Transcript Glycosyl amines

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
-----------------------------------------------------------------------------------------------------------------
OMe
O
OH
HO
HO
O
OH
HO
HO
OMe
(a)
OMe
HO
HO
O
HO
OH
OH
O
(b)
(e)
HOOMe
(d)
(d)
(a)
(c)
(b)
(e)
(d)
(c)
(e)
(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.
HO
HO
HO
HO
O
+
HO OMe
30 %
methyl α-D-xylopyranoside
O
methyl -D-xylopyranoside
MeOH
+
HO
OMe
HO
65 %
HO
HO
O
OH
D-xylose
(α,β-D-xylopyranose)
+
H+
HO
O
OH
+
HO
OMe
O
OH
OMe
OH
2%
methyl α-D-xylofuranoside
OH
3%
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 electronegative
substituent in position 2.
• 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.
O
O
X
X
OH
HO
HO
OH
O
HOOMe
66 %
methyl -D-glucopyranoside
HO
HO
O
OMe
HO
32,5 %
methyl -D-glucopyranoside
Anomeric effect
O
O
O
O
R
R
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.
..
O
..
O .
.
O
O
R
R
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 σ* orbital of the axial C-OR bond.
Mechanism of the Fischer glycosidation (I)
HO
+ H+
H
O
OH
OH
+
- H 2O
HO
+ H 2O
OH
+
O
OH
H
OH
- H+
D-xyl
- MeOH
+ MeOH
- MeOH
+ MeOH
- H+
+ H+
HO
OH
OH
OH
- H 2O
OMe
OH
HO
O
OH
OMe
+ H2O
OH
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.
Mechanism of the Fischer glycosidation (II)
HO
O
O
OH
OMe
OMe
OH
OH
OH
OH
+ H+ (b)
(a)
(b,d)
MeOH
- H+
(H+)
- MeOH (c)
HO
OH
OH
OMe
OMe
OH
HO
(d)
OH
OH
+
OMe
+ H+ (- MeOH)
OH
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.
Thermodynamic equilibria of the Fischer glycosidation of
D-glucose, D-mannose and D-galactose
OH
D-gluko
HO
HO
O
HO
HO
HOOMe
HO
D-mano
OH
OH
OMe
32,5 %
OH
OH
HO
HO
OMe
OH
HO
OH
O
OHHO
HO
OMe
5,3 %
HO
O
D-galakto
HO
58 %
OMe
0,7 %
0%
OH
O
OH
O
HO
HOOMe
O
OH HO
HO
OMe
94 %
OH
0,9 %
OH
OMe
HO
OH
0,6 %
O
HO
OMe
O
OH
HO
HO
66 %
O
HO
HO
O
OH
O
OH
OMe
HO
20 %
HO
OMe
OH
OH
6%
O
OH
HO
OH
OMe
OH
16 %
Internal glycosides (anhydrides of saccharides)
OH
O
H+
O
OH
O
H2O
(OH)3
(OH)3
D-Glc
D-Gal
D-Man
D-Tal
0,2 %
0,8 %
0,8 %
2,8 %
O
O
O
14 %
O
O
O
O
D-All
O
D-Gul
D-Alt
D-Ido
65 %
65 %
86 %
O
O
O
O
OH
O
O
O
O
O
O
HOTs
OH
HO
(OH)2
O
O
alebo
DMF
OH
(OH)3
(OH)2
D-Glc
D-Gal
D-Man
35 %
87 %
22 %
O
D-Tal
86 %
D-All
78 %
H+
H2O
D-Glc
0,2 %
D-Gal
0,8 %
D-Man
0,8 %
D-Tal
2,8 %
D-All
14 %
D-Gul
65 %
D-Alt
65 %
D-Ido
86 %
R = OH
Generation of the internal glycosides in water
(Reversion – generation of oligosaccharides in acidic aqueous solutions.)
HOTs
or
DMF
D-Glc
35 %
D-Gal
87 %
D-Man
22 %
D-Tal
86 %
D-All
78 %
Generation of the internal glycosides in aprotic solvents
Preparation of sugar dithioacetals
OH
OH
OH
SEt
HO
OH
OH
O
EtSH
OH
OH
OH
konc. HCl
HO
OH
SEt
SEt
HO
OH
D-xylose
HO
O
OH
SEt
OH
D-xylose diethyl dithioacetal
HgCl 2
CH=O
(
OAc )n
OAc
SO 2R
RSO 2
SR
RS
CdCO 3
(
H2O
O
OAc )n
(
Ac 2O
OAc
CH3COCH3
Py
[O]
RS
(
(
OH )n
OH
OH )n-1
OH
SR
OH )n
OH
H2
CH3
H
_
HO
CH=O
Ni
(
OH )n-1
OH
Sugar dithioacetals are being used for preparation of acyclic derivatives of sugars
OH
OH
1 % HCl/H2O, 20°C, 20 h
OH
OH OH
OH
OH
OH
SEt
SEt
HO
HO
O
OH
OH
OH
SEt
SEt
OH
1.
HgO, 5 h,
2.
2. EtOH, HgO, HgCl2
OH
OH
OEt
SEt
HO
OH
O
OH
OEt
OH OH
OH
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.
Relative reaction rates at 50 °C (for eight-membered ring = 1) for reaction
Br (CH2)n-2 COO
(CH2)n-2
C O + Br
O
n = Ring size
G. Illuminati, L. Mandolini, Acc. Chem. Res. 14, 95 (1981).
The Nef type glycosidation of 1-deoxy-1-nitroalditols
NO2
HO
OH
HO
1. NaOMe, MeOH
HO
OH
OH
O
2. HCl, MeOH, -30 °C
HO
OH
OMe
+
OH
OMe
HO
major (1,2-cis)
OH
O
HO
OH
minor (1,2-trans)
14%
76%
NaOMe
MeOH
+
- H , - NOH, - H2O
H
NO2Na
HO
+
H
HO
OH
OH
MeOH
OH H
HO
+ OH
N
OH
HO
HO
OH
H
OH
O
HO
HO
+
O Me
H OH
N
OH
OH
OH
M. Vojtech, M. Petrušová, B. Pribulová, L. Petruš, Tetrahedron Lett. 49 (2008) 3112–3116.
The Nef type glycosidation
of 1-deoxy-1-nitroalditols
at -30°C
M. Vojtech, M. Petrušová, B. Pribulová,
L. Petruš, Tetrahedron Lett. 49 (2008)
3112–3116.
_________________________________________________________________________
Nitrohexitol
cis-Furanoside
Yield (%)
trans-Furanoside
Yield (%)
_________________________________________________________________________
NO2
OH
OH
HO
O OMe
O OMe
HO
HO
OH
36
55
HO
OH
HO
OH
HO
OH
OH
NO2
OH
OH
OH
O OMe
O OMe
HO
HO
OH
11
78
HO
OH
HO
OH
HO
OH
OH
NO2
OH
OH
OH
O OMe
O OMe
HO
HO
HO
36
OH
54
OH
H
O
OH
HO
OH
OH
NO2
OH
OH
HO
O OMe
O OMe
HO
HO
HO
76
14
OH
OH
H
O
OH
HO
OH
OH
NO2
OH
OH
OH
O OMe
O OMe
HO
HO
HO
65
25
HO
OH
H
O
OH
HO
OH
OH
NO2
OH
OH
HO
O OMe
O OMe
HO
HO
HO
74
16
HO
HO
OH
OH
NO2
HO
HO
OH
OH
OH
OH
O OMe
OH
67
24
OH
OH
HO
OH
HO
OH
OH
NO2
OH
OH
OH
O OMe
O OMe
HO
H
O
OH
83
8
OH
OH
HO
OH
HO
OH
OH
_________________________________________________________________________
HO
O
OMe
HO
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.
Amadori reaction
anion of a weak acid
(strong_ base)
B
n
Glycosyl amine
_
_
_
B
_
n
n
n
1-amino-1-deoxy2-ketose
• Amadori reaction - base-catalyzed isomerization of the
aldose-derived glycosyl amines to 1-amino-1-deoxy-2ketoses. The reaction is similar to Lobry de BruynAlberda 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-ketosederived glycosyl amines to 2-amino-2-deoxy-aldoses is
called as the Heyns reaction.
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 1,3,5triazine 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.[3][4]
NH2
Melamine combines with cyanuric acid
to form melamine cyanurate, which has
N
N
been implicated in the Chinese protein
export contaminations.
http://en.wikipedia.org/wiki/Image:Melamine.svg
H2N
N
NH2
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.
Glycosyl amines of nucleic acids
RNA nucleosides:
HO
N
O
HO
N
O
OH
HO
OH
HO
O
N
N
N
HO
N
NH 2
NH 2
O
N
NH
N
HO
OH
Guanosine
O
O
N
N
O
HO
NH 2
Adenosine
HO
O
OH
Cytidine
NH
Uridine
DNA nucleosides:
HO
N
O
HO
N
NH 2
N
N
HO
O
N
HO
HO
O
N
O
NH
N
HO
NH 2
N
HO
O
O
N
O
HO
N
NH
O
NH 2
Deoxyadenosine
Deoxyguanosine
Deoxycytidine
Deoxythymidine
D-mannose
N-phenyl-β-D-mannopyranosylamine
(crystalline compound)
The above conversion (and the fact that the analogous N-phenyl-β-D-glucopyranosylamine does not easily crystallize) is being utilized for isolation of Dmannose from the equilibrium mixture of D-glucose and D-mannose (73:27)
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 (~ 1:2)
OH
OH
O
MeOH
O
H
OH
+
OMe
OH
OH
OH
D-glucopyranose
methyl-α-D-glucopyranoside
OH
OH
OH
O
O
O
OH
Me
OH
OH
OH
OH
methyl-
-α-D-glucopyranoside
OH
O
OH
O
OH
OH
other products
+
OH
OH
OH
-glycoside (the name includes the anomeric
oxygen atom) (≡ glycosyloxy)
glycosyl-
glycosides (in general) (not O-glycosides !!!)
OH
O NHPh
O
OH
OH
S-ethyl-α-D-thioglucopyranoside
(thioglycosides)
(not S-glycosides !!!)
O
OH
OH
SEt
OH
OH
OH
OH
OH
OH
N-phenyl-β-D-glucopyranosylamine
(glycosyl amines)
(not N-glycosides !!!)
OH
2-(β-D-glucopyranosyl)naphtalene
(C-glycosyl compounds)
(not C-glycosides !!!)
• Thioglycosides
(not S-glycosides !!!)
• Glycosyl amines
(not N-glycosides !!!)
• C-Glycosyl compounds
(not C-glycosides !!!)
• Glycosides
(not O-glycosides !!!)