process

Abstract

The present invention relates generally to stereoselective processes for making compounds of formula (II) involving a catalyst comprising a transition metal which is selected from iron, palladium, ruthenium, osmium, rhodium and iridium.

Description

[0001]PROCESS The present invention relates generally to stereoselective processes for making 2- oxygenated decalins of formula (II). The present invention further relates to processes for making further compounds derived from the 2-oxygenated decalins of formula (II). The present invention also relates to the intermediate products and products of these processes. The products of the processes of the present invention may be useful as olfactory vectors, for example in fragrances. 2-Oxygenated decalins may be used as fragrance molecules and / or may be intermediates in the synthesis of fragrance molecules. It is therefore desirable to provide alternative and / or improved methods for making 2-oxygenated decalins, for example that may require milder conditions and / or that allow for better control of the stereoisomers and / or regioisomers that are produced. The transformation of a decalin-2-one to a corresponding alcohol or acetate is precedented in literature, for example from J. Chem.Res 36 (1998) and Aust.J.Chem 28, 225 (1975). These methods, however, have the problem that stoichiometric amounts of aluminium hydrides are used, generating organometallic waste. Other methods use stoichiometric amounts of sodium in ammonia or NaBH4 for reduction (Helvetica Chimica Acta 56, 1414 – 1448, 1973). These methods have problems when performed on an industrial scale (particularly in the case of Na / NH3). Also, these methods generate considerable amounts of the undesired trans stereoisomer, which impairs the efficient access to the desired acetate cis stereoisomer of formula (II) via the desired cis alcohol stereoisomer. Another method uses PtO2 in acetic acid and hydrogen, but this requires relatively large amounts of this heterogeneous catalyst for complete conversion (Helvetica 72, 1390, 1989; WO2020173977), which in turn raises the costs of producing the desired acetate. The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. It is an object of the present invention to provide a process that addresses one or more of the problems associated with the known processes described above. 31230 PCT / 01.10.2024 The present invention is related to a process for the preparation of a compound of formula (II) from a ketone of formula (I). Therefore, the product of the process of the invention is a compound of formula (II). The products of the processes of the present invention may be useful as olfactory vectors, for example as a fragrance ingredient. As described herein, “relative” stereochemistry is represented by the bonds at the relevant stereocentres (e.g. C2, C4a and C8a) having parallel edges, for example or . As described herein, absolute stereochemistry is represented by the bonds at the relevant stereocentres having edges that diverge to form a wedge shape, for example . The stereochemistry of formula (I) is relative with respect to the C4a and C8a carbon centres, so that the hydrogen at C4a and methyl group at C8a are always trans to each other. The desired product is the stereoisomer shown in formula (II) which is cis with respect to the C2 and C8a carbon centres. The compound of formula (II) is also trans with respect to the C4a and C8a carbon centres. The stereochemistry shown in formula (II) is relative, which means that formula (II) may have either of the For example, the compound of formula (II) may be referred to as the (-)-(2S,4aS,8aR) isomer (IIa), or (+)-(2R,4aR,8aS) isomer (IIb). It is desirable to produce the stereoisomer of formula (II) which is cis with regard to the C2 and C8a carbon centres and trans with regard to the C4a and C8a carbon centres in preference (in a higher relative amount) to other stereoisomers, because it has been found that the 31230 PCT / 01.10.2024 stereoisomer of formula (II) may be used as an olfactory vector and is desirable for use in fragrance compositions. As described on page 19 of WO2020 / 173977, it has been found that the odour threshold of pure (-)-(2S,4aS,8aR)-5,5,8a-trimethyl-decahydronaphthalen-2-yl acetate is 6 times stronger (GC-threshold) than pure (+)-(2R,4aR,8aS)-5,5,8a-trimethyl- decahydronaphthalen-2-yl acetate. This is surprising as several literature references indicate that the (-)-isomer is less strong than the (+)-isomer (Gautier et al., Helv. Chim. Acta 1987, 70, 2039, describe (-)-isomer as less rich, and also Vial et al, Helv. Chim. Acta 1989, 72, 1390, describe racemic Polywood®(rac.-(2S,4aS,8aR)-5,5,8a- trimethyldecahydronaphthalen-2-yl acetate) as “strong woody, very characteristic, dry and warm”, whereas the pure (-)-isomer is described as only “woody, dry, amber like”). Accordingly, the literature teaches that the (+)-isomer is preferred and stronger than the (-)-isomer. In addition the (C2, C8a)-trans-isomer as shown below is also not a desired product of the present invention. Surprisingly, it has now been found that it is possible to produce the desirable cis stereoisomer (with respect to C2 and C8a) of formula (II) by a method that overcomes one or more problems of known processes and allows the efficient and relatively inexpensive large-scale production of a compound of formula (II). The process of the present invention may provide one or more of the following advantages: ^ products with high diastereomeric purity, and good selectivity for the desired product; ^ good product yield; ^ a process with reduced environmental impact (e.g. low levels / quantity of catalyst required, higher catalyst turnover number, less waste generated) ^ a less expensive process (less expensive reagents, negligible material and processing costs); and ^ an industrially feasible process (high substrate concentration, hydrogenation at 50 bar or less). 31230 PCT / 01.10.2024 Preferences and options for a given aspect, feature or parameter of the invention should, unless the context indicates otherwise, be regarded as having been disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention. The present invention provides a process for producing a compound of formula (II), formula (II) wherein R1and R2are independently selected from hydrogen, alkyl and cycloalkyl, R3is hydrogen or alkyl and R4is hydrogen, -C(O)H or -C(O)alkyl, wherein the process comprises contacting a compound of formula (I), formula (I) with a catalyst comprising a transition metal, wherein the transition metal is selected from iron, palladium, ruthenium, osmium, rhodium and iridium, and a source of hydrogen; and optionally contacting the compound of formula (I) and / or a compound of formula (II) in which R4is hydrogen with a formylating agent, or an acetylating agent. The process provided herein is a process for diastereoselectively (with respect to C2, C8a) synthesizing compounds of formula (II) from compounds of formula (I). This means that a compound of formula (I) is converted to a pure diastereoisomer of the compound of formula (II) or a mixture enriched in the diastereoisomer of formula (II). A mixture enriched in the diastereoisomer of formula (II) can be purified by known purification techniques to obtain the pure diastereoisomer of formula (II). In this context, “pure diastereoisomer” means that there is at least 90%, preferably at least 31230 PCT / 01.10.2024 95% (e.g. at least 98%, which includes at least 99%, 99.5 of the stereoisomer in a mixture. The compound of formula (I) is trans with respect to the C4a and C8a carbon centres. This means that it can have either of the absolute stereochemistries at C4a and C8a shown below. formula (Ia) formula (Ib) The compound of formula (I) may be provided as a pure form of the desired stereoisomer or a racemic form, or a mixture enriched in a desired stereoisomer. There may also be additional chiral centres at C3 and / or C4, depending on which groups are chosen for R1, R2, and R3. If any chiral centres are formed at C3 and / or C4, the compounds of formula (I) or (II) may be pure or enriched in a particular stereoisomer with regard to the chiral centres at C3 and / or C4, or racemic with respect to the stereochemistry around C3 and / or C4. Preferably, the compound of formula (I) has the absolute stereochemistry of a compound of formula (Ia). This means that it has the absolute stereochemistry of formula (Ia), with regard to the chiral centres at C4a and C8a. The compound of formula (Ia) may be provided as a pure form of the desired stereoisomer (for example, 4aS,8aR) or a mixture enriched in the desired stereoisomer (for example, 4aS,8aR). The compound of formula (I) (and formula (Ia)) may, for example, be obtained commercially. Alternatively, compounds of formula (I) may be synthesized by the 31230 PCT / 01.10.2024 process described in WO 2020 / 173977. Workup and extraction of the thus formed compounds of formula (I) are known to the person skilled in the art. Compounds of formula (I) may be used in crude form or purified by known methods, such as purified by solvent extraction (e.g. using methyl-tert-butyl ether solvent), flash column chromatography on silica gel and / or distillation. Preferably, the compound of formula (II) has the absolute stereochemistry shown below with respect to the C2, C4a and C8a stereocentres. The compound of formula (II) may be pure (for example, 2S,4aS,8aR) with respect to the desired stereoisomer, or a mixture enriched in the (for example, 2S,4aS,8aR) desired stereoisomer. Methods suitable for the workup and extraction of the thus formed products of formula (II) are known to the person skilled in the art. Products of formula (II) may be purified by known methods, such as purified by solvent extraction (e.g. using methyl-tert-butyl ether solvent), flash column chromatography on silica gel and / or distillation. Definitions of R1, R2, R3, and R4The term "alkyl" refers to a linear straight chain or branched-chain saturated hydrocarbon group. The alkyl may, for example, have from 1 to 6 carbon atoms, for example from 1 to 5 carbon atoms, for example from 1 to 4 carbon atoms, for example from 1 to 3 carbon atoms, for example 1 or 2 carbon atoms. For example, the alkyl may be methyl, ethyl, propyl, butyl, iso-propyl or sec-butyl. For example, if R1is alkyl, the alkyl may be methyl or ethyl. For example, if R2and / or R3is alkyl, the alkyl may be methyl, ethyl or propyl. For example, if R4is -C(O)alkyl, the alkyl may be methyl or ethyl. The term "cycloalkyl" refers to a cyclic hydrocarbon group, which may optionally contain one double bond and which may optionally be substituted with one or more alkyl groups (the term "alkyl" being as defined above). The cycloalkyl may, for example, have from 3 to 7 carbon atoms, for example from 3 to 6 carbon atoms, for example from 3, 4 or 5 31230 PCT / 01.10.2024 carbon atoms. The cycloalkyl may be a saturated cyclic hydrocarbon group. For example, the cycloalkyl may be cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl (optionally substituted with an alkyl group, for example 2-methyl-cyclopent-1-yl, or 1- methyl-cyclohex-1-en-4-yl). The cycloalkyl may be substituted with one or more (including 2, 3 or 4) alkyl groups having from 1 to 6 carbon atoms, for example one or more alkyl groups having 1 or 2 carbon atoms. R4is hydrogen, -C(O)H or -C(O)alkyl. In other words, formula (II) is wherein Alk denotes an alkyl group as previously defined, and R1, R2and R3are as previously defined. Preferably the alkyl group in –C(O)alkyl is methyl or ethyl, more preferably methyl. R4may be hydrogen or -C(O)alkyl (for example, -C(O)Me or -C(O)Et). Preferably, R4may be hydrogen, -C(O)Me, -C(O)Et or -C(O)H. More preferably, R4may be hydrogen, -C(O)Me or -C(O)H. More preferably, R4may be hydrogen or -C(O)Me. In this case, compounds of formula (II) may be 31230 PCT / 01.10.2024 and more preferably may be a compound of formula (IIa) as depicted below wherein R1, R2and R3are as described herein. R4may be hydrogen. R4may be -C(O)Me. R1and R2are independently selected from hydrogen, alkyl and cycloalkyl, and R3is hydrogen or alkyl. R1and R3may be hydrogen and R2may be alkyl (e.g. methyl or ethyl) or cycloalkyl. R1may be alkyl or cycloalkyl and R2and R3may be hydrogen. R1may be methyl and R2and R3may be hydrogen. R1and R3may be hydrogen and R2may be cyclopropyl. R1and R2may be alkyl (e.g. methyl or ethyl) and R3may be hydrogen. R1may be hydrogen and R2and R3may be alkyl (e.g. methyl). Preferably, R1, R2and R3are hydrogen. In this case, R4may be hydrogen, -C(O)alkyl (e.g. -C(O)Me or -C(O)Et, preferably -C(O)Me), or -C(O)H, and more preferably R4may be hydrogen, -C(O)Me, or -C(O)H. For example, R1, R2and R3are hydrogen, and R4may be -C(O)Me. For example, R1, R2and R3are hydrogen, and R4may be -C(O)H. For example, R1, R2and R3are hydrogen, and R4may also be hydrogen. 31230 PCT / 01.10.2024 Alkylation and Formylation The process of the present invention may be carried out in a single step, or it may be carried out as a stepwise process. There is therefore provided a process for the preparation of a compound of formula (II) by (a) the hydrogenation of a compound of formula (I) to a compound of formula (II) in which R4is H to form an alcohol in the presence of a transition metal catalyst followed by acetylation or formylation of the alcohol to an acetate or formate, respectively, or by (b) the reduction of a compound of formula (I) to a compound of formula (II) being carried out in a single step using a solvent which is capable of immediate acetylation or formylation of the emerging alcohol such as, for example, ethyl acetate. For example, a process for producing a compound of formula (II), may comprise forming a compound of formula (II) in which R4is hydrogen, and contacting said compound with (i) an acetylating agent to produce a compound of formula (II) in which R4is -C(O)alkyl, preferably -C(O)Me, or (ii) a formylating agent to produce a compound of formula (II) in which R4is -C(O)H. In one particular embodiment, the process of the present invention may be carried out as a single step. By “single step” it is meant that there is no need to form, isolate and purify an intermediate (for example a compound of formula (II) in which R4is hydrogen) before proceeding to a desired product such as a compound of formula (II) in which R4is - C(O)Me or -C(O)H. This may make the process much simpler and easier to perform, especially on a production scale and / or industrial scale. In a further embodiment, the process of the present invention may be carried out as a step-by-step process. By “step-by-step process” it is meant that an intermediate is formed, and optionally isolated, for example a compound of formula (II) in which R4is hydrogen, before optionally proceeding to another product, such as a compound of formula (II) in which R4is -C(O)Me or -C(O)H. As used herein, the term “formylating agent” means a substance that is able to provide a formyl group (-C(O)H). For example, a formylating agent may be used in the process of the present invention to contact a compound of formula (I) to provide a compound 31230 PCT / 01.10.2024 of formula (II) wherein R4is -C(O)H. A formylating agent in the context of the present invention is preferably formic acid. As used herein, the term “acetylating agent” means a substance that is able to provide an alkanoyl group (-C(O)alkyl). In particular, an acetylating agent is able to provide an acetyl (-C(O)Me) or propanoyl (-C(O)Et) group, preferably an acetyl group. For example, an acetylating agent may be used in the process of the present invention to contact a compound of formula (II) wherein R4is hydrogen to provide a compound of formula (II) wherein R4is -C(O)alkyl. For example, an acetylating agent may be used in the process of the present invention to contact a compound of formula (II) wherein R4is hydrogen to provide a compound of formula (II) wherein R4is -C(O)Me or -C(O)Et. For example, an acetylating agent may be used in the process of the present invention to contact a compound of formula (II) wherein R4is hydrogen to provide a compound of formula (II) wherein R4is -C(O)Me. In the present invention, the acetylating agent may be an alkyl acetate, alkanoic anhydride, sodium alkanoate, lithium alkanoate, potassium alkanoate, or a mixture thereof; preferably ethyl acetate, acetic anhydride, sodium acetate, or a mixture thereof. In one particular embodiment, the acetylating agent is acetic anhydride. As used herein, the term “alkanoic anhydride” means a substance with the chemical structure R’-C(O)-O-C(O)-R’, wherein each R’ group is independently an alkyl group, for example methyl or ethyl. For example, an alkanoic anhydride may be acetic anhydride (R’ is methyl), or propanoic anhydride (R’ is ethyl), preferably acetic anhydride. As used herein, the term “sodium alkanoate” means a substance with the chemical structure R”-C(O)-O- Na+, wherein R” is an alkyl, such as, for example, methyl, ethyl, propyl, or phenyl. For example, a sodium alkanoate may be sodium acetate (R” is methyl), or sodium propanoate (R” is ethyl), preferably sodium acetate. Catalyst The present invention is a highly selective process, in that the stereochemistry of formula (II) can be achieved. This may be, at least in part, due to the transition metal catalyst. Some advantages of the catalysts used in the process of the present invention, are that they may reduce the cost of the process as the low catalyst loading means that a relatively low amount of the catalyst is required, whilst retaining a high yield and good selectivity for the desirable C2,C8a-cis-stereoisomer of formula (II) versus the corresponding C2,C8a-trans-stereoisomer, with the selectivity often in excess of 90%. 31230 PCT / 01.10.2024 As used herein, the term “catalyst” means a species that is capable of increasing the rate of reaction, without being consumed by the reaction itself. Use of a catalyst may enable a more atom economical reaction, which may be considered to be a more environmentally friendly process. Surprisingly, it has been found that transition metal catalysts comprising iron, palladium, ruthenium, osmium, rhodium or iridium can be used for the process of the present invention. In one particular embodiment, the metal catalysts comprise iron or ruthenium. As used herein, the term “ruthenium(II)” means the chemical element ruthenium in a +2 oxidation state. The terms “ruthenium(II)” and “Ru(II)” are used interchangeably. Ruthenium(II) is able to form coordination complexes that may exhibit useful catalytic properties in the process of the present invention. An advantage of the process of the present invention is that lower levels of the catalyst may be used compared with prior art processes. This may reduce process costs. Using low levels of a transition metal catalyst may also reduce the environmental impact of the process, as it may reduce the amount of waste generated. The catalyst may be either homogeneous or heterogeneous. As used herein, the term “homogeneous catalyst” is used to relate to a catalyst that is soluble in the reaction medium. As used herein, the term “heterogeneous catalyst” is used to relate to a catalyst that is insoluble in the reaction medium. The procedure for both heterogeneous and homogeneous catalysts is similar, the main difference being whether the catalyst is dissolved or not in the reaction medium containing a compound of formula (I) and optionally a solvent. In the heterogeneous case, the catalyst is not dissolved in the reaction medium and is usually separated by filtration from the product mixture. In the homogeneous case, the catalyst is dissolved in the reaction medium and is usually separated from the product by distillation of the product leaving the homogeneous catalyst or its debris in the distillation residue. Preferably, the catalyst used in the process of the present invention is a homogeneous catalyst. In one particular embodiment, the ruthenium(II)-based homogeneous catalysts may be preferred in the process of the present invention. Homogeneous ruthenium (II)-based catalysts, such as IIIb, IIIc, IIId and IIIe as disclosed herein, may achieve much lower catalyst loadings compared to known processes and may be used with non-polar and / or 31230 PCT / 01.10.2024 non-corrosive solvents. This may mean that the process is more environmentally friendly. Ruthenium (II)-based catalysts may also make the process more efficient by reducing the steps that may be required in the work-up of the products, such as filtration and removal of byproducts. This may be particularly advantageous when the process of the present invention is carried out in a single step. Non-limiting examples of catalysts used in the process of the present invention include Ru(II)Cl2NxPySz, wherein N, P and S represent connections to ligand(s) via N, P and S atoms respectively with x = 1-2, y = 2 and z = 0-2. The N, P, and S atoms may be all included in one polydentate ligand, for example a tridentate ligand or a bidentate ligand (if z=0). The N, P and S atoms may be in separate ligands, for example two or three separate monodentate ligands, or bidentate ligands. For example, when x is 1, y is 2, and z is 0, Ru(II)Cl2NxPySz includes catalysts IIIc and IIId: A particular non-limiting example of the catalyst that may be used in the process of the present invention is: wherein R5is an alkyl or aryl group, pre ferably meth yl, ethyl, propyl, butyl, octyl, or benzyl, or R5, in conjunction wit h t h e s u l p hur atom to which it is attached and the adjacent carbon atom, ms an heteroaryl ring such as thiophenyl or benzothiophenyl, preferably wherein R5is methyl or n-butyl. For example, in this case, the catalyst may have the structure described in Examples 1 (R5forms a thiophenyl with the sulphur atom and adjacent carbon atom to which it is attached), 2 (R5forms a benzothiophenyl with the sulphur atom and adjacent carbon atom to which it is attached), 3 (R5is methyl), 4 (R5is n-butyl) or 5 (R5is n-octyl) of WO2015 / 110515, and may be prepared by the respective processes described in the corresponding examples of WO2015 / 110515. 31230 PCT / 01.10.2024 As used herein, the term “aryl” refers to aromatic monocyclic or multicyclic groups containing 5 to 15 carbon atoms in the ring system, preferably 5 to 10 carbon atoms in the ring system. The ring system may be monocyclic, bicyclic, or tricyclic, preferably monocyclic or bicyclic. The ring system may be a fused ring system. Aryl groups include, but are not limited to, groups such as unsubstituted or substituted phenyl, or benzyl. When referring to substitution of the aryl, the substitution may be at any position on the ring other than the point of attachment to the rest of the compound. For example, when the aryl is a phenyl there may be substitution of any hydrogen atom on the phenyl ring in the meta-, ortho-, or para- positions relative to the point of attachment to the rest of the compound. As used herein, the term “heteroaryl” refers to an aryl in which one or more carbon atoms in the ring system are substituted with a heteroatom. The ring system may be monocyclic, bicyclic, or tricyclic. The ring system may be a fused ring system. The heteroatoms in the ring system may be sulphur, nitrogen, oxygen or phosphorus. There may be one or more heteroatoms in the ring system, for example there may be one, two, three or four heteroatoms in the ring system, preferably there are one or two heteroatoms in the ring system, more preferably one heteroatom in the ring system. Heteroaryl groups include, but are not limited to, groups such as unsubstituted or substituted thiophenyl or benzoth iophenyl. Particular non-limiting exam ples of suitable catalysts used in the proc ess of the present invention include c atalys ts IIIa – IIIi as sh own below from which IIIb, IIIc and IIId are preferred. I IIi is typically k now n as Sh v o’s catalyst. 31230 PCT / 01.10.2024 Further non-limiting examples of catalysts used in the present invention include Rh / C, Pd / C, Ru / C, and Ru / Al2O3. A particularly favourable heterogeneous catalyst for use in the process of the present invention is Rh / C. As used herein, “ / ” in the context of a catalyst, for example Rh / C, Ru / C, Ru / Al2O3, means “on”. For example, Rh / C means rhodium on carbon, s o that the rhodium is on a carbon support. Preferably, the catalyst used in the process of the present invention is selected from the group consisting of an alkyl or aryl group, preferably methyl, ethyl, propyl, butyl, octyl, r benzyl, o r R5, in conjunction with the sulphur atom to w h ic h i t i s a nd the adjac ent carbon atom, forms a heteroaryl ring such as thiophenyl or benzothiophenyl, preferably wherein R5is methyl or n-butyl; 31230 PCT / 01.10.2024 and R7are independently C1-6 alkyl, preferably methyl, ethyl, propyl or butyl, more preferably ethyl, or an optionally substituted aryl, preferably optionally substituted benzyl; wherein one or more carbon atoms on the ligand backbone are optionally substituted; wherein R8and R9are independently C1-6 alkyl, preferably isopropyl, isobutyl, tert-butyl, or tert-pentyl, and wherein one or more carbon atoms on the ligand backbone are optionally substituted; 31230 PCT / 01.10.2024 Rh / C; Pd / C; Ru / C; and Ru / Al2O3. In one particular embodiment, the catalyst used in the process of the present invention is selected from Other catalysts that may be used in the process of the present invention include IIIk: IIIk wherein R6and R7are independently C1-6 alkyl, preferably methyl, ethyl, propyl or butyl, more preferably ethyl, or an optionally substituted aryl, preferably optionally substituted benzyl. Catalyst used in the process of the present invention may comprise at least one stereogenic centre. Preferably, the at least one stereogenic centre comprises a transition metal such as for example ruthenium (II), more preferably there are one or two stereogenic centres comprising transition metals (preferably ruthenium (II)) in the catalyst. For example, a stereogenic centre in the catalyst may be a transition metal surrounded by ligands to form a transition metal complex, such as, for example, the ruthenium ion in RuCl2(en)(PPh3)2. For example, the catalyst may have two stereogenic centres, both comprising ruthenium (II). Alternatively, there may be a stereogenic centre comprising ruthenium (II), and a second stereogenic centre comprising another ion, which is preferably a transition metal, such as, for example, iron. In any cases where there is more than one transition metal centre in the catalyst, there may be at least one bridging ligand to connect the transition metal centres together. The transition metal centres may also independently be stereogenic centres or not stereogenic centres. Preferably, in the case when there is more than one metal centre in the catalyst, there are two metal centres in the catalyst, and more preferably there are two metal centres and both metal centres are stereogenic centres. The stereogenic centres in the catalyst 31230 PCT / 01.10.2024 may have, for example, arrangements based on octahedral, trigonal bipyramidal, or tetrahedral geometry. As used herein, the term “stereogenic centre” refers to an atom or ion that gives different stereoisomers when the atoms or groups attached to it are exchanged. For example, in a transition metal complex, a transition metal attached to a number of ligands may be a stereogenic centre if when the ligands are exchanged, different stereoisomers are formed. For example, the catalyst may comprise a metal ion, preferably ruthenium (II), as a stereogenic centre, and at least one ligand. Ligands may be connected to a stereogenic centre by donating a pair of electrons to the ion at the stereogenic centre. Ligands may be monodentate or polydentate. Monodentate ligands are connected to the stereogenic centre through one atom in the ligand. Examples of monodentate ligands include but are not limited to triphenylphosphine (PPh3), halogens (for example, chlorine (Cl), fluorine (F), bromine (Br), iodine (I)), carbonyl (CO), and hydrogen (H). Polydentate ligands may be connected to the stereogenic centre (for example, a metal ion such as ruthenium(II)) by two or more atoms in the ligand. For example, polydentate ligands may be connected to the stereogenic centre by two, three, four, five or six donor atoms. Bidentate ligands are connected to the stereogenic centre by two ligand atoms, and tridentate ligands are connected to the stereogenic centre by three ligand atoms. Examples of polydentate ligands include but are not limited to SNP-Me, SNP-Bu, ethylenediamine (en), MACHO, and aromatic ligands such as phenyl rings optionally substituted with one or more groups such as phenyl or hydroxy. The catalysts may be prepared in a straightforward manner using common starting materials and reagents, according to literature methods. They may also be obtained commercially. The catalysts that may be used in the process of the present invention are known in the art. Table 1 below provides as summary of the specific catalysts and prior art in which the catalyst and variations thereof (including backbone substitution) have been described in more details. 31230 PCT / 01.10.2024 Table 1: Catalyst Prior art (incorporated by references) IIIa T.W.Funk et al. Adv. Synth. Catal.354, 597-601, 2012 IIIb M.Jackson et al. OPRD 10, 1054-1058 (2006) IIIc WO 2015110515 IIId WO 2015110515 IIIk WO2014036650 IIIl WO 2013023307 IIIm WO 2014139030 Process conditions and reagents Source of hydrogen The source of hydrogen may be hydrogen gas. In this case, the hydrogen gas pressure may be from about 1 x 105Pa (1 bar) to about 6 x 106Pa (60 bar), preferably from about 4 x 106Pa (40 bar) to about 5 x 106Pa (50 bar). The skilled person would understand that the hydrogen pressure can be adjusted to optimise the process, with regard, for example, to the catalyst chosen, desired yield, and selectivity for the desired stereoisomer. Alternatively, the process may comprise a transfer hydrogenation. In this case, the source of hydrogen is a hydrogen donor. In this case, the process does not require application of hydrogen pressure, but hydrogen pressure may optionally be applied. The hydrogen donor may be a solvent. For example, hydrogen may be generated in situ from solvents such as isopropanol, formic acid, or formate salts which undergo dehydrogenation to acetone or carbon dioxide in the presence of a transition metal catalyst. Under transfer hydrogenation conditions, excellent selectivity ratios for the desired stereoisomer (i.e. a compound of formula II) were achieved. Preferably, the source of hydrogen is hydrogen gas. When the source of hydrogen is hydrogen gas, less catalyst, less solvent and lower temperatures may be required than when the reaction is a transfer hydrogenation (i.e. the source of hydrogen is a hydrogen donor). Without wishing to be bound by theory, this may be because the use of hydrogen gas allows for a higher concentration of hydrogen in the mixture. When the process of the present invention is performed at an industrial scale it is typically favourable to minimise the amount of catalyst and solvent used and to use lower temperatures. 31230 PCT / 01.10.2024 Stereoselectivity The process provided herein is selective for a stereoisomer of formula (II), which means that it produces a stereoisomeric excess of the stereoisomer of formula (II) with C2 / C8a cis stereochemistry and C4a / C8a trans stereochemistry. The compound of formula (II) made by the processes described herein may, for example, have a stereoisomeric excess of at least about 90% of a stereoisomer of formula (II) with C2 / C8a cis stereochemistry and C4a / C8a trans stereochemistry. The stereoselectivity for the compound of formula (II) may be at least about 90%, preferably at least about 95%, more preferably at least about 97 %. For example, the process of the present invention may be at least about 90%, at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, at least about 95%, or at least about 96%, at least about 97%, at least about 98%, at least about 99% selective for the stereoisomer of formula (II) with C2 / C8a cis stereochemistry and C4a / C8a trans stereochemistry. For example, the process of the present invention may be up to about 100% selective for the stereoisomer of formula (II) with C2 / C8a cis stereochemistry and C4a / C8a trans stereochemistry. Stereoisomeric excess is a measurement of the difference between the amounts of each stereoisomer. For example, a mixture of 70 % of one stereoisomer and 30 % of the other stereoisomer has a stereoisomeric excess of 40 %. A racemic mixture has an stereoisomeric excess of 0 % and a completely pure stereoisomer has a stereoisomeric excess of 100 %. The amount of each stereoisomer in the mixture may, for example, be measured using methods such as gas chromatography on chiral columns and NMR spectroscopy in the presence of shift reagents. The stereoselectivity of the process of the invention is relative to the C2, C4a, and C8a carbon centres. The process of the present invention may involve compounds of formulae (I) and / or (II) with additional chiral centres in the C3 and / or the C4 positions. The process of the present invention may or may not be stereoselective with regard to these additional chiral centres. For example, if one or more additional chiral centres are present, compounds of formula (I) and / or formula (II) may be a racemic mixture, or provided in a mixture enriched in a stereoisomer or pure stereoisomer forms with respect to these additional chiral centres at C3 and / or C4. Temperature The process may be conducted at a temperature from about 25oC to about 150oC, preferably from about 30oC to about 85oC, more preferably from about 40oC to about 50oC. 31230 PCT / 01.10.2024 Contact time The process may have a contact time between the compound of formula (I), the source of hydrogen, and the catalyst of from about 1 second to about 80 hours, preferably wherein the contact time is from about 1 hour to about 72 hours, more preferably wherein the contact time is from about 4 hours to about 70 hours, more preferably wherein the contact time is from about 8 hours to about 24 hours, more preferably wherein the contact time is from about 20 hours to about 22 hours. Solvent Another advantage of the present invention may be that low quantities of solvents may be used, which may reduce the environmental impact of the process and may make the process less expensive. Furthermore, different compounds of formula (II), such as an alcohol, formate, or acetate, may be produced by selecting an appropriate solvent. The selection of the solvent may depend on the catalyst used and the hydrogen source. The choice of solvent is a straightforward one according to the practices of the art, but typical non-limiting examples include alcohols such as methanol, ethanol, isopropanol (generally all C1-15 alcohols) and aprotic solvents such as toluene, xylene, tetrahydrofuran and 2-methyltetrahydrofuran. If solvents such as acetates are used, non-limiting examples include alkyl acetates ROAc with R = C1-15 (that is a C1-15 alkyl acetate), preferably methyl acetate, ethyl acetate or butyl acetate, more preferably ethyl acetate. Alkyl acetates are preferred as solvents when R4is -C(O)Me. In addition, formic acid may be a suitable solvent, especially when R4is -C(O)H. As used herein, “alkyl acetate” means a substance with the chemical structure R’”-O- C(O)-Me, wherein R”’ is an C1-15alkyl, such as, for example, methyl, ethyl, propyl or butyl. The process may be conducted in a solvent such as: i) a polar aprotic solvent, preferably tetrahydrofuran, 2-methyltetrahydrofuran, or C1-15 alkyl acetate; more preferably tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, or butyl acetate; or ii) a polar protic solvent, preferably an alkanoic acid, more preferably methanoic acid; or an alcohol, preferably a C1-15 alcohol, more preferably C1-6 alcohol, more preferably methanol, ethanol or isopropanol; or a combination thereof; or iii) a nonpolar solvent, preferably toluene or xylene. 31230 PCT / 01.10.2024 As used herein, “alkanoic acid” means a substance with the chemical structure RCOOH (i.e. a carboxylic acid), wherein R is H or a C1-14 alkyl group, preferably H or a C1-6 alkyl group, more preferably H or a C1-3 alkyl group. Examples of alkanoic acids include but are not limited to methanoic acid (formic acid), ethanoic acid (acetic acid), propanoic acid, butanoic acid and so on. The solvent may act as an acetylating or formylating agent. For example, if the solvent is an alkyl acetate, the solvent may act as an acetylating agent. In this case, R4may be -C(O)Me. Alternatively, if the solvent is formic acid, the solvent may act as a formylating agent. In this case, R4may be -C(O)H. Preferably, R4is -C(O)Me and the solvent is a polar protic solvent, preferably ethyl acetate. In this case, the process is preferably carried out as a single step. Base The process may be conducted in the presence of a base, and preferably the base is NEt3, NaOMe, KOtBu, or KOMe. The amount in moles of the base is preferably from about 1 % to about 10 % of the amount in moles of the compound of formula (I). Catalyst loading and turnover number The present invention is based, at least in part, on the surprising finding that a turnover number of the catalyst used in the process of the present invention can be extremely high, which in turn may lead to a low catalyst loading compared to the substrate (compounds of formula (I)), whilst still achieving a quantitative conversion and high selectivity for compounds of formula (II). As used herein, the term “catalyst loading” means the amount of catalyst used in the process relative to the amount of the substrate (for example, a compound of formula (I)). It is favourable to have lower catalyst loading as this may limit the cost of the process. The catalyst loading of the process of the present invention may be less than about 3 mol% relative to the amount of the compound of formula (I). Preferably the catalyst loading may be from about 0.0001 mol% to about 2 mol% relative to the amount of the compound of formula (I). Preferably the catalyst loading may be from about 0.0001 mol% to about 0.5 mol% relative to the amount of the compound of formula (I). As used herein, the term “turnover number” means the number of moles of substrate (for example, a compound of formula (I)) that a catalyst can convert before the catalyst 31230 PCT / 01.10.2024 becomes inactivated or the reaction is stopped. It can be abbreviated to TON, and this acronym is used interchangeably with the term “turnover number”. It is favourable to have a higher turnover number as this means that the lifetime of the catalyst is extended. A high turnover number may reduce process costs and may reduce the environmental impact of the process, as the catalyst needs to be replaced less frequently. For example, homogeneous catalysis using Ru(II)- or Os(II)-catalysts may have a very high turnover number when used in a process of the present invention. The turnover number (TON) of the catalyst used in the process of the present invention may be at least about 10,000. Preferably, the turnover number (TON) of the catalyst is at least about 100,000. More preferably, the turnover number (TON) of the catalyst is at least about 1,000,000. Further process conditions Another advantage of the process of the present invention is that it can be carried out under industrially feasible conditions, such as using a high substrate concentration, and, where relevant, a hydrogen pressure of 5 x 106Pa (50 bar) or less. In other words, the reaction conditions needed for the process of the present invention are industrially applicable, such that scale-up to production quantities is possible. The reaction mixture may be carried out under hydrogen pressures of about 1 to about 50 bar (about 1 x 105Pa to about 5 x 106Pa) at a temperature from about 25 °C to about 150 °C for about 1 second to about 80 hours to convert the compound of formula (I) to a compound of formula (II). If formula (II) is an alcohol (i.e. R4is hydrogen) an acetate of formula (II) may be prepared from said alcohol of formula (II) by reaction with sodium acetate with heating. The processes described herein comprise contacting a compound of formula (I) with a catalyst and a source of hydrogen. The catalyst may for example be added under nitrogen to a compound of formula (I). The catalyst may for example be in a solvent. The catalyst may for example be added to a compound of formula (I), and optionally a base, in a solvent. The catalyst may for example be added to a compound of formula (I) in an autoclave. The compound of formula (I) may be contacted with hydrogen in an autoclave. The contacting of the compound of formula (I) with the source of hydrogen and the catalyst takes place under conditions suitable to convert the compound of formula (I) to the compound of formula (II). The conditions (e.g. temperature, pressure, contact time, catalyst loading etc.) for the contacting of the compound of formula (I) with the 31230 PCT / 01.10.2024 source of hydrogen and the catalyst may, for example, be selected according to the optimal conditions of the catalyst to be used in the reaction. The contacting of the compound of formula (II) and the source of hydrogen and the catalyst may, for example, take place in the presence of any species that assist the function of the catalyst. Definitions Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skills in the art to which this invention pertains. The term “comprises” or “comprising” will take its usual meaning in the art, namely indicating that the component includes but is not limited to the relevant features (i.e. including, among other things). As such, the term “comprises” will include references to the component consisting essentially of (such as consisting of) the relevant features. The term “consists of” or “consisting” will take its usual meaning in the art, namely indicating that the component includes and is limited to the relevant features. As used herein, “independently selected from” means that the same or different values may be selected for multiple instances of a given variable in a single formula. As used herein, the term “optionally substituted” means that a group may or may not have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom's normal valency is not exceeded and the identity of each substituent is independent of the others. Up to three H atoms in each residue are replaced with alkyl,or cycloalkyl, preferably C1-6alkyl or C3-6cycloalkyl, more preferably C1-3alkyl or C3-6cycloalkyl. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. As used herein, “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture. As used herein, the term “at least one” means that at least one of the features that follows the term, including but not limited to one, two, three, four, five, six, etc. of said feature. For example, “at least one stereogenic centre” may refer to one stereogenic centre, two stereogenic centres, three stereogenic centres, four stereogenic centres, five stereogenic centres, six stereogenic centres and so on. If a chiral centre or another form of an isomeric centre is present in a compound in the process of the present invention, all forms of such isomer or isomers, including 31230 PCT / 01.10.2024 enantiomers and diastereomers, are intended to be covered herein, unless indicated to the contrary. Unless indicated otherwise, compounds containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. Unless indicated otherwise, the compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. When the structure of the compounds used in this invention includes an asymmetric carbon atom such compound can occur as racemates, racemic mixtures, and isolated single enantiomers, unless indicated otherwise. All such isomeric forms of these compounds are expressly included in this invention. Each stereogenic carbon may be of the R or S configuration, unless indicated otherwise. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. For example, the resolution may be carried out by preparative chromatography on a chiral column. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. Where a numerical range is provided herein for any parameter, it is understood that all numerical subsets of that numerical range, and all the individual integer values contained therein, are provided as part of the invention. For example, a range of 1 to 6 carbon atoms includes the subset of 1 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 4 carbon atoms, etc., as well as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. The present invention is further described by the following non-limiting examples. 31230 PCT / 01.10.2024 EXAMPLES The labelling of the catalysts IIIa-IIIi in the following Examples corresponds to the catalysts IIIa-IIIi described earlier in this application. Example 1: Homogeneous hydrogenation of with catalyst RuCl2(SNP-Me)PPh3 (IIId) followed by acetylation RuCl2(SNP-Me)(PPh3) IIId (0.2 mg, 0.0003 mmol) in anhydrous tetrahydrofuran (2 ml) was added under nitrogen to (4aSR,8aRS)-5,5,8a-trimethyloctahydronaphthalen- 2(1H)-one (60 g, 0.3 mol) and potassium methoxide (2.2 g, 31 mmol) in water-free tetrahydrofuran (32 ml) in an autoclave. The autoclave was closed, flushed and evacuated four times with 10 bar of hydrogen. After 24 h stirring at 50 °C under 50 bar of hydrogen GC showed 99 % conversion. The pressure was released and the reaction mass transferred to a glass flask and rinsed with a few ml of tetrahydrofuran. The solvent was removed under reduced pressure giving 27 g of tetrahydrofuran and 63 g of (2SR,4aSR,8aRS)-5,5,8a-trimethyldecahydronaphthalen-2-ol as a crude orange solid with a purity of 99.1% and a (C2,C8a)-cis / trans ratio of 99.3 / 0.7 according to GC-FID. The analytical data (GCMS, NMR) of this product were consistent with the ones in the literature (M.Pfau et al. Tetrahedron: Asymmetry 8, 1101 (1997)). A mixture of the thus obtained (2SR,4aSR,8aRS)-5,5,8a-trimethyldecahydronaphtha- len-2-ol (57.6 g, 0.29 mol), acetic anhydride (42 g, 0.41 mol) and sodium acetate (120 mg, 1.5 mmol) in water-free xylene (67 ml) was stirred at 80°C for 6 h. After complete conversion the solvent was removed under reduced pressure. The reaction mixture was transferred into a separatory funnel, the phases were separated and the organic layer was washed with water (75 ml). After phase separation, the organic phase was washed with saturated aqueous NaHCO3 (75 ml) and brine (75 ml). The organic phase was dried over MgSO4, filtered and evaporated giving 77.17 g crude (2SR,4aSR,8aRS)-5,5,8a- trimethyldecahydronaphthalen-2-yl acetate as colorless oil. After addition of paraffin oil (5 g) and fractionated distillation at 130 °C / 0.02 mbar 60 g of (2SR,4aSR,8aRS)- 5,5,8a-trimethyldecahydronaphthalen-2-yl acetate were obtained with a purity of 96.5 – 99.5 % from which 33.3 g with a purity of 99% were judged as olfactorily fine by the perfumers. The analytical data (GCMS, NMR) of this product were consistent with the ones reported in the literature (R.L. Snowdon EP 0177742, priority 12.9.1984 to Firmenich SA). Example 2: The table below lists comparative results from different homogeneous hydrogenation catalysts in different solvents, which gave (2SR,4aSR,8aRS)-5,5,8a- 31230 PCT / 01.10.2024 trimethyldecahydronaphthalen-2-ol from (4aSR,8aRS)-5,5,8a-trimethyloctahydro- naphthalen-2(1H)-one under the same reaction condition as described in Example 1: Cat loading base solvent time temp p(H2) conv cis / tr aans c / s [mol%] [°C] [bar] ratio (mol%) IIIa 2% none THF 22 h 50 ° 10 98% 98:2 IIIa 2% none iPrOH 72 h 85 ° transfer 96% 98:2 IIIb 0.01% 5% toluene 20 h 50 ° 50 quant 100:0 NaOMe IIIb 0.25% 10% iPrOH 22 h 82 transfer quant 84:16 KOtBu IIIc 0.0001 10% THF 20 h 50 ° 50 quant 99:1 % KOMe IIId 0.0001 10% THF 20 h 50 ° 50 quant 99:1 % KOMe IIIe 0.0025 10% THF 20 h 100 ° 50 quant 71:28 % KOMe IIIf 0.5% none MeOH 4 h 50 ° 40 50% 100:0 IIIg 0.1% 1% KOtBu iPrOH 20 h 25 ° 50 79% 100:0 IIIh 0.5% NEt3 HCO2H 16 h 40 ° transfer quant 100:0 Abbreviations: Cat = catalyst, c / s = catalyst / substrate ratio, temp = temperature, p(H2) = hydrogen pressure, conv = conversion, THF = tetrahydrofurane, iPrOH = isopropanol, quant = quantitative, transfer = transfer hydrogenation. a) C2,C8a-cis-stereoisomer versus the corresponding C2,C8a-trans-stereoisomer Example 3: Reductive acetylation with catalyst RuCl2(en)(PPh3)2 (IIIb) To a 50 mL pressure vessel, (4aSR,8aRS)-5,5,8a-trimethyloctahydronaphthalen-2(1H)- one (5 g, 25.7 mmol), ethyl acetate (10 g), NaOMe (25 wt% in MeOH) (0.25 g) and RuCl2(en)(PPh3)2 (IIIb) (2 mg) were added. The pressure vessel was closed, flushed and evacuated four times with 10 bar of hydrogen. After 67 h stirring at 50 °C under 40 bar of hydrogen GC shows 99 % conversion to (2SR,4aSR,8aRS)-5,5,8a-trimethyldeca- hydronaphthalen-2-yl acetate with a (2,8a)-cis / trans ratio of 99.3 / 0.7. Example 4: Homogeneous hydrogenation with catalyst (IIIb) followed by acetylation To a 600 mL pressure vessel, (4aSR,8aRS)-5,5,8a-trimethyloctahydronaphthalen- 2(1H)-one (130 g, 6.69 mol), 130 g of toluene, of NaOMe (25 wt% in MeOH) (6.5 g) and RuCl2(en)(PPh3)2 (52 mg) (IIIb) were added. The pressure vessel was closed, flushed and evacuated four times with 10 bar of hydrogen. After 22 h stirring at 50 °C under 40 bar of hydrogen GC shows 99 % conversion to (2SR,4aSR,8aRS)-5,5,8a- trimethyldecahydronaphthalen-2-ol with a (2,8a)-cis / trans ratio of 99.2 / 0.8 according to GC. The pressure is released and the reaction mass transferred to a glass flask and rinsed with a few ml of toluene. 31230 PCT / 01.10.2024 To the toluene mixture of thus obtained (2SR,4aSR,8aRS)-5,5,8a-trimethyldecahydro- naphthalen-2-ol was added acetic anhydride (97 g, 950 mmol) and sodium acetate (272 mg, 3.31 mmol) was stirred at 80°C for 5 h. The reaction mixture was transferred into a separatory funnel and washed with water (100 ml). The phases were separated and the organic phase was washed with saturated aqueous NaHCO3 (100 ml) and brine (100 ml). The organic phase is dried over MgSO4, filtered and evaporated giving 146 g crude acetate (2SR,4aSR,8aRS)-5,5,8a-trimethyldecahydronaphthalen-2-yl acetate as an oil with a chemical yield of 92%. Example 5: Homogeneous hydrogenation of with Shvo catalyst (IIIi) To a 25 mL flask, (4aSR,8aRS)-5,5,8a-trimethyloctahydro-naphthalen-2(1H)-one (0.45 g, 2.31 mmol), ethyl acetate (1 g, 11.35 mmol), formic acid (0.13 g, 2.78 mmol) and Shvo catalyst (IIIi) (4 mg, 0.003 mmol) were added. After 23 h stirring at 80 °C under nitrogen GC shows 75% conversion to (4aSR,8aRS)-5,5,8a-trimethyldecahydro- naphthalen-2-yl formate. MS (EI, 70 eV): 209 (2, [M+• - CH3•]+), 163 (100), 124 (78), 107 (49), 95 (46), 93 (58), 81 (95), 69 (48), 67 (50), 55 (56), 41 (74) Example 6: Heterogeneous hydrogenation of racemic ketone with catalyst 5% Rh / C To a 10 mL pressure vessel, (4aSR,8aRS)-5,5,8a-trimethyloctahydro-naphthalen- 2(1H)-one (0.5 g, 2.57 mmol), ethyl acetate (0.5 g, 5.67 mmol) and 5% Rh / C (5 mg) were added. The pressure vessel was closed, flushed and evacuated four times with 10 bar of hydrogen. After 16 h stirring at 50 °C under 40 bar of hydrogen GC shows 99 % conversion to (2SR,4aSR,8aRS)-5,5,8a-trimethyldecahydronaphthalen-2-ol with a (2,8a)-cis / trans ratio of 97 / 3. 31230 PCT / 01.10.2024

Claims

CLAIMS 1. A process for producing a compound of formula (II),wherein R1and R2are independently selected from hydrogen, alkyl and cycloalkyl, R3is hydrogen or alkyl and R4is hydrogen, -C(O)H or -C(O)alkyl, wherein the process comprises contacting a compound of formula (I),formula (I) with a catalyst comprising a transition metal, wherein the transition metal is selected from iron, palladium, ruthenium, osmium, rhodium and iridium, and a source of hydrogen; and optionally contacting the compound of formula (I) and / or a compound of formula (II) in which R4is hydrogen with a formylating agent, or an acetylating agent.

2. A process according to claim 1, wherein R4is hydrogen or -C(O)Me.

3. A process according to claim 2, wherein the process further comprises contacting the compound of formula (II) in which R4is hydrogen with (i) an acetylating agent to produce a compound of formula (II) in which R4is -C(O)alkyl, preferably -C(O)Me or (ii) a formylating agent to produce a compound of formula (II) in which R4is -C(O)H.

4. A process according to any preceding claim, wherein R1, R2and R3are hydrogen.

5. A process according to any preceding claim, wherein formula (I) has the absolute stereochemistry of formula (Ia): 31230 PCT / 01.10.2024wherein R1, R2and R3are as defined in any preceding claim.

6. A process according to any preceding claim, wherein the catalyst comprises a transition metal selected from iron, palladium, ruthenium, osmium and rhodium, preferably iron, ruthenium, osmium or rhodium, more preferably, iron or ruthenium, more preferably ruthenium, most preferably ruthenium (II).

7. A process according to any preceding claim, wherein the catalyst is selected from the group consisting ofR5is an alkyl or aryl group, preferably methyl, ethyl,propyl, but octyl, orbenzyl, or R5,inconjunctionwiththesulphuratom to which it is attachedand the adjacent carbon atom, forms a heteroaryl ring such as thiophenyl or benzothiophenyl, preferably wherein R5is methyl or n-butyl;31230 PCT / 01.10.2024wherein R6and R7are independently C1-6 alkyl, preferably methyl, ethyl, propyl or butyl, more preferably ethyl, or an optionally substituted aryl, preferably optionally substituted benzyl;wherein one or more carbon atoms in the pyridyl ring are optionally substituted;preferably isopropyl, isobutyl, tert-butyl, or tert-pentyl, and wherein one or more carbon atoms in the pyridyl ring are optionally substituted; Alox; Rh / C; Pd on Noblyst; Ru / C; and Ru / Al2O3.

8. A process according to any preceding claim, wherein the catalyst is a homogeneous catalyst.

9. A process according to any of claims 1 to 8, wherein the process comprises a transfer hydrogenation, and the source of hydrogen is a hydrogen donor.

10. A process according to any preceding claim, wherein the stereoselectivity for the compound of formula (II) is at least about 90%, preferably at least about 95%, more preferably at least about 97 %.

11. A process according to any preceding claim, wherein the process is conducted in: 31230 PCT / 01.10.2024i) a polar aprotic solvent, preferably tetrahydrofuran, 2- methyltetrahydrofuran, or C1-15 alkyl acetate; more preferably tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, or butyl acetate; or ii) a polar protic solvent, preferably an alkanoic acid, more preferably methanoic acid; or an alcohol, preferably a C1-15 alcohol, more preferably C1-6 alcohol, more preferably methanol, ethanol or isopropanol; or a combination thereof; or iii) a nonpolar solvent, preferably toluene or xylene.

12. A process according to claim 11, wherein R4is -C(O)Me and the solvent is ethyl acetate, preferably wherein the process is carried out in a single step.

13. A process according to any preceding claim, wherein the process is conducted in the presence of a base, preferably wherein the base is NEt3, NaOMe, KOtBu, or KOMe.

14. A process according to any preceding claim, wherein the catalyst loading is less than about 3 mol% relative to the amount of the compound of formula (I), preferably wherein the catalyst loading is from about 0.0001 mol% to about 2 mol% relative to the amount of the compound of formula (I), more preferably wherein the catalyst loading is from about 0.0001 mol% to about 0.5 mol% relative to the amount of the compound of formula (I). 31230 PCT / 01.10.2024

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