The Heyns rearrangement revisited: An exceptionally simple two-step chemical synthesis of D-lactosamine from lactulose

Article abstract of DOI:10.1002/(SICI)1521-3773(19990315)38:6<827::AID-ANIE827>3.0.CO;2-N

Disaccharides containing D-glucosamine at the reducing end can be conveniently synthesized in good yields from O-glycosylated D-fructoses by the title reaction [Eq. (a)]. With all the disaccharides investigated, the method proceeded-presumably because of

Full text of DOI:10.1002/(SICI)1521-3773(19990315)38:6<827::AID-ANIE827>3.0.CO;2-N

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tose and allow access to 6 (Scheme 2) and/or suitable
derivatives thereof in seven to nine steps and overall yields
ranging from 10 to, at most, 30%.[ Enzyme-catalyzed
syntheses have employed d-galactosidases from various
The Heyns Rearrangement Revisited:
An Exceptionally Simple Two-Step Chemical
Synthesis of d-Lactosamine from Lactulose**
11]
Tanja M. Wrodnigg and Arnold E. Stütz*
[10, 12±14]
[15, 16]
sources,
or d-galactosyl transferases
as compo-
nents of multienzyme systems which serve co-factor recycling.
The Heyns rearrangement of lactulose (3) (Scheme 2) was
achieved by reaction with commercial grade benzylamine
followed by treatment of the resulting crude material with
glacial acetic acid in methanol to give N-benzyl-d-lactosamine
(4) in 65 ± 70% yield. A small proportion of the corresponding
d-mannosamine derivative was also formed, as was shown by
NMR spectroscopy. The N-benzyl group in 4 was removed by
conventional catalytic hydrogenation over palladium hydrox-
ide in methanol. Subsequent addition of acetic anhydride to
the reaction mixture containing 5 led to 6. Overall yields for
this three-step procedure were found to range between 38 and
Dedicated to Professor Robin Ferrier
on the occasion of his 60th birthday
In the 1950s, Heyns and Koch reported the formation of d-
glucosamine (2) from the reaction of d-fructose (1) with
[
1]
ammonia (Scheme 1). Yields of isolated product for this
reaction were found to be around 10% with rare exceptions of
0% depending on the reaction conditions employed.[ From
2]
3
4
5%. Changing the solvent in the hydrogenation step from
methanol to dilute aqueous HCl allowed access to free d-
lactosamine hydrochloride.
Scheme 1. Heyns rearrangement of d-fructose (1).
This sequence, which can be performed conveniently as a
one-pot procedure, does not require any protecting group
manipulations or elaborate chromatographic separation and
is well suited for scaling-up. A wide range of N-modified
derivatives suitable as intermediates en route to sophisticated
oligosaccharides are available in good yields by employing
the reaction of d-fructose with primary or secondary aliphatic
amines, N-substituted d-glucosamine derivatives were sub-
[
3]
sequently obtained by Carson as well as the Heyns group.
[
4]
The latter workers as well as Anet also examined the
reactivities of the other ketohexo-
[
5]
ses and the condensation products
[
6]
of d-fructose with aromatic amines
[
7]
and amino acids. In all reported
cases, yields rarely exceeded the
20% mark.
Apart from these studies with
simple ketoses, preparatively useful
applications of the Heyns rearrange-
ment have not been reported to date.
We focussed our attention on this
interesting and versatile reaction in
the context of a demand for multi-
gramm quantities of various glycosy-
lated N-acetyl-d-glucosamine deriv-
atives, for example, N-acetyl-d-lac-
tosamine (6, Scheme 2), which is a
X
constituent of the sialyl Lewis epit-
ope,[ a cell-type specific oligosac-
charide. Disaccharides such as 6 have
been available by either multistep
8]
[
9]
chemical syntheses, with the inher-
ent need for protecting group manip-
[
10]
ulations, or by enzymatic methods.
Scheme 2. a) BnNH
2
, 408C, then AcOH/MeOH; b) H
2
,Pd(OH)
2 2 3
/C, MeOH; c) MeOH, Ac O, NaHCO ;
The best chemical syntheses, in terms
of yields of isolated product as well
as scale-up potential, start from lac-
d) tetrachlorophthaloyl anhydride, NEt
chloride, NaHCO , H O.
3
, MeOH, then Ac O, pyridine; e) (trichloroethyl)oxycarbonyl
2
3
2
different acylating reagents. For example, with tetrachloro-
[
*] Prof. Dr. A. E. Stütz, Dipl.-Ing. T. M. Wrodnigg
Institut für Organische Chemie der Technischen Universität
Stremayrgasse 16, A-8010 Graz (Austria)
Fax: (‡43)316-873-8740
[17]
phthaloyl anhydride
and N-(2,2,2-trichloroethyl)oxycar-
bonyl chloride[ the corresponding N-tetrachlorophthaloyl
18]
(TCP) and N-(2,2,2-trichloroethyl)oxycarbonyl (Teoc) pro-
E-mail: stuetz@orgc.tu-graz.ac.at
tected analogues of d-lactosamine, 7 and 8, were obtained,
[
**] This work was supported by the Austrian FWF (Project 10805 CHE)
demonstrating the versatility of the approach.
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Other O-glycosylated ketoses reacted accordingly. By
quenching at the point of maximum aldosamine content, the
formation of undesired side products, such as 1-aminodeoxy-
d-fructose derivatives could be reduced to a minimum. As in
the case of 4, unoptimized yields of O-glycosylated free d-
glucosamine derivatives obtained in the two-step approach
based on benzylamine ranged between 40 and 70%. Con-
sequently, N-acylated derivatives, for example, N-acetyl-6-O-
[1] K. Heyns, W. Koch, Z. Naturforsch. 1952, 7, 486 ± 488.
[
[
2] K. Heyns, K.-H. Meinecke, Chem. Ber. 1953, 86, 1453 ± 1462.
3] a) J. F. Carson, J. Am. Chem. Soc. 1955, 77, 1881 ± 1884; b) J. F. Carson,
J. Am. Chem. Soc. 1955, 77, 5957 ± 5959; c) J. F. Carson, J. Am. Chem.
Soc. 1956, 78, 3728 ± 3731.
[4] E. F. L. J. Anet, Aust. J. Chem. 1957, 10, 193 ± 197.
[
5] K. Heyns, H. Paulsen, R. Eichstedt, M. Rolle, Chem. Ber. 1957, 90,
039 ± 2049.
2
[6] K. Heyns, W. Beilfuû, Chem. Ber. 1973, 106, 2680 ± 2692; K. Heyns, W.
Beilfuû, Chem. Ber. 1973, 2693 ± 2709.
(
a-d-glucopyranosyl)-d-glucosamine (10) (40%) and N-ace-
[7] a) K. Heyns, H. Breuer, H. Paulsen, Chem. Ber. 1957, 90, 1374 ± 1386;
b) K. Heyns, H. Breuer, Chem. Ber. 1958, 91, 2750 ± 2762; c) K. Heyns,
M. Rolle, Chem. Ber. 1959, 92, 2439 ± 2450.
tylmaltosamine (12) (33%) could be prepared from isomal-
tulose (9) and maltulose (11), respectively, in satisfactory
overall yields.
[
[
8] M. Fukuda, Bioorg. Med. Chem. 1995, 3, 207 ± 215, zit. Lit.
9] a) H. Paulsen, Angew. Chem. 1990, 102, 851 ± 867; Angew. Chem. Int.
Ed. Engl. 1990, 29, 823 ± 839; b) K. Toshima, K. Tatsuta, Chem. Rev.
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Danishefsky, J. Am. Chem. Soc. 1998, 120, 1600 ± 1614.
Generally, yields are superior to those obtained with
unsubstituted d-fructose which can be rationalized by consid-
ering the destabilizing effects caused by unfavorable inter-
actions of the large glycosyl residues at O-4 with other polar
functional groups, particularly 5-OH, around the ketopyra-
nose ring. This clearly contributes considerably to the driving
force of the rearrangement reaction. The most telling example
in this context is the ring enlargement of the highly crowded
ketofuranose ring in isomaltulose (9) to the distinctly more
relaxed 2-aminodeoxyaldopyranose chair in compound 10.
[10] a) C.-H. Wong, R. L. Halcomb, Y. Ichikawa, T. Kajimoto, Angew.
Chem. 1995, 107, 569 ± 593; Angew. Chem. Int. Ed. Engl. 1995, 34,
5
21 ± 546, zit. Lit.; b) R. L. Halcomb in Enzyme Catalysis in Organic
Synthesis (Eds.: K. Drauz, H. Waldmann), VCH, Weinheim, 1995,
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[
11] a) R. Kuhn, W. Kirschenlohr, Liebigs Ann. Chem. 1956, 600, 135 ± 143;
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Experimental Section
[
12] a) K. Sakai, R. Katsumi, H. Ohi, T. Usui, Y. Ishido, J. Carbohydr.
Chem. 1992, 11, 553 ± 565; b) T. Usui, S. Kubota, H. Ohi, Carbohydr.
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F. C. A. Gaeta, J. C. Paulson, C.-H. Wong, Tetrahedron Lett. 1993, 34,
A mixture of the O-glycosyl-d-fructose (100 mmol) and benzylamine
(
3 4
700 mmol) was stirred at 408C until TLC (CHCl /MeOH/NH OH, 2:4:1)
indicated that the starting material was largely converted into a slightly less
polar main product. Conventional removal[2] of excess amine gave a crude
material which was dissolved in MeOH/glacial acetic acid (25:1) and the
3
091 ± 3094; d) S. Takayama, M. Shimazaki, L. Qiao, C.-H. Wong,
Bioorg. Med. Chem. Lett. 1996, 6, 1123 ± 1126; e) J. Fang, W. Xie, J. Li,
P. G. Wang, Tetrahedron Lett. 1998, 39, 919 ± 922.
mixture was kept for 12 h at 258C. Pd(OH)
the reaction mixture containing the 2-benzylaminodeoxyaldose was stirred
under an atmosphere of H at ambient pressure. After removal of the
catalyst by filtration, excess Ac O and solid NaHCO was added to the
2
/C (20%, 2 g) was added and
[13] T. Kimura, S. Takayama, H. Huang, C.-H. Wong, Angew. Chem. 1996,
08, 2503 ± 2505; Angew. Chem. Int. Ed. Engl. 1996, 35, 2348 ± 2350.
[14] G. F. Hermann, U. Kragl, C. Wandrey, Angew. Chem. 1993, 105, 1399 ±
400; Angew. Chem. Int. Ed. Engl. 1993, 32, 1342 ± 1343.
[15] a) C.-H. Wong, S. L. Haynie, G. M. Whitesides, J. Org. Chem. 1982, 47,
418 ± 5420; b) J. Thiem, T. Wiemann, Synthesis 1992, 141 ± 145; c) Y.
2
1
2
3
filtrate containing the free 2-aminodeoxy disaccharide. After 1 h, the
reaction mixture was concentrated under reduced pressure. N-Acylated
products were purified by filtration over a plug of silica gel (Merck 60) by
1
5
employing a mixture of CHCl
3 4
/MeOH/NH OH (8:4:1). Compound 6 was
Ichikawa, Y.-C. Lin, D. P. Dumas, G.-J. Shen, E. Garcia-Junceda,
M. A. Williams, R. Bayer, C.Ketcham, L. E. Walker, J. C. Paulson, C.-
H. Wong, J. Am. Chem. Soc. 1992, 114, 9283 ± 9298.
NMR spectroscopically identical with a commercial sample (Sigma, A
7
2
791). The NMR spectra (300 MHz) of compounds 10 and 12 in D O
[19]
matched previously reported data.
[
[
16] A. Zervosen, L. Elling, J. Am. Chem. Soc. 1996, 118, 1836 ± 1840.
17] J. S. Debenham, R. Madsen, C. Roberts, B. Fraser-Reid, J. Am. Chem.
Soc. 1995, 117, 3302 ± 3303; J. C. Castro-Palomino, R. R. Schmidt,
Tetrahedron Lett. 1995, 36, 5343 ± 5346.
7
: Compound 7 was prepared from 5 ´ HCl following the established
[17] 13
procedure.
C NMR (50.9 MHz, CDCl
3
, 258C): d ˆ 162.4, 140.5, 129.8,
1
6
26.5 (TCP), 100.9 (C-1'), 90.3 (C-1), 76.5 (C-4), 71.1, 71.0, 70.8, 69.2, 67.2,
7.7 (C-3, C-5, C-2', C-3', C-4', C-5'), 60.8, 60.6 (C-6, C-6'), 53.5 (C-2),
[18] W. Dullenkopf, J. C. Castro-Palomino, L. Manzoni, R. R. Schmidt,
signals of N,O-acetyl groups were in the expected regions.
: To a 5% aqueous solution of intermediate 5 ´ HCl containing excess
sodium bicarbonate, 1.5 equivalents of (trichloroethyl)oxycarbonyl chlor-
Carbohydr. Res. 1995, 296, 135 ± 147.
8
[19] S. Koto, N. Morishima, M. Owa, S. Zen, Carbohydr. Res. 1984, 130,
73 ± 83.
[
18]
ide were added and the mixture was stirred at 228C until all starting
[18]
material had reacted. Conventional work-up and purification on silica
gel (CHCl /MeOH/NH
OH conc. 300:100:2) gave compound 8: [a] ˆ ‡18
c ˆ 2.7 in MeOH); C NMR (50.9 MHz, CD OD, 258C): d ˆ 157.0 (C ˆ
O), 105.1 (C-1'), 97.2 (CCl ), 92.6 (C-1), 81.2 (C-4), 77.2 (C-5'), 75.7 (CH ),
4.8 (C-3'), 72.7 (C-2'), 71.6, 71.3 (C-3, C-5), 70.4 (C-4'), 62.7 (C-6'), 61.9
C-6), 57.5 (C-2).
3
4
13
(
3
3
2
7
(
Received: June 30, 1998
Revised version: November 4, 1998 [Z12069IE]
German version: Angew. Chem. 1999, 111, 854 ± 856
Keywords: amino aldehydes ´ carbohydrates ´ lactosamines
´
lactuloses ´ rearrangements
8
28
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Angew. Chem. Int. Ed. 1999, 38, No. 6