Fischer%20glycosidation

1
Fischer glycosidation

• The method of preparation of glycosides from
  free aldoses or ketoses and aliphatic
  alcohols in the presence of anhydrous acids,
  usually hydrogen chloride.
• In the course of the reaction a decrease in
  concentration of the starting aldose or
  ketose (in general, glycose) is accompanied by a
  rapid, but transient, build-up of furanosides
  which then isomerize slowly to pyranosides until
  equilibrium is attained.
• The proportions of various glycosidic forms
  present in the equilibrium mixtures at the
  completion of Fischer glycosidation depend upon
  the relative thermodynamic stabilities of the
  isomers.

• The percentage composition of methyl glycoside
  mixtures at equilibrium in methanol at 35º C
• --------------------------------------------------
  --------------------------------------------------
  ------------
• Aldose ?-pyranoside ?-pyranoside
  ?-furanoside ?-furanoside
• --------------------------------------------------
  --------------------------------------------------
  ------------
• D-arabinose 24 47
  22 7
• D-ribose 12
  66 5 17
• D-xylose 65
  30 2
  3
• D-lyxose 89
  10 1
  0
• D-glucose 66
  32,5 0,6
  0,9
• D-mannose 94 5.3
  0,7 0
• D-galactose 58 20
  6 16
  
• --------------------------------------------------
  --------------------------------------------------
  -------------

2

(a)
(b)
(e)
(d)
(d)
(a)
(c)
(b)
(e)
(d)
(e)
(c)
(a)
(b), (c)
?
The time dependence of glycosidation of D-xylose
(c) in 0,5 HCl in methanol at 25 C
Source Monosaccharides. Their Chemistry and
Their Roles in Natural Products, P.M. Collins,
R.J. Ferrier, Wiley, Chichester, 1995.
3

methyl a-D-xylopyranoside
methyl ?-D-xylopyranoside
MeOH
H
D-xylose (a,ß-D-xylopyranose)
methyl a-D-xylofuranoside
methyl ?-D-xylofuranoside
Equilibrium mixture of methyl D-xylosides
originating from the Fischer glycosidation of
D-xylose in methanolic solution of hydrogen
chloride at 35º C. Methyl D-xylopyranoside is
the major product, due to the anomeric effect,
which is characteristic for the tetrahydropyran
rings with an electronegativesubstituent in
position 2.
4

• Anomeric effect a decrease of the stability of
  the equatorial anomer, due to the interaction of
  its electronegative substituent X with free
  electron pairs of the pyranose oxygen atom, which
  causes the relative increase of the stability of
  the axial anomer. This effect, for the first time
  observed in saccharides, is a general phenomenon
  of both cyclic and acyclic molecules containing
  1,3-grouping of heteroatoms.

methyl ?-D-glucopyranoside
methyl ?-D-glucopyranoside
5
Anomeric effect
The simplest explanation of the effect is, that
the equatorial position of the anomeric
substituent has the dipoles of both heteroatoms
partly parallel and thus repulsing. On the other
side, its axial position has these dipoles
approximately antiparallel, so that is
representing a more stable and energetically less
demanding structure.
An alternative and more accepted explanation is
that the axial position is stabilized by the
conjugation between the axial free electron pair
of the pyranose oxygen atom and the s orbital
of the axial C-OR bond.
6

Mechanism of the Fischer glycosidation (I)
Bolded route of transformation is more probable.
Source Monosaccharides. Their Chemistry and
Their Roles in Natural Products, P.M. Collins,
R.J. Ferrier, Wiley, Chichester, 1995.
7

Mechanism of the Fischer glycosidation (II)
Bolded route of transformation is more probable.
Source Monosaccharides. Their Chemistry and
Their Roles in Natural Products, P.M. Collins,
R.J. Ferrier, Wiley, Chichester, 1995.
8

Thermodynamic equilibria of the Fischer
glycosidation of D-glucose,
D-mannose and D-galactose
9

Internal glycosides (anhydrides of saccharides)
D-Glc D-Gal D-Man D-Tal D-All
D-Gul D-Alt D-Ido 0,2 0,8
0,8 2,8 14 65
65 86
D-Glc D-Gal D-Man
D-Tal D-All 35
87 22
86 78
10

D-Glc D-Gal D-Man D-Tal D-All
D-Gul D-Alt D-Ido 0,2 0,8
0,8 2,8 14 65
65 86
Generation of the
internal glycosides in water (Reversion
generation of oligosaccharides in acidic
aqueous solutions.)
11

D-Glc D-Gal D-Man
D-Tal D-All 35
87 22
86 78
Generation of the internal glycosides in aprotic
solvents
12

Preparation of sugar dithioacetals
D-xylose
D-xylose diethyl dithioacetal
13

( )n
( )n
( )n-1
( )n
( )n
( )n-1
Sugar dithioacetals are being used for
preparation of acyclic derivatives of sugars
14

1 HCl/H2O, 20C, 20 h

1. HgO, 5 h,
2. 2. EtOH, HgO, HgCl2

Acyclic dithioacetals can also be used for
preparation of foranoid derivatives of sugars.
There is being applied the knowledge that the
closure of the five membered rings is more rapid
than that the closure of the six membered rings.
15
Relative reaction rates at 50 C (for
eight-membered ring 1) for reaction
G. Illuminati, L. Mandolini, Acc. Chem. Res. 14,
95 (1981).
16
The Nef type glycosidation of 1-deoxy-1-nitroaldit
ols
M. Vojtech, M. Petrušová, B. Pribulová, L.
Petruš, Tetrahedron Lett. 49 (2008) 31123116.
17
The Nef type glycosidation of 1-deoxy-1-nitroaldit
ols at -30C
M. Vojtech, M. Petrušová, B. Pribulová, L.
Petruš, Tetrahedron Lett. 49 (2008) 31123116.
18
Glycosyl amines

• Derivatives of sugars in which the glycosyl
  moiety is linked to a primary, secondary or a
  tertiary amino group. If two glycosyl moieties
  are linked to a secondary amino group, the
  derivatives are named as bisglycosyl amines.
• According to the non-saccharidic nature of the
  amino group, they are devided into unsubstituted,
  aliphatic and aromatic glycosyl amines.
• Aromatic glycosyl amines are much more stable
  than aliphatic ones. Similarly as free aldoses or
  ketoses (glycoses), they undergo mutarotation. A
  treatment with mineral acids causes their
  decomposition to glycose and amine or ammonia. A
  characteristic reaction of glycosyl amines is the
  Amadori reaction for which the best catalysts are
  strongly basic anions of weak acids.

19
Amadori reaction
anion of a weak acid (strong base)
Glycosyl amine
1-amino-1-deoxy- 2-ketose
20

• Amadori reaction - base-catalyzed isomerization
  of the aldose-derived glycosyl amines to
  1-amino-1-deoxy-2-ketoses. The reaction is
  similar to Lobry de Bruyn-Alberda van Ekenstein
  reaction of aldoses.
• The reaction stays at the beginning of the origin
  of Maillard melanoids, brown polymers produced by
  subsequent reactions of the products of the
  Amadori reaction, carbonyl compounds and amino
  acids. Thus the Maillard reactions also are
  responsible for the formation of brown products
  (melanoids) when foods containing carbohydrates
  and proteins are processed under heating
  http//brewery.org/library/Maillard_CS0497.html
• Similar base-catalyzed isomerization of the
  2-ketose-derived glycosyl amines to
  2-amino-2-deoxy-aldoses is called as the Heyns
  reaction.

21
Melanin is a class of compounds found in the
plant, animal, and protista kingdoms, where it
serves predominantly as a pigment. The class of
pigments are derivatives of the amino acid
tyrosine. The increased production of melanin in
human skin is called melanogenesis. It is
stimulated by the DNA damages that are caused by
UVB-radiation,1 and it leads to a delayed
development of a tan. This melanogenesis-based
tan takes more time to develop, but it is long
lasting.2 http//en.wikipedia.org/wiki/Melanin
Melamine is an organic base and a trimer of
cyanamide, with a 1,3,5-triazine skeleton. Like
cyanamide, it contains 66 nitrogen by mass and,
if mixed with resins, has fire retardant
properties due to its release of nitrogen gas
when burned or charred, and has several other
industrial uses. Melamine is also a metabolite of
cyromazine, a pesticide. It is formed in the body
of mammals who have ingested cyromazine.2 It
has been reported that cyromazine can also be
converted to melamine in plants.34
Melamine combines with cyanuric acid to form
melamine cyanurate, which has been implicated in
the Chinese protein export contaminations.
http//en.wikipedia.org/wiki/ImageMelamine.svg
22
Glycosyl amines (2)

• Many glycosyl amines occur in Nature and play
  important roles in living matter. The most
  important are glycosyl amines derived from
  D-ribose or 2-deoxy-D-ribose and purine or
  pyrimidine beses (nucleosides), isolated from the
  hydrolyzates of nucleic acids. Another important
  group of glycosyl amines mediates the linkage
  between sugars and proteins in glycoproteins.
• Glycosyl amines can be obtained directly from
  amines with glycoses. Their more advantageous
  methods of preparation start from glycosyl
  halogenides or otherwise activated glycoses
  either directly by treatment with amine or
  through glycosyl azide followed by its reduction.
  
• In synthetic applications, they are being used
  for preparation of amino saccharides and
  glycamines (aminodeoxyalditols). Good
  crystallizing N-(4-nitrophenyl)glycosyl-amines
  are being used for characterization of sugars.

23
Glycosyl amines of nucleic acids
RNA nucleosides
DNA nucleosides
24

D-mannose
N-phenyl-ß-D-mannopyranosylamine
(crystalline compound)
The above conversion (and the fact that the
analogous N-phenyl-ß-D-gluco-pyranosylamine does
not easily crystallize) is being utilized for
isolation of D-mannose from the equilibrium
mixture of D-glucose and D-mannose (7327) built
up by the Bílik reaction. D- or L-ribose is
being isolated similarly from its equilibrium
mixture with the respective D- or L-arabinose (
12)
25

other products
D-glucopyranose
methyl-a-D-glucopyranoside
methyl-
-glycoside (the name includes the anomeric
oxygen atom) ( glycosyloxy)
glycosides (in general) (not O-glycosides !!!)
-a-D-glucopyranoside
glycosyl-
S-ethyl-a-D-thioglucopyranoside
(thioglycosides) (not S-glycosides !!!)
N-phenyl-ß-D-glucopyranosylamine
(glycosyl amines) (not N-glycosides !!!)
2-(ß-D-glucopyranosyl)naphtalene (C-glycosyl
compounds) (not C-glycosides !!!)
26

• Thioglycosides (not S-glycosides !!!)
• Glycosyl amines (not N-glycosides !!!)
• C-Glycosyl compounds (not C-glycosides !!!)
• Glycosides (not O-glycosides !!!)