A clean conversion of D-glucosamine hydrochloride to a pyrazine in the presence of phenylboronate or borate

Article abstract of DOI:10.1002/1099-0690(200110)2001:20<3899::aid-ejoc3899>3.0.co;2-g

D-Glucosamine was found to undergo a condensation to give 2-(arabo-tetrahydroxybutyl)-5-(erythro-2,3,4-trihydroxy-butyl)-pyrazine (2) as practically the sole product in the presence of phenylboronate or borate. The reaction proceeds in aqueous solutions a

Full text of DOI:10.1002/1099-0690(200110)2001:20<3899::aid-ejoc3899>3.0.co;2-g

FULL PAPER
A Clean Conversion of
D
-Glucosamine Hydrochloride to a Pyrazine in the
Presence of Phenylboronate or Borate
Jan Rohovec,[a] Jan Kotek,[a] Joop A. Peters,*[a] and Thomas Maschmeyer[a]
Keywords: Carbohydrates / Nitrogen heterocycles / Borates / Amino aldehydes
D
-Glucosamine was found to undergo a condensation to give
yield. In D2O solutions, the incorporation of one deuterium
2-(arabo-tetrahydroxybutyl)-5-(erythro-2,3,4-trihydroxy- into the methylene group of the trihydroxybutyl arm was
butyl)-pyrazine (2) as practically the sole product in the pres-
ence of phenylboronate or borate. The reaction proceeds in
aqueous solutions at room temperature in 3 h in 58% isolated
found. The borate esters of the product were investigated by
11B and 13C NMR spectroscopy.
Introduction
Borate and phenylboronate are known to enhance the se-
lectivity in a variety of reactions with carbohydrates, includ-
ing isomerization,[1] esterification,[2] isopropylidation,[3] oxi-
dation with bromine,[4] hydrogenation,[5] dehydration,[6] and
alkaline oxidative degradation of aldohexoses by hydrogen
peroxide.[7] Generally, the rationale for the selectivity en-
hancement is the formation of borate or boronate esters of
the desired product. Moreover, these boron compounds ex-
ert a protecting role with respect to degradation reactions.
Aminosaccharides are able to undergo a variety of
unique reactions, due to the presence of both amino and
carbonyl groups, which may result in complex reaction mix-
tures due to, for example, Amadori rearrangements of ini-
tially formed Schiff bases, followed by further rearrange-
ment and dehydration steps leading to browning.[8] The na-
ture of the products formed is strongly dependent on the
reaction conditions, particularly on the pH. It has been re-
ported that -glucosamine (1), in aqueous solutions, can be
converted into complex mixtures of products, containing
the pyrazine derivatives deoxyfructosazine [2-(arabo-tetra-
hydroxybutyl)-5-(erythro-2,3,4-trihydroxybutyl)-pyrazine]
(2) and fructosazine [2,5-bis(arabo-tetrahydroxybutyl)pyr-
azine] (3) as major components (see Scheme 1).[9Ϫ11] Be-
sides pyrazine derivatives, 5-hydroxymethyl-2-furaldehyde
and products of its decomposition have also been observed.
The starting amino sugar 1, as well as products 2 and 3,
are of pharmaceutical interest, as they are reagents for
DNA strand cleavage.[9]
Scheme 1. The main reaction pathways for the cyclocondensation
of two molecules glucosamine
amount of cysteine can increase the yield of 2.[9] Better
yields of compound 2 have been obtained by heating -
glucosamine in acetic acid.[12] The disadvantage of this pro-
cedure is that the purification of compound 2 from the
brown complex reaction mixture obtained is tedious.
Here, we report a clean and selective conversion of glu-
cosamine hydrochloride into compound 2 in the presence
of phenylboronic acid or boric acid and NaOH. The borate
esters of the product were investigated by 11B and 13C
NMR spectroscopy.
Results and Discussion
The reaction of glucosamine hydrochloride in aqueous
solution and in the presence of phenylboronic acid and
NaOH gave compound 2 almost exclusively (96%) in 2 h.
The reaction mixture was only slightly yellow and no ela-
borate separation steps were needed to isolate 2. After re-
moval of the phenylboronate by extraction with diethyl
ether and recrystallization of the residue, pure 2 was ob-
tained in 58% yield. Similar results were obtained with di-
sodium tetraborate, sodium metaborate or a solution of
boric acid in sodium hydroxide.
The distribution of the reaction products can be influ-
enced by the addition of amino acids (glycine, cysteine) and
by the pH of the reaction mixture. The effect of the buffer
used to maintain the pH has been studied: a mixture of
pyrazine derivatives 2 and 3 is always formed, leading to the
need for an HPLC separation. The use of a stoichiometric
[a]
Department of Applied Organic Chemistry and Catalysis,
Delft University of Technology, Julianalaan 136, 2628 BL
Delft, Netherlands
The explanation for the formation of 2 during the reac-
tion is based on a previously published mechanism,[9,12] tak-
ing into account the formation of borate (or boronate) es-
Fax: (internat.) ϩ31 15 27 84289
E-mail: J.A.Peters@tnw.tudelft.nl
Eur. J. Org. Chem. 2001, 3899Ϫ3901
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1020Ϫ3899 $ 17.50ϩ.50/0
3899

J. Rohovec, J. Kotek, J. A. Peters, T. Maschmeyer
FULL PAPER
ters. The reaction in the presence of borate was too fast to borate ester 7 is converted into free 2 by acidification with
follow by NMR spectroscopy, and only the borate esters of HCl.
the reaction product 2 could be observed and identified (see
To support the proposed reaction mechanism, we per-
below). However, from the high reactivity and selectivity of formed an experiment using D2O and NaOD as the reac-
the reaction in the presence of borate, it can be concluded tion medium. 13C NMR measurements and an APT experi-
that borate esters play an important role in the mechanism. ment[16] on the product showed no deuteration of the pyr-
The starting compound glucosamine may occur in the pyr- azine ring carbons, while one deuterium was incorporated
anose, furanose and open forms. From previous studies re- into the methylene group, -CHD-. This leads to the conclu-
garding the stability of borate esters of diol groups in vari- sion that the deuterium is incorporated into 2 during the
ous configurations,[13,14] it is evident that the open form has protonation/deprotonation step of the intermediate 6 upon
the highest affinity for borate. A good model is the corres- formation of the aromatic ring.
ponding -glucosamine oxime, for which the local associ-
We studied the borate esters of 2 in solution by 11B and
ation constants for borate ester formation at the threo-3,4- 13C NMR spectroscopy in the system disodium tetraborate
diol and at the erythro-4,5-diol moieties have been deter- (excess)/glucosamine hydrochloride. From integration of the
mined to be logK ϭ 2.6 and logK ϭ 1.5, respectively.[15] spectra it can be deduced that compound 2 is bound to
Here K is defined by K ϭ [BϪL]/[BϪ][L], where BϪL de- three borate moieties (see Scheme 3). The formation of bo-
notes the borate ester, BϪ free borate [B(OH)4Ϫ] and L the
free sugar. As a result of the high affinity of borate for the
open form of glucosamine, the population of this form is
relatively high in the mixture of borate esters. Condensation
of two molecules of the borate esters of the open form of
glucosamine (4) then gives the borate esters of the dihy-
dropyrazine derivative 5. The elimination of water then re-
sults in the borate esters of the corresponding pyrazine (6).
This reaction step could be assisted by the borate ester moi-
ety. The isomerisation of 6 by protonation/deprotonation
gives the borate ester of 2 (7) (see Scheme 2). Under the
conditions applied, a competitive oxidation of 5 to the bor-
ate ester of 3 does not proceed to a large extent (4%). The the species
Scheme 3. Schematic representation of the borate esters of com-
pound 2; the B atoms are labeled with the 11B chemical shifts of
Scheme 2. Proposed mechanism for the cyclocondensation of two molecules of glucosamine in the presence of borate
3900
Eur. J. Org. Chem. 2001, 3899Ϫ3901

A Clean Conversion of D-Glucosamine Hydrochloride to a Pyrazine
FULL PAPER
ethyl ether (5 ϫ 40 mL) followed by evaporation of the solvent.
The light-orange aqueous phase was evaporated to dryness in va-
cuo, with the bath temperature kept below 40 °C. The semi-solid
residue was extracted with 15 mL of methanol/ethanol (2:1 v/v)
and then with pure ethanol. The extract was evaporated to dryness
and the procedure was repeated in order to remove the last portion
of NaCl. The residue obtained was triturated in 5 mL of MeOH
with heating to the boiling point. Dry ethanol (15 mL) was then
added dropwise with stirring, after which the mixture was allowed
to cool to room temperature. The light grey product was filtered
rate esters starts at pH ഠ 6.5; this relatively low pH value
(in comparison to glucose, for example) can be explained
by the stabilization of the ester by the pyrazine nitrogen
atom. A similar stabilization of the borate esters of amino-
diols has been described for the system boric acid/3-di-
methylamino-1,2-propandiol.[17] The effect of the pyrazine
nitrogen atoms may be responsible for the formation of 2.
The type of borate esters (mode of borate coordination)
was established using known characteristic values of 11B
NMR chemical shifts for various types of borate es- off, washed with ethanol and dried at 80 °C. Recrystallization from
ters.[14,17] The results are summarized in the Table 1.
MeOH/EtOH afforded 0.88 g (58%) of analytically pure 2; m.p.
157Ϫ158 °C (ref.[12] 161Ϫ162 °C); [α]2D1 ϭ Ϫ78.9 (c ϭ 0.033 )
Table 1. Comparison of the 11B chemical shifts of compound 2
with literature values
1
(ref.[12] Ϫ78). Ϫ H NMR (399.9 MHz, D2O): δ ϭ 2.93 (m, 1 H),
3.17 (m, 1 H), 3.64 (m, 3 H), 3.77 (d, 1 H), 3.81 (m, 3 H), 3.98 (m,
1 H), 5.13 (d, 1 H), 8.50 (d, 1 H), 8.65 (d, 1 H) Ϫ 13C NMR
(100.6 MHz, D2O): δ ϭ 39.15 (CH2), 64.08, 64.56, 72.64, 72.91,
72.96, 75.02, 76.05, (7 C, CHOH), 143.82 and 145.72 (2 C arom.
CH), 154.84 and 155.64 (2 C, arom. C).
Type of borate coordination
in the ester
11B chemical shift
typical range
observed
1,2-Bidentate
Tridentate
1,2-Bidentate with
interaction to nitrogen
Ϫ12.6 to Ϫ14.9[a]
Ϫ18.1 to Ϫ19.4[a]
Ϫ10.5 to Ϫ12.0[b]
Ϫ13.4
Ϫ18.3
Ϫ8.7; Ϫ6.3
Acknowledgments
Thanks are due to Ms T. W. Smoor for experimental assistance.
[a] Ref.[7]
Ϫ
[b] Ref.[17] converted into the H3BO3 chemical-shift scale.
For interaction of boronate with an aliphatic amino group.
[1]
K. B. Hicks, E. V. Symanski, P. E. Pfeffer, Carbohydr. Res.
1983, 112, 37Ϫ50.
[2]
Thus, the 11B NMR spectrum reveals the presence of 1,2-
bidentate and tridentate coordinated borate anions and two
non-equivalent borate anions having an interaction with ni-
trogen. At the same time, the sum of the intensities of the
signals at δ ϭ Ϫ18.3 and Ϫ8.7 is approximately equal to
the intensity of the signals at δ ϭ Ϫ13.3 or δ ϭ Ϫ6.3, prob-
ably due to an equilibrium between these forms. The struc-
tures of the borate esters in solution are depicted schematic-
ally in Scheme 3.
R. J. Ferrier, Adv. Carbohydr. Chem. 1978, 35, 31Ϫ80.
[3]
C. J. Griffiths, H. Weigel, Carbohydr. Res. 1980, 81, 17Ϫ21.
[4]
B. Augustinsson, E. Scholander, Carbohydr. Res. 1984, 126,
162Ϫ164.
[5]
M. Makkee, A. P. G. Kieboom, H. van Bekkum, Carbohydr.
Res. 1985, 138, 237Ϫ245.
[6]
J. E. McMurry, M. D. Evion, J. Am. Chem. Soc. 1985, 107,
2712Ϫ2720.
[7]
R. van den Berg, J. A. Peters, H. van Bekkum, Carbohydr. Res.
1995, 267, 65Ϫ77.
[8]
F. Ledl, E. Schleicher, Angew. Chem. 1990, 29, 597Ϫ626; An-
gew. Chem. Int. Ed. Engl. 1990, 29, 565Ϫ594.
[9]
K. Sumoto, M. Irie, N. Mibu, S. Miyano, Y. Nakashima, K.
Watanabe, T. Yamaguchi, Chem. Pharm. Bull. 1991, 39,
Experimental Section
792Ϫ794.
[10]
S. J. Eitelman, M. S. Feather, Carbohydr. Res. 1979, 77
205Ϫ211.
G. Candiano, G. M. Ghiggeri, R. Gusmano, L. Zetta, E.
NMR Experiments: NMR experiments were performed on a Varian
Unity-Inova 300 spectrometer in D2O as solvent at 25 °C. For the
1H and 13C NMR measurements tert-butyl alcohol was used as an
internal standard with the methyl signal calibrated at δ ϭ 1.2 and
31.2, repsectively. The 11B chemical shifts are reported with respect
to 0.1  H3BO3 in D2O as external standard (substitution method).
[11]
Benfenati, G. Icardi, Carbohydr. Res. 1988, 184, 67Ϫ75.
[12]
R. Kuhn, G. Krüger, H. J. Haas, A. Seeliger, Ann. 1961, 644,
122Ϫ127.
[13]
M. van Duin, J. A. Peters, A. P. G. Kieboom, H. van Bekkum,
Tetrahedron 1985, 41, 3411Ϫ3421.
R. van den Berg, J. A. Peters, H. van Bekkum, Carbohydr. Res.
1994, 253 1Ϫ12.
J. van Haveren, M. H. B. van den Burg, J. A. Peters, J. G.
Batelaan, A. P. G. Kieboom, H. van Bekkum, J. Chem. Soc.,
Perkin Trans. 2 1991, 321Ϫ327.
[14]
Deoxyfructosazine (2): Phenylboronic acid (3.05 g, 25 mmol) was
added to a solution of NaOH (1.00 g, 25 mmol) in 60 mL of water.
The resulting suspension was stirred until a clear solution was
formed. -Glucosamine hydrochloride (2.16 g, 10 mmol) was then
added portionwise during 5 min. and the mixture obtained was
stirred at room temperature for 3 h. During this time the color of
the reaction mixture turned to light yellow. The pH was decreased
to 2Ϫ3 by dropwise addition of 10% HCl. Phenylboronic acid pre-
cipitated and was quantitatively recovered by extraction with di-
[15]
[16]
S. L. Patt, J. N. Shoolery, J. Magn. Reson. 1982, 46, 535Ϫ539.
T. Oi, T. Takeda, H. Kakihana, Bull. Chem. Soc. Jpn. 1992,
[17]
65, 1903Ϫ1909.
Received February 21, 2001
[O01085]
Eur. J. Org. Chem. 2001, 3899Ϫ3901
3901