Doubly carbon-branched pentoses: synthesis of both enantiomers of 2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose using only acetonide protection

Article abstract of DOI:10.1016/j.tetlet.2009.06.098

An acetonide is the only protecting group used in the synthesis of both the enantiomers of 2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose via the enantiomeric 3-C-methyl-l-erythronolactone [from 2-C-methyl-d-ribono-lactone or d-ribose] and 3-C-methyl-d-erythronolactone [from d-tagatose or l-ribose]. NMR studies on unprotected C-methyl arabinoses show that methyl branching significantly affects the ratios of pyranose and furanose forms present in aqueous solution.

Full text of DOI:10.1016/j.tetlet.2009.06.098

Tetrahedron Letters 50 (2009) 5088–5093
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Doubly carbon-branched pentoses: synthesis of both enantiomers of
2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose using
only acetonide protection
a
a
a
b
b
K. Victoria Booth , Sarah F. Jenkinson , Daniel Best , Fernando Fernández Nieto , Ramón J. Estévez ,
c
d
a,
*
Mark R. Wormald , Alexander C. Weymouth-Wilson , George W. J. Fleet
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Departamento de Química Orgánica, Universidade de Santiago, 15782 Santiago de Compostela, Spain
Glycobiology Institute, Department of Biochemistry, Oxford University, South Parks Road, Oxford OX1 3QU, UK
a
b
c
d
Dextra Laboratories Ltd, The Science and Technology Centre, Whiteknights Road, Reading RG6 6BZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An acetonide is the only protecting group used in the synthesis of both the enantiomers of 2,4-di-C-
methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose via the enantiomeric 3-C-methyl- -erythrono-
lactone [from 2-C-methyl- -ribono-lactone or -ribose] and 3-C-methyl- -erythronolactone [from -tag-
atose or -ribose]. NMR studies on unprotected C-methyl arabinoses show that methyl branching
significantly affects the ratios of pyranose and furanose forms present in aqueous solution.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 May 2009
Revised 10 June 2009
Accepted 19 June 2009
Available online 25 June 2009
L
D
D
D
D
L
Although most carbohydrates have linear carbon chains, singly
branched sugars with one methyl or hydroxymethyl branch are
found in Nature, frequently as a component of a larger molecule.
lowed by deprotection gives 2-C-methyl-
D
-arabinose 5 which has
0
13
been used in the synthesis of 2 -C-methyl nucleosides. This Letter
describes the preparation, by a similar strategy, of the two enanti-
omers of 2,4-di-C-methyl arabinoses 9D and 9L and of 2-deoxy-
1
For example, 3-C-methyl-D-mannose occurs in a polysaccharide of
2
Helicobacter pylori; the carbohydrate portion of apoptolidins, po-
2,4-di-C-methyl-L-arabinose 11L from the two enantiomers of
tential anti-cancer compounds, is essential for anti-tumor activity
the acetonides 3-C-methyl erythronolactones 7D and 7L via the
1,5-lactones 8D and 8L, respectively (Scheme 2). 2-deoxy-2,4-di-
and contains a 3-C-methyl branched sugar.3 Also 2-C-methyl-
D-
erythritol phosphate is an intermediate in the non-mevalonate bio-
synthesis of terpenes providing a strategy for the inhibition of the
growth of many pathogens including mycobacteria such as tuber-
C-methyl-
2,4-Di-C-methyl-
L
-arabinose 11D would be similarly accessible from 8D.
-arabinose 9L was efficiently synthesized from
-glucose 6 or -ribose 10D whereas 9D was obtained from
-tagatose 12 or -ribose 10L. The only protection necessary
L
either
either
D
D
D
4
culosis. Many recent papers have demonstrated the chemothera-
L
0
0
5
peutic potential of 2 - and 4 -C-methyl nucleoside analogues,
for all the syntheses was an isopropylidene group. The effect of the
introduction of carbon branching on the pyranose-furanose equi-
librium forms of arabinose was studied by NMR.
3-C-Methyl-
synthesis of the 2,4-di-C-methylarabinoses 9L and 11L, was pre-
pared from both -glucose 6 and -ribose 10D (Scheme 3). -Glu-
6
particularly for the treatment of hepatitis C. There have been very
few studies on di-C-methyl carbohydrates, although the synthesis
0
0
of bioactive 2 ,4 -di-C-methyl nucleosides has recently been
L-erythronolactone 7L, the key intermediate for the
7
reported.
8
The Kiliani reaction of cyanide on monosaccharides is a very
D
D
D
powerful and general method for access to C-branched sugars
cose 6 on reaction with dimethylamine in aqueous acetic acid,
followed by treatment of the resulting Amadori ketose with cal-
cium hydroxide, gave the branched lactone 13 in approximately
9
and polylols, including all four of the diastereomeric ketohexos-
1
0
es as well as the syntheses of C-3 branched sugars from C-2
11
14
branched sugars [such as hamamelose] and of b-sugar amino
acids from unprotected Amadori ketoses.12 Thus the protected
deoxyribulose 3, prepared by the addition of methylmagnesium
25% yield on a kilogram scale. Acetonation of 13, followed by
reduction with lithium borohydride, gave the triol 14 in quantita-
tive yield. Periodate oxidation of 14 formed the lactol 15L, further
oxidation of which using bromine water afforded the lactone
bromide to the acetonide of
D-erythronolactone 2 derived from
1
5,16
arabinose 1, reacts with cyanide to give the protected 1,5-lactone
7L
in an overall yield from 13 of 93%.
-lactone 7L was also synthesized from
Scheme 3). The branching hydroxymethyl group was introduced
via a Ho crossed aldol reaction between the acetonide of ribose
and formaldehyde to give the protected -hamamelose 16D in
4
with high diastereoselectivity (Scheme 1); reduction of 4 fol-
The
L
D-ribose 10D
(
*
Corresponding author.
E-mail address: george.fleet@chem.ox.ac.uk (G.W.J. Fleet).
D
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.098

K. Victoria Booth et al. / Tetrahedron Letters 50 (2009) 5088–5093
5089
HO
O
O
O
OH
Me
O
steps
OH
OH
O
O
(ii)
OH Me OH
HOH C
CHO
2
steps
OH
O
(i)
Me
O
HOH C
CHO
Me
2
O
O
OH
O
O
O
O
OH
1
D-arabinose
2
3
4
5 2-C-methyl-D-arabinose
Scheme 1. Reagents: (i) MeMgBr; (ii) NaCN.
OH OH
Me OHHO Me
HOH C
CHO
HO MeMe OH
HOH C
CHO
OH OH
CHO
CH2OH
HOH2C
HOH2C
2
2
OH OH
D-glucose
OH
OH
OH
O
steps
steps
steps
steps
Me
6
9L
9D
12 D-tagatose
O
O
O
O
O
O
O
O
(
(
i)
(i)
OH
Me
Me
D sugars in blue L sugars in red
Me
O
Me
ii)
O
Me
(ii)
O
O
OH
O
O
O
O
7
L
8L
8D
7D
steps
steps
steps
CHO
steps
CHO
OH
OH
Me OH Me
HOH2C
HO Me Me
HOH2C
OH
OH
HOH2C
CHO
HOH2C
CHO
OH
0D D-ribose
OH
11L
OH
11D
OH
10L L-ribose
1
Scheme 2. Reagents: (i) MeMgBr; (ii) NaCN.
OH
O
O
OH OH
O
HOH2C
O
HOH2C
OH
Me
O
(i)
(ii)
(iii)
OH
(iv)
CHO
Me
HOH2C
Me
OH
Me
O
O
O
O
O
O
OH OH
HO
6
D-glucose
13
14
15L
7L
(ix)
O
O
O
O
OH
OH
2
HOH C
OH
CH2OH
(vi)
OH
O
O
(v)
(vii)
(viii)
HOH2C
HOH C
2
IH C
HOH2C
CHO
2
O
O
O
O
O
O
O
O
OH
0D D-ribose
1
16D
17L
18L
19L
Scheme 3. Reagents and conditions: (i) Me
NaIO , MeOH, H O, 45 min, 100%; (iv) Br , BaCO
4%; (vii) Br , BaCO , H O, 90%; (viii) (CF SO O, pyridine, CH
2
NH, AcOH, H
, H O, 0 °C to rt, 18 h, 93%;(v) Me
Cl
, ꢂ30 °C; then Bu
2
O; then Ca(OH)
2
, H
2
O, ꢁ25%; (ii) Me
CO, CuSO
NI, DMF, 76%; (ix) Pd/C (10%), H
2
CO, CuSO
4
, cat. H
2
SO
O, Na
, Et
3
4
, 16 h; then LiBH
CO , H O, 88%; (vi) NaBH
N, 85%.
4
, THF, 1.5 h, 100% over two steps; (iii)
4
2
2
3
2
2
4
2
, cat. H SO
4
; then CH
2
2
3
2
4
, H O; then NaIO , AcOH,
2
4
9
2
3
2
3
)
2 2
2
2
4
2
8
8% yield as previously described.17 Reduction of 16D by sodium
very easy hydrolysis of the mono-C-methyl analogue 4.14 3,4-O-
borohydride followed by sodium periodate oxidation afforded the
protected -apiose 17L (94%) which on treatment with bromine
water gave the
Isopropylidene-1,5-lactones invariably crystallize in a boat confor-
2
2
L
mation; the diastereoselectivity may be rationalized by less ste-
ric congestion in the arabino lactone 8L [with a flagpole hydroxy
group] than in the ribo epimer 21L [with the larger flagpole methyl
substituent]. DIBALH reduction of the lactone 8L gave the pro-
22
L
-apionolactone 18L [mp 90–92 °C; ½
a
ꢀ
+70.5 (c,
D
1
8
0
.95) ] in 90% yield. Esterification of the free alcohol in 18L with
triflic anhydride in dichloromethane in the presence of pyridine
gave the corresponding triflate which on reaction with tetra-n-
butylammonium iodide afforded the iodide 19L [mp 60–62 °C;
1
D
7
tected lactol 22L [mp 84–86 °C; ½
aꢀ
+26.6 (c, 0.60)] in 67% yield
with 22% recovery of the starting material 8L. Although removal
of the isopropylidene protecting group in the lactone 8L in good
yield was not possible, the protected lactol 22L with acid ion ex-
18
18
½
aꢀ
+27.7 (c, 1.29)] in 76% yield. Hydrogenation of 19L in the
D
presence of palladium and triethylamine gave the 3-C-methyl lac-
tone 7L, identical to the material prepared from
yield [64% overall yield of 7L from 16D].
D
-glucose 6, in 85%
change resin, afforded the target di-C-methyl-
L
-arabinose 9L [mp
1
7
132–134 °C; ½
a
ꢀ
+13.0 (c, 0.90 in MeOH)] in quantitative yield;
D
Reaction of the lactone 7L with methylmagnesium bromide
gave the protected 4-C-methyl deoxy- -ribulose 20L (87% yield).
Treatment of 20L with sodium cyanide resulted in a highly diaste-
9L crystallized as the hydrate of the a
-pyranose form.23
L
For the 2-deoxy sugar 11L, the lactone 8L was esterified with
triflic anhydride and allowed to stand at room temperature; the
1
9
24
reoselective Kiliani reaction to give the arabinonolactone 8L in
7% yield together with a small amount (3%) of the epimeric ribon-
unsaturated lactone 23L was formed as a stable crystalline solid
7
in 63% yield. All attempts to base catalyze this elimination failed
and gave complex mixtures. Hydrogenation of 23L in the presence
of palladium in ethanol gave a single C-methyl compound 24L in
2
0
olactone 21L. The structure of 8L was confirmed by X-ray crystal
analysis. The high yield of the protected lactone is due to lack of
2
1
25
hydrolysis of the ketal protecting group in 8L in comparison to the
72% yield; a significant nOe between C2H and C5H was strongly

5
090
K. Victoria Booth et al. / Tetrahedron Letters 50 (2009) 5088–5093
2
5
suggestive of the production of the more stable arabino product
4L even though this would require hydrogenation from the most
hindered face. Reduction of 24L by DIBALH gave the lactol 25L [mp
acid to give the tetraol 28 [mp 81–82 °C; ½
a
ꢀ
+10.9 (c, 1.0)] in 90%
D
3
3
2
yield. Sequential oxidation with periodate to 15D and then bro-
1
D
7
mine water gave the lactone 7D [mp 82–84 °C; ½
a
ꢀ
-106.6 (c,
2
5
17
D
7
6–79 °C; ½
a
ꢀ
ꢂ49.6 (c, 0.15)], which was crystallized as the b-
1.34); ½
a
ꢀ
+101.6 (c, 0.80) for the enantiomer 7L] in 90% yield
D
2
6
pyranose anomer, in 59% yield. Removal of the isopropylidene
[overall 75% yield from 26]. The lactone 7D was also prepared from
-ribose 10L, via the protected hamamelose 16L, by the same se-
quence of reactions described for the -isomer in Scheme 3.
The lactone 7D was then subjected to analogous reactions to
those on 7L to form the di-C-methyl -arabinonolactone 8D {mp
112–114 °C; ½ ꢂ139.4 (c, 1.20); for the enantiomer 8L, ½
+131.8 (c, 1.50)}. DIBALH reduction followed by deprotection, as
described for the -enantiomer 8L in Scheme 4, afforded the free
protecting group by acid ion exchange resin gave 2-deoxy-2,4-di-
L
2
D
2
C-methyl-
2% yield.
In the
required
L
-arabinose 11L [oil, ½
a
ꢀ
ꢂ12.7 (c, 0.56 in MeCN)] in
D
8
D
-series the synthesis of 2,4-di-C-methyl-
-erythronolactone 7D which was prepared from both
D
-arabinose 9D
D
2
2
23
D
D
aꢀ
a
ꢀ
D
D
D
5
-tagatose 12 and -ribose 10L (Scheme 5). Although the price of
L
-tagatose in the 2007–2008 Aldrich catalogue is £331.00 for
L
2
7
22
D
g, it is now available cheaply in large quantities [around £5
di-C-methyl sugar 9D {½
a
ꢀ
ꢂ15.5 (c, 1.10 in MeOH); for the enan-
28
29
17
D
per kg] by either chemical or biotechnological procedures and
tiomer 9L, ½
aꢀ
+13.0 (c, 0.90 in MeOH)}.
30
34
has been developed as a low calorie sweetener. The potential of
-tagatose as a chiral building block is beginning to be recog-
Full NMR analyses
methyl-arabinose 9, and 2,4-di-C-methyl-2-deoxy-arabinose 11
were carried out in D O to study the effect of introducing C-methyl
of 2-C-methyl-arabinose 5, 2,4-di-C-
D
3
1
nized. For example,
D-tagatose 12 underwent an efficient Kiliani
2
reaction to give a mixture of diastereomeric lactones which on
treatment with acetone and acid resulted in the easy isolation of
the diacetonide 26 in 51% yield. Appel reaction of the alcohol 26
with triphenylphosphine and iodine in the presence of imidazole
afforded the corresponding iodide which on hydrogenation gave
the 2-C-methyl branched lactone 27 in 92% yield.32 Reduction of
groups on the equilibrium between pyranose and furanose forms,
1
and between anomers; the 1D H NMR spectra are shown in Figure
1
13
1, and the H and C assignments are given in Tables 1 and 2. For
all compounds, the pyranose forms were identified by the HMBC
0
peak between C1 and C5H/C5H , and between C5 and C1H; the
furanose forms were identified by the HMBC peak between C4
and C1H. There was no evidence of the open-chain keto form with-
in the detection limit in any of the samples (<2%). The furanose
2
7 with lithium borohydride in THF formed a diol from which
the terminal acetonide was removed selectively by aqueous acetic
Me
H
OH
OH
O
O
O
O
O
O
HO
Me
O
(ii)
Me
Me
Me
OH
O
(i)
Me
O
Me
Me
Me
Me
+
O
O
O
O
O
O
O
O
OH
Me
O
O
O
O
O
O
7L
20L
8L
21L
(v)
(
iii)
CHO
CHO
Me
HO
H
H
O
OH
Me
O
OH
Me
O
O
Me
O
O
Me
(iv)
(viii)
(vi)
Me
OH
Me
(vii)
Me
OH
Me
O
Me
O
O
HO
Me
O
Me
O
OH
HO
Me
O
O
O
O
O
O
O
CH OH
2
CH OH
2
1
1L
25L
24L
23L
O, 77%; (iii) DIBALH, CH
22L
9L
Ò
+
Scheme 4. Reagents and conditions: (i) MeMgBr, THF, ꢂ78 °C, 45 min, 87%; (ii) NaCN, H
2
Cl
2 2
, ꢂ78 °C, 1.5 h, 67%; (iv) Dowex (50 W X8 H ), H
2
O,
O,
Ò
+
9
9
0 °C, 1.5 h, 100%; (v) (CF
0 °C, 1.5 h, 82%.
3
SO
)
2 2
O, pyridine, CH
2
Cl
2
; then DMF, rt, 16 h, 63%; (vi) H
2
, 20% Pd/C, EtOH, 72%; (vii) DIBALH, CH
Cl
2 2
, ꢂ78 °C, 59%; (viii) Dowex (50 W X8 H ), H
2
CHO
HO
OH
HOH C
2
O
O
O
O
O
O
OH
Me
O
O
O
HO
OH
HO
HO
(
i)
(iv)
(
ii)
(iii)
HO
OH
HO
O
Me
OH
CH2OH
Me
O
O
O
O
O
O
O
O
CH OH
CH2OH
2
1
5D
1
2 D-tagatose
26
27
28
10L L-ribose
(
v)
O
O
O
O
HOH2C
HO MeMe OH
HOH C
CHO
O
OH
CH OH
Me
OH
Me
2
2
O
Me
O
O
O
O
OH
O
1
6L
7D
4
N, EtOH, 92%; (iii) LiBH , THF, 0 °C to rt, 16 h;
9
D
8D
, imidazole, PhMe; then H
Scheme 5. Reagents and conditions: (i) NaCN, H
2
O; then Me
2
CO, H
2
SO
4
, 51%; (ii) Ph
, H O, 93%.
3
P, I
2
2
, Pd/C, Et
3
then AcOH, H O, 16 h, 90%; (iv) NaIO , H O, rt, 4 h, 96%; (v) Br
2
4
2
2
, BaCO
3
2

K. Victoria Booth et al. / Tetrahedron Letters 50 (2009) 5088–5093
5091
Reduced vertical scale
α-fur
β-fur
a
β-pyr
α-pyr
α-fur
β-fur
β-pyr
b
c
α-pyr
α-fur
β-fur
β-pyr
α-pyr
Chemical Shift (ppm)
Figure 1. 1H NMR spectra of (a) 2,4-di-C-methyl-2-deoxy-arabinose 11L, (b) 2,4-di-C-methyl-arabinose 9L, and (c) 2-C-methyl-arabinose 5L. The vertical scales of the methyl
regions have been reduced. The peak at 2.22 ppm in each spectrum is acetone added as an internal standard.
b-anomers of all three sugars and the pyranose b-anomers of 5 and
could be identified by the strong C1H to C2CH NOEs. The pyra-
nose b-anomer of 11 could be identified by the large trans-diaxial
For the b-pyranose form of 2,4-di-C-methyl-arabinose 9, the rela-
tively high chemical shift for C1H suggests that this proton is equa-
torial and the large difference between the chemical shifts of C5H
9
3
0
4
coupling between C1H and C2H. The proportions of furanose and
and C5H implies that C1OH is axial, consistent with a C
formation. For the -pyranose form, the relatively low chemical
shift for C1H indicates that this proton is axial, thus suggesting that
1
ring con-
pyranose forms are shown in Figure 2 [shown for the
L
-enantio-
a
mers]. For the b-pyranose form of 2-C-methyl-arabinose 5, the
3
0
4
large
J
HH coupling between C4H and C5H indicates that these
the ring is also in the C
1
conformation. For the a-anomer, this con-
1
two protons are axial. This defines the ring conformation as
For the
C4H and either C5H or C5H indicates that C4H is equatorial and
hence the ring is in the 4
conformation. These conformations
are those predicted on steric grounds, both having two axial and
three equatorial substituents; however, in the -form the axial
substituents are on the same side of the ring, whilst in the b-form
4
C .
formation would be predicted on steric grounds, placing four of the
1
4
a
-pyranose form, the lack of a large coupling between
six groups equatorial. For the b-anomer, both the C
4 1
and C con-
0
formations place three groups axial and three equatorial.
3
C
1
The large JHH coupling between C1H and C2H indicates that
these two protons are axial in the b-pyranose form of 2,4-di-C-
a
methyl-2-deoxy-arabinose 11. This defines the ring conformation
1
as C
4
, which maximizes the number of equatorial substituents rel-
-pyranose form, the relatively
they are on the opposite sides, hence the
a/b ratio is less than one.
ative to axial substituents. For the
a
high chemical shift for C1H implies that this proton is equatorial
Table 1
and the large difference between the chemical shifts of C5H and
1
3C chemical shifts of C-methyl-arabinoses (referenced to acetone at 30.90 ppm)
0
C5H suggests that C1OH is axial. This implies that the ring confor-
1
3
mation is also
C
4
, consistent with the identical
J
HH coupling be-
C1
C2
C3
C4
C5
C2C
C4C
0
tween C2H and C3H and between C3H and C5H . For the b-
2-C-Methyl-arabinose 5
anomer, this conformation would be predicted on steric grounds,
a
-Fur
b-Fur
-Pyr
b-Pyr
21%
30%
20%
29%
103.16
100.71
98.32
81.02
78.54
73.96
73.24
77.81
76.36
74.59
73.66
84.79
81.91
67.31
65.82
62.4
15.98
18.04
17.1
—
—
—
—
63.23
63.85
63.61
placing three of the five groups equatorial. For the a-anomer, steric
4
1
a
1 4
arguments would favor the C conformation rather than the C ;
95.95
20.97
however, the observed peak broadening may indicate some dy-
namic ring behavior. C-Methyl branching increases the proportion
of furanose forms relative to pyranose forms compared to the par-
2,4-Di-C-methyl-arabinose 9
a
-Fur
b-Fur
-Pyr
b-Pyr
9%
102.26
99.55
99.34
97.63
81.76
79.72
75.05
73.14
79.23
78.49
78.52
75.09
86.62
84.47
72.23
72.12
67.86
68.7
71.82
67.05
16.6
19.24
13.7
19.61
18.37
22.39
22.93
16%
46%
29%
35
ent arabinose 1, more so for the 2-C-methyl 5 than for the di-
a
methyl 9 and 11 sugars (Fig. 2). The b-furanose form relative to
19.99
a
-furanose is stabilized by C2-methylation, 5; C2,C4-dimethyla-
2
,4-Di-C-methyl-2-deoxy-arabinose 11
tion, 9 and 11, stabilizes the b-anomer still further. This is as ex-
pected as both methyl groups are on the same side of the ring as
C1OH in the
causes more complex changes in ring conformation and stability.
C2-Methylation does not alter the stable ring conformations of
the a- and b-anomers relative to arabinose, but makes the b-ano-
a
-Fur
b-Fur
-Pyr
b-Pyr
7%
100.23
103.41
95.36
42.65
45.11
36.11
39.28
75.44
75.83
75.66
76.02
88.6
67.75
67.85
63.27
68.28
8.02
9.85
12.01
12.77
19.52
18.49
22.55
22.84
17%
15%
61%
87.75
69.69
69.88
a
a
a
a-anomer. For the pyranose forms, C-methylation
97.17
%
ages were estimated from peak area in the 1H 1D spectrum.
a
Broad peaks in the 1D spectrum.

5
092
K. Victoria Booth et al. / Tetrahedron Letters 50 (2009) 5088–5093
Table 2
1
H chemical shifts (ppm) and 3-bond coupling constants (Hz) of C-methyl-arabinoses (referenced to acetone at 2.220 ppm)
0
C1H
C2H
C3H
C4H
C5H
C5H
C2CH
3
C4CH
3
2-C-Methyl-arabinose 5
a
-Fur
b-Fur
-Pyr
b-Pyr
21%
30%
20%
29%
5.137
4.975
4.584
4.794
—
—
—
—
3.853 (J3,4 5.8)
4.004 (J3,4 6.7)
3.685 (J3,4 5.0)
3.771 (J3,4 3.6)
4.068
3.765
4.003
4.082
3.773 (J4,5 3.6)
3.773 (J4,5 3.3)
3.871 (J4,5 5.3)
3.852 (J4,5 4.7)
3.708 (J4,5
3.668 (J4,5
3.658 (J4,5
3.605 (J4,5
0
0
0
0
5.5)
6.5)
3.1)
8.5)
1.292
1.256
1.285
1.263
—
—
—
—
a
2,4-Di-C-methyl-arabinose 9
a
-Fur
b-Fur
-Pyr
b-Pyr
9%
5.074
4.958
4.517
4.917
—
—
—
—
3.921
4.069
3.387
3.634
—
—
—
—
3.55
3.56
3.712
3.884
3.55
3.56
3.523
3.456
1.292
1.279
1.229
1.303
1.23
16%
46%
29%
1.166
1.153
1.199
a
2,4-Di-C-methyl-2-deoxy-arabinose 11
a
-Fur
b-Fur
-Pyr
b-Pyr
7%
5.260 (J1,2 4.9)
5.126 (J1,2 6.5)
4.952 (J1,2 3.3)
4.679 (J1,2 8.8)
2.44 (J2,3 5.7)
2.317 (J2,3 5.7)
2.073 (J2,3 2.6)
1.852 (J2,3 2.6)
3.959
4.06
3.57
—
—
—
—
3.403
3.522
3.886
3.68
3.403
3.484
3.276
3.437
1.049 (J2,Me 7.2)
1.057 (J2,Me 7.2)
1.05 (J2,Me 7.1)
0.993 (J2,Me 6.9)
1.296
1.22
1.269
1.327
17%
15%
61%
a
3.596
%
ages were estimated from peak area in the 1H 1D spectrum.
Figure 2. Ring conformations and relative populations for the a-pyr, b-pyr, a
-fur, and b-fur forms of (a) 11L, (b) 9L, (c) 5L, and (d) arabinose 1L. * ring conformations not
unambiguously determined by NMR.
mer more stable than the
the ring conformation of the b-anomer relative to arabinose 1
and again increases its stability relative to the -anomer, although
the latter is still more stable. C2,C4-Dimethylation combined with
loss of the C2-hydroxy group in 11 changes the ring conformation
a
-anomer. C2,C4-Dimethylation alters
References and notes
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(a) Daum, M.; Peintner, I.; Linnenbrink, A.; Frerich, A.; Weber, M.; Paululat, T.;
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a
of the a-anomer and makes the b-anomer far more stable.
2008, 47, 3568–3572.
In summary, this Letter reports the first synthesis of unpro-
tected di-C-methyl branched monosaccharides by an efficient Kili-
ani reaction on a branched deoxyketose. The effect of C-methyl
branching on the ratios of pyranose to furanose anomers in arabi-
nose has been studied.
2.
Kocharova, N. A.; Knirel, Y. A.; Widmalm, G.; Jansson, P.; Moran, A. P.
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Acknowledgment
5
We thank the Spanish Science and Innovation Ministry for a
grant to Fernando Fernández.

K. Victoria Booth et al. / Tetrahedron Letters 50 (2009) 5088–5093
713; (c) Maddaford, A.; Wainwright, P.; Glen, R.; Fisher, R.; Dragovich, P. S.; 20. Selected data for 2,4-di-C-methyl-3,4-O-isopropylidene-
5093
3
L
-ribono-1,5-lactone
+127.3 (c, 0.90); mmax (thin film): 3463 (s, br s, OH),
2
2
Gonzalez, J.; Kung, P. P.; Middleton, D. S.; Pryde, D. C.; Stephenson, P. S.; Sutton,
S. C. Synthesis 2007, 1378–1384.
21L: mp 62–64 °C; ½
aꢀ
D
1753 (s, C@O); d : 1.43 (6H, s, C(CH
H
3
2
) ), 1.46 (3H, s, CH
3
-4), 1.49 (3H, s, CH
3
-4),
0
6
.
(a) Eldrup, A. B.; Prhavc, M.; Brooks, J.; Bhat, B.; Prakash, T. P.; Song, Q.; Bera, S.;
Bhat, N.; Dande, P.; Cook, P. D.; Bennett, C. F.; Carroll, S. S.; Ball, R. G.;
Bosserman, M.; Burlein, C.; Colwell, L. F.; Fay, J. F.; Flores, O. A.; Getty, K.;
LaFemina, R. L.; Leone, J.; MacCoss, M.; McMasters, D. R.; Tomassini, J. E.; Von
Langen, D.; Wolanski, B.; Olsen, D. B. J. Med. Chem. 2004, 47, 5284–5297; (b)
Pierra, C.; Benzaria, S.; Amador, A.; Moussa, A.; Mathieu, S.; Storer, R.; Gosselin,
G. Nucleosides, Nucleotides Nucleic Acids 2005, 24, 767–770.
3.54 (1H, s, OH), 4.15 (1H, s, H3), 4.18–4.31 (2H, a-dd, H6, H6 , J 0.7, J 13.0); d
C
:
19.8 (CH
85.7 (C3), 110.0 (C(CH
3
-2), 24.5 (CH
3
-4), 26.5, 27.3 (C(CH
), 174.1 (C@O).
3 2
) ), 71.8 (C2), 73.9 (C5), 77.5 (C4),
3
)
2
21. Booth, K. V.; Watkin, D. J.; Jenkinson, S. F.; Fleet, G. W. J. Acta Crystallogr., Sect. E
2007, 63, o1128–o1130.
22. (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.;
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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,
S. F.; da Cruz, F. P.; Fleet, G. W. J. Acta Crystallogr., Sect. E 2006, 62, o321–o323;
(e) Booth, K. V.; Watkin, D. J.; Jenkinson, S. F.; Fleet, G. W. J. Acta Crystallogr.,
Sect. E 2007, 63, o1759–o1760.
7
.
.
Maddaford, A.; Guyot, T.; Leese, D.; Glen, R.; Hart, J.; Zhang, X.; Fisher, R.;
Middleton, D. S.; Doherty, C. L.; Smith, N. N.; Pryde, D. C.; Sutton, S. C. Synlett
007, 3149–3154.
(a) Hudson, C. S. Adv. Carbohydr. Chem. 1945, 1, 2–36; (b) Hudson, C. S. J.
Am. Chem. Soc. 1951, 73, 4498–4499; (c) Pratt, J. W.; Richtmeyer, N. K.;
Hudson, C. S. J. Am. Chem. Soc. 1953, 75, 4503–4505; (d) Bichard, C. J. F.;
Wheatley, J. R.; Fleet, G. W. J. Tetrahedron: Asymmetry 1994, 5, 431–440;
2
8
23. Booth, K. V.; Jenkinson, S. F.; Watkin, D. J.; Fleet, G. W. J. Acta Crystallogr., Sect. E
2007, 63, o3592–o3593.
(
e) Beacham, A. R.; Bruce, I.; Choi, S.; Doherty, O.; Fairbanks, A. J.; Fleet, G.
2
D
1
W. J.; Skead, B. M.; Peach, J. M.; Saunders, J.; Watkin, D. J. Tetrahedron:
Asymmetry 1991, 2, 883–900.
(a) Ferrier, R. J. J. Chem. Soc. 1962, 3544–3549; (b) Kiliani, H. Ber. Dtsch. Chem.
Ges. 1885, 18, 3066–3072; (c) Kiliani, H. Ber. Dtsch. Chem. Ges. 1886, 19, 221–
24. Selected data for unsaturated lactone 23L: mp 68–69 °C; ½
a
ꢀ
+156.9 (c, 0.57);
), 3.82 (1H, d,
,5 12.1), 4.60 (1H, s, H3), 5.87 (1H, s, H2 ), 6.33
d
H
: 1.42 (3H, s, CH
H5, J5,5
(1H, s, H2 ); d
110.9 (C(CH
3
-4), 1.44 (3H, s, C(CH
)
3 2
), 1.46 (3H, s, C(CH
3
)
2
0
0
9
.
0
12.1), 4.18 (1H, d, H5 , J
5
0
0
0
C
: 22.6 (CH
3
-4), 26.9, 27.6 C(CH
), 130.1 (C2 ), 135.1 (C2), 167.0 (C1).
3
)
2
), 72.5 (C5), 79.3 (C4), 81.3 (C3),
0
2
27; (d) Kiliani, H. Ber. Dtsch. Chem. Ges. 1928, 61, 1155–1169; (e) Woods, R. J.;
3
)
2
2
1
Neish, A. C. Can. J. Chem. 1953, 31, 471–475; Woods, R. J.; Neish, A. C. Can. J.
Chem. 1954, 32, 404–414; Gorin, P. A. J.; Perlin, A. S. Can. J. Chem. 1956, 36, 480–
25. Selected data for deoxylactone 24L; mp 117 °C; ½
film): 1745 (s, C@O); d (C , 400 MHz): 0.75 (3H, s, CH
-2, JCH3-2,2 6.8), 1.38 (3H, s, C(CH ), 1.71 (1H, dq, H2,
12.5), 3.59 (1H, d, H3, J3,2 2.4), 3.79 (1H,
, 100 MHz): 13.0 (CH -2), 22.5 (CH -4), 26.6, 27.3
), 38.0 (C2) 72.4 (C5), 79.3 (C4), 82.8 (C3), 109.6 (C(CH ), 171.6 (C1).
a
ꢀ
+156.3 (c, 0.735);
v
max (thin
D
H
6
D
6
3
-4), 1.13 (3H, s,
4
85.
C(CH
3
)
2
), 1.29 (3H, d, CH
3
3 2
)
1
1
0. (a) Hotchkiss, D. J.; Soengas, R.; Simone, M. I.; van Ameijde, J.; Hunter, S.;
Cowley, A. R.; Fleet, G. W. J. Tetrahedron Lett. 2004, 45, 9461–9464; (b) Soengas,
R.; Izumori, K.; Simone, M. I.; Watkin, D. J.; Skytte, U. P.; Soetart, W.; Fleet, G.
W. J. Tetrahedron Lett. 2005, 46, 5755–5759.
J2,3 2.4, J2,CH3-2 6.8), 3.14 (1H, d, H5, J5,5
0
0
0
d, H5 , J
(C(CH
5
0
,5 12.5). d
C
(C
6
D
6
3
3
3
)
2
3 2
)
26. Booth, K. V.; Jenkinson, S. F.; Fleet, G. W. J.; Watkin, D. J. Acta Crystallogr., Sect. E
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1. (a) Parker, S.; Watkin, D. J.; Simone, M. I.; Fleet, G. W. J. Acta Crystallogr.,
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27. Porwell, J. Aldrich Handbook of Fine Chemicals; 2007, p 2253.
28. (a) Beadle, J. R.; Saunders, J. P.; Wajda, T. J. Process for Manufacturing tagatose,
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89–94; Izumori, K. Naturwissennshaften 2002, 89, 120–124.
1
1
1
2. Jenkinson, S. F.; Hotchkiss, D. J.; Cowley, A. R.; Fleet, G. W. J.; Watkin, D. J. Acta
Crystallogr., Sect. E 2008, 64, o294–o295.
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Tetrahedron Lett. 2007, 48, 4441–4445.
30. Skytte, U. P. Cereal Foods World 2002, 47, 224–227.
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Dwek, R. A.; Kiran, G. P.; Devendar, R.; Takata, G.; Morimoto, K.; Izumori, K.;
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Haraguchi, S.; Gullapalli, P.; Rao, D.; Morimoto, K.; Takata, G.; Jones, N. A.;
Jenkinson, S. F.; Wormald, M. R.; Dwek, R. A.; Fleet, G. W. J.; Izumori, K.
Tetrahedron: Asymmetry 2008, 19, 739–745.
32. Jones, N. A.; Rao, D.; Yoshihara, A.; Gullapalli, P.; Morimoto, K.; Takata, G.;
Hunter, S. J.; Wormald, M. R.; Dwek, R. A.; Izumori, K.; Fleet, G. W. J.
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1
5. All NMR spectra and specific rotations were determined in CHCl
otherwise stated.
3
except where
1
6. Selected data for 2,3-O-isopropylidene-3-C-methyl-L-erythrono-1,4-lactone
1
7
7
L: mp 82–84 °C; ½
aꢀ
+101.6 (c, 0.80); d
H
: 1.40, 1.49 (2 ꢃ 3H, s, CH
3
), 1.54
,4 10.6), 4.46 (1H, s,
D
0
0
0
(
3H, s, H3 ), 4.15 (1H, d, H4, J4,4
0
10.6), 4.44 (1H, d, H4 , J
4
0
33. Other than specific rotation, the physical properties of all the enantiomers
reported were identical.
34. NMR spectra for the C-methyl arabinoses 5, 9, and 11 were recorded on a
0
H2); d
C(CH
7. (a) Ho, P. Tetrahedron Lett. 1978, 1623–1626; (b) Ho, P.-T. Can. J. Chem. 1979, 57,
81–383; (c) Ho, P.-T. Can. J. Chem. 1985, 63, 2221–2224.
C
: 21.9 (C3 ), 27.7, 28.5 (C(CH
)
3 2
), 75.6 (C4), 79.4 (C2), 83.5 (C3), 114.0
(
)
3 2
), 174.7 (C@O).
1
13
1
1
1
Varian UnityINOVA 500 ( H—500 MHz: C—125 MHz) spectrometer, in D
2
O,
3
with a probe temperature of 30 °C. Chemical shifts were measured relative to
1
13
8. Best, D.; Jenkinson, S. F.; Watkin, D. J.; Booth, K. V.; Fleet, G. W. J. Acta
Crystallogr., Sect. E 2007, 63, o1056–o1057.
internal standards ( H—acetone at 2.220 ppm: C—acetone at 30.9 ppm). Two-
dimensional gradient COSY, HSQC, HMBC, and HSQC-TOCSY spectra were used
to aid assignment of 1H and C spectra. ROESY spectra were recorded with a
400 ms mixing time. All chemical shifts (d) are quoted in ppm and coupling
constants (J) in Hz.
13
9. Selected data for 2,4-di-C-methyl-3,4-O-isopropylidene-
L
-arabinono-1,5-
2
3
lactone 8L: mp 120–124 °C; ½
a
ꢀ
+131.8 (c, 1.50); d
), 1.43 (3H, s, H4 ), 1.58 (3H, s, H2 ), 2.81 (1H, s, OH), 4.01 (1H, s, H3),
H
: 1.38, 1.40 (2 ꢃ 3H, s,
D
0
0
C(CH
3
)
2
0
0
0
4
2
1
.13 (1H, d, H5, J5,5
0
11.4), 4.62 (1H, d, H5 , J
5
0
,5 11.4); d
C
: 23.0 (C2 ), 24.7 (C4 ),
),
35. (a) Zheng, R.; Wei, W.; Shi, Q. J. Phys. Chem. A 2009, 113, 157–164; (b) Angyal, S.
J. Adv. Carbohydr. Chem. Biochem. 1984, 42, 15–68; (c) Angyal, S. J. Adv.
Carbohydr. Chem. Biochem. 1991, 49, 19–35.
6.7, 27.4 (C(CH
71.5 (C@O).
)
3 2
), 72.7 (C2), 74.1 (C5), 79.3 (C4), 84.7 (C3), 110.1 (C(CH )
3 2