH
CH3
OH
O
HO
HO OH
HO
OH
Me
O
O
HO
Me
O
CH2OH
CH2OH
2-C-methyl-D-
ribonolactone
2-C-methyl-D-
arabinonolactone
D-erythronolactone
D-glucose
3
4
6
1
2
5
7
OHC
OH
HO
Me2NH2C
HO
O
O
O
O
HOH2C
O
(iii)
OH
Me
O
O
OH
Me
(ii)
(iv)
(i)
HOH2C
O
O
O
+
OH
CH3
HO OH
OH
OH
O
HO
HO
HO
OH
O
O
HO
Me
O
CH2OH
CH2OH
2-C-methyl-L-
ribonolactone
2-C-methyl-L-
arabinonolactone
L-erythronolactone
L-glucose
1L
2L
3L
4L
5J
6L
7L
Scheme 1. Reagents and conditions: (i) Me2NH, AcOH, EtOH; (ii) CaO, H2O; (iii) Me2CO, H+; then MeMgBr; (iv) NaCN, H2O; then H+, H2O.
3
CH3
OH OH
OH OH
OH
O
1
O
OH
CH2OH
CH2OH
CH2
OH
HOH2C
HOH2C
HOH2C
HO
O
HO
4
OH
2
HO
HO
O
OH
O
OH
9
CH3
12
8
15
HOH2C
HO
14
O
O
OH OH
O
3
CH3
OH OH
OH OH
1
HOH2C
OH
CH2OH
HO
O
HOH2C
HOH2C
OH
HO OH
16
HO
OH
O
13
11
10
O
HO H3C
HO H3C
HOH2C
OH
OH
COOH
O
HOH2C
COOH
HOH2C
CH3
products
products
OH
OH
HO OH
3
18- erythro
19 - threo
Scheme 2. Base-catalyzed isomerization of fructose 8.
cyclopropanone 13 can then isomerize to the diketone 14. The
alternative ene diol 10 can also dehydrate with the loss of the
OH group at C-3; it is therefore likely to be an advantage for the
formation of diketone 14 to optimize the enol diol 9 rather than
10. The balance between the different dehydrations is crucial to
the formation of the key diketone intermediate 14. A subsequent
benzilic acid rearrangement of the diketone—in its open chain
14, pyranose 15 or furanose 16 form—leads to the branched ribonic
acid 18, invariably isolated as its crystalline lactone 3; none of the
epimeric 2-C-methylarabinonolactone 19 is formed under these
conditions.
The key steps are the conversion to (and the correct dehydra-
tion of) the ene diol 9; it would appear likely that improving the
leaving group [for example, to a mesylate] would improve the
chances of diketone 14 being formed relative to competing reac-
tions; such a modification of the C-1 CH2OH would require a
lengthy sequence involving protection and deprotection. The
Amadori rearrangement is the direct conversion of an unprotected
aldose with an amine to form a 1-amino-1-deoxy-ketose;14 for
example, dibenzylamine reacts with glucose 1 in methanol in the
presence of acetic acid to give the Amadori ketose 20 as a crystal-
line material15 in 86% yield (Scheme 3).16
Treatment of the Amadori product 20 with calcium hydroxide
in water afforded, after acidic work-up, the branched ribono-1,4-
lactone 3 in 16% yield.17 This sequence involves an initial tauto-
merization to the ene diol 22, a nitrogen equivalent of the required
ene diol 9, followed by loss of dimethylamine to form the same
diketone 14 as the precursor for the benzilic acid rearrangement.
The formation of an equivalent of the wrong ene diol 10 is not
possible.
Although 20 was readily crystallized, its lack of solubility in
water made the scale-up of the calcium oxide reaction difficult.
Dimethylamine in industrial methylated spirits and acetic acid
gave the corresponding Amadori dimethylamine analogue 2, which
in a one-pot reaction gave the ribono-lactone 3 via the ene diol 21
and the diketone 14. Again none of the epimeric arabinono-1,4-lac-
tone 7 was formed which was consistent with the diketone 14
being a common intermediate both in this procedure and in the
isomerization of fructose 8. The absence of epimer 7 allows the di-
rect crystallization of pure lactone 3 with no need for any chro-
matographic separation. When
hexose, was subjected to the Amadori-calcium oxide sequence,
both 2-C-methyl- -lyxono-1,4-lactone and 2-C-methyl- -xylono-
1,4-lactone were formed which proved more difficult to sepa-
D-galactose, the other cheap
D
D

K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
2419
OH OH
OH OH
OH OH
OH O
O
HOH2C
(iii)
(i)
(ii)
O
CHO
CH2NR2
CH2NR2
CH3
HOH2C
HOH2C
HOH2C
HOH2C
CH3
HO
OH
HO
O
HO
OH
HO
14
O
HO OH
2:
21:
R = Me
22: R = Bn
3
1
R = Me
20: R = Bn
Scheme 3. Reagents and conditions: (i) (PhCH2)2NH, AcOH, EtOH or Me2NH in MeOH; (ii) CaO, H2O; (iii) H+.
rate;18
D
-galactose also gives unbranched saccharinic acids
removal of the acetonide to give the unprotected deoxy ribulose 27
so that the Kiliani reaction was performed on the protected ribu-
lose 5. Treatment of 5 with aqueous sodium cyanide, followed by
work-up with acid, gave the protected d-lactone 6 (36%) together
easily.19
D
-Glucose 1 was converted to the branched ribonolactone 3 by
this procedure on a scalable process [157 g of 1 gave 38 g of 3, 27%;
1260 g of 1 gave 229 g of 3, 20%]. Additional ribonolactone 3 was
present in the mother liquors and residues but further isolation
of the material proved to cumbersome and not cost effective.
with a mixture of the deprotected c
-lactones 727 and 3 (23%) in
an approximate ratio of 5 to 1 and a combined yield of 59%.
Changes to the concentration and/or the length of time that the
reaction mixture was in contact with the AmberliteÒ resin caused
a variation in the ratio of protected and unprotected arabinonolac-
tone observed; however, the combined yield was consistently
approximately 60%.
L-Glucose 1L [42 g] afforded 2-C-methyl-L-ribonolactone 3L [10 g]
in 25% yield.
2.2. Protected 2-C-methyl-D-arabinono-1,5-lactone 6 and 2-C-
methyl-
1-deoxy-
D
-arabinono-1,4-lactone 7 by the Kiliani extension of
-ribulose 5
The protected d-lactone 6 can easily be isolated by flash chro-
matography and ready crystallization, but the unprotected lac-
tones 3 and 7 are difficult to separate from each other. A slow
D
The Kiliani reaction of cyanide on protected and unprotected
aldoses allows easy access to a wide range of sugars,20 including
C-3 branched sugars from C-2 branched sugars.21 The reaction of
cyanide with ketoses gives branched carbohydrates;22 in particular
all four of the diastereomeric ketohexoses 2423 give the erythro-
diols 25 as the major diastereomer, typically formed in a 4:1 ratio
to the minor threo-diols 26 (Scheme 4). It might be expected that
recrystallization of the mixture of c-lactones afforded the pure
arabinonolactone 7; alternatively, the ribonolactone 3 may be
removed from the mixture as its acetonide 29. The isopropylidene
protecting group in the 1,5-lactone 6 was removed in quantitative
yield by treatment with aqueous trifluoroacetic acid to give 2-C-
methyl-
6
D-arabinono-1,4-lactone 7. The structures of the protected
28 and unprotected 729 arabinonolactones were firmly established
the unprotected 1-deoxy-
D
-ribulose 27 would give a predominance
by X-ray crystallographic analysis.
of 18 relative to 19, and thus of the ribonolactone 3 rather than the
arabinonolactone 7.
The diastereoselectivity of the Kiliani reaction may result from
one of a number of reversible steps.30 The crystal structures of
3,4-O-isopropylidene-1,5-lactones, including 6, are generally in a
boat conformation.31 The protected ribulose 5 can reversibly form
either cyanohydrin 30 or 31 (Scheme 6). The nitriles are then
hydrolyzed by an initial cyclization to the imidates 32 and 33,
respectively, which are further hydrolyzed to the lactones 6 and
34. Under the basic conditions of the Kiliani the lactones formed
D
-Erythronolactone 4, obtained by Humphlett oxygenation of an
alkaline solution of
-arabinose24 or by hydrogen peroxide oxida-
tion of erythrobic acid, formed a highly crystalline acetonide 2825
D
(Scheme 5). Reaction of the protected D-erythronolactone 28 with
methyl magnesium bromide in THF afforded lactol 526 as a mixture
of anomers in 99% yield. The sensitivity of 5 to acid precluded the
O
HOH2C
OH OH
HO
H3C
O
(ii)
OH
COOH
HOH2C
Me
HOH2C
COOH
HO
OH
CH2OH
HO
HO
OH
OH OH
HO
HOH2C
O
25
18
3
- erythro major
CH2OH
(i)
(i)
HOH2C
CH3
HO
24
O
OH
(ii)
OH OH
O
HO
H3C
OH
HOH2C
OH
O
27
COOH
OH
HOH2C
OH
HOH2C
COOH
HO
CH2OH
HO
Me
26
19
7
- threo minor
Scheme 4. Kiliani reaction on ketoses. Reagents and conditions: (i) NaCN, H2O; (ii) H+.
(iii)
O
O
O
O
O
O
O
OH
Me
HOH2C
(iv)
HOH2C
(i)
(ii)
HOH2C
O
O
O
O
OH
+
+
Me
Me
OH
O
Me
O
O
O
O
HO
Me
HO OH
minor isomer
O
O
O
28
5
6
7
3
29
Scheme 5. Reagents and conditions: (i) MeMgBr, THF, ꢀ78 °C, 99%; (ii) NaCN, H2O; then AmberliteÒ IR 120 H+, 59%; (iii) CF3COOH, H2O, 100%; (iv) Me2CO, CuSO4, conc H2SO4.

2420
K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
HO
HO
HO
O
O
Me
N
Me
NH
Me
HO
Me
HOOC
OH
O
O
O
O
O
O
O
H
O
O
OH
O
30
32
6
35
O
Me
+ NaCN
O
OH
Me
Me
Me
5
OH
OH
NH
OH
O
OH
Me
HO
O
O
O
N
O
O
O
O
O
O
O
HOOC
OH
31
33
Scheme 6. Diastereoselectivity of the Kiliani reaction.
34
36
O
O
O
O
O
O
O
O
O
OH
Me
OH
Me
O
O
O
(iv)
(ii)
(vi)
(iii)
(i)
(v)
OH
Me
OH
O
O
Me
O
O
O
O
HO
OH
O
O
O
O
O
O
39
38
37
4
40
41
42
Scheme 7. Reagents and conditions: (i) Et2CO, CuSO4, conc H2SO4, 85%; (ii) MeMgBr, THF, ꢀ78 °C, 98%; (iii) NaCN, H2O; then AmberliteÒ IR 120 H+, 21%; (iv) SOCl2, Me2SO,
70%; (v) MeMgBr, THF, ꢀ78 °C, 81%; (vi) NaCN, H2O; then AmberliteÒ IR 120 H+, 15%.
the salt of the open chain acids 35 and 36. A rationale for the pref-
erential formation of the arabino compound 6 is that the closure of
30 to 32 [with a flagpole hydroxyl group] leads to a less sterically
congested imidate than the closure of 31–33, where the methyl
group has an unfavorable interaction with the flagpole proton. At
the end of the reaction, the acid-catalyzed closure of the salt of
35 allows the formation of the protected lactone 6, although some
hydrolysis of the acetal protecting group prior to ring closure
occurs giving the unprotected arabinonolactone 7. In contrast, clo-
sure of 36 to the more congested lactone 34 is not competitive with
removal of the isopropylidene group so that only the unprotected
ribono-1,4-lactone 3 is formed.
In order to avoid competitive hydrolysis of the acetonide in the
closure of the open chain salt 35, other protecting groups were
briefly investigated to determine if better yields of the correspond-
ing protected 1,5-lactones (Scheme 7) could be obtained. Treat-
ment of erythronolactone 4 with pentanone in the presence of
copper sulfate and sulfuric acid gave the non-crystalline ketal 37
(85%), which on treatment with methyl magnesium bromide gave
the protected 1-deoxy ribulose 38 (98%). However, the Kiliani
ascension on 38 proceeded in a low yield to give a non-crystalline
lactone 39 (21%). Protection of 4 with thionyl chloride in dimethyl-
sulfoxide gave the formaldehyde acetal 40 (70%), which gave the
ribulose 41 (81%) on treatment with methyl magnesium bromide.
However, reaction of 41 with sodium cyanide followed by acid
work-up gave a poor yield of the protected arabinonolactone
4232 (15%). No advantage was found in this brief study of other
protecting groups.
isolated by direct crystallization to produce hundreds of grams of
material with no chromatography. The epimer 2-C-methyl arabin-
onolactone may be obtained in a protected 1,5-lactone 6 or unpro-
tected 1,4-lactone 7 by the Kiliani cyanide extension on a protected
1-deoxyribulose 5, easily synthesized from
D-erythronolactone 4;
L-erythronolactone 4L is equally available. The epimeric sacchari-
nic acid lactones 3 and 7 are likely to be of value as carbohydrate
chirons for enantiopure targets containing branched carbon chains.
4. Experimental
Proton nuclear magnetic resonance spectra (dH) were recorded
on a Bruker AV400 (400 MHz) or a Bruker AVC500 (500 MHz) spec-
trometer and were calibrated according to the chemical shift of
residual protons in the deuterated solvent. 13C NMR spectra (dC)
were recorded on a Bruker AV400 (100.6 MHz) and were calibrated
according to the chemical shift of the deuterated solvent. Chemical
shifts (d) are quoted in ppm and coupling constants (J) in Hertz.
The following abbreviations are used to denote multiplicities: s,
singlet; d, doublet; dd, double–doublet; ddd, double–double–dou-
blet; t, triplet; a, apparent. Infrared spectra were recorded on a Bru-
ker Tensor 27 FT IR spectrophotometer using thin films on NaCl or
Ge plates and peaks are given in cmꢀ1. Low-resolution mass spec-
tra (LRMS) were recorded on a Fisons Platform (ESI) spectrometer
or a Micromass VG Autospec 500 OAT (CI(NH3)) spectrometer.
High-resolution mass spectra (HRMS) were recorded on a Micro-
mass LCT (ESI) spectrometer, a Micromass VG Autospec 500 OAT
(CI(NH3)) spectrometer or a Micromass GCT (FI) spectrometer.
Optical rotations were measured on a Perkin–Elmer 241 polarime-
ter with a path length of 1 dm; concentrations (c) are quoted in g/
100 mL. Elemental analyses were performed by the microanalysis
service of the Inorganic Chemistry Laboratory (Oxford). Melting
points (mp) were measured on a Kofler hot-block apparatus and
are uncorrected. Thin-layer chromatography (TLC) was carried
out on aluminum sheets coated with 60F254 silica from Merck,
3. Conclusion
This paper reports a convenient and scalable synthesis of either
enantiomer of 2-C-methyl ribono-1,4-lactone 3 from the enantio-
mers of glucose 1 in a one-pot procedure via an Amadori ketose
and subsequent treatment with calcium oxide; the product is

K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
2421
and plates were developed by dipping in either 0.2% w/v cerium
(IV) sulfate and 5% ammonium molybdate in 2 M sulfuric acid or
10% sulfuric acid in EtOH with subsequent heating. Flash column
chromatography was carried out using Sorbsil C60 40/60 silica. Sol-
vents were used as supplied (HPLC grade) and commercially avail-
able reagents were used as supplied. ‘JT’ refers to oil jacket
temperature of reactor vessels, as controlled by Julabo heater/chil-
ler units.
oxide (589 g, 10.5 mol); 96% sulfuric acid (710 mL, 13.3 mol). The
procedure was carried out as above; however, additional purifica-
tion, in the form of exhaustive treatment with aqueous acetone/
Fuller’s Earth and a subsequent reflux with Norit activated charcoal
in acetone, was required before crystallization was possible. The
total mass of 2-C-methyl-D-ribonolactone 3 obtained was 228.7 g
(20%).
4.1.3. 2-C-Methyl-
The procedure was carried out as previously described above for
the preparation of 2-C-methyl- -ribonolactone 3L using the follow-
ing amounts: -Glucose 1L (42.4 g, 0.235 mol); dimethylamine
L-ribono lactone 3L
4.1. 2-C-Methyl-
ribono-1,4-lactone 3L
D-ribono-1,4-lactone 3 and 2-C-methyl-L-
L
L
4.1.1. 2-C-Methyl-
Dimethylamine (33% in absolute ethanol, 159 mL, 0.90 mol)
was added dropwise over 0.5 h to a solution of -glucose 1
D
-ribono-1,4-lactone 3
(33% in absolute ethanol, 43.2 mL, 0.243 mol); industrial methyl-
ated spirits (64 mL); acetic acid (13.6 mL, 0.235 mol); water
(89 mL); calcium oxide (19.8 g, 0.353 mol); 96% sulfuric acid
(23.9 mL, 0.424 mol). After direct crystallization of lactone 3
(5.37 g), the mother liquor was concentrated, and the residue puri-
fied by column chromatography (40-60 petrol/acetone 4:1?1:1)
and crystallization to give further product (4.20 g). The total yield
of 2-C-methyl- -ribono lactone 3L was 9.57 g (25%); mp 158–
D
(157 g, 0.87 mol) in industrial methylated spirits (235 mL) and
acetic acid (50.3 mL, 0.87 mol) in a 2 L jacketed reactor with JT
17 °C [this step was exothermic; JT was set to 17 °C to ensure the
internal temperature remained at 20 °C]. The reaction mixture
was then heated (JT 75 °C) over 0.5 h, cooled to 55 °C over 0.5 h,
and stirred at 55 °C for 1.5 h. TLC analysis (14:3:1:1:1, EtOH–
H2O–Py–AcOH–nBuOH) showed the formation of a single major
product (Rf 0.39) 2; no glucose (Rf 0.79) remained. The solution
was concentrated at 50 mbar, JT 50 °C, until bubbling ceased
(1.5 h) and the brown oil was diluted with distilled water
(330 mL). The reactor was evacuated and filled with nitrogen and
JT was adjusted to 0 °C. Calcium oxide (73.3 g, 1.31 mol) was added
in 4 portions at 10 min intervals [the reaction was exothermic; the
internal temperature rose by approximately 5 °C after each
addition]. Under a nitrogen atmosphere (maintained by inflated
balloon), the reaction mixture was heated to JT 25 °C over
20 min and then heated to JT 40 °C over 18 h and stirred at JT
40 °C for a further 4 h. TLC analysis (14:3:1:1:1, EtOH–H2O–Py–
AcOH–nBuOH) after this time indicated the absence of the Amadori
ketose 2, and the formation of a product (Rf 0.00) 3. JT was lowered
to 0 °C, and 96% sulfuric acid (88 mL, 1.65 mol) was added over
1.5 h, keeping JT at 0 °C. The pH was checked at this point to ensure
it was in the range 2.4–2.7. Addition of extra sulfuric acid was
occasionally necessary. Once addition was complete, JT was set
to rise to 45 °C over 0.5 h and the reaction mixture stirred at JT
45 °C for 12 h. The mixture was then allowed to cool to room tem-
perature before filtration; the reactor and filter cake were rinsed
with distilled water (500 mL). TLC analysis (14:3:1:1:1, EtOH–
H2O–Py–AcOH–nBuOH) of the filtrate revealed a major product
(Rf 0.92). The filtrate (approx 1 L) was concentrated at 50 °C to give
a brown residue which was re-dissolved in a mixture of acetone
(800 mL) and water (80 mL); Fullers Earth (90 g) was added. The
reaction mixture was refluxed for 0.5 h and the organic phase
decanted and filtered. The solid remaining in the flask was then
159 °C;
½
a 2D1
ꢂ
¼Lꢀ87:6 (c 0.8, water); {lit.17 mp 160–162 °C;
½
a 2D1:5
ꢂ
¼ ꢀ87:7 (c 0.6, water)}; the 1H and 13C NMR spectra were
identical to those of the enantiomer 3 above.
4.1.4. 3,4-O-Isopropylidene-2-C-methyl-
lactone 6 and 2-C-methyl- -arabinono-1,4-lactone 7
4.1.4.1. 1-Deoxy-3,4-O-isopropylidene- -ribulose 5.
magnesium bromide (3 M solution in Et2O, 39 mL) was added
dropwise to a solution of the protected -erythronolactone 28
D-arabinono-1,5-
D
D
Methyl
D
(16.72 g, 0.106 mol) in dry THF (400 mL) at ꢀ78 °C. The reaction
mixture was stirred at ꢀ78 °C for 30 min after which time satu-
rated aqueous ammonium chloride (30 mL) was added and the
reaction mixture allowed to warm to room temperature. The mix-
ture was partitioned between ethyl acetate (200 mL) and water
(300 mL). The aqueous layer was extracted with ethyl acetate
(2 ꢁ 100 mL), and then the combined organics were dried over
MgSO4 and concentrated under reduced pressure to give the ke-
tose 5 as a mixture of anomers (18.2 g, 99%), which was used
without further purification; mp 82–85 °C [lit.26 87–89 °C]; mmax
(thin film): 3223 (OH); dH (400 MHz, CDCl3): [a 1:5 mixture of
anomers, A—major anomer] 1.32, 1.47 (5.04H, 2 ꢁ s,
2 ꢁ C(CH3)2A), 1.36, 1.48, (0.96H, 2 ꢁ s, 2 ꢁ C(CH3)2B), 1.52, 1.55
(3H, 2 ꢁ s, H1A, H1B), 2.69 (1H, s, OH), 3.62 (0.16H, dd, H-5B, J5,4
B
4.1, J5,5 11.0), 3.89–3.93 (1H, m, H-50 , H-5), 3.99 (0.84H, dd,
0
H-50 , J5,4 3.8, J5,5 10.3), 4.24 (0.16H, d, H-3B, J3,4 6.2), 4.39
A
0
(0.84H, d, H-3A, J3,4 5.9), 4.74–4.79 (0.16H, m, H-4B), 4.84
(0.84H, dd, H-4A, J4,5 3.8, J4,3 5.9); dC (100.6 MHz, CDCl3): 22.3,
24.9, 26.3 (3 ꢁ CH3A), 21.9, 24.8, 26.1 (3 ꢁ CH3B), 68.4 (C-5B),
70.9 (C-5A), 80.1 (C-4B), 80.8 (C-4A), 82.0 (C-3B), 85.0 (C-3A),
103.0 (C-2B), 105.9 (C-2A), 112.4 (CMe2A), 113.4 (CMe2B); m/z
(CIꢀ): 173 [MꢀH]ꢀ, 100%. Found: C, 55.18; H, 8.11; C8H14O4
requires: C, 55.16; H, 8.10.
extracted
a further three times with 10% aqueous acetone
(275 mL ꢁ 3), refluxing for 5 min and decanting the acetone each
time. The combined filtrates were concentrated in vacuo at 40 °C
to give 109 g of a solid brown crude. Recrystallization from hot ace-
tone gave the lactone 3 as a cream colored solid (37.5 g, 27%); mp
4.1.5. 3,4-O-Isopropylidene-2-C-methyl-
lactone 6, 2-C-methyl- -arabinono-1,4-lactone 7 and 2-C-
methyl- -ribono-1,4-lactone 3
D-arabinono-1,5-
157–158 °C; ½a 2D0
ꢂ
¼ þ87:6 (c 0.86, water); {lit.17 mp 158–159 °C;
D
½
a 1D3:5
ꢂ
¼ þ87:5 (c 0.76, water)}; dH (400 MHz, CD3OD): 1.43 (3H, s,
D
0
CH3-2), 3.73 (1H, dd, H-5 J5,4 4.5, J5,5 12.8), 3.93 (1H, d, H-3 J3,4
The protected ketose 5 (8.70 g, 50.1 mmol) was stirred with so-
dium cyanide (3.20 g, 65.1 mmol) in water (60 mL) at room tem-
perature for 48 h. The mixture was then refluxed for another
48 h. At this point, a test (Prussian blue test) for cyanide was neg-
ative. The reaction mixture was passed through an AmberliteÒ IR
120 (H+) column, eluted with water (3 ꢁ column volumes) and
the combined aqueous washings concentrated. TLC (ethyl
acetate/cyclohexane, 1:1) of the residue showed the formation
of multiple products. The residue was then purified by flash
column chromatography (ethyl acetate/cyclohexane, 1:1?5:1) to
7.8), 3.97 (1H, dd, H-50, J5 ,4 2.4, J5 ,5 12.8), 4.32 (1H, ddd, H-4 J4,5
0
0
0
2.4, J4,5 4.5, J4,3 7.8) dC (100.6 MHz, CD3OD): 20.0 (CH3-2), 60.0
(C-5), 72.6 (C-2), 72.6 (C-3), 83.4 (C-4), 177.0 (C-1).
4.1.2. Scale up procedure—6 L jacketed reactor for 1.25 kg
glucose
D
-Glucose 1 (1.26 kg, 7.00 mol); dimethylamine (33% in abso-
lute ethanol, 1.28 L, 7.21 mol); industrial methylated spirits
(1.89 L); acetic acid (405 mL, 7.01 mol); water (2.66 L); calcium

2422
K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
yield 3,4-O-isopropylidene-2-C-methyl-D-arabinono-1,5-lactone 6
one major product (Rf 0.83) and a small amount of unreacted
(3.70 g, 36%; Rf 0.70 ethyl acetate/cyclohexane, 3:1) as a white
starting material (Rf 0.07). The solution was neutralized with so-
lid sodium carbonate, filtered through Celite, and the filtrate
concentrated in vacuo. The residue was purified by column chro-
matography (ethyl acetate/cyclohexane, 1:1) to give the pentyli-
crystalline solid; mp 108–109.5 °C; ½a D22
¼ ꢀ124:7 (c 1.01, CHCl3);
ꢂ
mmax (thin film): 3447 (OH), 1743 (C@O); dH (400 MHz, CD3CN):
1.33, 1.35, 1.44 (9H, 3 ꢁ s, 3 ꢁ CH3), 4.01 (1H, s, OH), 4.26 (1H,
0
dd, H-5, J5,4 1.0, J5,5 12.3), 4.31 (1H, d, H-3, J3,4 7.5), 4.57 (1H,
dene derivative 37 as a light yellow oil (686 mg, 85%);
ddd, H-4, J4,5 1.0, J4,5 2.0, J4,3 7.5), 4.85 (1H, dd, H-50, J5 ,4 2.0, J5 ,5
12.3); dC (100.6 MHz, CD3CN): 21.7, 23.6, 25.9 (3 ꢁ CH3), 68.7 (C-
5), 72.2 (C-2), 72.6 (C-4), 79.4 (C-3), 109.4 (CMe2), 171.1 (C-1);
m/z (CI+): 220 [M+NH4]+, 100%; HRMS (ESI+): Found: 225.0731
[M+Na]+; C9H14NaO5 requires: 225.0733. Found: C, 53.48; H,
7.00; C9H14O5 requires C, 53.46; H, 6.98; and an inseparable mix-
½
a 2D3
ꢂ
¼ ꢀ113:0 (c 1.0, CHCl3); mmax (thin film): 1784 (C@O); dH
0
0
0
(400 MHz, CDCl3): 0.88 (3H, t, CH3, J 7.5), 0.90 (3H, t, CH3, J
7.5), 1.61–1.67 (2H, q, CH2, J 7.5), 1.66–1.71 (2H, q, CH2, J 7.5),
4.38–4.41 (1H, dd, H-4, J4,3 3.8, J4,4 11.0), 4.46 (1H, d, H-40, J4 ,4
11.0), 4.76 (1H, d, H-2, J2,3 5.8), 4.88–4.90 (1H, dd, H-3, J3,4 3.9,
J3,2 5.8); dC (100.6 MHz, CDCl3): 7.2 (CH3), 8.1 (CH3), 29.2
(CH2), 29.7 (CH2), 70.4 (C-4), 74.8 (C-2), 75.7 (C-3), 118.1
(CH3C), 173.9 (C@O); m/z (TOF MS CI+): 204 [M+NH4]+, 100%;
187 [M+H]+, 10%; HRMS (TOF MS CI+): Found: 204.1244
[M+NH4]+; C9H18NO4 requires: 204.1236. Found: C, 58.00, H,
7.44; C9H14O4 requires: C, 58.05, H, 7.58.
0
0
ture of lactones 2-C-methyl-D-arabinono-1,4-lactone 7 and 2-C-
methyl- -ribono-1,4-lactone 3 (1.90 g, 23%; Rf 0.13 ethyl acetate/
D
cyclohexane, 3:1) in an approximate ratio of 10:1 as a colorless
glass. The relative amounts of the protected 6 and unprotected 7
lactones depended on the length of time the reaction mixture
was in contact with the ion exchange resin but the combined yield
was approximately 60%.
4.1.8. 1-Deoxy-3,4-O-isopentylidene-
Methyl magnesium bromide (3 M in ether, 0.99 mL,
2.96 mmol) was added to a solution of the protected -erythron-
D-ribulose 38
4.1.6. 2-C-Methyl-D-arabinono-1,4-lactone 7 and
D
2,3-O-isopropylidene-2-C-methyl-
D
-ribono-1,4-lactone 29
olactone 37 (500 mg, 2.69 mmol) in dry THF (11 mL) at ꢀ78 °C;
after 1 h, three further portions of methyl magnesium bromide
(0.18 mL, 0.54 mmol) were added at 20 min intervals. After 2 h,
the reaction mixture was quenched with saturated aqueous
ammonium chloride (1 mL) and partitioned between ethyl acetate
(30 mL) and water (15 mL). The aqueous layer was extracted with
ethyl acetate (2 ꢁ 10 mL), and the combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo
to give the lactols 38 (530 mg, 98%) as a 1:4 mixture of anomers,
as a colorless oil; mmax (thin film): 3418 (OH); dH (400 MHz,
CDCl3): [A—major anomer] 0.86–1.00 (6H, m, CH3), 1.36 (0.6H, s,
MeB), 1.56 (2.4H, s, MeA), 1.56–1.74 (4H, m, CH2), 3.60–3.64
The mixture of the unprotected lactones, 3 and 7 (2.83 g,
17.5 mmol), was dissolved in acetone (50 mL) and the solution
stirred under argon in the presence of copper sulfate (5.58 g,
34.9 mmol) and conc. sulfuric acid (1 drop). After 16 h, TLC
(ethyl acetate) indicated the formation of a minor product (Rf
0.51) and the remaining starting material (Rf 0.22). Solid sodium
carbonate was then added to the mixture until pH
6 was
reached. The reaction mixture was filtered through Celite, the
solvent removed, and the resulting pale yellow residue purified
by flash column chromatography (ethyl acetate/cyclohexane,
1:1) to give unchanged 2-C-methyl-D-arabinono-1,4-lactone 7,
(1.65 g, 58%) (recrystallized from ethyl acetate/cyclohexane);
(0.2H, dd, H-5B, J5,4 4.2, J5,5 10.9), 3.93 (0.8H, d, H-5A, J5,5 10.2),
0
0
mp 65–68 °C; ½a 2D2
ꢂ
¼ þ77:5 (c 1.03, H2O) [lit.33 63–65 °C; [lit.8
3.94 (0.2H, d, H-50 , J5 ,5 10.9), 3.99–4.03 (0.8H, dd, H-50 , J5 ,4
B
A
0
0
a 2D0
ꢂ
¼ þ82:5 (c, 0.90, H2O)], [lit.27
½
aꢂD
¼ þ69:0 (c 1.60, H2O)];
3.9, J5 ,5 10.2), 4.25 (0.2H, d, H-3B, J3,4 6.3), 4.40 (0.8H, d, H-3A,
0
½
mmax (thin film): 3273 (OH), 1760 (C@O); dH (400 MHz, DMSO-
J3,4 5.9), 4.71–4.80 (0.2H, m, H-4B), 4.85–4.88 (0.8H, dd, H-4A,
d6): 1.19 (3H, s, CH3), 3.50 (1H, dd, H-5, J5,4 4.8, J5,5 5.5), 3.72
J4,5 3.9, J4,3 5.9); dC (100.6 MHz, CDCl3): 7.6 (CH3A, CH3B), 7.8
0
0
(1H, dd, H-50, J5 ,4 2.3, J5 ,5 5.5), 3.92–3.96 (1H, m, H-4), 3.98–
4.03 (1H, m, H-3), 5.10 (1H, a-t, J 4.2, OH), 5.73 (1H, d, J 5.3,
OH), 5.81 (1H, s, OH); dC (100.6 MHz, DMSO-d6): 18.8 (CH3),
60.4 (C-5), 74.3 (C-3), 75.8 (C-2), 82.5 (C-4), 178.8 (C-1); m/z
(ESIꢀ): 161 [MꢀH]ꢀ, 100%; HRMS (ESIꢀ): Found: 161.0455
[MꢀH]ꢀ; C6H9O5 requires: 161.0450 and 2,3-O-isopropylidene-
(CH3B), 8.4 (CH3A), 21.8 (MeB), 22.4 (MeA), 28.8 (CH2B), 29.0
(CH2A, CH2B), 29.3 (CH2A), 68.8 (C-5B), 71.4 (C-5A), 80.3 (C-4B),
81.1 (C-4A), 82.2 (C-3B), 85.2 (C-3A), 103.4 (C-2B), 106.0 (C-2A),
116.7 ((CH3CH2)2CA), 117.5 ((CH3CH2)2CB); m/z (ESIꢀ): 201
[MꢀH]+, 100%; HRMS (ESI-): Found: 201.1129 [MꢀH]+; C10H17O4
requires: 201.1121.
0
0
2-C-methyl-D-ribono-1,4-lactone 29 (0.334 g, 11%) as a colorless
oil; ½a 2D1
ꢂ
¼ ꢀ28:1 (c 1.03, CHCl3) [lit.6a
½
a 1D9
ꢂ
¼ ꢀ35:6 (c 1.40, ace-
4.1.9. 3,4-O-Isopentylidene-2-C-methyl-D-arabinono-
1,5-lactone 39
tone)]; mmax (thin film): 3484 (OH), 1783 (C@O); dH (400 MHz,
MeOD): 1.40, 1.41 (6H, 2 ꢁ s, 2 ꢁ C(CH3)2), 1.63 (3H, s, H20),
Sodium cyanide (348 mg, 7.09 mmol) was added to a solution of
the lactols 38 (1.10 g, 5.46 mmol) in water (40 mL) and dioxane
(40 mL). The reaction mixture was stirred for 54 h, refluxed for
36 h and then passed down an AmberliteÒ IR 120 (H+) column
and eluted with water (3 column volumes). The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography (ethyl acetate/cyclohexane, 1:4?10% methanol in ethyl
acetate) to give the protected lactone 39 (248 mg, 21%; Rf 0.53
ethyl acetate/cyclohexane, 3:1), oil; mmax (thin film): 3416 (OH),
1739 (C@O); dH (400 MHz, CDCl3): 0.82 (3H, t, CH3, J 7.5), 0.88
(3H, t, CH3, J 7.5), 1.56–1.68 (4H, m, CH2), 4.29 (1H, d, H-3, J3,4
3.77 (1H, dd, H-5, J5,4 2.8, J5,5 12.4), 3.83 (1H, dd, H-50, J5 ,4
0
0
0
3.10, J5 ,5 12.4), 4.53 (1H, a-t, J 3.9, H-4), 4.59 (1H, br s, H-3);
m/z (ESIꢀ): 403 [2MꢀH]ꢀ, 100%.
A sample of 2-C-methyl-D-arabinono-1,4-lactone 7, (100%) was
also prepared by hydrolysis of the protected lactone 6 (101 mg,
0.5 mmol) in water (1.5 mL), 1,4-dioxane (0.7 mL), and trifluoro-
acetic acid (2 mL). The reaction mixture was stirred for 18 h at
room temperature after which time TLC (ethyl acetate/cyclohex-
ane, 3:1) showed complete conversion of the starting material 6
(Rf 0.70) to the deprotected lactone 7 (Rf 0.13), identical to the
material described above.
0
7.6), 4.37 (1H, d, H-5, J5,5 12.2), 4.50–4.52 (1H, a-dd, H-4, J 1.0,
J4,3 7.5), 4.88–4.91 (1H, dd, H-50, J5 ,4 2.1, J5 ,5 12.2); dC
(100.6 MHz, CDCl3,): 6.9 (CH3), 8.6 (CH3), 22.1 (Me), 28.1 (CH2),
28.6 (CH2), 68.9 (C-5), 71.7 (C-2), 72.2 (C-4), 78.9 (C-3), 113.5
(CH3CH2C), 172.0 (C@O).
0
0
4.1.7. 2,3-O-Isopentylidene-
Copper sulfate (1.39 g, 8.68 mmol) and concentrated sulfuric
acid (0.2 mL) were added to a solution of -erythronolactone 4
D-erythronolactone 37
D
(512 mg, 4.34 mmol) in 3-pentanone (11 mL). The reaction mix-
ture was stirred at room temperature for 18 h after which time
TLC (ethyl acetate/cyclohexane, 3:1) showed the formation of
The unprotected lactone 7 was also obtained (174 mg, 20%; Rf
0.03 ethyl acetate/cyclohexane, 3:1), identical to the material pre-
pared above.

K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
2423
4.1.10. 2,3-O-Methylidene-
Thionyl chloride (0.68 mL, 9.32 mmol) was added over 30 min
to a stirred solution of -erythronolactone 4 (1.0 g, 8.47 mmol) in
DMSO (4.1 mL, 84.7 mmol) at room temperature. The reaction mix-
ture was heated at 65 °C for 2 h and then allowed to cool to room
temperature. Water (10 mL) was added and the reaction mixture
was extracted with ethyl acetate (3 ꢁ 20 mL); the combined organ-
ic extracts were dried (magnesium sulfate) and concentrated in va-
cuo. The residue was purified by column chromatography (ethyl
acetate/cyclohexane, 1:3?ethyl acetate) to give the protected lac-
D-erythrono-1,4-lactone 40
References
1. (a) Lichtenthaler, F. W.; Peter, S. C. R. Chim. 2004, 7, 65–90; (b) Corma, A.;
Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411–2502; (c) Murphy, P. V. Eur. J.
Org. Chem. 2007, 4177–4187; (d) Bols, M. Carbohydrate Building Blocks, ISBN 0-
471-13339-6; John Wiley & Sons: New York, 1996.
2. (a) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J. J. Org. Chem. 1983, 48, 5186–
5198; (b) Monneret, C.; Florent, J. C. Synlett 1994, 305–318; (c) Lopez-Herrera,
F. J.; Sarabia-Garcia, F.; Pino-González, M. S.; García-Aranda, J. F. J. Carbohydr.
Chem. 1994, 13, 767–775; (d) Simone, M. I.; Soengas, R.; Newton, C. R.; Watkin,
D. J.; Fleet, G. W. J. Tetrahedron Lett. 2005, 46, 5761–5765; (e) Barrett, A. G. M.;
Bezuidenhoudt, B. C. B.; Dhanak, D.; Gasiecki, A. F.; Howell, A. R.; Lee, A. C.;
Russell, M. A. J. Org. Chem. 1980, 54, 3321–3324.
3. Dukhan, D.; Bosc, E.; Peyronnet, J.; Storer, R.; Gosselin, G. Nucleosides
Nucleotides Nucl. 2005, 24, 577–580.
4. Maddaford, A.; Guyot, T.; Leese, D.; Glen, R.; Hart, J.; Zhang, X.; Fisher, R.;
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2007, 3149–3154.
5. Rao, D.; Yoshihara, A.; Gullapalli, P.; Morimoto, K.; Takata, G.; da Cruz, F. P.;
Jenkinson, S. F.; Wormald, M. R.; Dwek, R. A.; Fleet, G. W. J.; Izumori, K.
Tetrahedron Lett. 2008, 49, 3316–3321.
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Tetrahedron: Asymmetry 2007, 18, 500–512; (b) da Cruz, F. P.; Horne, G.; Fleet,
G. W. J. Tetrahedron Lett. 2008, 49, 6812–6815.
7. (a) Bio, M. M.; Xu, F.; Waters, M.; Williams, J. M.; Savary, K. A.; Cowden, C. J.;
Yang, C.; Buck, C.; Song, Z. J.; Tschaen, D. M.; Volante, R. P.; Reamer, R. A.;
Grabowski, E. J. J. J. Org. Chem. 2004, 69, 6257–6266; (b) Girardet, J.-L.; Gunic,
E.; Esler, C.; Cieslak, D.; Pietrzkowski, Z.; Wang, G. J. Med. Chem. 2000, 43, 3704–
3713.
D
tone 40 as
a crystalline solid (0.77 g, 70%); mp 39–41 °C;
½
a 2D1
ꢂ
¼ ꢀ120 (c 1.01, CHCl3); mmax (thin film): 3419 (OH), 1778
0
(C@O); dH (400 MHz, CDCl3): 4.37 (1H, d, H-4, J4,4 10.8), 4.45–
4.46 (1H, m, H-40), 4.73–4.76 (2H, m, H-2, H-3), 4.92 (1H, s, OCH2O),
4.97 (1H, s, OCH2O); dC (100.6 MHz, CDCl3): 71.2 (C-4), 74.1, 75.4
(C-2 and C-3), 96.6 (OCH2O), 173.5 (C-1); HRMS (FI): Found:
130.0260 [MÅ]; C5H6O4 requires: 130.0266.
4.1.11. 1-Deoxy-3,4-O-methylidene-
Methyl magnesium bromide (3 M solution in ether, 1.80 mL) was
added dropwise to stirred solution of lactone 40 (0.65 g,
D-ribulose 41
a
5.00 mmol) in THF (6 mL) at ꢀ70 °C and stirred at this temperature
for 1 h. Saturated aqueous ammonium chloride (6 mL) was added
and the reaction mixture was allowed to warm to room tempera-
ture. The mixture was partitioned between ethyl acetate (20 mL)
and water (20 mL) and the aqueous layer was extracted with ethyl
acetate (2 ꢁ 20 mL). The combined organic extracts were dried over
magnesium sulfate and concentrated in vacuo. Column chromatog-
raphy (ethyl acetate/cyclohexane, 1:3?1:1) gave the lactols 41 as a
8. Jenkinson, S. F.; Jones, N. A.; Moussa, A.; Stewart, A. J.; Heinz, T.; Fleet, G. W. J.
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13. Bols, M. Carbohydrate Building Blocks; John Wiley
colorless amorphous solid (0.59 g, 81%); ½a D21
¼ ꢀ61 (c 1.0, CHCl3);
ꢂ
& Sons: New York,
mmax (thin film): 3100 (OH); dH (400 MHz, CDCl3): [1:6 mixture of
1996.
anomers, A—major anomer] 1.35 (0.42H, s, MeB), 1.54 (2.58H, s,
14. (a) Hodge, J. E. Adv. Carbohydr. Chem. 1955, 10, 169–205; (b) Funcke, W.;
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R.; Bruce, I.; Choi, S.; Doherty, O.; Fairbanks, A. J.; Fleet, G. W. J.; Skead, B.
M.; Peach, J. M.; Saunders, J.; Watkin, D. J. Tetrahedron: Asymmetry 1991, 2,
883–900.
21. (a) Parker, S.; Watkin, D. J.; Simone, M. I.; Fleet, G. W. J. Acta Crystallogr., Sect. E
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MeA), 3.72 (0.14H, dd, H-4B, J4,3 4.6, J4,4 11.2), 3.97 (0.86H, d, H-4A,
0
B
J4,4 10.6), 3.98 (0.14H, dd, H-40 , J4 ,3 1.5, J4 ,4 11.2), 4.08 (0.86H, dd,
0
0
0
H-40 , J4 ,3 4.1, J4 ,4 10.6), 4.18 (0.14H, d, H-2B, J2,3 6.1), 4.34 (0.86H,
A
0
0
d, H-2A, J2,3 5.8), 4.76–4.77 (0.14H, ddd, H-3B, J3,4 1.5, J3,4 4.6, J3,2
0
6.1), 4.82 (0.86H, dd, H-3A, J3,4 4.1, J3,2 5.8), 4.95 (0.86H, s, OCH2OA),
0
4.96 (0.86H, s, OCH2OA), 5.01 (0.14H, s, OCH2OB), 5.16 (0.14H, s,
OCH2OB); dC (100.6 MHz, CDCl3): 21.9 (MeB), 22.2 (MeA), 68.5
(C-4B), 71.2 (C-4A), 80.0 (C-3B), 80.3 (C-3A), 81.6 (C-2B), 84.0 (C-2A),
96.0 (OCH2OA), 96.8 (OCH2OB), 103.6 (C-1B), 105.5 (C-1A); HRMS
(FI): Found: 147.0652 [M+H]+; C6H11O4 requires: 147.0657.
4.1.12. 3,4-O-Methylidene-2-C-methyl-D-arabinono-1,5-lactone 42
Sodium cyanide (0.25 g, 5.07 mmol) was added to a stirred sus-
pension of the protected 1-deoxy ribulose 41 (0.57 g, 3.90 mmol)
in H2O (6 mL) and the reaction mixture was stirred at room tem-
perature for 18 h and then refluxed for 48 h. The reaction mixture
was allowed to cool to room temperature and then passed through
AmberliteÒ IR 120 ion exchange resin. The mixture was concen-
trated in vacuo and subjected to column chromatography (ethyl
acetate/cyclohexane, 1:3?1:1) to afford the title compound 42 as
a crystalline solid (0.10 g, 15%); mp 100–102 °C (from ethyl ace-
tate/cyclohexane);
CDCl3): 1.67 (3H, s, Me), 3.04 (1H, s, OH), 4.25 (1H, d, H-3 J3,4
½
a 2D1
ꢂ
¼ ꢀ126 (c 1.0, CHCl3); dH (400 MHz,
24. Humphlett, W. J. Carbohydr. Res. 1967, 4, 157–164.
25. Cohen, N.; Banner, B. L.; Laurenzano, A. J.; Carozza, L. Org. Synth. 1984, 63, 127–
135.
7.9), 4.46–4.50 (2H, m, H-4, H-5), 4.82 (1H, s, OCH2O), 4.97 (1H,
dd, H-50, J5 ,4 1.9, J5 ,5 12.0), 5.17 (1H, s, OCH2O); dC (100.6 MHz,
CDCl3): 22.1 (Me), 68.7 (C-5), 71.5 (C-4), 72.2 (C-3), 78.8 (C-2),
94.9 (OCH2O), 171.4 (C@O); HRMS (ESI+): Found: 197.0421
[M+Na]+; C7H10O5Na requires: 197.0420.
26. Cubero, I. I.; Lopez-Espinosa, M. T. P. Carbohydr. Res. 1986, 154, 71–80.
27. Aparicio, F. J. L.; Cubero, I. I.; Olea, M. D. P. Carbohydr. Res. 1984, 129, 99–109.
28. Punzo, F.; Watkin, D. J.; Jenkinson, S. F.; Fleet, G. W. J. Acta Crystallogr., Sect. E
2005, 61, o127–129.
29. Punzo, F.; Watkin, D. J.; Jenkinson, S. F.; Fleet, G. W. J. Acta Crystallogr., Sect. E
2005, 61, o326–o327.
0
0
30. Serianni, A. S.; Nunez, H. A.; Barker, R. J. Org. Chem. 1980, 45, 3329–3341.
31. (a) Baird, P. D.; Dho, J. C.; Fleet, G. W. J.; Peach, J. M.; Prout, K.; Smith, P. W. J.
Chem. Soc., Perkin Trans. 1 1987, 1785–1791; (b) Bruce, I.; Fleet, G. W. J.;
Girdhar, A.; Haraldsson, M.; Peach, J. M.; Watkin, D. J. Tetrahedron 1990, 46, 19–
32; (c) Punzo, F.; Watkin, D. J.; Jenkinson, S. F.; da Cruz, F. P.; Fleet, G. W. J. Acta
Crystallogr., Sect. E 2005, 61, o511–o512; (d) Punzo, F.; Watkin, D. J.; Jenkinson,
Acknowledgments
Support from Idenix Pharmaceuticals, Novartis Pharma AG,
Summit PLC, and Dextra Laboratories Ltd is gratefully
acknowledged.

2424
K. V. Booth et al. / Tetrahedron: Asymmetry 19 (2008) 2417–2424
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33. Novak, J. J. K. Collect. Czech. Chem. Commun. 1974, 39, 869–882.
(e) Booth, K. V.; Watkin, D. J.; Jenkinson, S. F.; Fleet, G. W. J. Acta Crystallogr.,
Sect. E 2007, 63, o1128–o1130; (f) Booth, K. V.; Watkin, D. J.; Jenkinson, S. F.;
Fleet, G. W. J. Acta Crystallogr., Sect. E 2007, 63, o1759–o1760.