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Fischer glycosidation
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 3D-lyxose 89 10 1 0 D-glucose 66 32,5 0,6 0,9 D-mannose 94 5.3 0,7 0D-galactose 58 20 6 16 -----------------------------------------------------------------------------------------------------------------
• 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.
(b), (c)
(a)
(d)
(e)
The time dependence of glycosidation of D-xylose (c) in 0,5 % HCl in methanol at 25 °C
OOH
OH
OHOMe O
OH
OH
OH
OMe
OHO
HO
HOOMe
OHO
HO
HO
OMe
O H
O
OH
OH
OH
AND Enantiomer(a) (b) (e) (d)
(c)
Source: Monosaccharides. Their Chemistry and Their Roles in Natural Products, P.M. Collins, R.J. Ferrier, Wiley, Chichester, 1995.
(a)
(b)
(c)
(e)(d)
O
HO
HO
HO
OMe
OOH
OH
OHOMeO
OH
OH
OH
OMe
OHO
HO
HOOMe
OHO
HO
HO OH
+
+
+
+
2 % 3 %
65 % 30 %
methyl α-D-xylopyranoside methyl -D-xylopyranoside
methyl α-D-xylofuranoside methyl -D-xylofuranoside
MeOH
H+
D-xylose
(α,β-D-xylopyranose)
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.
• 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.
OHO
HO
HOOMe
OH
66 % 32,5 %
OHO
HO
HOOMe
OH
O
X
O
X
methyl -D-glucopyranoside methyl -D-glucopyranoside
Anomeric effect
O
O R
OO R
OO R
O
O 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.
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.
OOH
OH
OH
OMe
OOH
OH
OH
HO
OH
OH
OH
OH
H
OHOH
OH
OH
OMe
OH
+
- H2O
+ H2O
+ H2O
- H2O
+ H+
+ H+
- H+
- H++ MeOH
- MeOH
- MeOH + MeOHD-xyl
+
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.
O
OH
OH
OH
OMe
OHOH
OH
OH
OMe
OMe
O
OH
OH
OH
OMe
OHOH
OH
OH
OMe+
+ H+ (- MeOH)
- H+
- MeOH (c)
+ H+ (b)
(d)
(b,d)MeOH
(H+)
(a)
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.
O
OH
OH
OMeOH
HOOOH
OHOMe
OH
HOOHO
HO
HOOMe
OH
0,6 % 0,9 %66 % 32,5 %
OHO
HO
HOOMe
OH
D-gluko
OOH
OHOMe
OH
HO
OHO
HO
HOOMe
OH
6 % 16 %58 %
OHO
HO
HOOMe
OH
D-galaktoO
OH
OH
OMe
OH
HO
20 %
OOHHO
OMe
OH
HOO
HO
HO HO
OMe
OH
0,7 % 0 %94 % 5,3 %
D-mano
O
HO
HO HOOMe
OH
OOHHO
OMeOH
HO
Thermodynamic equilibria of the Fischer glycosidation of
D-glucose, D-mannose and D-galactose
O
OH
OH
O
O
(OH)3 (OH)3
H+
H2O
O
OH
OH
(OH)3
OOH
OO
OH
O
HOTs
DMFalebo
(OH)2
(OH)2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
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 %
Internal glycosides (anhydrides of saccharides)
R = OH
H+
H2O
RR
R
O
O
RRR
O
OR
R R
O
O
R R R
O
OR
R
R
O
O
R
R
R
O
OR
R
R
O
O
R
R
R
O
O
(OH)3(OH)3
O
OOH
OH
O
D-Glc D-Gal D-Man D-Tal D-All D-Gul D-Alt D-Ido0,2 % 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.)
HOTs
DMF or
(OH)3
(OH)3
O
O H
O
OOH
O
(OH)3
O
OH
O H
D-Glc D-Gal D-Man D-Tal D-All 35 % 87 % 22 % 86 % 78 %
Generation of the internal glycosides in aprotic solvents
O
OH
HO
OH
OH
OH OH
HO
OH
OH
SEt
OOH
OH
OH
SEt
OH SEt
HO
OH
OH
SEt
EtSH
konc. HCl
D-xylose
D-xylose diethyl dithioacetal
Preparation of sugar dithioacetals
RS SR
OH
OH
RSO2 SO2R
O
OH
OH
H
CH=O
OH
OH
RS SR
OAc
OAc
CH=O
OAc
OAc
CH3
OH
OH
HO_
HgCl2
CdCO3
H2O
CH3COCH3Ac2O
Py[O]
H2
Ni
( )n ( )n
( )n
( )n
( )n-1
( )n-1
Sugar dithioacetals are being used for preparation of acyclic derivatives of sugars
OH SEtHOOH
OH
SEt
OH
OH OH
HO
OH
OH
SEt
O
OH
OH
OH
SEt
OH
O
OH
OH
OH
OH
OEtOH
HO
OH
OH
SEt
OEt
1 % HCl/H2O, 20°C, 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.
Relative reaction rates at 50 °C (for eight-membered ring = 1) for reaction
Br (CH2)n-2 (CH2)n-2
O
C OCOO-
n = Ring size
+ Br-
G. Illuminati, L. Mandolini, Acc. Chem. Res. 14, 95 (1981).
OH
OH
OH
OH
NOH
OH
OH
H +
OH
OH
OH
OH
OH
NO2
NO2Na
OH
OH
OH
OH
OH
O
OH
OH OH
OMeOH O
OH
OH OH
OMeOH+
- H , - NOH, - H2O
+
major (1,2-cis) minor (1,2-trans)
NaOMeMeOH
H+
+
MeOH
ONH
OH
OH OH
H
OHOH
OH
O
H
Me
1. NaOMe, MeOH
2. HCl, MeOH, -30 °C
76% 14%
The Nef type glycosidation of 1-deoxy-1-nitroalditols
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.
OHOHOHOH
NO2NO2OH
OOH
OH OH
OMeOH OOH
OH OH
OMeOH OMe
OHOH
OHOHOH
NO2
OOH
OH OH
OMeOH OOH
OH OH
OMeOH
OH
OHOH
NO2NO2
OH
OH OOH
OH OH
OMeOH OMe
OHOH
OHOH
NO2
OH
OOH
OH OH
OMeOH OOH
OH OH
OMeOH
OOH
OH OH
OH OMe
54 36
76 14
65 25
74 16
_________________________________________________________________________ Nitrohexitol cis-Furanoside Yield (%) trans-Furanoside Yield (%)_________________________________________________________________________
_________________________________________________________________________
OH
OHOHOH
NO2
OH OOH
OH OH
OMeOH OOH
OH OH
OMeOH67 24
OH
OHOH
NO2
OHOH O
OH
OH OH
OMeOH OOH
OH OH
OMeOH55 36
OHOHOH
NO2
OHOH O
OH
OH OH
OMeOH OOH
OH OH
OMeOH83 8
OHOH
NO2NO2OHOH
OH
OOH
OH OH
OH OMe OOH
OH OH
OH OMe78 11
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
n
B_
nB_
n
_
_
_ n- B
BH O
CH2-NHR
(CHOH)
CH2OH
O H
NR
(CHOH)
CH2OH
O HH
(CHOH)
CH2OH
N-R
O H
(CHOH)
CH2OH
N-R
(OH)3
O
O H
NH-R
anion of a weak acid (strong base)
Glycosyl amine
1-amino-1-deoxy- 2-ketose
• 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.
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.[3][4]
Melamine combines with cyanuric acid to form melamine cyanurate, which has been implicated in the Chinese protein export contaminations. http://en.wikipedia.org/wiki/Image:Melamine.svg
N
N
N
NH2
NH2 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
NO
N
N
OHHON
NH2
HO
Adenosine
N
N
NO
NH
O
NH2
OHHO
HO
Guanosine
HO
OHO
NNH
O
O
Deoxythymidine
Cytidine
HO
OHO
NNH
OHO
O
Uridine
NO
OH
N
OHO
HO NH2
NO
N
N
HON
NH2
HO
Deoxyadenosine
N
N
NO
NH
O
NH2
HO
HO
Deoxyguanosine Deoxycytidine
NON
OHO
HO NH2
RNA nucleosides:
DNA nucleosides:
MeOH, water
Ph-NH2 O
O H
OH
NH
O H
O H
O
O H
O H
O H
O HHO
D-mannose N-phenyl-β-D-mannopyranosylamine
(crystalline compound)
The above conversion (and the fact that the analogous N-phenyl-β-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 (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)
O
OH
OH
OH
OH
OH
MeOH
H+
O
OH
OH
OH
OH
OMe
+
O
OH
OH
OH
OH
O Me
O
OH
OH
OH
OH
O
O
OH
OH
OH
OH
SEt
O
OH
OH
OH
OH
NHPh
O
OH
OH
OH
OH
O
OH
OH
OH
OH
other products
methyl-α-D-glucopyranoside
-α-D-glucopyranoside
methyl-
-glycoside (the name includes the anomeric oxygen atom) (≡ glycosyloxy)
glycosides (in general) (not O-glycosides !!!)
glycosyl-
S-ethyl-α-D-thioglucopyranoside (thioglycosides)
(not S-glycosides !!!)
N-phenyl-β-D-glucopyranosylamine (glycosyl amines)
(not N-glycosides !!!)
2-(β-D-glucopyranosyl)naphtalene (C-glycosyl compounds)
(not C-glycosides !!!)
D-glucopyranose
• Thioglycosides (not S-glycosides !!!)
• Glycosyl amines (not N-glycosides !!!)
• C-Glycosyl compounds (not C-glycosides !!!)
• Glycosides (not O-glycosides !!!)
