Aldonic acids – acyclic derivatives of aldoses containing in their chain terminal position a carboxyl group instead of the carbonyl group. They can be obtained from any aldose by oxidation of its carbonyl group to carboxyl group. Their names are derived from the names of original aldoses by changing the suffix from -ose to -onic acid.

OHH

COOH

CH2OH

HO H

OHH

OHH

OHH

CH=O

CH2OH

HO H

OHH

OHH

[O]

D-glucose D-gluconic acid

Aldonic acids

CH2OH

OH

OH

HO

OH

COOH

OOH

OH

OH

O

OH

OOH

OH

HO

OH

OH

OO

OH

HO

OH

OH

D-glucose

D-gluconic acid

D-glucono-1,5-lactone D- glucono-1,4- lactone

Br2, H2O pH 4-6

Tollens reagent

[Ag(NH3)2]+

Why lactones preferentially exist in 5-membered rings

OH

COOH

OH

COOHO

O

OO

OO

OO

O+

O

O+

O

The reason

91 % 9 % 27 % 73 %

H2O

25 °C 25 °C

H2O

Lactones, due to their resonance structures, contain two sp2 atoms (carbon C-1 and oxygen ring atom), and thus, their pertinent four ring atoms are placed in a plane. Therefore the reason is that the five-membered rings much better suit such planar arrangements than the six-membered rings do.

Uronic acids (syn., glycuronic acids) – derivatives of aldoses containing in their chain terminal positions an aldehyde group and a carboxyl group. They can be derived from any aldose by changing its terminal hydroxymethyl group to carboxyl group. Similarly as aldoses, they normally exist in cyclic hemiacetal structures. Also similarly as aldonic acids, uronic acids simultaneously are also forming lactones and in aqueous solutions form with them equilibrium mixtures. According to the aldose, from which the uronic acid is derived, is also created its name; e. g., D-glucuronic acid is derived from D- glucose .

Uronic acids abundantly occur as constituents of plant, animal and microbial polysaccharides. Methods of their preparation are based on the oxidation of the primary hydroxyl group of aldoses, reduction of monolactones of aldaric acids (similar method to the reduction of aldonic acid lactones to aldoses).

O

OHOH

OHHO

OH

O

OHOH

OHHO

COOH

O

OHO

OHH

H

O

OHOOH

OH

HO

OH

OH

OOH

HO

OH

OH

COOH

D-glucose D-glucuronic acid D-glucurono-6,3-lactone

Aldaric acids – derivatives of aldoses, dicarboxylic acids formally derived from any aldose by oxidation of both terminal groups (aldehydic and primary alcoholic) to carboxylic groups. Their names are created from the names of original aldoses by changing their suffix –ose to –aric acid, e. g., D-glucaric acid from D-glucose. Because of the same functional groups at both ends of their carbon chains, similar rules are valid for their nomenclature as for alditols. Also total number of their stereoisomers is lower in comparison with that of aldoses.

They can be prepared from aldoses or aldonic acids by oxidation with nitric acid, or from uronic acids by oxidation with bromine water.

Similarly as aldonic acids or uronic acids, also aldaric acids form lactones, in some cases also dilactones (if stereochemical arrangement of their OH groups allows that).

O

OH

OH

OH

HO

OH

OH

OH

OH

HO

COOH

COOH

O

OHO

OHH

H

O

OHNO3 evaporation

D-glucose D-glucaric acid D-glucaro-1,4:6,3-dilactone

Saccharinic acids- derivatives of monosaccharides with unbranched or branched chain, containing a carboxylic group and having a hydroxyl group substituted with hydrogen atom. Thus, they can be considered deoxyaldonic acid. There are three isomeric types; saccharinic acids, isosaccharinic acids and metasaccharinic acids.

Saccharinic acids are built-up at a prolonged treatment of alkaline medium on monosaccharides (and reducing oligosaccharides) and are products of the benzil rearrangement of -dicarbonyl derivatives of sugars, which can be secondary products of the Lobry de Bruyn – Alberda van Ekenstein isomeization of aldoses or ketoses.

OH

OH

OH

H

OH

H

H

H

H

COOH

Metasaccharinic acid (3-deoxyaldonic acid)

S

N Na

O

OO

+-

Saccharin

OH

OH

OH

OH

H

H

H

H

HC

(MeO) HO

O

HO_

OH

OH

OH

OH

H

H

H

HC O

(MeO) HO

_

OH

OH

OH

OH

H

H

H

HC O

(MeO) HO

_

OH

OH

OH

OH

H

H

H

HC O

OH

OH

O

OH

H

H

H

C O

H

H

HO_

OH

OH

O

OH

H

H

H

H

C

H

OHO_

OH

OH

OH

OH

H

H

H

H

C

H

OHO

HO_

- HO (MeO )_

- HO_

H2O

_

D-glucose(3-O-methyl-D-glucose)

metasaccharinic acid

Saccharinic acids build-up

Substitution of the -hydroxyl group to the carbonyl group of aldose or ketose favours the saccharinic acid build-up, preceeding via -elimination from the enediolate form and providing -dicarbonyl intermediate necessary for the benzil rearrangement.

enediolate

benzil rearrangement

O

HO OH

HOAcNH

HO

OHCOOH

H

O

OH

OH

CH2OH

HO

CH3CONH OH

COOH

HOH2C

HO OH

HO NHAc

OH

C

O

COOHH2

CH2OH

OH

OH

HO

AcHN

OH

CH2

O

COOH

CH2OH

OH

OH

HO

AcHN

O

CH3

O

COOH

T

T A

Neuraminic acid (Sialic) (Neu5Ac)

Pyruvic acid

N-Acetyl-D-mannosamine

T = tautomeizationA = aldolization

= direction of the substituent orientation at cyclization

Neuraminic acid is aldolization product of pyruvicacid and N-acetyl-D-mannosamine

O

HO OH

HOAcNH

HO

OHCOOH

H

Neuraminic acid (Sialic acid) (Neu5Ac)

                                                  

                Zanamivir

5-(acetylamino)-4-[(aminoiminomethyl)amino]-2,6-

anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid

Active ingredient of Relenza,the first drug for treatment of

influenza based on the neuramidinase inhibition

OHO

OH

HOAcNH

HO

OHCOOH

Neuraminic acid (Sialic acid) (Neu5Ac)

Active ingredient of protichrípkového lieku Tamiflu,

another drug for treatment of influenza based on the

neuramidinase inhibition

Reduction of aldoses to alditols

CH2OH

OH

OH

HO

OH

O

CH2OH

OH

OH

HO

HO

OH

CH2OH

OH

OH

HO

O

OH

CH2OH

OH

OH

HO

OH

OHi ii

D-glucose D-glucitol (sorbitol) D-fructose D-mannitol

i = NaBH4/pH 8 or NaHg/EtOH or H2/Ni/pressure

Methods of elongation of the carbon chain of aldoses (Ascent of series)

• Kiliani-Fischer procedure - method of elongation of the carbon chain of aldoses. Base or acid catalyzed addition of cyanohydrin to an aldose aldózu provides a pair of epimeric nitriles of aldonic acids, which are converted by hydrolysis to one carbon elonged aldonic acids. These are converted by evaporation of aqueous solution to lactones, which are in mild acidic medium solution reduced with sodium amalgam or at low temperature with sodium borohydride to the correcponding aldoses.

Kiliani-Fischer procedure

CH=O

RHOCH

R

CN

HCOH

R

CN+

HCN

H3O

HOCH

R

COOH

HCOH

R

COOH+

+

OOH

OH

OH

O

OH

OOH

OH

OH

OH

OHNaBH4 O

OH

OH

HO

OH

OH

0 °C, pH 3

D-glucono-1,4-llactone D-glucofuranose D-glucopyranose

tautomerization

Methods of elongation of the carbon chain of aldoses (Ascent of series)

• Sowden procedure - method of elongation of the carbon chain of aldoses. Base catalyzed addition of nitromethane to an aldose affords nitronic salts of an epimeric pair 1-deoxy-1-nitroalditols, which can be transformed to one carbon elonged aldoses by treatment with a strong acid (usually sulfuric acid, Nef reaction).

• Two other modifications of the Sowden procedure, developed at the Institute of Chemistry, Slovak Academy of Sciences, Bratislava, are using either hydrogen peroxide/sodium molybdate treatment or ozone treatment of the nitronate salts, instead of their sulfuric acid treatment.

Sowden procedure

(or H2O2/Na2MoO4 or O3/H2O)H2SO4

RR

RR

CH

R CH3ONa

CH3NO2

CH=O

HCOH

CH=O

HOCH

CHNO2Na

HCOH

NO2Na

HOCHCH=O

+

+

Two other modifications of the Sowden procedure, developed at the Institute of Chemistry, Slovak Academy of Sciences, Bratislava, are using either hydrogen peroxide/sodium molybdate or ozone treatment, instead of sulfuric acid treatment of the nitronate salts.

Aldolization of sugars

Cyclic hemiketal forms of ketoses

_

OHH

O H

O

H

O H

O

O H

O

O H

O H

O H

O

O H

O H

O H

O H

O H

O

O H

O H

O H

O H

O

O H

O H

O H

O H

O

H

O H

O

O H

O H

H2O

Ba(OH)2

HO

(OH)3

(OH)2OH

OH

OH

OH

+

++

+

qvantitatively

D-fructose D-sorbose

D-psicose D-tagatose

Major products

Minor products

dihydroxyacetone

D-glyceraldehyde

Aldolization of trioses is not reverse reaction, as resulting ketoses are stabilized by cyclization to their hemiketal tautomeric forms.

Methods of contraction of the carbon chain of aldoses (Descent of series)

• Wohl degradation - method of contraction of the carbon chain of aldoses. Starting aldose is by treatment with hydroxylamine transformed to aldose oxime, which by treatment with acetic anhydride and sodium acetate undergoes simultaneous acetylation and dehydration affording aldononitrile peracetate. Following treatment with Ag2O in aqueous ammonia causes its deacetylation and simultaneous elimination of cyanohydrin affording one carbon shorter aldose. There are several modifications of the procedure, especially for the last step simplifications, e.g., by treatment with sodium methoxide in methanol.

• Substantially, this procedure is opposite to the Kiliani-Fischer procedure of elongation of the carbon chain of aldoses.

Wohl degradation

O

NH-OH

OH

(OH)3

(CHOH)

CH2OH

N-OH

OH

n

O

OH

OH

(OH)3

NH2OH

(CHOH)

CH2OH

O

OH

n

Ac2O

NaOAc (CHOAc)

CH2OAc

N

OAc

n

Ag2O

NH4OH (CHOH)

CH2OH

N

OH

n

(CHOH)

CH2OH

O

n (CHOH)

CH2OH

O

OH

n-1

B

- AgCN

- AcNH2

CH=O

RHOCH

R

CN

HCOH

R

CN

+HCN H3O

HOCH

R

COOH

HCOH

R

COOH+

+

OOH

OH

OH

O

OH

OOH

OH

OH

OH

OHNaBH4 O

OH

OH

HO

OH

OH

O

NH-OH

OH

(OH)3

(CHOH)

CH2OH

N-OH

OH

n

O

OH

OH

(OH)3

NH2OH

(CHOH)

CH2OH

O

OH

n

Ac2O

NaOAc (CHOAc)

CH2OAc

N

OAc

n

Ag2O

NH4OH (CHOH)

CH2OH

N

OH

n

(CHOH)

CH2OH

O

n (CHOH)

CH2OH

O

OH

n-1

B

- AgCN

- AcNH2

Reciprocity of the Kiliani-Fischer method of aldose carbon chain elongation and Wohl method of aldose carbon chain contraction

Methods of contraction of the carbon chain of aldoses (Descent of series)

• Ruff degradation - method of contraction of the carbon chain of aldoses. Soluble (usually calcium) salts of aldonic acids by treatment with hydrogen peroxide in presence of ferric ions undergo oxidative decarboxylation and produce a one carbon shorter aldose.

O C O

R

OHH

O C O

R

OH CO2

HC=O

R

HO

-H2O+

_ _

- Fe2+

Fe3+· ·

Fe2+ + H2O2 Fe3+ + HO + HO-·

R = aldose moiety or aldonic acid moiety

Methods of contraction of the carbon chain of aldoses (Descent of series)

• Weerman degradation - method of contraction of the carbon chain of aldoses. Aldonamide, derived from an aldonic acid, by treatment with alkaline hypochlorite or hypobromide undergoes the Hofmann degradation via isocaynate and decomposes to a one carbon shorter aldose. The new aldose, however, easily undergoes unwanted oxidation to aldonic acid at the conditions applied (with NaOBr or NaOCl).

O

C NH

H

R

HO

O

C N

H

R

HO

Br

C

N

R

HO

NH2

R

HOCH=O

R

O

NaOBr OH

- HBr

H2O

- CO2 - NH3

_

R = aldose moiety or aldonic acid moiety