Green aldose isomerisation: 2-C-methyl-1,4-lactones from the reaction of Amadori ketoses with calcium hydroxide

Article abstract of DOI:10.1016/j.tetlet.2006.11.137

Saccharinic acids, branched 2-C-methyl-aldonic acids, may be accessed via a green procedure from aldoses by sequential conversion to an Amadori ketose and treatment with calcium hydroxide; d-galactose and d-glucose are converted to 2-C-methyl-d-lyxono-1,4

Full text of DOI:10.1016/j.tetlet.2006.11.137

Tetrahedron Letters 48 (2007) 517–520
Green aldose isomerisation: 2-C-methyl-1,4-lactones from
the reaction of Amadori ketoses with calcium hydroxide
David J. Hotchkiss,a Raquel Soengas,a Kathrine V. Booth,a
Alexander C. Weymouth-Wilson,b Vanessa Eastwick-Fieldc and George W. J. Fleeta,*
aChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bDextra Laboratories Ltd., The Science and Technology Centre, Whiteknights Road, Reading RG6 6BZ, UK
cCMS Chemicals, 9 Milton Park, Abingdon, Oxfordshire OX14 4RR, UK
Received 19 September 2006; revised 15 November 2006; accepted 22 November 2006
Available online 12 December 2006
Abstract—Saccharinic acids, branched 2-C-methyl-aldonic acids, may be accessed via a green procedure from aldoses by sequential
conversion to an Amadori ketose and treatment with calcium hydroxide; D-galactose and D-glucose are converted to 2-C-methyl-D-
lyxono-1,4-lactone (with a small amount of 2-C-methyl-D-xylono-1,4-lactone) and 2-C-methyl-D-ribono-1,4-lactone. Inversion of
configuration at C-4 of the branched lactones allows access to 2-C-methyl-L-ribono-1,4-lactone and 2-C-methyl-L-lyxono-1,4-lac-
tone, respectively. D-Xylose affords 2-C-methyl-D-threono-1,4-lactone and 2-C-methyl-D-erythrono-1,4-lactone, whereas L-arabi-
nose, under similar conditions, gave the enantiomers 2-C-methyl-L-threono-1,4-lactone and 2-C-methyl-L-erythrono-1,4-lactone.
Ó 2006 Published by Elsevier Ltd.
At present, all commercially available carbohydrate
scaffolds contain linear carbon chains.1 The Kiliani
cyanide ascensions2,3 on unprotected ketohexoses—
D-fructose, L-sorbose,4 D-tagatose and D-psicose5—
provide an accessible set of derivatives bearing a C-2
hydroxymethyl group of value in the efficient synthesis
of complex homochiral targets;6 the Kiliani reaction of
the C-2 branched sugars7,8 gives C-3 branched sugars.
The isomerisation of aldoses or ketoses into 2-C-
methyl-aldonic acids by calcium hydroxide in very low
yields is one of the oldest9 and most complex organic
reactions with typically less than 0.5% of branched
2-C-methyl-aldonic acids being formed;10 after optimi-
sation of the reaction of fructose with calcium hydroxide
a yield of around 11% of 2-C-methyl-D-ribonic acid 3D
can be obtained in several weeks.11 This letter estab-
lishes the generality of the calcium hydroxide isomerisa-
tions of Amadori ketoses, derived from cheap aldoses,
to 2-C-methyl-branched aldonic acids as a new strategy
for the synthesis of branched sugar chirons.
oxide gives the branched ribose derivative 3D, isolated
as its lactone;12 a practical procedure is given below
for the transformation of D-galactose 6 via the Amadori
ketose 5 to 2-C-methyl-lyxonic acid 4D. Although the
yields are modest, the low cost of glucose and galactose
make 3D and 4D accessible starting materials for homo-
chiral targets with methyl-branched carbon chains.
There are currently no cheaply available L-aldohexoses;
however, inversion of configuration at C-4 of 1,4-lac-
tones can be accomplished efficiently on a multi-kilo-
gram scale.13 Thus the epimerisations of D-ribono-3D
to L-lyxono-4L and of D-lyxono-4D to L-ribono-3L allow
both enantiomers to be synthesised.
Pentoses also undergo the same transformation (Scheme
2). Thus, D-xylose 7 was converted to Amadori deriva-
tive 8; subsequent reaction of 8 with calcium oxide
allows the isolation of both 2-C-methyl-D-erythrono-
9D and D-threono-10D acids. L-Arabinose 12, the only
readily available L-pentose, allows the formation of
enantiomers 9L and 10L from L-ribulosamine 11.
The sole previous report of this transformation (Scheme
1) is the conversion of D-glucose 1 with dimethylamine
to fructosamine 2, which with aqueous calcium hydr-
D-Galactose 6 on reaction with dibenzylamine in acetic
acid/ethanol (Scheme 3) underwent the Amadori rear-
rangement to give tagatosamine 5, which crystallised
as the a-anomer,14 in 88% yield.15 Treatment of
Amadori ketose 5 with calcium oxide in water, followed
*
Corresponding author. E-mail addresses: george.fleet@chem.ox.
ac.uk; george.fleet@sjc.ox.ac.uk
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.137

518
D. J. Hotchkiss et al. / Tetrahedron Letters 48 (2007) 517–520
CO2H
OH
CO2H
OH
Me
H
Me
H
(iii)
OH
OH
HO
H
(ii)
H
OH
CH2NBn2
CHO
OH
CH2NMe2
CHO
OH
CH2OH
CH2OH
O
H
H
HO
H
O
H
H
HO
HO
H
L-lyxono
(i)
D-ribono
(i)
HO
HO
H
H
OH
HO
H
H
H
4L
3D
H
OH
(ii)
OH
H
OH
H
OH
OH
CH2OH
CO2H
CH2OH
CH2OH
CH2OH
CO2H
HO
Me
H
HO
Me
H
D-galactose
D-glucose
D-tagatosamine
D-fructosamine
(iii)
HO
H
HO
HO
5
1
2
6
OH
H
CH2OH
CH2OH
D-lyxono
L-ribono
4D
3L
Scheme 1. Reagents and conditions: (i) Me2NH or Bn2NH; (ii) CaO, H2O; (iii) invert at C-4.
CO2H
OH
CO2H
Me
Me
H
HO
H
+
OH
OH
(ii)
CHO
CHO
OH
CH2NMe2
CH2NMe2
O
CH2OH
CH2OH
H
HO
HO
OH
H
H
HO
H
O
H
D-erythrono
D-threono
10D
(i)
(i)
H
OH
HO
H
HO
HO
H
H
9D
(ii)
H
OH
CH2OH
CH2OH
CH2OH
CH2OH
CO2H
CO2H
OH
L-arabinose
D-xylose
D-xylulosamine
HO
HO
Me
H
Me
HO
L-ribulosamine
+
H
12
7
8
11
CH2OH
CH2OH
L-erythrono
L-threono
9L
10L
Scheme 2. Reagents: (i) Me2NH; (ii) CaO, H2O.
CH2NBn2
OH
O
O
OH
Me
O
O
O
(iii)
O
OH
Me
HOH2C
HO
O
OH
OH
HOH2C
HOH2C
(i)
O
(ii)
+
O
Me
O
HO
OH
HO
14
HO OH
OH
OH
13D
15
6
5
(iii)
O
HOH2C
O
O
HOH2C
(v)
O
XOH2C
(vi)
O
O
O
Me
HOH2C
Me
Me
O
O
O
O
O
HO OH
OH
Me
HO
none isolated
16D X=H
17D X=SO2CF3
18L
19L
(iv)
20
O
(v)
O
(vi)
O
XOH2C
HOH2C
O
(iii)
HOH2C
HOH2C
HO
O
OH
OH
HOH2C
O
O
O
(vii)
O
Me
Me
Me
Me
HO OH
O
O
O
O
HO OH
OH
18D X=H
21D X=SO2CH3
1
19D
16L
13L
(viii)
Scheme 3. Reagents: (i) Bn2NH, AcOH, EtOH; (ii) CaO, H2O; (iii) Me2CO, CuSO4, concd H2SO4; (iv) (CF3SO2)2O, pyridine, CH2Cl2; (v) KOH,
diaoxane, H2O; (vi) CF3COOH, H2O; (vii) Ref. 12; (viii) CH3SO2Cl, pyridine, DMAP.
by an acid work-up, gave as the easily isolated and sep-
arated products 2-C-methyl-branched lyxono-13D (12%
yield) and xylono-14 (2% yield) lactones. There is a sig-
nificant preference for the formation of cis-diol 13D
rather than trans-isomer 14; in contrast, when glucose
1 was subjected to the same procedure only the cis-diol
ribono-lactone 19D was formed with none of the epi-
meric trans-diol arabino-lactone 20 being formed.12

D. J. Hotchkiss et al. / Tetrahedron Letters 48 (2007) 517–520
519
A practical method for the synthesis of branched D-
lyxonolactone 13D (the lactone derived from 4D) is as
follows: A suspension of the Amadori ketose 5 (41.2 g,
115 mmol) in water (750 mL) was stirred at 70 °C with
calcium oxide (32 g, 570 mmol) for 24 h. The reaction
mixture was cooled to room temperature, filtered
through CeliteÒ and then passed through AmberliteÒ
IR-120 H+ ion exchange resin, using water as the eluant.
The water was then removed under reduced pressure to
afford a crude orange oil which was purified by flash
column chromatography (ethyl acetate/cyclohexane,
(6:1) ! ethyl acetate) to afford 2-C-methyl-D-lyxono-
1,4-lactone 13D (1.98 g, 12%)16 and D-xylono-epimer
14 (338 mg, 2%).17 The structure of the unprotected lyx-
ono-lactone 13D was confirmed by X-ray crystallo-
graphic analysis;18 reaction of xylono-epimer 14 with
A similarly efficient epimerisation of D-ribono-lactone
19D (equivalent to the open chain aldonic acid 3D) into
L-lyxono-lactone 13L (equivalent to the aldonic acid 4L)
was achieved in 68% overall yield. Lactone 19D, pre-
pared in 20% yield from D-glucose 1,12 was protected
21
as its 2,3-acetonide 18D (mp 52–54 °C; ½aꢀD ꢁ35.6 (c
1.42, Me2CO)) in 100% yield. Reaction of 18D with
mesyl chloride in pyridine afforded mesylate 21D (oil,
24
½aꢀD ꢁ24.7 (c 0.97, CHCl3)) in 100% yield. Treatment
of 21D with potassium hydroxide in aqueous dioxane
followed by an acid work-up gave inversion at C-4 to
22
give the protected lactone 16L (mp 64–66 °C, ½aꢀD
ꢁ74.1 (c 0.64, Me2CO), 91% yield) which was deprotec-
ted by aqueous trifluoroacetic acid to afford the
18
branched L-lyxono-lactone 13L (oil, ½aꢀD ꢁ77.3 (c 0.4,
water)) in 75% yield.
acetone in the presence of anhydrous copper sulfate
23
and acid gave 3,5-acetonide 15 (mp 155–158 °C, ½aꢀD
2-C-Methyl-D-erythrono-1,4-lactone 23D, the lactone of
9D, was discovered as a natural product in Astragalus
lusitanicus21 and Cicer ariatinum;22 D-threono-epimer
22D was isolated from Anthylis tetraphylla23 and also
found in tobacco smoke.24 2-C-Methyl-D-erythritol
was discovered in the petals of Phlox subulata and is
involved in flower development.25 The mevalonate-inde-
pendent biosynthesis of isoprenoids via 2-C-methyl-D-
erythritol phosphate is a target against malaria and
pathogenic bacteria26 and has increased the effort in
the synthesis of 2-C-methyl tetroses.27
+82.2 (c 0.67, CHCl3)), an X-ray structure of which
was also determined.19 It is easy to distinguish between
the diastereomers by their 13C spectra; the chemical shift
of the 2-C-methyl group of lyxono-isomer 13D (d 20.7)
where the diol unit is cis is at a significantly lower field
than xylono-isomer 14 (d 16.8), where the diol unit is
trans.
The branched D-lyxono-lactone 13D was converted
into L-ribono-lactone 19L, epimeric at C-4. Acetona-
tion of 13D gave the 5 ring 2,3-O-isopropylidene
23
derivative 16D (mp 64–66 °C, ½aꢀD +77.2 (c 1.75,
Previous syntheses of lactones 22D and 23D—all of
which involve several steps and need protection of
oxygen functional groups—include asymmetric aldol
condensations28,29 and use of protected chiral pool
starting materials of lactic acid30 and mannitol.31
Although very small amounts of D-lactones 22D and
23D are obtained by the reaction of calcium hydroxide
with D-xylose,32 the sequential Amadori rearrange-
ment-calcium hydroxide treatment of the pentoses
D-xylose 7 and L-arabinose 12 produced enantiomeric
lactones 22D and 23D or 22L and 23L, respectively,
without any protection necessary.
Me2CO)) in 99% yield; in contrast to the reaction of
lyxonolactone itself,20 none of the 6 ring 3,5-ketal
was formed. Esterification of the free alcohol in 16D
with triflic anhydride in dichloromethane in the pres-
ence of pyridine gave triflate 17D (mp 79–81 °C,
21
½aꢀD +60.9 (c 0.60, Me2CO)) in 100% yield. Reaction
of the triflate 17D with potassium hydroxide in aque-
ous dioxane caused ring opening and subsequent
epoxide formation; work-up with acid gave inversion
of configuration at C-4 and closure to the protected
22
lactone 18L (mp 52–54 °C, ½aꢀD +34.2 (c 1.05,
Me2CO)) in 82% yield. Removal of the ketal from
18L with aqueous trifluoroacetic acid gave the unpro-
Thus, D-xylose 7 was subjected to the Amadori rear-
rangement by treatment with ethanolic dimethylamine
in acetic acid to give the xylulosamine 8 (Scheme 4);
crude residue 8 obtained by removal of the solvent
was treated with calcium oxide. After workup with acid
ion exchange resin, a mixture of the branched D-threono-
22D (10%)33 and D-erythrono-23D (4%)34 lactones was
22
tected L-ribono-lactone 19L (mp 160–162 °C, ½aꢀD
ꢁ87.7 (c 0.60, water) {lit.11 for the D-enantiomer
22
19D mp 160–161 °C, ½aꢀD +93 (water)}) in 90% yield.
The overall yield for the conversion of D-lyxono-lac-
tone 13D (the lactone of 4D) to L-ribono-lactone 19L
(the lactone of 3L) was 73%.
O
O
Me
OH
O
O
+
+
OH
(ii)
HO
HO Me
CH2NMe2
OH
CH2NMe2
OH
O
OH
OH
O
OH
OH
O
O
23D
22D
(i)
(i)
(ii)
HO
HO
HO
OH
HO
OH
O
OH
OH
O
O
O
11
7
8
12
Me
OH
HO
OH
HO Me
22L
23L
Scheme 4. Reagents: (i) Me2NH, AcOH, EtOH; (ii) CaO, H2O; then H+.

520
D. J. Hotchkiss et al. / Tetrahedron Letters 48 (2007) 517–520
A. Org. Process Res. Dev. 2006, 10, 484–486, and
references therein.
14. Harding, C. C.; Cowley, A. R.; Watkin, D. J.; Punzo, F.;
Hotchkiss, D.; Fleet, G. W. J. Acta Crystallogr. 2005, E61,
o1475–o1477.
obtained. Neither of the lactones was crystalline; very
careful chromatography was necessary to obtain pure
samples of each separate diastereomer. The enantio-
meric branched L-threono-22L and L-erythrono-23L lac-
tones were obtained using an identical procedure from
L-arabinose 12 via the intermediate ribulosamine 11;
the ratio of L-threono-22L/L-erythrono-23L was also
approximately 3:1. Again the diastereomers could be
differentiated by 13C spectroscopy; the chemical shift
of the 2-C-methyl group of the cis-diol erythrono-isomer
23 (d 19.9) is at significantly lower field than the trans-
diol threono-isomer 22 (d 16.6).
15. Grunnagel, R.; Haas, H. J. Liebigs Ann. Chem. 1969, 721,
¨
234–235.
16. 2-C-Methyl-D-lyxono-1,4-lactone 13D: mp 106–107 °C;
23
½aꢀD +70.4 (c 0.9, Me2CO) mmax (film): 3421, 1773 cmꢁ1
;
dH (CD3OD, 400 MHz): 1.43 (3H, s, CH3), 3.88 (2H, m,
H-5 and H-50), 4.07 (1H, d, J3,4 3.8 Hz, H-3), 4.54 (1H,
0
ddd, J4,5 5.0 Hz, J3,4 3.8 Hz, J4,5 5.9 Hz, H-4); dC
(CD3OD, 100.6 MHz): 20.7 (CH3), 60.4 (C-5), 74.2 (C-
3), 74.5 (C-2), 81.5 (C-4), 179.4 (C-1).
23
17. 2-C-Methyl-D-xylono-1,4-lactone 14: mp 161–162 °C; ½aꢀD
It is noteworthy that the products from the aldohexoses
(glucose and galactose) have a 2,3-cis-diol in the lactone
ring as the major products, whereas the aldopentoses
(xylose and arabinose) form predominantly the lactone
with a trans-diol.
+87.3 (c 0.5 in water); mmax (film): 3254, 1776 cmꢁ1; dH
(CD3OD, 400 MHz): 1.39 (3H, s, CH3), 3.82–3.90 (2H, m,
H-5 and H-50), 4.03 (1H, d, J3,4 3.7 Hz, H-3), 4.71 (1H,
0
ddd, J3,4 3.7 Hz, J4,5 5.0 Hz, J4,5 6.4 Hz, H-4); dC
(CD3OD, 100.6 MHz): 16.8 (CH3), 60.4 (C-5), 75.3 (C-
3), 76.5 (C-2), 82.9 (C-4), 178.2 (C-1).
In summary, the isomerisation of aldoses to saccharinic
(2-C-methyl-aldonic) acids by an Amadori rearrange-
ment followed by treatment with aqueous calcium oxide
is shown to be general and provides access by green
aqueous procedures to a group of hitherto unavailable
branched carbohydrate chirons.
18. Punzo, F.; Watkin, D. J.; Hotchkiss, D.; Fleet, G. W. J.
Acta Crystallogr. 2006, E62, o98–o100.
19. Watkin, D. J.; Parry, L. L.; Hotchkiss, D. J.; Eastwick-
Field, V.; Fleet, G. W. J. Acta Crystallogr. 2005, E61,
o3302–o3303.
´
20. Bleriot, Y.; Gretzke, D.; Krulle, T. M.; Butters, T. D.;
¨
Dwek, R. A.; Nash, R. J.; Asano, N.; Fleet, G. W. J.
Carbohydr. Res. 2005, 340, 2713–2718; Fleet, G. W. J.;
Petursson, S.; Campbell, A.; Mueller, R. A.; Behling, J.
R.; Babiak, K. A.; Ng, J. S.; Scaros, M. G. J. Chem. Soc.,
Perkin Trans. 1 1989, 665.
Acknowledgments
21. Teresa, J. P.; Aubanell, J. C. H.; San Feliciano, A.; del
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A generous gift of 2-C-methyl-D-ribonolactone from
Novartis Pharma AG Basel is gratefully acknowledged.
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23
33. 2-C-Methyl-D-threono-1,4-lactone 22D: oil, ½aꢀD ꢁ18.8 (c
1.1, H2O); mmax (film): 3406, 1775 cmꢁ1; dH (CD3OD,
400 MHz): 1.36 (3H, s, CH3), 3.98 (1H, dd, J3,4 4.4 Hz,
0
0
J4,4 9.4 Hz, H-4), 4.19 (1H, m, H-3), 4.50 (1H, dd, J3,4
5.4 Hz, J4,4 9.4 Hz, H-40); dC (CD3OD, 100.6 MHz): 16.6
(CH3), 71.8 (C-4), 74.5 (C-3), 74.9 (C-2), 179.0 (C-1).
0
22
34. 2-C-Methyl-D-erythrono-1,4-lactone 23D: oil, ½aꢀD ꢁ35.0 (c
0.3, H2O); mmax (film): 3398, 1774 cmꢁ1; dH (CD3OD,
400 MHz): 1.41 (3H, s, CH3), 4.06 (1H, dd, J3,4 1.8 Hz,
0
0
J3,4 4.1 Hz, H-3), 4.16 (1H, dd, J3,4 1.85 Hz, J4,4 10.2 Hz,
H-4), 4.45 (1H, dd, J3,4 4.1 Hz, J4,4 10.2 Hz, H-40); dC
(CD3OD, 100.6 MHz): 19.9 (CH3), 72.3 (C-4), 73.4 (C-2),
73.5 (C-3), 179.4 (C-1).
0
0