EP4379068A1

EP4379068A1 - Iridoid or seco-iridoid derivatives and their use in a tanning process

Info

Publication number: EP4379068A1
Application number: EP22306770.3A
Authority: EP
Inventors: Loic FONTAINE; Thomas Lecourt; Alexandra Le Foll; Stéphane MARCOTTE
Original assignee: Centre National de la Recherche Scientifique CNRS; Hermes Sellier SAS; Institut National des Sciences Appliquees de Rouen; Universite de Rouen Normandie
Current assignee: Centre National de la Recherche Scientifique CNRS; Hermes Sellier SAS; Institut National des Sciences Appliquees de Rouen; Universite de Rouen Normandie
Priority date: 2022-12-01
Filing date: 2022-12-01
Publication date: 2024-06-05

Abstract

The present invention relates to the field of tanning. More particularly, the present invention relates to particular iridoid or seco-iridoid derivatives, and their use in a tanning process. It also relates to a process for cross-linking collagen using such derivatives.

Description

TECHNICAL FIELD

TECHNICAL BACKGROUND

Natural tannins have long been used in processes for tanning skin and stabilizing collagen. Tanning mixtures are mainly composed of polyphenolic tannins, which are divided into two classes: condensed tannins and hydrolysable tannins. The effectiveness of tanning is usually reflected by its ability to stabilize collagen, namely to limit collagen denaturation and impart good resistance to enzymatic hydrolysis. Collagen stabilization can be assessed by measuring the increase in shrinkage temperature, which is correlated to the collagen denaturation temperature. The polyphenolic tannins give rise to a shrinkage temperature around 75-85°C. Other parameters can also be considered for assessing the effectiveness of tanning, such as the mechanical resistance of the hide and its sensory parameters, such as hide filling and suppleness.
However, due to their astringency, natural polyphenolic tannins lead to a tension of the hide. In order to limit such tension, a pre-tanning step using a metal salt, such as aluminum, iron, zirconium, titanium, or chromium, or synthetic tannins, such as glutaraldehyde or oxazolidine, is required.
Recently, a new class of natural tanning or pre-tanning agents has been identified: iridoids and seco-iridoids. Among these compounds, genipin can be obtained from geniposide which is extracted from the fruit of Gardenia jasminoides or Genipa americana. Genipin allows to stabilize the collagen and to reach shrinkage temperatures of 80°C (Zhang et al., JALCA, 2011, 106, 121). Genipin has also been used in combination with an aluminum-based tanning (Ding et al., JALCA, 2008, 103, 377), which resulted in a soft and full leather having a shrinkage temperature of 92°C. Genipin has also been used to cross-link gelatin (Taylor et al., JALCA, 2009, 104, 79). Genipin is readily available in large quantities due to its use as a food coloring agent.
Other natural iridoids have been used in processes for tanning or pre-tanning hides. In particular, WO2009/065915 describes a tanning method using aglycone derivatives of iridoids and seco-iridoids, different from genipin. Such derivatives can be extracted from olive leaves and are hydrolyzed to give aglycone forms of oleuropein. The mixture obtained by extraction of the leaves in the presence of endogenous enzyme or by the use of acid is not purified and also comprises polyphenolic compounds and compounds derived from hydrolyzed oleuropein, such as (4E)-4-formyl-3-(-1-formyl-2-methoxy-2-oxoethyl)hex-4-enoic acid.
However, such methods use the aglycone form of iridoids or seco-iridoids, which are highly reactive. This high reactivity can cause several limitations, in particular with regard to the stability, storability, and toxicity. Protected forms of such iridoids or seco-iridoids, in particular glycoside forms, are usually more stable and less toxic, however they are not active in tanning and cannot be easily activated under mild conditions compatible with tanning. In particular, glycosides can only be activated by means of enzymatic hydrolysis, which is expensive, not always reproducible, and not convenient for large-scale processes.
Therefore, there remains a need to provide efficient pre-tanning or tanning agents that are more stable, have a lower toxicity, and can be activated under mild conditions which can be easily used in tanning processes.

SUMMARY OF THE INVENTION

In this respect, the inventors have demonstrated that the above limitations could be overcome by protecting the dihydropyranyloxy moiety of iridoid or seco-iridoid compounds with a particular acyclic acetal group. These protected iridoid or seco-iridoid derivatives can advantageously be obtained starting from the corresponding glycoside forms, by successively subjecting the latter to an oxidation and a reduction. This acetal protecting group can be easily removed before and/or during a tanning process, typically using acidic conditions, thereby releasing the active aglycone form.
Hence, the present invention relates to the use of a compound of formula (I), in a tanning process:
wherein:

X is a moiety of an iridoid, a seco-iridoid or a derivative thereof, and
each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-aryl, or -C(O)-(C₁-C₁₂ aliphatic group),

In a particular embodiment, X is a moiety of aucubin, catalpol, harpagide, ajugol, geniposide, loganin, loganic acid, antirrhinoside, linarioside, feretoside, geniposidic acid, gardenoside, apodanthoside, desacetylasperulosidic acid, scandoside, methoxycinnamoyl scandoside methyl ester, demethyloleuropein, ligustroside, ligustrosidic acid, ligustaloside A, ligustaloside B, nuzhenide, secologanin, secoxyloganin, oleuropein (or equivalently "oleuropeoside"), hydroxyframoside A, hydroxyframoside B, sweroside, swertiamarin, gentiopicroside, amarogentin, or morroniside, preferably geniposide or gentiopicroside.
In a particular embodiment, said compound of formula (I) is a compound of formula (1-2):
wherein:

each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-aryl, or -C(O)-(C₁-C₁₂ aliphatic group),
R₁₀ is a hydrogen, -C(O)OH, or -C(O)-O-(C₁-C₁₂ aliphatic group),
R₁₁ is a C₂-C₁₂ aliphatic group, -CH₂-C(O)H, -CH₂-C(O)OH, or -CH₂-C(O)-O-(C₁-C₁₂ aliphatic group),
R₁₁' is a hydrogen or -OH,
R₁₂ is -CH₂-C(O)H, a C₂-C₁₂ aliphatic group, -C(O)-CH₂-R₅, or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, a C₁-C₁₂ aliphatic group, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),
R₁₂' is a hydrogen or -OH,

₁₁

₁₂

₁₃

₁₄

₁₅

₁₆

₁₇

₁₈

₁₉

₂₀

₂₁

₂₂

₂₃

₂₄

₂₅

₂₆

₁

₁₂

₁

₁₂

₁

₁₂

₁

₁₂

₂

₉

₁

₁₂

or R₁₄ and R₁₅ form together a -O- group,
or R₁₀ and R₁₁ form together a chain of formula (II-6):
or R₁₂ and R₁₂' form together a group of formula R₂₇-CH=, where R₂₇ is a C₁-C₁₂ aliphatic group, -C(O)OH, or -C(O)O-(C₁-C₁₂ aliphatic group),
said aliphatic groups being each independently optionally substituted by one or more hydroxy, aryl or glycosyl derivative, said aryl being optionally substituted by one or more hydroxy or (C₁-C₆)alkoxy,
or a salt thereof.

In a more particular embodiment, said compound is represented by the following formula (I-1):
wherein:

each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-aryl, or -C(O)-(C₁-C₁₂ aliphatic group),
R₂ is a hydrogen atom or a (C₁-C₁₂) aliphatic group,
R₃ is -CH₂-C(O)H or -CH₂-CH₂-OH,
R₄ is -C(O)-CH₂-R₅ or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, a C₁-C₁₂ aliphatic group, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),

or R₃ and R₄ form together the following chain of formula (II):
wherein R₆, R₇, and R₈ are each independently a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group), and R₉ is a hydrogen atom or -CH₂-R₉', where R₉' is a hydrogen atom, -OH,
or -O-C(O)-(C₁-C₁₂ aliphatic group),
or a salt thereof.

In some embodiments, R₂ is a C₁-C₁₂ aliphatic group, preferably a C₁-C₆ alkyl.
In some embodiments, R₄ is -C(O)-CH₂-R₅ or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group), preferably a hydrogen atom, -OH or -O-C(O)-(C₁-C₆ alkyl).
In some embodiments, R₃ and R₄ form together a chain of formula (II) as defined herein wherein:

R₆ is hydrogen; and/or
R₇ is -OH or -O-C(O)-(C₁-C₁₂ aliphatic group), preferably -OH or -O-C(O)-(C₁-C₆ alkyl); and/or
R₈ is -OH; and/or
R₉ is a hydrogen atom or -CH₂-R₉', where R₉' is a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl).

In a particular embodiment, each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-phenyl, or -C(O)-(C₁-C₆ alkyl), preferably a hydrogen or -C(O)-CH₃, more preferably a hydrogen.
In a particular embodiment, a use according to the invention is a use for tanning a hide or a skin.
In another particular embodiment, a use according to the invention is a use in a method for manufacturing a leather or a leather substitute.
In a further particular embodiment, a use according to the invention is a use for tanning a collagen-containing material.
The present invention also relates to a compound as defined herein per se, with the proviso that said compound is not one of the following compounds:
Another object of the present invention is a process for cross-linking collagen in a material comprising a step of contacting said material with a compound as defined herein. Said material may in particular be a hide or a skin.

FIGURES

Figures 1, 2, 3 and 4: Images of materials obtained after tanning of a collagen powder using compounds of the invention under various tanning conditions.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The expression "C_x-C_y" in which x and y are integers, as used in the present disclosure, means that the corresponding chemical group comprises from x to y carbon atoms. If, for example, the expression C₁-C₆ is used, it means that the corresponding chemical group may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5 or 6 carbon atoms. If, for example, the expression C₂-C₅ is used, it means that the corresponding chemical group may comprise from 2 to 5 carbon atoms, especially 2, 3, 4, or 5 carbon atoms.
The term "aliphatic" refers to a saturated or unsaturated, cyclic or acyclic (preferably acyclic), linear or branched hydrocarbon chain. The expression "C₁-C₁₂ aliphatic" refers to an aliphatic having 1 to 12 carbon atoms. In particular, the aliphatic may be an alkyl, an alkenyl, or an alkynyl.
The term "alkyl" refers to a saturated, linear or branched hydrocarbon chain. The expression "C₁-C₆ alkyl" refers to an alkyl having 1 to 6 carbon atoms. Examples of alkyl (or C₁-C₆ alkyl) include, for instance, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.
The term "alkenyl" refers to an unsaturated, linear or branched hydrocarbon chain, having at least one carbon-carbon double bond. The expression "C₂-C₆ alkenyl" refers to an alkenyl having 2 to 6 carbon atoms. Examples of alkenyl (or C₂-C₆ alkenyl) include for instance, ethenyl, propenyl, butenyl, pentenyl, or hexenyl.
The term "alkynyl" refers to an unsaturated, linear or branched hydrocarbon chain, having at least one carbon-carbon triple bond. The expression "C₂-C₆ alkynyl" refers to an alkynyl having 2 to 6 carbon atoms. Examples of alkynyl (or C₂-C₆ alkynyl) include, for instance, ethynyl, propynyl, butynyl, pentynyl, or hexynyl.
The term "alkoxy" refers to a -O-(alkyl) group, where alkyl is as defined above. The expression "C₁-C₆ alkoxy" refers to an alkoxy having 1 to 6 carbon atoms. Examples of alkoxy (or C₁-C₆ alkoxy) include, for instance, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, or hexyloxy.
The term "aryl" refers to a mono- or bi-cyclic aromatic hydrocarbon having from 6 to 12 carbon atoms. For instance, the term "aryl" includes phenyl, biphenyl, or naphthyl. In a preferred embodiment, the aryl is a phenyl.
The term "halogen" refers to a fluorine atom, a chlorine atom, bromine atom, or iodine atom.
The symbol "
" means a single or double bond.
The "salts" of the compounds as defined herein include usual salts formed from inorganic or organic acids or bases as well as quaternary ammonium salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic etc. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc salts.
The present invention relates to the use of a compound of formula (I), in a tanning process:
wherein:

In a particular embodiment, each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-phenyl, or -C(O)-(C₁-C₆ alkyl), preferably a hydrogen or -C(O)-(C₁-C₆ alkyl), more preferably a hydrogen or -C(O)-CH₃, even more preferably a hydrogen.
A "dihydropyranyl-oxy" moiety can typically be represented as follows (said moiety being optionally substituted at any position):
As used herein, an "iridoid" refers to a compound comprising a dihydropyranyl-oxy moiety, fused with a cyclopentyl, cyclopentenyl, or tetrahydropyranyl moiety. More particularly, the iridoid may comprise one of the following ring structures (each ring structure, including the oxy of the dihydropyranyl-oxy, being optionally substituted at any position):
As used herein, a "seco-iridoid" refers to a compound comprising a dihydropyranyl-oxy moiety substituted by at least two hydrocarbon chains having each independently at least two carbons. More particularly, the seco-iridoid may comprise one of the following ring structures (each ring structure, including the at least two hydrocarbon chains and the oxy of the dihydropyranyl-oxy, being optionally substituted at any position):
The iridoids or seco-iridoids are usually in a glycoside form (i.e. the oxy of the dihydropyranyloxy being in the form of a glucosyl group) or aglycone form (i.e. the oxy of the dihydropyranyl-oxy being in the form of a hydroxy group).
As used herein, a "moiety of an iridoid, a seco-iridoid or a derivative thereof' refers to an iridoid, a seco-iridoid or a derivative thereof, deprived of an atom or a group of atoms, while preserving the backbone of said iridoid, seco-iridoid or derivative thereof. In particular, a "moiety of an iridoid, a seco-iridoid or a derivative thereof' refers to:

an iridoid, a seco-iridoid or a derivative thereof, deprived of a hydroxy group, when said iridoid, seco-iridoid or derivative thereof is an aglycone;
an iridoid, a seco-iridoid or a derivative thereof, deprived of a glucosyl group, when said iridoid, seco-iridoid or derivative thereof is a glycoside.

In other words, when the iridoid (or seco-iridoid or derivative thereof) is in a glycoside form, a compound of formula (I) typically refers to the corresponding iridoid (or seco-iridoid or derivative thereof) wherein the glucosyl is formally replaced with the following moiety:
wherein Y₁, Y₂, Y₃ are as defined herein.
In other words, when the iridoid (or seco-iridoid or derivative thereof) is in an aglycone form, a compound of formula (I) typically refers to the corresponding iridoid (or seco-iridoid or derivative thereof) wherein the hydroxy is formally replaced with the following moiety:
wherein Y₁, Y₂, Y₃ are as defined herein.
In a particular embodiment, X is a moiety of aucubin, catalpol, harpagide, ajugol, geniposide, loganin, loganic acid, antirrhinoside, linarioside, feretoside, geniposidic acid, gardenoside, apodanthoside, desacetylasperulosidic acid, scandoside, methoxycinnamoyl scandoside methyl ester, demethyloleuropein, ligustroside, ligustrosidic acid, ligustaloside A, ligustaloside B, nuzhenide, secologanin, secoxyloganin, oleuropein (or equivalently "oleuropeoside"), hydroxyframoside A, hydroxyframoside B, sweroside, swertiamarin, gentiopicroside, amarogentin, and morroniside.
In a preferred embodiment, X is a moiety of geniposide (or the aglycone form thereof, genipin) or a moiety of gentiopicroside (or the aglycone form thereof).
In an embodiment where X is a moiety of geniposide (or the aglycone form thereof, genipin), the compound of formula (I) can typically be represented as follows:
wherein Y₁, Y₂, Y₃ are as defined herein (preferably, hydrogens).
In an embodiment where X is a moiety of gentiopicroside (or the aglycone form thereof), the compound of formula (I) can typically be represented as follows:
wherein Y₁, Y₂, Y₃ are as defined herein (preferably, hydrogens).
In a particular embodiment, the compound of formula (I) is a compound of formula (1-2):
wherein:

or R₁₁ and R₁₂ form together one of the chains of formula (II-2), (II-3), (II-4), or (II-5):
where each of R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, or R₂₆ is independently a hydrogen, a halogen, -OH, -C(O)OH, -C(O)O-(C₁-C₁₂ aliphatic group), -O-C(O)-(C₁-C₁₂ aliphatic group), a C₁-C₁₂ aliphatic group, a hydroxy-(C₁-C₁₂ aliphatic group), or -CH₂-R₉', where R₉' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),
or R₁₄ and R₁₅ form together a -O- group,
or R₁₀ and R₁₁ form together a chain of formula (II-6):
or R₁₂ and R₁₂' form together a group of formula R₂₇-CH=, where R₂₇ is a C₁-C₁₂ aliphatic group, -C(O)OH, or -C(O)O-(C₁-C₁₂ aliphatic group),
said aliphatic groups being each independently optionally substituted by one or more hydroxy, aryl or glycosyl derivative, said aryl being optionally substituted by one or more hydroxy or (C₁-C₆)alkoxy,
or a salt thereof.

A preferred C₁-C₁₂ aliphatic group is a C₁-C₆ alkyl or a C₂-C₆ alkenyl. It is understood that this applies to C₁-C₁₂ aliphatic group as such, but can also apply to any group mentioned above comprising C₁-C₁₂ aliphatic group, such as -C(O)O-(C₁-C₁₂ aliphatic group).
In formula (1-2), said aliphatic groups (in particular, C₁-C₁₂ or C₂-C₁₂ aliphatic group) are each independently optionally substituted by one or more hydroxy (preferably one or two), aryl (preferably a phenyl) or glycosyl derivative, said aryl being optionally substituted by one or more hydroxy or (C₁-C₆)alkoxy. It is understood that this applies to aliphatic group as such, but also applies to any group mentioned above comprising aliphatic group, such as -C(O)O-(C₁-C₁₂ aliphatic group). An example of C₂-C₁₂ aliphatic group substituted by a hydroxy is -CH2-CH₂-OH.
In some embodiments, each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-phenyl, or - C(O)-(C₁-C₆ alkyl), preferably a hydrogen or -C(O)-(C₁-C₆ alkyl), more preferably a hydrogen or -C(O)-CH₃, even more preferably a hydrogen.
In some embodiments, R₁₀ is a hydrogen, -C(O)OH, or -C(O)-O-(C₁-C₆ alkyl), wherein said C₁-C₆ alkyl is optionally substituted by a phenyl substituted one or two hydroxy.
In some embodiments, R₁₁' is a hydrogen.
In some embodiments, R₁₂' is a hydrogen.
In some embodiments, R₁₁ and R₁₂ form together a chain of formula (II-2) as defined above,

wherein each of R₁₃, R₁₄, R₁₅, and R₁₆ is independently a hydrogen, a halogen (such as a chlorine), -OH, or a C₁-C₁₂ aliphatic group (preferably a C₁-C₆ alkyl, such as a methyl) optionally substituted by a hydroxy,
or R₁₄ and R₁₅ form together a -O- group.

In an embodiment where R₁₁ and R₁₂ form together a chain of formula (II-2), it is preferred that at least two of R₁₃, R₁₄, R₁₅, and R₁₆ are not hydrogens.
In some embodiments, R₁₁ and R₁₂ form together a chain of formula (II-3) as defined above, wherein each of R₁₇, R₁₈, and R₁₉ is independently a hydrogen, -OH, a hydroxy-(C₁-C₆ alkyl) (such as hydroxymethyl), -C(O)-(C₂-C₆ alkenyl), said C₂-C₆ alkenyl being optionally substituted by a phenyl substituted by a methoxy.
In an embodiment where R₁₁ and R₁₂ form together a chain of formula (II-3), it is preferred that R₁₈ is hydrogen and, R₁₇ and R₁₉ are not hydrogens.
In a particular embodiment, R₁₁ and R₁₂ form together a chain of formula (II-3) as defined above, wherein R₁₇ and R₁₈ are hydrogens and R₁₉ is -CH₂-O-C(O)-CH₃. In such embodiment, the compound of formula (1-2) may for instance be the following compound:
wherein Y₁, Y₂, and Y₃ are as defined herein (preferably -C(O)CH₃).
In some embodiments, R₁₁ and R₁₂ form together a chain of formula (II-4) as defined above, wherein each of R₂₀, R₂₁, R₂₂, and R₂₃, is independently a hydrogen, -OH, -C(O)OH, or a hydroxy-(C₁-C₁₂ aliphatic group), preferably hydrogen, -OH, -C(O)OH, or hydroxy(C₁-C₆ alkyl) such as hydroxymethyl.
In an embodiment where R₁₁ and R₁₂ form together a chain of formula (II-4), it is preferred that R₂₀ and R₂₁ are hydrogens and, one or both of R₂₂ and R₂₃ are not hydrogens.
In some embodiments, R₁₁ and R₁₂ form together a chain of formula (II-5) as defined above, wherein each of R₂₄, R₂₅, or R₂₆ is independently a hydrogen, -OH, or a C₁-C₁₂ aliphatic group (such as a C₁-C₆ alkyl, typically a methyl), or a hydroxy-(C₁-C₁₂ aliphatic group).
In an embodiment where R₁₁ and R₁₂ form together a chain of formula (II-5), it is preferred that at least two of R₂₄, R₂₅, or R₂₆ are not hydrogens.
In some embodiments, R₁₀ and R₁₁ form together a chain of formula (II-6) as defined above. In such embodiment, it is preferred that R₁₂' is a hydrogen and R₁₂ is not a hydrogen (preferably R₁₂ is a C₂-C₁₂ aliphatic group, more preferably a C₂-C₆ alkenyl such as an ethenyl).
In some embodiments, the compound of formula (1-2) is such that:

R₁₁ is a -CH₂-C(O)H, -CH₂-C(O)OH, or -CH₂-C(O)-O-(C₁-C₆ alkyl), said C₁-C₆ alkyl being optionally substituted by a glycosyl derivative or a phenyl substituted by one or two hydroxy.
R₁₂ is -CH₂-C(O)H, or a C₂-C₁₂ aliphatic group (preferably a C₂-C₆ alkenyl such as an ethenyl), or R₁₂ forms together with R₁₂' a group of formula R₂₇-CH=, where R₂₇ is a C₁-C₁₂ aliphatic group (preferably a C₁-C₆ alkyl such as a methyl), or -C(O)OH.

A particular glycosyl derivative is represented as follows:
In a particular embodiment, a compound as defined herein is represented by the following formula (I-1):
wherein:

or R₃ and R₄ form together the following chain of formula (II):
wherein R₆, R₇, and R₈ are each independently a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group), and R₉ is a hydrogen atom or -CH₂-R₉', wherein R₉' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),
or a salt thereof.

Compounds of formula (I), (1-2) or (1-1) as represented herein include all possible stereoisomers, and include not only racemic compounds but also the optically active isomers as well. The term "stereoisomer" refers to compounds which have identical molecular formulae as identified herein but which differ in the layout of their atoms in space. Stereoisomers which are not mirror images of each other, are designated as "diastereoisomers", and stereoisomers which are non-superposable mirror images of each other are designated as "enantiomers" or "optical isomers". "Stereoisomers" refer to racemates, enantiomers and diastereoisomers.
For instance, the compound of formula (1-1) as defined herein can be a compound of formula (III), a compound of formula (IV), or a mixture thereof:
wherein, in formulae (III) and (IV):

Y₁, Y₂, Y₃, R₂, R₃ and R₄ are as defined herein,
when R₄ is -C(O)-CH₂-R₅, then R₅ is as defined herein,
when R₄ is -CH(OH)-CH₂-R₅' then R₅' is as defined herein,
when R₃ and R₄ form together said chain of formula (II), then R₆, R₇, R₈, and R₉ are as defined herein.

Preferably, the compound of formula (1-1) is a compound of formula (III) or a mixture of a compound of formula (III) and a compound of formula (IV). More preferably, a compound as defined herein is a compound of formula (III).
In a particular embodiment, each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-phenyl, or -C(O)-(C₁-C₆ alkyl), preferably a hydrogen or -C(O)-(C₁-C₆ alkyl), more preferably a hydrogen or -C(O)-CH₃, even more preferably a hydrogen.
R₂ is a hydrogen atom or a C₁-C₁₂ aliphatic group. More particularly, R₂ may be a hydrogen atom or a C₁-C₆ alkyl group.
Preferably, R₂ is a C₁-C₁₂ aliphatic group, more preferably a C₁-C₆ alkyl, such as a methyl.
In a particular embodiment, the compound of formula (1-1) is such that:

R₃ is -CH₂-C(O)H or -CH₂-CH₂-OH (preferably -CH₂-C(O)H); and
R₄ is -C(O)-CH₂-R₅ or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, a C₁-C₁₂ aliphatic group, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group).

In some embodiments, R₄ is -C(O)-CH₂-R₅ or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group), preferably a hydrogen atom, -OH or -O-C(O)-(C₁-C₆ alkyl).
In a particular embodiment, R₄ is -C(O)-CH₂-R₅, where R₅ is as defined herein.
In particular, R₅ is a hydrogen atom, a C₁-C₆ alkyl group, -OH, or -O-C(O)-(C₁-C₆ alkyl group). Preferably, R₅ is a hydrogen atom or -O-C(O)-(C₁-C₁₂ aliphatic group), more preferably a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl), even more preferably, a hydrogen atom or -O-C(O)-CH₃.
In another particular embodiment, R₄ is -CH(OH)-CH₂-R₅', where R₅' is as defined herein. Preferably, R₅' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₆ alkyl group), more preferably a hydrogen atom, -OH, or -O-C(O)-CH₃.
In a preferred embodiment, the compound of formula (1-1) is such that:

R₃ is -CH₂-C(O)H or -CH₂-CH₂-OH; and
R₄ is -C(O)-CH₂-R₅, where R₅ is a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl) (such as -O-C(O)-CH₃) or -CH(OH)-CH₂-R₅', where R₅' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₆ alkyl group) (such as -O-C(O)-CH3).

For instance, R₃ can be -CH₂-C(O)H and R₄ can be -C(O)-CH₂-R₅, where R₅ is a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl) (such as -O-C(O)-CH₃).
For instance, R₃ can be -CH₂-CH₂-OH and R₄ can be -CH(OH)-CH₂-R₅', where R₅' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₆ alkyl group) (such as -O-C(O)-CH₃).
In a more preferred embodiment, the compound of formula (1-1) is such that:

R₂ is a C₁-C₆ alkyl group;
R₃ is -CH₂-C(O)H or -CH₂-CH₂-OH; and
R₄ is -C(O)-CH₂-R₅, where R₅ is a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl) (such as -O-C(O)-CH₃) or -CH(OH)-CH₂-R₅', where R₅' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₆ alkyl group) (such as -O-C(O)-CH₃).

In another particular embodiment, R₃ and R₄ form together a chain of formula (II) as defined herein. In such embodiment, the compound of formula (1-1) can be represented as follows:
wherein Y₁, Y₂, Y₃, R₂, R₆, R₇, R₈, and R₉ are as defined herein.
More particularly, the stereochemistry of the compound of formula (I-II) may be as follow:
wherein Y₁, Y₂, Y₃, R₂, R₆, R₇, R₈, and R₉ are as defined herein.
Preferably, a compound as defined herein is a compound of formula (III-II) or a mixture (in particular, a racemic mixture) of a compound of formula (III-II) and a compound of formula (IV-II). More preferably, a compound as defined herein is a compound of formula (III-II).
It is understood that, in any formula represented herein, such as formula (I), (1-1), (1-2), (II), (II-2), (II-3), (II-4), (II-5), (II-6), (III), (IV), (I-II), (III-II) or (IV-II), each stereogenic center that is not defined encompasses both (R) and (S) configurations.
In a particular embodiment, R₆, R₇, and R₈ are each independently a hydrogen atom, -OH, or - O-C(O)-(C₁-C₆ alkyl group) and R₉ is a hydrogen atom or -CH₂-R₉', where R₉' is a hydrogen atom, -OH, or -O-C(O)-( C₁-C₆ alkyl group).
In a particular embodiment, at least two among R₇, R₈, and R₉ (for instance, all of R₇, R₈, and R₉) are not hydrogen atoms.
In a preferred embodiment, R₆ is hydrogen.
In a particular embodiment, R₇ is hydrogen, -OH or -O-C(O)-(C₁-C₆ alkyl), for instance hydrogen, -OH or -O-C(O)-CH₃.
In another particular embodiment, R₇ is -OH or -O-C(O)-(C₁-C₁₂ aliphatic group). Preferably, R₇ is -OH or -O-C(O)-(C₁-C₆ alkyl), more preferably -OH or -O-C(O)-CH₃.
In another particular embodiment, R₇ is -O-C(O)-(C₁-C₁₂ aliphatic group), for instance -C(O)-CH₃.
In a particular embodiment, R₈ is hydrogen or -OH. Preferably, R₈ is -OH.
In a particular embodiment, R₉ is a hydrogen atom.
In another particular embodiment, R₉ is -CH₂-R₉'.
In some embodiments, R₉' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₆ alkyl), preferably a hydrogen atom, -OH or -O-C(O)-CH₃.
In some embodiments, R₉' is a hydrogen atom or -O-C(O)-(C₁-C₁₂ aliphatic group). Preferably, R₉' is a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl), more preferably a hydrogen atom or -O-C(O)-CH₃.
In some embodiments, R₉' is -O-C(O)-(C₁-C₁₂ aliphatic group), for instance -C(O)-CH₃.
In a particular embodiment, the compound of formula (1-1) (or of formula (I-II)) is such that R₃ and R₄ form together a chain of formula (II) wherein:

R₆ is hydrogen;
R₇ is hydrogen, -OH or -O-C(O)-(C₁-C₆ alkyl), preferably hydrogen, -OH or -O-C(O)-CH₃;
R₈ is hydrogen or -OH; and
R₉ is a hydrogen atom or -CH₂-R₉', with R₉' being a hydrogen atom, -OH, or -O-C(O)-(C₁-C₆ alkyl), preferably a hydrogen atom, -OH, or -O-C(O)-CH₃.

In a more particular embodiment, the compound of formula (1-1) (or of formula (I-II)) is such that:

R₂ is a C₁-C₆ alkyl group;
R₃ and R₄ form together a chain of formula (II) wherein:
- R₆ is hydrogen;
- R₇ is hydrogen, -OH or -O-C(O)-(C₁-C₆ alkyl), preferably hydrogen, -OH or - O-C(O)-CH₃;
- R₈ is hydrogen or -OH; and
- R₉ is a hydrogen atom or -CH₂-R₉', with R₉' being a hydrogen atom, -OH, or - O-C(O)-(C₁-C₆ alkyl), preferably being a hydrogen atom, -OH, or -O-C(O)-CH₃.

In a preferred embodiment, the compound of formula (1-1) is such that R₃ and R₄ form together a chain of formula (II) (in particular, is a compound of formula (I-II)) wherein:

R₆ is hydrogen;
R₇ is OH or -O-C(O)-(C₁-C₆ alkyl), preferably -OH or -O-C(O)-CH₃;
R₈ is -OH; and
R₉ is a hydrogen atom or -CH₂-R₉', with R₉' being a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl), preferably being a hydrogen atom or -O-C(O)-CH₃.

In a more preferred embodiment, the compound of formula (1-1) (or of formula (I-II)) is such that:

R₂ is a C₁-C₆ alkyl group;
R₃ and R₄ form together a chain of formula (II) wherein:
- R₆ is hydrogen;
- R₇ is OH or -O-C(O)-(C₁-C₆ alkyl), preferably -OH or -O-C(O)-CH₃;
- R₈ is -OH; and
- R₉ is a hydrogen atom or -CH₂-R₉', with R₉' being a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl), preferably being a hydrogen atom or -O-C(O)-CH₃.

In a particular embodiment, the compound of formula (1-1) is chosen among the following compounds:

wherein Y₁, Y₂, and Y₃ are as defined herein.
For instance, the compound of formula (1-1) may be one of the following compounds:
The compounds as defined herein (e.g. compounds of formula (I), (1-2) or (1-1)) can be prepared by any suitable technique known to the skilled artisan. In particular, the compounds as defined herein can be prepared as detailed in the examples. More specifically, such compounds may be prepared by contacting an iridoid or a seco-iridoid in its glycoside form, successively with sodium metaperiodate followed by sodium borohydride in water. Subsequent classical steps, such as hydroxylation, oxidation, reduction, or acylation can be carried out to functionalize or insert particular substituents on the iridoid or seco-iridoid.
The compounds as defined herein (e.g. compounds of formula (I), (1-2) or (1-1)) are particularly suitable for use in a tanning process, as tanning or pre-tanning agents.
Advantageously, a compound as defined herein can be activated, typically by contacting with an acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid (preferably hydrochloric acid), before and/during the tanning process. A compound as defined herein may be contacted with said acid at room temperature, preferably for a duration comprised between 30 min and 48 hours. As used herein "room temperature" refers to a temperature comprised between 15 °C and 40 °C, preferably between 20 °C and 30 °C.
The "pre-tanning" refers to a particular step of a tanning process, which is a preliminary step where a first tanning agent (i.e. "pre-tanning agent") is contacted with the collagen-containing material, e.g. the hide, before being contacted with a second tanning agent (i.e. "tanning agent"). Advantageously, the pre-tanning also enables the shaving of the leather before the second tanning agent is applied.
A tanning process may comprise or not a pre-tanning step. A compound as defined herein may be used as a pre-tanning agent and/or tanning agent in a process comprising a pre-tanning step. In such embodiment, if one among the pre-tanning agent and the tanning agent is not a compound as defined herein, it may be chosen from the group consisting of: polyphenolic extract for various vegetable, mainly gallnut, quebracho, oak, metal salt of chromium, iron, zirconium, titanium, aluminum, mainly with chloride and sulfate as counter ion, and synthetics chemicals like formol, glutaraldehyde, oxazolidine, zeolite, formol phenol (and derivate like cresol, phenol sulfonic acids) condensate, formol bisphenol (A, B, S and F) condensate, formol melamine condensate, and a mixture thereof.
A compound as defined herein may be used as a tanning agent in a tanning process not comprising a pre-tanning step.
The tanning process may in particular be a process for tanning a collagen-containing material, and more particularly for tanning a hide or a skin.
In said tanning process, said collagen-containing material, or said hide or skin, is treated (typically, contacted) with one or more compounds as defined herein, or a composition comprising the same.
As used herein, the term "collagen" refers to naturally occurring collagens or modified collagens. The term "collagen" as used herein also refers to collagens prepared using recombinant techniques. The term collagen includes collagen, collagen fragments, collagen dispersion obtained from hide grinding and various purification steps (e.g. enzymatic or acidic hydrolysis), collagen fibers obtained through precipitation of dispersed or soluble collagen (e.g. salt, brine or ammoniac precipitation), collagen-like proteins, triple helical collagen, alpha chains, monomers, gelatin, trimers and combinations thereof. Recombinant expression of collagen and collagen-like proteins is known in the art (see in particular EP 1,232,182 ; US 6,428,978 ; US 8,188,230 ). In some embodiments, the collagen can be a chemically-modified collagen, a truncated collagen, unmodified or post-translationally modified, or amino acid sequence-modified collagen. In some embodiments, the collagen can be plant-based collagen. In some embodiments, a collagen solution can be fibrillated into collagen fibrils. As used herein, collagen fibrils refer to nanofibers composed of tropocollagen or tropocollagen-like structures. In some embodiments, a recombinant collagen can comprise a collagen fragment of the amino acid sequence of a native collagen molecule capable of forming tropocollagen (trimeric collagen). A recombinant collagen can also comprise a modified collagen or truncated collagen having an amino acid sequence at least 70, 80, 90, 95, 96, 97, 98, or 99% identical or similar to a native collagen amino acid sequence. In some embodiments, the collagen fragment can be a 50 kDa portion of a native collagen. Methods of producing recombinant collagen and recombinant collagen fragments are known in the art. (see in particular US 2019/0002893 , US 2019/0040400 , US 2019/0093116 , and US 2019/0092838 ).
The collagen-containing material refers to a material comprising or consisting of collagen. The collagen-containing material may be from any origin, in particular from an animal (e.g. goat, bovine such as calf, cow or cattle, ovine such as sheep or lamb, reptile such as crocodile or lizard, or fish such as trout or salmon). In a particular embodiment, said collagen-containing material is a hide or a skin. The hide or skin may be from any animal, (e.g. goat, bovine such as calf, cow or cattle, ovine such as sheep or lamb, reptile such as crocodile or lizard, or fish such as trout or salmon).
The treating or contacting step may be carried out under classical conditions known to the skilled artisan. For instance, the collagen-containing material (in particular, said hide or skin) may be contacted with said one or more compounds as defined herein in an aqueous solution, optionally comprising further auxiliary agents such as, proteins, peptides, protein hydrosylates, polyamines, pH buffer, sodium chloride, sodium sulfate, sodium citrate, ammonium chloride, naphthalene sulfonic polymer, preservatives, or slippery agent.
The concentration of compound(s) as defined herein in the aqueous solution is typically comprised between 0.1 wt% and 40 wt%, preferably between 0.5% and 25%. The pH of the aqueous solution may be within a range from 1 to 15, preferably from 7 to 11. Said pH may be adjusted by using a buffer, such as a carbonate or phosphate buffer. The treating or contacting step may be carried out at a temperature comprised between 4 °C and 70 °C, preferably between 20 °C and 50 °C, more preferably between 30 °C and 40 °C. The treating or contacting step may be carried out for a duration comprised between 1 hour and 90 hours, preferably between 15 hours and 50 hours. In some embodiments, the compound(s) as defined herein may be used in a tanning process in combination with other tanning agents, such as mineral, vegetal, organic or enzymatic tanning agents (e.g. polyphenolic extract for various vegetable, mainly gallnut, quebracho, oak, metal salt of chromium, iron, zirconium, titanium, aluminum, mainly with chloride and sulfate as counter ion, and synthetics chemicals like formol, glutaraldehyde, oxazolidine, zeolite, formol phenol (and derivate like cresol, phenol sulfonic acids) condensate, formol bisphenol (A, B, S and F) condensate, formol melamine condensate, and a mixture thereof). The tanning step can be carried out in a tanning drum, a reactor or any other adapted device.
Advantageously, a compound as defined herein is contacted with an acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid (preferably hydrochloric acid), before and/or during the contacting with the collagen-containing material. Said acid is typically used in the form of an acid aqueous solution.
Particularly, a process for tanning a collagen-containing material using a compound as defined herein can comprise:

i) contacting a solution comprising a compound as defined herein with an acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid (preferably hydrochloric acid) so as to obtain a solution of a hydrolyzed compound,
ii) adjusting the solution of a hydrolyzed compound to a pH between 7 to 11, typically by adding a buffer (such as a carbonate or phosphate buffer) and
iii) contacting the resulting solution with the collagen-containing material.

Steps i), ii), and iii) can be carried out successively or simultaneously. Steps i), ii), and iii) can be carried out in any order, for instance in any one of the following orders:

(i), (ii), and (iii); or
(i), (iii), and (ii);
preferably in this order i), ii), and iii).

A stabilizing salt may be added during the tanning process, for instance in the above steps (ii) or (iii), in order to prevent the degradation of the collagen-containing material which may occur under strong acid or basic conditions. Examples of such stabilizing salt include, but are not limited to, cation sulfates, cation hydrogen sulfates, cation naphthalene sulfonates, cation chloride, cation phosphate, cation citrate, cation succinate, cation tartrate, cation formate, cation acetate, cation propionate, cation sulfamate, or a mixture thereof, wherein the cation is preferably selected from the group consisting of sodium, potassium, calcium and magnesium.
In a more particular embodiment, a process for tanning a collagen-containing material using a compound as defined herein comprises:

o') contacting an iridoid, seco-iridoid, or derivative thereof in a glycoside form with sodium metaperiodate followed by sodium borohydride, so as to obtain a compound of formula (I) as defined herein,
i') contacting a solution comprising said compound of formula (I) as defined herein with an acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid (preferably hydrochloric acid) so as to obtain a solution of hydrolyzed compound,
ii') adjusting the solution of a hydrolyzed compound to a pH between 7 to 11, typically by adding a buffer (such as a carbonate or phosphate buffer), and
iii') contacting the resulting solution with the collagen-containing material.

Steps i'), ii'), and iii') can be carried out successively or simultaneously. Steps i'), ii'), and iii') can be carried out in any order, after step o'), for instance in any one of the following orders:

(i'), (ii'), and (iii'); or
(i'), (iii'), and (ii');
preferably in this order i'), ii'), and iii').

A stabilizing salt as defined above may be added during the tanning process, for instance in the above steps (ii') or (iii').
In step o'), said iridoid, seco-iridoid, or derivative thereof is preferably chosen from aucubin, harpagide, catalpol, ajugol, geniposide, loganin, loganic acid, antirrhinoside, linarioside, feretoside, geniposidic acid, gardenoside, apodanthoside, desacetylasperulosidic acid, scandoside, methoxycinnamoyl scandoside methyl ester, demethyloleuropein, ligustroside, ligustrosidic acid, ligustaloside A, ligustaloside B, nuzhenide, secologanin, secoxyloganin, oleuropein, hydroxyframoside A, hydroxyframoside B, sweroside, swertiamarin, gentiopicroside, amarogentin, and morroniside, preferably geniposide or gentiopicroside.
Advantageously, compounds as defined herein have a low toxicity, in particular compared with the aglycone form of iridoids or seco-iridoids. Compounds as defined herein advantageously have a median lethal dose (LD₅₀) higher than that of the corresponding aglycone form. Compounds as defined herein may also allow to obtain a high-quality leather or leather substitute. In particular, said leather or leather substitute may:

be colorless or slightly colored (for instance, yellow, orange, beige), and/or
have a shrinkage temperature of at least 65°C (for instance from 65°C to 90°C), or at least 70 °C (for instance, from 70°C to 85°C), as measured by DSC, and/or
have a high-quality grain and leather surface.

The shrinkage temperature may in particular be suitable to shave leather and to prepare the step of tanning (i.e. the step subsequent to the pre-tanning, if present in the tanning process). The high-quality grain and leather surface may in particular be suitable for aniline finishing, and be characterized by a very low shrinking of the grain.
Hence, in a particular embodiment, compounds as defined herein are used in a method for manufacturing a leather or leather substitute. A "leather substitute" refers typically to a material having similar properties as leather, and obtained by a tanning process applied to a substitute of an animal skin or hide. Said leather or leather substitute can be used in the fashion, accessories, household's appliances and other furniture industries, and especially for manufacturing bags, shoes, watch straps, belts or wallets.
Another object of the present invention is a process for cross-linking collagen in a material comprising a step of contacting said material with a compound as defined herein. Said material may in particular be a hide or skin.
Another object of the present invention is a compound as defined herein (e.g. compounds of formula (I), (1-2) or (1-1)) per se, with the proviso that said compound is not one of the following compounds (including any stereoisomer thereof):
In particular, said compound per se is a compound of formula (I) as defined herein, with the proviso that X is not a moiety of geniposide or loganin (or the aglycone form thereof).
The invention will also be described in further detail in the following examples, which are not intended to limit the scope of this invention, as defined by the attached claims.

EXAMPLES

Example 1. Preparation of iridoid derivatives of formula (I)

Sodium metaperiodate (1.15 g, 5.3 mmol, 2 eq) was added to a solution of geniposide (1 g, 2.6 mmol) in water (7 mL) and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was cooled to 0 °C. Sodium borohydride (0.4 g, 10.8 mmol, 4 eq) was carefully added and the mixture was stirred at room temperature. After 2 h, water was evaporated under reduced pressure to obtain a white solid which was stirred in an acetic anhydride/pyridine mixture (1:1, 20 mL) overnight. Solvents were then evaporated under reduced pressure to give an orange solid which was dissolved in EtOAc (30 mL). The organic layer was washed with HCl aqueous solution (1 M), a saturated aqueous solution of NaHCO₃ and brine. The organic layer was then dried over MgSO₄ and evaporated under reduced pressure to give a yellow liquid which was purified by silica gel chromatography (cyclohexane/ethyl acetate 65/35) to afford compound 1 (1.18 g, 2.2 mmol, 87%) as a yellow oil.
¹H NMR (300 MHz, CDCl₃) δ(ppm) 7.44 (d, J = 1.3 Hz, 2H, H-3, H-3'), 5.90 (br s , 1H, H-7'), 5.86 (br s , 1H, H-7), 5.28-5.19 (m, 2H, H-11, H-11'), 5.09-5.01 (m, 2H, H-1, H-1'), 4.82 (br s, 2H, H-10a', H-10b'), 4.71 (br s, 2H, H-10a, H-10_b), 4.30-3.98 (m, 14H, H-12_a, H-12_b, H-12a', H-12_b', H-14_a, H-14_b, H-14a', H-14_b', H-15, H-15', H-16a, H-16b, H-16a', H-16b'), 3.72 (s, 3H, OMe), 3.24 (q, J = 7.8 Hz, 1H, H-5), 2.96-2.81 (m, 2H, H-6a, H-6a'), 2.81-2.71 (m, 2H, H-9, H-9'), 2.24-2.21 (m, 1H, H-6_b), 2.08 (s, 6H, CH ₃-C=O), 2.07 (12H, s, CH ₃-C=O), 2.04 (6H, s, CH ₃-C=O).
¹³C NMR (75 MHz, CDCl₃) δ (ppm) 170.6 (C=O), 169.4 (C=O), 167.3 (C=O), 151.4 (C-3), 151.4 (C-3'), 137.7 (C-4), 137.0 (C-4), 132.0 (C-7'), 131.3 (C-7), 111.8 (C-8), 98.0 (C-11, C-11'), 96.4 (C-1), 74.2 (C-15), 64.5 (C-12), 63.6 (C-14, C-16), 62.2 (C-10), 61.7 (C-10'), 51.4 (O=C-O-CH₃), 46.4 (C-9), 46.3 (C-9'), 38.8 (C-6), 35.0 (C-5), 21.0 (CH₃-C=O), 20.8 (CH₃-C=O, CH₃-C=O), 20.7 (CH₃-C=O).
HRMS (ESI) m/z: calculated for C₂₄H₃₂O₁₃Na [M + Na]⁺ 551.1741 ; found 551.1730.
R _f = 0.33 (SiO₂, cyclohexane/AcOEt 65/35).
Potassium carbonate (680 g, 4.9 mmol, 3 eq), potassium ferricyanide (III) (2.7 g, 8.2 mmol, 5 eq), potassium osmate(VI) dihydrate (0.024 g, 0.06 mmol, 0.04 eq), and quinuclidine (0.015 g, 0.13 mmol, 0.08 eq) were suspended in THF/ H₂O (2/1, 12 mL). After 5 min of stirring, a solution of 1 (866 g, 1.6 mmol) in THF (4 mL) was added to the reaction mixture. The dark suspension was vigorously stirred at room temperature overnight and sodium sulfite (1 g, 8.2 mmol, 5 eq) was introduced. After 20 min, ethyl acetate (20 mL) was added and the mixture was vigorously stirred 2h. After filtration over a pad of celite, the aqueous layer was extracted with EtOAc. Combined organic layers were washed with HCl aqueous solution (1M), saturated aqueous NaHCO₃ and brine, dried over MgSO₄, filtered, and evaporated under reduced pressure. The obtained yellow oil was purified by silica gel chromatography (cyclohexane/ethyl acetate 1/3) to afford compound 2 as a yellow oil (530 g, 0.93 mmol, 59 %).
¹ H NMR (300 MHz, CDCl₃ ) δ(ppm) 7.31 (d, J = 0.7 Hz, 1H, H-3), 5.55 (d, J = 2.2 Hz, 1H, H-1), 5.18-5.09 (m, 1H, H-11), 4.30-3.91 (m, 10H, H-7, H-10a, H-10b, H-12_a, H-12_b, H-14_a, H-14_b, H-16a, H-16_b,) 3.72 (s, 3H, OMe), 3.25-3.10 (m, 1H, H-5), 2.77 (dd, J = 10.1 Hz, J = 2.2 Hz, 1H, H-9), 2.37-2.24 (m, 1H, H-6a), 2.09 (6H, s, CH ₃-C=O), 2.08 (3H, s, CH ₃-C=O), 2.03 (3H, s, CH₃-C=O), 1.90-1.74 (m, 1H, H-6_b).
¹³ C NMR (75 MHz, CDCl₃ ) δ(ppm) 171.2 (C=O), 171.1 (C=O), 170.9 (C=O), 170.5 (C=O), 166.9 (C=O), 149.6 (C-3), 97.8 (C-11), 93.3 (C-1), 79.9 (C-8), 74.0 (C-7), 73.5 (C-15), 66.2 (C-10), 64.2 (C-12), 63.6 (C-14, C-16), 51.4 (O=C-O-CH₃), 47.9 (C-9), 37.0 (C-6), 26.9 (C-5), 20.9 (CH₃-C=O, CH₃-C=O), 20.8 (CH₃-C=O), 20.6 (CH₃-C=O).
HRMS (ESI) m/z: calculated for C₂₄H₃₄O₁₅Na [M + Na]⁺ 585.1795 ; found 585.1794.
R _f = 0.25 (SiO₂, cyclohexane/AcOEt 1/3).
To a stirred solution of 2 (1.32 g, 2.3 mmol) in anhydrous MeOH (25 mL) at 0 °C was added a 0.65 M solution of MeONa in MeOH (1.1 mL, 0.7 mmol, 0.3 eq). After 20 min at room temperature, the solution was neutralized with Dowex X50 ion exchange resin, filtrated and evaporated under reduced pressure to afford 3 (900 mg, 2.3 mmol, 100%) as an uncoloured oil without further purification.
¹ H NMR (300 MHz, Methanol-d4) δ(ppm) 7.40 (d, J = 0.9 Hz, 1H, H-3), 5.71 (d, J =4.1 Hz, 1H, H-1), 5.18-5.09 (t, J = 5.0 Hz, 1H, H-11), 3.97 (dd, J = 6.4 Hz, J = 5.0 Hz, 1H, H-7), 3.80-3.50 (m, 12H, H-10a, H-10b, H-12a, H-12_b, H-14a, H-14_b, H-15, H-16a, H-16b, CH ₃-C=O) 3.13 (td, J = 9.3 Hz, J = 6.0 Hz, 1H, H-5), 2.52 (dd, J = 9.3 Hz, J = 4.1 Hz, 1H, H-9), 2.19 (ddd, J = 14.0 Hz, J = 9.3 Hz, J = 5.0 Hz, 1H, H-6a), 1.77 (td, J = 14.1 Hz, J = 6.4 Hz, 1H, H-6b)
¹³ C NMR (75 MHz, Methanol-d4) δ(ppm) 166.0 (C=O), 151.9 (C-3), 113.7 (C-4) 101.8 (C-11), 94.6 (C-1), 82.4 (C-11), 82.4 (C-8), 74.1 (C-7), 65.3 (C-10), 64.7 (C-12), 63.4 ppm (C-14), 63.2 (C-16), 51.7 (O=C-O-CH₃), 49.2 (C-9), 38.9 (C-6), 29.1 (C-5).
HRMS (ESI) m/z: calculated for C₁₆H₂₆O₁₁Cl [M + Cl]^- 429.1164; found 429.1143.

Example 2. Tanning process using iridoid derivatives of formula (I)

In a brown vial, a solution of iridoid derivative (17 mg, 8.5% w/w) in 2M aqueous HCl (0.17 mL) was stirred at room temperature during 1h and then diluted in a carbonate buffer (pH 9 ; 3 mL, 1500% w/w). Collagen powder (200 mg) was added after 24 hours of rehydration in ultra-pure water (3mL). The vial was heated at 37 °C for 48 hours with moderate stirring. The collagen powder was finally filtered and thoroughly rinsed with ultrapure water (ca. 20 mL).

The impact of the time of acid hydrolysis (Tables 1, 2 and 3), the tanning agent content (Table 4), and the pH of hydrolysis (Table 5) on the tanning process were assessed by measuring shrinkage temperatures. Reference collagen powder had a shrinkage temperature of 60°C. Shrinkage temperatures were determined by Differential Scanning Calorimetry (DSC). The temperatures shown in Tables 1-5 below are average values.

Table 1

Entry	Iridoid derivative	Acid Hydrolysis time	Shrinkage Temperature	Colour of the collagen powder
1	Compound 1	4 h	68 °C	Violet

Table 2

Entry	Iridoid derivative	Acid Hydrolysis time	Shrinkage Temperature	Colour of the collagen powder
1	Compound 2	2 h	68 °C	Pale yellow
2	Compound 2	4 h	71 °C	Yellow
3	Compound 2	6 h	73 °C	Yellow
4	Compound 2	9 h	76 °C	Yellow
5	Compound 2	24 h	76 °C	Yellow

Table 3

Entry	Iridoid derivative	Acid hydrolysis time	Shrinkage Temperature	Colour of the collagen powder
1	Compound 3	0.5 h	75 °C	Pale yellow
2	Compound 3	1 h	76 °C	Pale yellow
3	Compound 3	2 h	76 °C	Pale yellow
4	Compound 3	4 h	77 °C	Yellow
5	Compound 3	8 h	77 °C	Yellow
6	Compound 3	24 h	75 °C	Yellow

Table 4

Entry	Iridoid derivative	Tanning agent content (w/w)	Shrinkage Temperature	Colour of the collagen powder
1	Compound 3	8.5 %	76 °C	Pale yellow
2	Compound 3	17 %	77 °C	Yellow
3	Compound 3	34 %	77 °C	Yellow

Table 5

Entry	Iridoid derivative	Acid hydrolysis time and pH	Shrinkage Temperature	Colour of the collagen powder
1	Compound 3	pH 0 ; 4 h	73 °C	Yellow
2	Compound 3	pH 0 ; 4 h	74 °C	Yellow
3	Compound 3	pH 1 ; 24 h	70 °C	Pale yellow

These experiments (Tables 1-5, Figures 1-3) show that the iridoid derivatives can be effectively used in a tanning process, under various conditions. Good shrinkage temperatures of at least ~ 70 °C and up to 77 °C were obtained, by using a moderate amount of iridoid derivative and especially when using sufficient acidic conditions and time during the hydrolysis step.

Example 3. Direct tanning process using iridoid derivatives of formula (I)

Sodium metaperiodate (220 mg, 1 mmol, 2 eq) was added to a solution of the iridoid glycoside (0.5 mmol) in water (1.4 mL) and the mixture was stirred at room temperature for 2 h. After the reaction mixture was cooled to 0 °C, sodium borohydride (78 mg, 2 mmol, 4 eq) was carefully added and the mixture was stirred at room temperature for 2 h, and then 6 M hydrochloric acid (0.7 mL, 4.2 mmol, 8.4 eq) was added for the acid hydrolysis step.
After 1 hour, the hydrolysate (0.17 mL) was diluted in a carbonate buffer of pH 9 (3 mL, 1500 % w/w) in a brown vial. Collagen powder (200 mg) was added after 24 hours of rehydration in ultra-pure water (3mL). The vial was heated at 37 °C for 48 hours with moderate stirring. The collagen powder was finally filtered and thoroughly rinsed with ultrapure water (ca. 20 mL).

The impact of the iridoid derivative (Table 6), the time of hydrolysis (Table 7), the amount of sodium metaperiodate and sodium borohydride (Table 8) on the tanning process were assessed by measuring shrinkage temperatures. Shrinkage temperatures were determined by Differential Scanning Calorimetry (DSC). The temperatures shown in Tables 6-8 below are average values.

Table 6

Entry	Iridoid glycoside	Shrinkage Temperature	Colour of the collagen powder
1	Geniposide	84 °C	Dark blue
2	Dihydroxylated geniposide	78 °C	Pale yellow
3	Gentiopicroside	84 °C	Orange

Table 7

Entry	Iridoid glycoside	Hydrolysis time	Shrinkage Temperature	Colour of the collagen powder
1	Geniposide	15 minutes	80 °C	Dark blue
2	Geniposide	60 minutes	84 °C	Dark blue
3	Geniposide	120 minutes	83 °C	Dark blue

Table 8

Entry	Iridoid glycoside	Equivalents	Shrinkage Temperature	Colour of the collagen powder
1	Dihydroxylated geniposide	NaIO₄ (2 eq)	75 °C	Pale yellow
1	Dihydroxylated geniposide	NaBH₄ (4 eq)	75 °C	Pale yellow
2	Dihydroxylated geniposide	NaIO₄ (4 eq)	78 °C	Pale yellow
2	Dihydroxylated geniposide	NaBH₄ (8 eq)	78 °C	Pale yellow

These experiments (Tables 6-8, Figure 4) demonstrate that the iridoid derivatives can be effectively used in a direct tanning process (namely without being isolated after conversion of the glycoside), under various conditions. Good shrinkage temperatures of at least 75 °C and up to 84 °C were obtained.

Claims

Use of a compound of formula (I), in a tanning process:
wherein:
- X is a moiety of an iridoid, a seco-iridoid or a derivative thereof, and

- each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-aryl, or -C(O)-(C₁-C₁₂ aliphatic group),
or a salt thereof.
Use according to claim 1, wherein X is a moiety of aucubin, harpagide, catalpol, ajugol, geniposide, loganin, loganic acid, antirrhinoside, linarioside, feretoside, geniposidic acid, gardenoside, apodanthoside, desacetylasperulosidic acid, scandoside, methoxycinnamoyl scandoside methyl ester, demethyloleuropein, ligustroside, ligustrosidic acid, ligustaloside A, ligustaloside B, nuzhenide, secologanin, secoxyloganin, oleuropein, hydroxyframoside A, hydroxyframoside B, sweroside, swertiamarin, gentiopicroside, amarogentin, or morroniside, preferably geniposide or gentiopicroside.
Use according to claim 1, wherein said compound is represented by the following formula (1-2):
wherein:
- each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-aryl, or -C(O)-(C₁-C₁₂ aliphatic group),

- R₁₀ is a hydrogen, -C(O)OH, or -C(O)-O-(C₁-C₁₂ aliphatic group),

- R₁₁ is a C₂-C₁₂ aliphatic group, -CH₂-C(O)H, -CH₂-C(O)OH, or -CH₂-C(O)-O-(C₁-C₁₂ aliphatic group),

- R₁₁' is a hydrogen or -OH,

- R₁₂ is -CH₂-C(O)H, a C₂-C₁₂ aliphatic group, -C(O)-CH₂-R₅, or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, a C₁-C₁₂ aliphatic group, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),

- R₁₂' is a hydrogen or -OH,

or R₁₁ and R₁₂ form together one of the chains of formula (II-2), (II-3), (II-4), or (II-5):

where each of R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, or R₂₆ is independently a hydrogen, a halogen, -OH, -C(O)OH, -C(O)O-(C₁-C₁₂ aliphatic group), -O-C(O)-(C₁-C₁₂ aliphatic group), a C₁-C₁₂ aliphatic group, a hydroxy-(C₁-C₁₂ aliphatic group), or -CH₂-R₉', where R₉' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),

or R₁₄ and R₁₅ form together a -O- group,

or R₁₀ and R₁₁ form together a chain of formula (II-6):

or R₁₂ and R₁₂' form together a group of formula R₂₇-CH=, where R₂₇ is a C₁-C₁₂ aliphatic group, -C(O)OH, or -C(O)O-(C₁-C₁₂ aliphatic group),

said aliphatic groups being each independently optionally substituted by one or more hydroxy, aryl or a glycosyl derivative, said aryl being optionally substituted by one or more hydroxy or (C₁-C₆)alkoxy,

or a salt thereof.
Use according to claim 3, wherein said compound is represented by the following formula (1-1):
wherein:
- each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-aryl, or -C(O)-(C₁-C₁₂ aliphatic group),

- R₂ is a hydrogen atom or a (C₁-C₁₂) aliphatic group,

- R₃ is -CH₂-C(O)H or -CH₂-CH₂-OH,

- R₄ is -C(O)-CH₂-R₅ or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, a C₁-C₁₂ aliphatic group, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),

or R₃ and R₄ form together the following chain of formula (II):

wherein R₆, R₇, and R₈ are each independently a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group), and R₉ is a hydrogen atom or -CH₂-R₉', wherein R₉' is a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group),

or a salt thereof.
Use according to claim 4, wherein R₂ is a C₁-C₁₂ aliphatic group, preferably a C₁-C₆ alkyl.
Use according to claim 4 or 5, wherein R₄ is -C(O)-CH₂-R₅ or -CH(OH)-CH₂-R₅', where R₅ and R₅' are each independently a hydrogen atom, -OH, or -O-C(O)-(C₁-C₁₂ aliphatic group), preferably a hydrogen atom, -OH or -O-C(O)-(C₁-C₆ alkyl).
Use according to one of claims 4 to 6, wherein R₃ and R₄ form together the following chain of formula (II) wherein:
- R₆ is hydrogen; and/or

- R₇ is -OH or -O-C(O)-(C₁-C₁₂ aliphatic group), preferably -OH or -O-C(O)-(C₁-C₆ alkyl); and/or

- R₈ is -OH; and/or

- R₉ is a hydrogen atom or -CH₂-R₉', with R₉' being a hydrogen atom or -O-C(O)-(C₁-C₆ alkyl).
Use according to any one of claims 1 to 7, wherein each of Y₁, Y₂, and Y₃ is independently a hydrogen, -C(O)-phenyl, or -C(O)-(C₁-C₆ alkyl), preferably a hydrogen or -C(O)-CH₃, more preferably a hydrogen.
Use according to any one of claims 1 to 8, for tanning a hide or a skin.
Use according to any one of claims 1 to 8, in a method for manufacturing a leather or a leather substitute.
Use according to any one of claims 1 to 8, for tanning a collagen-containing material.
A compound as defined in any one of claims 1 to 8, with the proviso that said compound is not one of the following compounds:
A process for cross-linking collagen in a material comprising a step of contacting said material with a compound as defined in any one of claims 1 to 8, and 12.
The process according to claim 13, wherein said material is a hide or a skin.