Zinc-proline catalyzed pathway for the formation of sugars

Article abstract of DOI:10.1039/b404465g

Zn-proline catalyzes the aldolisation of unprotected glycolaldehyde in water to give tetroses and hexoses; threose (33% of the product mixture) was formed with 10% enantiomeric excess of the D-isomer.

Full text of DOI:10.1039/b404465g

Zinc–proline catalyzed pathway for the formation of sugars†
Jacob Kofoed, Miguel Machuqueiro, Jean-Louis Reymond* and Tamis Darbre*
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland.
E-mail: tamis.darbre@ioc.unibe.ch; Fax: +41 31 631 80 57; Tel: +41 31 631 43 70
Received (in Cambridge, UK) 25th March 2004, Accepted 7th May 2004
First published as an Advance Article on the web 27th May 2004
Zn–proline catalyzes the aldolisation of unprotected glycolalde-
hyde in water to give tetroses and hexoses; threose (33% of the
product mixture) was formed with 10% enantiomeric excess of
under conditions that are compatible with a prebiotic environment.
Zn is an abundant transition metal and it is found in a large number
of metalloenzymes including aldolases involved in the metabolism
of sugars.10 Furthermore, chiral amino acids were possibly present
in the prebiotic period, either formed on earth or from extra-
terrestrial origine.7,11
the -isomer.
D
The prebiotic formation of sugars has been a subject of several
studies and speculations. One prevailing theory accepted today has
sugars being formed by a sequence of aldol reactions, starting with
formaldehyde (formose reaction). This reaction can be initiated by
an alkaline earth catalyst such as calcium hydroxide to give a
complex mixture containing straight- and branched-chain C3–C7
sugars.1–4 Eschenmoser and coworkers have shown that the
aldolisation of glycolaldehyde phosphate in 2M NaOH solution
gives a mixture of tetrose and hexose derivatives (ratio 1 : 10), due
to the lack of aldose–ketose tautomerisation.5 Pentoses (ribose,
arabinose, xylose and lysose) can also be formed under alkaline
conditions from formaldehyde and glycoaldehyde, although they
rapidly decompose to generate polymeric mixtures. However,
pentoses, formed by aldol reaction of glycolaldehyde and formal-
dehyde, can be stabilized by complexation with borate, a process
that could have relevance in the prebiotic synthesis of pentoses.6
The origin of sugar chirality has only recently been addressed.
Amino acids were reported to act as asymmetric catalysts for the
conversion of glycolaldehyde to tetroses in aqueous medium.
Threose was formed with enatiomeric excess ( ~ 10%) in the
presence of alanine or isovaline, whereas proline did not act as a
catalyst in this context.7 Proline catalyzed aldolization of propio-
naldehyde in DMF has been reported to give carbohydrates with
47% ee.8
Aqueous glycolaldehyde solution was stirred at room tem-
perature in the presence of a catalytic amount (15 mol%) of
Zn(Pro)2 complex (Scheme 1). After 7 days, the water was removed
by lyophilization and the reaction mixture was peracetylated and
analyzed by gas-chromatography.‡ Commercial sugars were
equilibrated and peracetylated, and used as references. The product
consisted of tetroses (51%), hexoses (27%) and unidentified
compounds (22%). The tetroses consisted of 65% threose and 35%
erythrose.12 The hexose mixture contained mainly glucose, ga-
lactose (together 40% of the hexose mixture) and talose (10% of the
hexose mixture). Similar results were obtained with zinc complexes
of the amino acids arginine or lysine. However, conversion with
Zn(Arg)2 was lower than with Zn(Pro)2 with around 50% of starting
glycolaldehyde still present in the reaction mixture after 7 days.
When glycolaldehyde was stirred in the presence of proline alone,
under the same reaction conditions, formation of sugars was not
1
observed and only glycoladehyde could be detected by H NMR.
Proline, therefore, does not act as a catalyst for the aldol reaction
under our reaction conditions.
The product mixture from the Zn(Pro)2 catalyzed reaction was
reduced with NaBH4 and peracetylated to produce a less complex
mixture of tetrol and hexitol acetates. Chiral GC allowed the
separation of the threitol acetate enantiomers. The threitol formed
was non-racemic (ee ~ 10%),13 similar to the enantiomeric excess
obtained with isovaline as catalyst.
The cross-aldolization of glycolaldehyde and racemic glycer-
aldehyde under the same conditions as above, gave a mixture of
tetroses and pentoses (Scheme 1).§ The identification of the
pentoses was made by comparison of the 1H NMR chemical shifts
for anomeric protons of the a-/b-pyranoses of commercial sugars
with the chemical shifts of the reaction products. The pentose
mixture contained ribose (34%), lyxose (32%), arabinose (21%)
and xylose (13%), which were stable under the reaction conditions.
The reaction mixture did not turn brown after one week, neither was
formation of polymeric material observed.
We are interested in developing catalysts for the asymmetrical
aldol reaction in aqueous media and we have shown that the
Zn(Pro)2 complex as well as Zn(Arg)2 and Zn(Lys)2 are able to
catalyze the direct reaction between aldehydes and ketones in water
with moderate enantioselectivity.9 Herein, we report that unpro-
tected glycolaldehyde can be converted to mainly tetroses and
hexoses in water using the Zn(Pro)2 complex as catalyst (Scheme 1)
The excess of threose over erythrose at the C4-level and the
preferential formation of glucose, galactose and talose at the C6-
level indicate a catalyzed aldol reaction occurring with stereo-
differentiation both in the addition of C2 to C2 and the addition of
C2 to C4.14 We postulate formation of a Zn-chelated glycoaldehyde
enolate as the nucleophile which can attack the electrophilic
carbonyl group of the aldehyde. Commercially available tetroses
(threose and erythrose) and hexoses (glucose, galactose, mannose,
talose, fructose) remained unchanged upon incubation with
Zn(Pro)2 under the conditions of the glycolaldehyde reaction (25
°C, 7 days), showing that the Zn(Pro)2 complex did not catalyze
stereoisomerization of different sugars.
In conclusion, the Zn–proline complex catalyzed the aldolisation
of glycoaldehyde in aqueous medium, at room temperature and in
the absence of strong bases. Threose was the main product and an
Scheme 1 Zn(Pro)2 catalyzed pathway for the formation of sugars.
enantiomeric excess of the natural
D-tetrose was observed. The
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b4/b404465g/
cross aldolisation of glycoaldehyde and glyceraldehyde gave
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C h e m . C o m m u n . , 2 0 0 4 , 1 5 4 0 – 1 5 4 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

F. Barbas III, Chem. Commun., 2002, 24, 3024.For a recent proline
catalyzed synthesis of protected sugars see: A. B. Northrup, I. K.
Mangion, F. Hettche and D. W. C. Macmillan, Angew. Chem. Int. Ed.,
2004, 43, 2152.For amine catalyzed aldol reactions in water see: T. J.
Dickerson and K. D. Janda, J. Am. Chem. Soc., 2002, 124, 3220; Y.
Chen and J.-L. Reymond, J. Org. Chem., 1995, 60, 6970.
tetroses and pentoses that were stable under the reaction conditions.
The Lewis acid catalyzed formation of sugars in water described
here adds a new reaction in the group of transformations that have
been cited in the discussion of possible prebiotic routes to sugars.
The diastereomeric and enantiomeric selection observed adds
support to the possibility that amino acids could have been the
source of chirality for the prebiotic sugar synthesis. The fact that a
metal coordinated to an amino acid is able to catalyze the synthesis
of sugars in water with a catalytic asymmetric effect, suggests also
that such systems could have been metalloenzyme precursors.
Furthermore, threofuranosyl oligonucleotides have been mentioned
as possible RNA analog, that could have been more easily
synthesized under prebiotic conditions.15,16
9 T. Darbre and M. Machuqueiro, Chem. Commun., 2003, 1090.
10 G. Schultz and M. Dreyer, J. Mol. Biol., 1996, 259, 458.
11 S. L. Miller, J. Am. Chem. Soc., 1955, 77, 2351.
12 The acetylated tetroses were separated from the acetylated hexoses by
chromatography and identified by 1H NMR. The chemical shifts of
anomeric protons corresponded to published values (a-threose d = 6.13
ppm, b-threose d = 6.42 ppm, a-erythrose d = 6.34 ppm, b-erythrose
d = 6.15 ppm) A. Barco, S. Benetti, C. De Risi, G. P. Pollini, G.
Spalluto and V. Zanirato, Tetrahedron, 1996, 52, 4719; J. Thiem and H.-
P. Wessel, Liebigs Ann. Chem., 1981, 2216.
13 A solution of sugar mixture (500 mg) and NaBH4 (100 mg) in H2O (10
mL) was stirred for 3 hours. Excess NaBH4 was destroyed with acetic
acid and the solution was lyophilized overnight. The dry residue was
stirred for 24 h in a mixture of acetic acid (3 mL) and pyridine (3 mL)
with DMAP (30 mg) as catalyst, then quenched with H2O (20 mL) and
extracted with CH2Cl2 (3 3 20 mL). The organic phase was extracted
with respectively 1N HCl (60 mL), brine (60 mL) and H2O (60 mL),
dried (Na2SO4) and evaporated to dryness. The tetritol tetraacetates
were separated from the hexitol hexaacetates by flash chromatography
(hexane/ethyl acetate (2 : 1)) and identified by 1H NMR and chiral phase
GC. NMR (CDCl3, 300 MHz) d 2.04–2.08 (m, 12H, 4 3 OAc), 4.03 (m,
1H, CH2), 4.16 (m, 1H, CH2), 4.30 (m, 2H, CH2), 5.24 (m, 1H, CH),
5.30 (m, 1H, CH). Anal. chiral GC (240 °C, 106 Kpa, 1,35 ml min21):
Notes and references
‡ Sugar synthesis: A solution of glycolaldehyde (60 mg, 1 mmol) and Zn-
amino acid complex (0.15 mmol) in H2O (5 ml) was stirred for 7 days at
room temperature. The solvent was removed by lyophilization and the
residue was peracetylated and analyzed by gas-chromatography.
§ Cross-aldolization: A solution of glycolaldehyde (60 mg, 1 mmol),
glyceraldehyde (90 mg, 1 mmol) and Zn-amino acid complex (0.15 mmol)
in H2O (5 mL) was stirred for 7 days at room temperature. The solvent was
removed by lyophilization.
1 (a) A. Butlerow, Liebigs Ann. Chem., 1861, 120, 295; (b) E. H. Ruckert,
E. Pfeil and G. Scharf, Chem. Ber., 1965, 98, 2558; (c) G. Harsch, H.
Bauer and W. Voelter, Liebigs Ann. Chem., 1984, 623.
2 J. D. Sutherland and J. N. Whitfield, Tetrahedron, 1997, 53, 11493.
3 (a) N. W. Gabel and C. Ponnamperuma, Nature, 1967, 216, 453; (b) C.
Reid and L. E. Orgel, Nature, 1967, 216, 455.
4 (a) R. F. Socha and A. H. Weiss, J. Catal., 1981, 67, 207; (b) A. L.
Weber, J. Mol., Evol., 1992, 35, 1.
5 D. Müller, S. Pitsch, A. Kittaka, E. Wagner, C. E. Wintner and A.
Eschenmoser, Helv. Chim. Acta, 1990, 73, 1410.
6 A. Ricardo, M. A. Carrigan, A. N. Olcott and S. A. Benner, Science,
2004, 303, 196.
7 S. Pizzarello and A. L. Weber, Science, 2004, 303, 1151.
8 N. S. Chowdari, D. B. Ramachary, A. Córdova and C. F. Barbas III,
Tetrahedron Lett., 2002, 43, 9591.A proline catalyzed asymmetric aldol
reaction to give sugars has also been reported in mixed solvents
(DMSO/H2O 10 : 1, dioxane/H2O 10 : 1): A. Córdova, W. Notz and C.
tR = 90.7 (meso-erythritol tetraacetate), tR = 109.6 min (
D-threitol
tetraacetate), tR = 113.8 min ( -threitol tetraacetate), ee, ~ 10%. L-
L
threitol tetraacetate was synthesized as reference for chiral GC and
1
NMR: H NMR (CDCl3, 300 MHz) d 2.09–2.13 (m, 12H, 4 3 OAc),
4.08 (m, 2H, CH2), 4.36 (m, 2H, CH2), 5.35 (m, 2H, CH). Anal. chiral
GC (240 °C, 106 Kpa, 1.35 ml min21): tR = 114.7 min.
14 When erythrose was stirred with glycolaldehyde and Zn(Pro)2 under the
conditions described, a predominant formation of glucose over the other
hexoses is observed by GC; when threose was stirred with glycolalde-
hyde and Zn(Pro)2 , talose, and galactose were formed in larger
amount.
15 K. U. Schöning, P. Scholz, S. Guntha, X. Wu, R. Krishnamurthy and A.
Eschenmoser, Science, 2000, 290, 1347.
16 L. E. Orgel, Science, 2000, 290, 1306.
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