TECHNICAL FIELD

The present invention relates to a process for preparation of bicyclic compounds from acetylenic intermediates.

BACKGROUND

(-)-Galiellalactone is a tricyclic natural product isolated from wood-inhabiting fungi with submicromolar inhibition of IL-6/STAT3 signaling. Compounds, like galiellalactone or related tricyclic compounds, that modulate or inhibit such IL-6/STAT signaling and/or therewith coupled PI3K/NF-KB signaling, are promising as medicaments in the treatment of e.g. various forms of cancer.

A synthetic route to (-)-Galiellalactone have been disclosed by Johansson et al in J Antibiotics 2002, 55(7), 663-665. However, this route is not suitable for synthesis of various types of analogs of galiellalactone.

Further, Pd-catalyzed carbonylation assisted intramolecular Diels-Alder reactions of 4-alken-2-ynyl carbonates, to give polycyclic compounds, are described in Mandai et al, Tet. Lett. 1991, 32/52, 7687-7688. Although, such polycyclic compounds possibly may include bicyclic compounds that may be used as late intermediates in the synthesis of galiellalactone or related tricyclic compounds, employment of the therein disclosed reaction conditions results, however, in only a low yield of such bicyclic compounds.

Hence, improved methods for the synthesis of bicyclic late intermediates, from which galiellalactone and related tricyclic compounds may be synthesized, are highly desired.

SUMMARY

The present invention seeks to mitigate, alleviate, circumvent or eliminate at least one, such as one or more, of the above-identified deficiencies.

According to one aspect of the invention, there is provided a method for the preparation of compounds of formula (I)

(I) comprising reacting a compound of formula (II)

(I I) with carbon monoxide at a pressure from 1.5 to 8 bar, in a solvent comprising an alcohol of formula R ₅ OH, in the presence of a palladium catalyst or palladium pre- catalyst, and a ligand coordinating to the palladium in the catalyst or the pre-catalyst, at a temperature of 0 to 80 °C, wherein R _ls Ri', R ₂ , R ₂ ', R3, R3 ', R4 and R ₄ ' are

independently selected from the group consisting of H, CI -5 alkyl, CI -5 fluoroalkyl, C3-8 non-aromatic carbocycle, CO-5 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneOC(0)Cl-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)2 in which the CO-5 alkyl may be the same or different, CO-3 alkyleneNHCO-5 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneN(C0-5 alkyl)C(0)Cl-5 alkyl, CO-3 alkyleneNHaryl, CO-3

alkyleneNHheteroaryl, CO-3 alkyleneC(O)NHC0-5 alkyl, CO-3 alkyleneC(0)N(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneC(0)N(C4- 5 alkylene), CO-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8 -membered non-aromatic heterocycle, C0-3 alkylene aryl, C0-3 alkylene heteroaryl, halo, CO-1 alkylene cyano, SCO-5 alkyl, C0-3 alkyleneSO2C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(0)C1-C5 fluoroalkyl, N(C0-C3 alkyl)S02Cl-C5 alkyl, and N(C0-C5 alkyl)S02Cl-5 fluoroalkyl; X is a leaving group; and R ₆ is selected from the group consisting of CI -5 alkyl, CI -5 fluoroalkyl, and a C3-8 non-aromatic carbocycle.

According to yet another aspect of the invention, the palladium catalyst or palladium pre-catalyst is selected from the group consisting of Pd ₂ (dba)3, palladium acetate, bis(triphenylphosphine)palladium(II) dichloride,

tetrakis(triphenylphosphine)palladium(0), palladium dichloride, palladium black and palladium on carbon.

According to yet another aspect of the invention, the ligand is a phosphine ligand.

According to yet another aspect of the invention, the ligand is a bidentate ligand, such as DPPP or xantphos.

According to yet another aspect of the invention, the ligand may be DPPP. According to yet another aspect of the invention, X is selected from the group consisting of halogen, CI -5 alkyl S(0) ₂ 0, aryl S(0) ₂ 0, heteroaryl S(0) ₂ 0, CI -5 alkyl OC(0)0, C 1 -5 alkyl C(0)0, aryl OC(0)0, aryl C(0)0, heteroaryl OC(0)0, and heteroaryl C(0)0.

According to yet another aspect of the invention, X may be CI -5 alkyl OC(0)0, such as CH30C(0)0.

According to yet another aspect of the invention, R _ls Ri', R ₂ , R ₂ ' R ₃ , R ₃ ', R4 and R ₄ ' are independently selected from the group consisting of H, CI -5 alkyl, aryl, CH2aryl, heteroaryl and CH2heteroaryl; and R ₆ is CI -5 alkyl.

According to yet another aspect of the invention, R _ls Ri', R4 and R ₄ ' are independently selected from the group consisting of H, CI -5 alkyl, aryl, and CH2aryl; R ₂ , R ₂ ' R ₃ and R ₃ ' are H; R ₆ is methyl; X is CH ₃ OC(0)0; the palladium catalyst or palladium pre-catalyst is Pd ₂ (dba) ₃ or Pd(OAc) ₂ ; the ligand is DPPP or xantphos; the solvent is a 5 : 1 to 1 : 1 mixture of toluene and methanol; and the temperature is a temperature from 16 to 60 °C, such as 20 to 60 °C.

According to yet another aspect of the invention, the temperature may be a temperature from 16 to 60 °C, such as 20 to 30 °C.

According to yet another aspect of the invention, the pressure may be a pressure from 3 to 7 bar, such as 5 bar.

According to yet another aspect of the invention, there is provided a compound of formula (la) or (Ila)

wherein

Ri, Ri', R ₂ , R ₂ ', R3, R3 ', R4 and R4' are independently selected from the group consisting of H, CI -5 alkyl, CI -5 fluoroalkyl, C3-8 non-aromatic carbocycle, CO-5 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneOC(0)Cl-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)2 in which the CO-5 alkyl may be the same or different, CO-3 alkyleneNHCO-5 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneN(C0-5 alkyl)C(0)Cl-5 alkyl, CO-3

alkyleneNHaryl, CO-3 alkyleneNHheteroaryl, CO-3 alkyleneC(O)NHC0-5 alkyl, CO-3 alkyleneC(0)N(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, C0- 3 alkyleneC(0)N(C4-5 alkylene), CO-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromatic heterocycle, CO-3 alkylene aryl, CO-3 alkylene heteroaryl, halo, CO-1 alkylene cyano, SCO-5 alkyl, CO-3 alkyleneSO2C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(0)C 1 -C5 fluoroalkyl, N(C0-C3 alkyl)S02C 1 -C5 alkyl, and N(C0-C5 alkyl)S02C 1 -5 fluoroalkyl; 5 is selected from the group consisting of CI -5 alkyl, CI -5 fluoroalkyl, and a C3-8 non-aromatic carbocycle; X is selected from the group consisting of halogen, CI -5 alkyl S(0) ₂ 0, aryl S(0) ₂ 0, heteroaryl S(0) ₂ 0, CI -5 alkyl OC(0)0, aryl OC(0)0, aryl C(0)0, heteroaryl OC(0)0, and heteroaryl C(0)0; and at least one of R ₂ , R ₂ ', R3, R3 ', R4 and R ₄ ' is comprising a carbon atom, an oxygen atom or a nitrogen atom; as a free base, an acid in its non-charged protonated form, a pharmaceutically acceptable addition salt, solvate, solvate of a salt thereof, a pure diastereomer, a pure enantiomer, a diastereomeric mixture, a racemic mixture, a scalemic mixture, a corresponding tautomeric form resulting from a hydrogen shift between two hetero- atoms and/or the corresponding tautomeric form resulting from a keto-enol

tautomerization.

According to yet another aspect of the invention, R _ls Ri', R ₂ , R ₂ ' R3, R3 ', R4 and R ₄ ' of (la) or (Ila) are independently selected from the group consisting of H, CI -5 alkyl, aryl, CH2aryl, heteroaryl and CH2heteroaryl; and 5 is CI -5 alkyl. According to yet another aspect of the invention, X of (Ha) may be CI -5 alkyl OC(0)0, such as MeOC(0)0.

According to yet another aspect of the invention, a compound of formula (la) or (Ha) may be used in therapy.

Further, advantageous features of various embodiments of the invention are defined in the dependent claims and within the detailed description below.

DETAILED DESCRIPTION

Definitions:

In the context of the present application and invention, the following definitions apply:

The term "addition salt" is intended to mean salts formed by the addition of a pharmaceutical acceptable acid, such as organic or inorganic acids, or a pharmaceutical acceptable base. The organic acid may be, but is not limited to, acetic, propanoic, methanesulfonic, benzenesulfonic, lactic, malic, citric, tartaric, succinic or maleic acid. The inorganic acid may be, but is not limited to, hydrochloric, hydrobromic, sulfuric, nitric acid or phosphoric acid. The base may be, but is not limited to, ammonia and hydroxides of alkali or alkaline earth metals. The term "addition salt" also comprises the hydrates and solvent addition forms, such as hydrates and alcoholates.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. As used herein, "alkyl" used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number is intended. For example "CI -6 alkyl" denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. When the specific number denoting the alkyl-group is the integer 0 (zero), a hydrogen-atom is intended as the substituent at the position of the alkyl-group. For example, "N(C0 alkyl)2" is equivalent to "NH2" (amino).

As used herein, "alkylenyl" or "alkylene" used alone or as a suffix or prefix, is intended to include straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number is intended. For example "CI -6 alkylenyl" or "CI -6 alkylene" denotes alkylenyl or alkylene having 1, 2, 3, 4, 5 or 6 carbon atoms. When the specific number denoting the alkylenyl or alkylene-group is the integer 0 (zero), a bond is intended to link the groups onto which the alkylenyl or alkylene-group is substituted. For example, "NH(C0 alkylene)NH2" is equivalent to "NHNH2" (hydrazino). As used herein, the groups linked by an alkylene or alkylenyl-group are intended to be attached to the first and to the last carbon of the alkylene or alkylenyl-group. In the case of methylene, the first and the last carbon is the same. For example, "H2N(C2 alkylene)NH2", "H2N(C3 alkylene)NH2", "N(C4 alkylene)", "N(C5 alkylene)" and "N(C2 alkylene)2NH" is equivalent to 1,2-diamino ethane, 1,3-diamino propane, pyrrolidinyl, piperidinyl and piperazinyl, respectively.

Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.

Examples of alkylene or alkylenyl include, but are not limited to, methylene, ethylene, propylene, and butylene.

As used herein, "alkoxy" or "alkyloxy" is intended to mean an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy. Similarly, "alkylthio" or "thioalkoxy" represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.

As used herein, "fluoroalkyl", "fluoroalkylene" and "fluoroalkoxy", used alone or as a suffix or prefix, refers to groups in which one, two, or three of the hydrogen(s) attached to any of the carbons of the corresponding alkyl, alkylene and alkoxy-groups are replaced by fluoro.

Examples of fluoroalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl and 3-fluoropropyl.

Examples of fluoroalkylene include, but are not limited to, difluoromethylene, fluoromethylene, 2,2-difluorobutylene and 2,2,3-trifluorobutylene.

Examples of fluoroalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy and 2,2-difluoropropoxy.

As used herein, "non-aromatic carbocycle", whether alone or as a suffix or prefix, is intended to mean non-aromatic saturated and unsaturated carbomonocycles, having from 3 to 8 ring carbon atoms, such as cyclopropanyl, cyclopentanyl, cyclohexanyl, cyclopentenyl and cyclohexenyl. If a prefix, such as C3-C6, is given, when said carbocycle comprises the indicated number of carbon atoms, eg. 3, 4, 5 or 6 carbon atoms. Accordingly, "C6 non-aromatic carbocycle" for example includes cyclohexyl and cyclohexenyl. Non-aromatic unsaturated carbocycles are to be distinguished from aryls, as aryl refers to aromatic ring structures, comprising at least one aromatic ring.

As used herein, "cycloalkyl", whether alone or as a suffix or prefix, is intended to mean a saturated carbomonocycle, having from 3 to 8 ring carbon atoms, such as cyclopropanyl, cyclopentanyl and cyclohexanyl. If a prefix, such as C3-C6, is given, when said cycloalkyl comprises the indicated number of carbon atoms, e.g. 3, 4, 5 or 6 carbon atoms. Accordingly, C6 cycloalkyl corresponds to cyclohexyl.

As used herein, "cycloalkenyl", whether alone or as a suffix or prefix, is intended to mean a monounsaturated carbomonocycle, having from 4 to 8 ring carbon atoms, such as cyclopentenyl and cyclohexenyl. If a prefix, such as C3-C6, is given, when said cycloalkenyl comprises the indicated number of carbon atoms, eg. 3, 4, 5 or 6 carbon atoms. Accordingly, C6 cycloalkenyl corresponds to cyclohexenyl.

As used herein, the term "substitutable" refers to an atom to which a hydrogen may be covalently attached, and to which another substituent may be present instead of the hydrogen. A non- limiting example of substitutable atoms include the carbon-atoms of pyridine. The nitrogen-atom of pyridine is not substitutable according to this definition. Further, according to the same definition, the imine nitrogen at position 3 in imidazole is not substitutable, while the amine nitrogen at position 1 is.

As used herein, the term "aryl" refers to a ring structure, comprising at least one aromatic ring, made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 carbon atoms would be polycyclic, for example naphthyl. The aromatic ring may be substituted at one or more ring positions. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or

heterocyclyls.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1 ,4-disubstituted benzenes, respectively. For example, the names 1 ,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.

As used herein, "heteroaryl" or "hetaryl" refers to an aromatic heterocycle, having at least one ring with aromatic character, (e.g. 6 delocalized electrons) or at least two conjugated rings with aromatic character, (e.g. 4n + 2 delocalized electrons where "n" is an integer), and comprising up to about 14 carbon atoms, and having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl or hetaryl groups include monocyclic and bicyclic (e.g., having 2 fused rings) systems. The aromatic ring of the heteroaryl or hetaryl group may be substituted at one or more ring positions.

Examples of heteroaryl or hetaryl groups include without limitation, pyridyl

(i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, benzimidazolyl, indolinyl, and the like.

As used herein, "non-aromatic heterocycle" refers to a monocycle comprising at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Such monocyclic rings may be satutated or unsaturated. However, non-aromatic heterocycles are to be distinguished from heteroaryl groups.

Examples of non-aromatic heterocycle groups include without limitation morpholinyl, piperazinyl, 3H-diazirin-3-yl, oxiranyl, aziridinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydro-2H-pyranyl.

As used herein, the term "relative stereochemistry", such as when e.g. referring to e.g. a drawing of a structure, is relating to the relative spatial arrangement of e.g. substituents or groups of a structure. For example, if the relative stereochemistry is indicated by drawing substituents or groups of a molecule in certain directions, the corresponding mirror image of that molecule will have the same relative

stereochemistry. On the other hand, if the "absolute stereochemistry" is indicated by drawing substituents or groups of a molecule in certain directions, a particular enantiomer of that molecule is intended.

Embodiments

Throughout the following description of processes and syntheses it is to be understood that, where appropriate, suitable protecting groups will be attached to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups, as well as examples of suitable protecting groups, are well known within the art. Further such procedures and groups are described in the literature, such as in "Protective Groups in Organic Synthesis", 3rd ed., T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation may be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to the one skilled in the art of organic synthesis.

Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.

References and descriptions on other suitable transformations are for example given in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", 2nd ed., R. C. Larock, Wiley- VCH, New York (1999). References and descriptions of other suitable reactions are described in textbooks of organic chemistry well known to the one skilled in the art, such as "March's Advanced Organic

Chemistry", 5th ed., M. B. Smith, J. March, John Wiley & Sons (2001) or, "Organic Synthesis", 2nd ed., M. B. Smith, McGraw-Hill, (2002).

Techniques for purification of intermediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, size exclusion chromatography, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by the one skilled in the art.

The terms "room temperature" and "ambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25°C. The term "reflux" shall mean, unless otherwise stated, in reference to an employed solvent using a temperature at or slightly above the boiling point of the named solvent. It is understood that microwaves may be used for the heating of reaction mixtures.

The terms "flash chromatography" or "flash column chromatography" shall mean preparative chromatography on silica using an organic solvent, or mixtures thereof, as mobile phase.

In the various schemes given below, generic groups, such as R-groups, have the same representation as given herein, if not specifically defined.

In the various schemes given below, the indicated stereochemistry is intended to mean relative stereochemistry, unless noted otherwise. Compounds of formula (I)

(I)

wherein R _ls Ri', R ₂ , R ₂ ', R ₃ , R ₃ ', R4 and R ₄ ' are independently selected from the group consisting of H, CI -5 alkyl, CI -5 fluoroalkyl, C3-8 non-aromatic carbocycle, CO-5 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneOC(0)Cl-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)2 in which the CO-5 alkyl may be the same or different, CO-3 alkyleneNHCO-5 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneN(C0-5 alkyl)C(0)C 1 -5 alkyl, CO-3 alkyleneNHaryl, CO-3 alkyleneNHheteroaryl, CO-3 alkyleneC(O)NHC0-5 alkyl, CO-3 alkyleneC(0)N(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, C0- 3 alkyleneC(0)N(C4-5 alkylene), CO-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromatic heterocycle, CO-3 alkylene aryl, CO-3 alkylene heteroaryl, halo, CO-1 alkylene cyano, SCO-5 alkyl, CO-3 alkyleneSO2C0-5 alkyl, nitro, C(O)C0-C5 alkyl,

C(0)C1-C5 fluoroalkyl, N(C0-C3 alkyl)S02Cl-C5 alkyl, and N(C0-C5 alkyl)S02Cl-5 fluoroalkyl; and 5 is selected from the group consisting of CI -5 alkyl, CI -5 fluoroalkyl, and a C3-8 non-aromatic carbocycle; may be prepared by a Pd-catalyzed carbonylation assisted intramolecular Diels-Alder reaction.

It was surprisingly found that compounds of formula (II),

(II) wherein R _ls Ri', R ₂ , R ₂ ', R ₃ , R ₃ ', R4 and R ₄ ' are as defined for formula (I), and wherein X is a leaving group assisting oxidative addition of Pd(0) species, when undergoing Pd-catalyzed carbonylation assisted intramolecular Diels-Alder reactions under conditions comprising a relatively low reaction temperature, such as 0 to 80°C, and elevated CO-pressure, i.e. more than atmospheric pressure, such as a pressure of 1.5 to 8 bar, resulted in a significantly increased yield of compounds of formula (I) in comparison to use of atmospheric pressure.

For example, treatment of the below shown carbonate, according to the conditions described in Mandai et al, Tet. Lett. 1991, 32/52, 7687-7688, resulted only in a 15% yield of the corresponding bicyclic product (Scheme 1). Upon use of relative high pressure of CO (5 bar), the yield was increased to 36% for the same bicyclic product (cf. example 9 below).

0

0 ^"">> OMe

15%

Scheme 1

It is well known to the skilled organic chemist that forcing reaction conditions, such as increasing the pressure of a gaseous reagent such as carbon monoxide, generally result in the increased formation of undesired byproducts. As seen in the experimental part herein below (cf. example 8, entry 8) use of carbon monoxide at a pressure of 10 bar in the Pd-catalyzed carbonylation assisted intramolecular Diels-Alder reaction of the invention resulted in the low yield of 3 % in one case, i.e. even lower than the yield at atmospheric pressure at elevated temperature (cf. example 8, entry 2).

Thus, preparation of compounds of formula (I) may, according to an embodiment, be performed by reacting a compound of formula (II) with carbon monoxide at a pressure from 1.5 to 8 bar, i.e. above 1 atmosphere but below 10 bar, in a solvent comprising an alcohol of formula ReOH, wherein 5 is selected from the group consisting of CI -5 alkyl, CI -5 fluoroalkyl, and a C3-8 non-aromatic carbocycle, in the presence of a palladium catalyst or palladium pre-catalyst, and a ligand coordinating to palladium in the catalyst or the pre-catalyst of 0 to 80 °C. As readily known to the skilled person, a ligand coordinating to palladium in a catalyst may be an ion or molecule that binds to a central (metal) atom through donation of one or more of the ligand's electron pairs, thus forming a bond which stabilizes and alters the reactivity of the central (metal) atom.

The alcohol, being part of the solvent, is ending up as the alcohol part R ₆ 0 of the ester in the product (I).

According to one embodiment, the substituents of the substrate (II) and the product (I), Ri, Ri ', R ₂ , R ₂ ', R ₃ , R ₃ ', R ₄ and R ₄ ', may be independently selected from the group consisting of H, CI -5 alkyl, CI -5 fluoroalkyl, C3-8 non-aromatic carbocycle, CO-5 alkyleneOCO-5 alkyl, CO-3 alkyleneOC 1 -5 fluoroalkyl, CO-3 alkyleneOC(0)C 1 -5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)2 in which the CO-5 alkyl may be the same or different, CO-3 alkyleneNHCO-5 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneN(C0-5 alkyl)C(0)Cl-5 alkyl, CO-3 alkyleneNHaryl, CO-3 alkyleneNHheteroaryl, CO-3 alkyleneC(O)NHC0-5 alkyl, CO-3 alkyleneC(0)N(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, C0- 3 alkyleneC(0)N(C4-5 alkylene), CO-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromatic heterocycle, CO-3 alkylene aryl, CO-3 alkylene heteroaryl, halo, CO-1 alkylene cyano, SCO-5 alkyl, CO-3 alkyleneSO2C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(0)C1-C5 fluoroalkyl, N(C0-C3 alkyl)S02Cl-C5 alkyl, and N(C0-C5 alkyl)S02Cl-5 fluoroalkyl.

Preferably, any aryl is phenyl or naphtalenyl, that may be further substituted with 0 to 4, preferably 0 to 2, substituents. Examples of such substituents include CI -5 alkyl, like methyl or ethyl, CI -5 fluoroalkyl, like trifluoromethyl, halo, like F or CI, or CO-5 alkyleneOCO-5 alkyl, like CH20CH3.

According to one embodiment, one of Ri and Ri ' may be CI -5 alkyl, such as methyl, and the other of Ri and Ri ' may be H.

According to one embodiment, both of Ri and Ri ' may be CI -5 alkyl, such as methyl.

According to one embodiment, both of Ri and Ri ' may be H.

According to one embodiment, both of R ₂ and R ₂ ' may be H.

According to one embodiment, both of R ₃ and R ₃ ' may be H.

According to one embodiment, both of R ₄ and Rt' may be H.

According to one embodiment, R ₂ , R ₂ ' R ₃ and R ₃ ' may be H.

According to one embodiment, R4 and Rt' may be independently selected from CI -5 alkyl, such as both of R4 and R ₄ ' being methyl. According to one embodiment, one of R ₄ and R ' may be CI -5 alkyl, such as methyl, and the other of R ₄ and R4' may be H.

According to one embodiment, one of R ₄ and Rzt' may be CO-3 alkylene aryl, such as phenyl or benzyl, and the other of R ₄ and R ₄ ' may be H.

According to one embodiment, R ₂ , R ₂ ', R3 and R3 ' may be independently selected from the group consisting of H, CI -5 alkyl, such as methyl, and CO-3 alkylene aryl, such as phenyl or benzyl.

According to one embodiment, R _{l s} Ri ', R ₂ , R ₂ ' R3, R3 ' , R ₄ and R ₄ ' may be independently selected from the group consisting of H, CI -5 alkyl, such as methyl, aryl, such as phenyl, CH2aryl, such as benzyl, heteroaryl and CH2heteroaryl, while 5 simultaneously may be CI -5 alkyl, such as methyl or ethyl.

According to one embodiment, R _{l s} Ri ', R ₄ and R ₄ ' may be independently selected from the group consisting of H, CI -5 alkyl, such as methyl, aryl, such as phenyl, and CH2aryl, such as benzyl.

According to one embodiment, X of the substrate (II) may be any leaving group known in the art to assist oxidative addition of a Pd(0) species.

Thus, X of the substrate (II) may, according to one embodiment, be halogen, such as CI, Br or I, preferably CI or Br, CI -5 alkyl S(0) ₂ 0, such as mesylate, aryl S(0) ₂ 0, such as tosylate or brosylate, heteroaryl S(0) ₂ 0, CI -5 alkyl OC(0)0, such as methyl carbonate, CI -5 alkyl C(0)0, such as acetate, aryl OC(0)0, aryl C(0)0, heteroaryl OC(0)0, and heteroaryl C(0)0.

According to one embodiment, X of the substrate (II) may be CI -5 alkyl OC(0)0, such as mesylate.

According to one embodiment, the alcohol used as part of the solvent may be an aliphatic alcohol, preferably a short chain aliphatic alcohol. 5 of R ₅ OH, may be, for example, CI -5 alkyl, such as methyl or ethyl, CI -5 fluoroalkyl, and a C3-8 non- aromatic carbocycle.

According to one embodiment, the alcohol used as part of the solvent may be methanol or ethanol.

According to one embodiment, 5 may be methyl.

According to one embodiment, a compound of formula (II) may be treated with a Pd(0) source in the preparation of bicycle (I). Alternatively, Pd(0) may be formed in situ from Pd(II), preferably together with a suitable ligand.

The ligand coordinating to palladium in the catalyst or pre-catalyst may be a phoshine ligand. Further, the ligand is preferably a bidenate ligand, such as xantphos or DPPP. Other bidentate ligands include, for example, 1,1- bis(diphenylphosphino)methane, 1 , 1 '-bis(diphenylphosphino)ferrocene, 1,1- bis(diphenylphosphino)butane and 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl.

The use of DPPP as ligand may allow formation of compounds of formula (I) at a relatively low temperature, such as a temperature of 16 to 40 °C. The use of Xantphos as ligand instead of DPPP may increase the yield of the corresponding compound of formula (I), but an elevated temperature, such as a temperature of 40 to 80 °C, may then be required.

According to one embodiment, the Pd(0)- or Pd(II)-compound employed as catalyst or pre-catalyst in the Pd-catalyzed carbonylation assisted intramolecular Diels- Alder reactions disclosed herein may be any of Pd ₂ (dba)3, palladium acetate, bis(triphenylphosphine)palladium(II) dichloride,

tetrakis(triphenylphosphine)palladium(0), palladium dichloride, palladium black and palladium on carbon. Preferably, the catalyst or pre-catalyst is Pd ₂ (dba) ₃ or Pd(OAc) ₂ .

According to one embodiment, the Pd-catalyzed carbonylation assisted intramolecular Diels- Alder reactions disclosed herein may be conducted at a temperature from 0 to 80 °C, preferably 16 to 60 °C, more preferred 20 to 30 °C or 22 to 30 °C. Thus, the Pd-catalyzed carbonylation assisted intramolecular Diels- Alder reactions disclosed herein may be conducted without having to heat the reaction mixture, i.e. at room temperature.

According to one embodiment, the Pd-catalyzed carbonylation assisted intramolecular Diels- Alder reactions disclosed herein may be conducted under a CO atmosphere above atmospheric pressure, such as at a pressure of 1 bar to 8 bar, preferably 1.5 to 8 bar, more preferred 2 to 7 bar, and most preferred 3 to 6 bar. The source of CO may be a conventional gas tube or formed in situ from e.g. Mo(CO)6.

According to one embodiment, the Pd-catalyzed carbonylation assisted intramolecular Diels- Alder reactions disclosed herein may be conducted under a CO atmosphere of 5 bar, such as 4.7 to 5.3 bar.

According to one embodiment, the Pd-catalyzed carbonylation assisted intramolecular Diels- Alder reactions disclosed herein may be conducted in a suitable solvent, such as a mixture of a hydrocarbon, such as a non-polar hydrocarbon, and an alcohol. The hydrocarbon may be benzene, toluene, xylene, 1,4-dioxane, or the like. The alcohol may be an alcohol of a type as described herein. The volumetric proportions of the hydrocarbon and the alcohol may be from 5: 1 to 1 : 1, respectively, preferably about 2: 1. The hydrocarbon may be substituted, fully or partly, with other solvents such as DMF, THF or the like in order to e.g. increase the solubility of the reacting components.

According to one embodiment, the preparation of galiellalactone or related tricyclic compounds may, for example, be achieved by regio- and stereoselective epoxidation of the electron rich double bond of compounds of formula (I) using mCPBA, dimethyldioxirane, trifluoromethyldioxirane, peracids or the like. Subsequent ester hydrolysis (conversion of R ₆ 0 into O ^" or OH), under basic or acidic conditions of the obtained epoxide, followed by acid catalyzed epoxide opening and subsequent lactonization, then yields galiellalactone or the related tricyclic compounds.

According to another embodiment, there is provided a compound of formula (la) or (Ila)

wherein at least one of R ₂ , R ₂ ', R3, R3 ', R4 and R ₄ ' is comprising a carbon atom, an oxygen atom or a nitrogen atom; R _ls Ri', R ₂ , R ₂ ', R3, R3 ', R ₄ and R ₄ ' may be independently selected from the group consisting of H, CI -5 alkyl, CI -5 fluoroalkyl, C3-8 non-aromatic carbocycle, CO-5 alkyleneOCO-5 alkyl, CO-3 alkyleneOCl-5 fluoroalkyl, CO-3 alkyleneOC(0)Cl-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)2 in which the CO-5 alkyl may be the same or different, CO-3 alkyleneNHCO-5 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneN(C0-5 alkyl)C(0)Cl-5 alkyl, CO-3 alkyleneNHaryl, CO-3

alkyleneNHheteroaryl, CO-3 alkyleneC(O)NHC0-5 alkyl, CO-3 alkyleneC(0)N(Cl-5 alkyl)2 in which the CI -5 alkyl may be the same or different, CO-3 alkyleneC(0)N(C4- 5 alkylene), CO-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8 -membered non-aromatic heterocycle, CO-3 alkylene aryl, CO-3 alkylene heteroaryl, halo, CO-1 alkylene cyano, SCO-5 alkyl, CO-3 alkyleneSO2C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(0)C1-C5 fluoroalkyl, N(C0-C3 alkyl)S02Cl-C5 alkyl, and N(C0-C5 alkyl)S02Cl-5 fluoroalkyl;

5 may be selected from the group consisting of CI -5 alkyl, CI -5 fluoroalkyl, and a C3- 8 non-aromatic carbocycle; and X may be selected from the group consisting of halogen, CI -5 alkyl S(0) ₂ 0, aryl S(0) ₂ 0, heteroaryl S(0) ₂ 0, CI -5 alkyl OC(0)0, aryl OC(0)0, aryl C(0)0, heteroaryl OC(0)0, and heteroaryl C(0)0.

Further, R Ri', R ₂ , R ₂ ' R ₃ , R ₃ ', R4 and R ₄ ' of (la) or (Ila) may be

independently selected from the group consisting of H, CI -5 alkyl, aryl, CH2aryl, heteroaryl and CH2heteroaryl. In addition, 5 may be CI -5 alkyl, such as methyl. Yet further, X of (Ila) may be CI -5 alkyl OC(0)0, such as CH30C(0)0.

Such compound of formula (la) or (Ila) may further exist in the form of a free base, an acid in its non-charged protonated form, a pharmaceutically acceptable addition salt, solvate, solvate of a salt thereof, a pure diastereomer, a pure enantiomer, a diastereomeric mixture, a racemic mixture, a scalemic mixture, a corresponding tautomeric form resulting from a hydrogen shift between two hetero-atoms and/or the corresponding tautomeric form resulting from a keto-enol tautomerization.

In addition, such compound of formula (la) or (Ila), or compositions comprising one of these, may be used in therapy. For example, such a compound or composition may be useful in the treatment of an IL-6/STAT signaling related disorder or a PBK/NF-KB signaling related disorder due to e.g. their similarities with

galiellalactone or related tricyclic compounds. Examples of such disorders includes solid cancer, hematological cancer, benign tumor, hyperproliferative disease, inflammation, autoimmune disease, graft or transplant rejection, delayed physiological function of grafts or transplants, neurodegenerative disease or viral infection.

Another embodiment relates to a process for preparing a compound according to formula (II) as a free base, acid, or salts thereof. Further, additionally embodiments relate to synthetic intermediates, which are useful in the synthesis of a compound of formula (II) as a free base, acid, or salts thereof. Specific and generic examples of such intermediates are given below.

Compounds of formula (II), where X is a leaving group, may be prepared by converting the hydroxyl group of a corresponding compound, wherein X is OH, into a leaving group. This may be done by treatment with an acylating reagent, such as methanesulfonyl chloride, p-toluenesulfonyl chloride, di-tert-butyl dicarbonate, methyl chloroformate or ethyl chloroformate, in the presence of a base, such as triethylamine, pyridine, potassium carbonate, sodium hydroxide, diisopropylethylamine, or with a halogenating agent, such as thionylchloride, PC15, PC13, HBr or PBr3.

Compounds of formula (II), wherein X is OH, may be prepared by the addition of alkynes (III) to aldehydes (IV). Alkynes (III) may be converted to nucleophilic metal acetylides e.g. by deprotonation of the alkyne with a suitable base, e.g. n-BuLi, to make the corresponding metal acetylide. These nucleophilic alkynes may then be reacted with aldehydes of formula (IV) to form compounds of formula (II), wherein X is OH.

A lithium acetylide nucleophile may be formed in situ by the treatment of dibromo alkenes (V) with n-BuLi. The acetylide may add directly to an aldehyde (IV) to form a compound of formula (II), where X is OH. Vinyl acetylenes of formula (VI) may be prepared from trimethylsilyl acetylene and readily available vinyl intermediates of formula (VII), wherein X is a halogen or triflate, through a palladium catalyzed Sonogashira coupling. After the coupling, the trimethylsilyl group may be removed to afford a compound of formula (III).

Compounds of formula (II), wherein X is OH, may be prepared by a palladium catalyzed Sonogashira coupling between readily available vinyl intermediates of formula (VII), where X is a halogen or triflate, and a propargyl alcohol of formula (VIII). Propargyl alcohols of formula (VIII) may be prepared by the addition of trimethylsilyl acetylene to an aldehyde (IV), followed by subsequent desilylation.

Aldehydes of formula (IV) may be prepared from vinyl allyl ethers (IX) through a Claisen rearrangement. The Claisen rearrangement may be thermal or catalyzed by a Lewis acid. Vinyl allyl ethers (IX) are commonly prepared by reacting an allylic alcohol with an alkyl vinyl ether in the presence of a catalytic amount of a protic or Lewis acid.

Aldehydes of formula (IV) may be prepared by the reduction of the corresponding ester (X, Xi=Oalkyl) or amide (X, Xi=N[alkyl]alkyl). The reduction may be directly to the adehyde or via reduction to the corresponding alcohol and subsequent oxidation. Esters (X, Xi=Oalkyl) or amides (X, Xi=N[alkyl]alkyl) may be prepared by alkylation of amides or esters of formula (XI) using a suitable base and reactive alkylation reagents such as (XII) or (XIII) wherein X ₂ is a good leaving group such as a halogen or acetate.

Although the present invention has been described above with reference to specific illustrative embodiments, it is not intended to be limited to the specific form set forth herein. Any combination of the above mentioned embodiments should be appreciated as being within the scope of the invention. Rather, the invention is limited only by the accompanying claims and other embodiments than the specific above are equally possible within the scope of these appended claims. Examples

General Methods

All materials were obtained from commercial sources and were used without further purification unless otherwise noted. THF was distilled from

sodium/benzophenone ketyl under N ₂ , toluene was distilled from CaH ₂ under N ₂ . All reactions were carried out in standard dry glassware and atmospheric surroundings unless otherwise stated. Thin layer chromatography (TLC) was carried out on Merck precoated silica gel aluminum sheets (60 F254), detected under UV light and visualized with anisaldehyde/sulfuric acid or PMA. Column chromatography was performed on Si0 ₂ (Matrex LC-gel: 60A, 35-70 MY, Grace). 1H and ¹³ C NMR spectra were recorded using a Bruker DR400 at room temperature. Chemical shifts are given in ppm relative to TMS using the residual solvent signal of CDCI ₃ as internal standard (7.27 and 77.23 respectively) Mass spectra were recorded on a JEOL JMDX 303 spectrometer. Abbreviations

DMF N,N'-Dimethylformamide

THF Tetrahydrofurane

sat. Saturated

h hour

r.t. room temperature

eq, equiv equivalents

quant quantitative

aq aqueous

Ph phenyl

mCPBA meta-Chloroperoxybenzoic acid

OAc acetate

DPPP l ,3-Bis(diphenylphosphino)propane

Me Methyl

Et Ethyl

CO Carbon monoxide

xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium(0)

Pd(OAc) ₂ palladium acetate

«-BuLi n-Butyllithium

Below follows non-limiting examples on the synthesis of compounds of formula (II) or (Ila).

General procedure for the synthesis of alkyne carbonates of formula (II) or (Ila) (scheme 2, examples I to 6)

3) CIC02 Me

Scheme 2

CBr ₄ (2.0 eq) and PPh ₃ (4.0 eq) were added to a solution of crotonaldehyde (1.0 eq) in CH ₂ CI ₂ at 0°C. The mixture was stirred for 30 min in the dark after which it was diluted with hexanes and filtered through Celite. The filtrate was carefully concentrated and dissolved in dry THF (150 mL). The solution was cooled to -78°C under nitrogen. n-BuLi (1.6 M in hexanes, 1.0 eq) was added dropwise after which the solution was stirred for 1 hour. Additional n-BuLi (1.6 M in hexanes, 1.0 eq) was added dropwise, upon complete addition the mixture was stirred at room temperature for 1 hour after which it was cooled to -78°C. The corresponding 4-pentenal (1.1 eq) was added dropwise over 15 min, the reaction mixture was stirred for 20 min after which methyl chloro formate (1.1 eq) was added dropwise. Upon completion the reaction was quenched with saturated NH ₄ Cl(aq), the mixture was diluted with EtOAc and the phases were separated, the aqueous phase was extracted with additional EtOAc. The combined organic phases were dried over Na ₂ S0 ₄ and concentrated. The crude product was purified through column chromatography on silica gel (heptane/EtOAc 1000: 1).

Example 1

(£)-deca-l,8-dien-6-yn-5-yl methyl carbonate

Obtained after flash chromatography as a yellow liquid in 71 % yield. 1H NMR (CDCI3) δ 6.20 (IH, dqd, J=15.8 and 6.8 Hz), 5.81 (IH, qdt, J=10.2 and 6.6 Hz), 5.50 (IH, td, J=15.8 and 1.8 Hz), 5.35 (IH, dt, J=6.6 and 1.5 Hz), 5.06 (IH, qdd, J=17.1 and 1.6 Hz), 5.01 (IH, td, J=10.2 and 1.5 Hz), 3.81 (3H, s), 2.23 (2H, dqd, J=6.8 and 1.2 Hz), 1.92 (2H, m), 1.79 (3H, dd, J=6.8 and 1.8)

1 ³ C NMR (CDCI3) δ 155.2, 141.5, 137.1, 115.8, 110.0, 85.4, 83.9, 68.4, 55.1,

34.3, 29.3, 18.6

Example 2

(£)-4,4-dimethyldeca-l,8-dien-6-yn-5-yl methyl carbonate

Obtained after flash chromatography as a yellow liquid in 65% yield.

1H NMR (CDCI ₃ ) δ 6.19 (IH, dqd, J=15.7 and 6.7 Hz), 5.80 (IH, qdt, J=10.2 and 7.5 Hz), 5.51 (IH, dp, J=15.7 and 1.8 Hz), 5.09 (IH, m), 5.05(1H, dp, J=15.2 and 0.9 Hz), 3.81 (3H, s), 2.14 (2H, d, J= 7.5 Hz), 1.78 (3H, dd, J=6.8 and 1.6 Hz), 1.02 (3H, s), 1.00 (3H, s)

¹³ C NMR (CDCI ₃ ) δ 155.5, 141.2, 134.2, 118.4 110.2, 86.1, 82.8, 76.0, 55.2, 43.0, 38.5, 23.1, 22.8, 18.8

Example 3

(£)-methyl 4-phenyldeca-l,8-dien-6-yn-5-yl carbonate

Obtained after flash chromatography as a mixture of diastereoisomers (91 :9) as a yellow liquid in 70% yield. Major isomer

1H NMR (CDCI3) δ 7.28 (5H, m), 6.12 (IH, dqd, J=15.8 and 6.8 Hz), 5.66 (IH, qdt, J=10.2 and 6.8 Hz), 5.51 (IH, dd, J=5.9 and 1.7), 5.45 (IH, dqvi, J=15.8 and 1.8 Hz), 5.06 (IH, dqd, J=17.1 and 1.8 Hz), 4.96 (IH, m), 3.78 (3H, s), 3.14 (9.3 and 5.9 Hz), 2.70 (IH, m), 2.58 (IH, m), 1.77 (3H, dd, 7.0 and 1.8 Hz)

¹³ C NMR (CDCI3) δ 155.2, 141.4, 139.4, 135.5, 129.2, 128.4, 127.4, 117.2, 110.0, 86.9, 82.7, 72.0, 55.2 49.6, 35.5, 18.9

Example 4

(£)-4-benzyldeca-l,8-dien-6-yn-5-yl methyl carbonate

Obtained after flash chromatography as a mixture of diastereoisomers (62:38) as a yellow liquid in 69% yield.

Major isomer

1H NMR (CDCI3) δ 7.31 (2H, m), 7.22 (3H, m), 6.25 (IH, dqd; J= 15.7 and 6.9 Hz), 5.81 (lH, m), 5.57 (IH, dqvi J= 15.9 and 1.8), 5.35 (IH, m), 5.11 (2H, m), 3.79 (3H, s), 2.82 (2H, m), 2.35 (IH, m), 2.20 (2H, m), 1.83 (3H, dd, J=6.8 and 1.8 Hz) 1 ³ C NMR (CDCI3) δ 155.0, 141.4, 139.8, 136.0, 129.1, 128.6, 126.3, 117.4,

110.0, 86.5, 82.6, 70.5, 54.9, 44.7, 36.1, 33.9, 18.7

Minor isomer

1H NMR (CDCI3) δ 7.31 (2H, m), 7.22 (3H, m), 6.25 (IH, dqd; J= 15.7 and 6.9 Hz), 5.81 (IH, m), 5.55 (IH, dqvi J= 11.9 and 1.8), 5.35 (IH, m), 5.11 (2H, m), 3.83 (3H, s), 2.82 (2H, m), 2.35 (IH, m), 2.20 (2H, m), 1.81 (3H, dd, J=4.8 and 1.8 Hz) 1 ³ C NMR (CDCI3) δ 155.1, 141.3, 139.9, 135.9, 129.3, 128.5, 126.2, 117.4, 110.0, 86.4, 82.6, 70.5, 55.0, 44.6, 35.6, 34.0, 18.7. Example 5

Methyl 3-phenyl-deka-6-yn-l,8-dien-5-yl carbonate

O

O O Ph

Obtained as a 1 : 1 diastereomeric mixture of a total yield of 65% yield as a faint yellow oil after flash chromatography using heptane/EtOAc (60: 1) as eluent.

Isomer

1H NMR (CDC1 ₃ ) δ 7.32 (2H, m), 7.22 (3H, m), 6.21 (1H, m), 5.96 (1H, m), 5.51 (lH, m), 5.11 (3H, m), 3.81 (3H, s), 3.55 (1H, qva, J=7.1 Hz), 2.32 (1H, m), 2.18 (1H, m), 1.79 (3H, dd, J=4.7 and 1.8 Hz)

¹³ C NMR (CDCI3) δ 155.0, 142.8, 141.5, 140.6, 128.9, 127.8, 126.9, 115.4, 110.0, 85.5, 83.9, 67.5, 55.1, 46.0, 40.3, 18.9

Isomer

1H NMR (CDCI3) δ 7.32 (2H, m), 7.22 (2H, m), 6.21 (1H, m), 5.96 (1H, m), 5.51 (1H, m), 5.11 (3H, m), 3.78 (3H, s), 3.55 (1H, qva, J=7.1 Hz), 2.32 (1H, m), 2.18 (1H, m), 1.81 (3H, dd, J=4.6 and 1.7 Hz)

¹³ C NMR (CDCI3) δ 155.0, 142.6, 141.5, 140.8, 128.9, 127.8, 126.9, 115.4, 110.0, 85.7, 84.0, 67.5, 55.1, 45.9, 40.5, 18.9 Example 6

Methyl 10-methyl-undeka-4-yn-2,9-dien-6-yl carbonate

O

O ^{* s} OMe

Obtained as a faint yellow oil in 48% yield after flash chromatography using heptane/EtOAc (60: 1) as eluent.

1H NMR (CDCI ₃ ) δ 6.18 (1H, dqva, J=15.8 and 6.8 Hz), 5.51 (1H, ddd,

J=15.8, 3.6 and 1.8 Hz), 5.31 (1H, dt, J=6.7 and 1.6 Hz), 5.10 (1H, m), 3.80 (3H, s), 2.16 (2H, qva, J=7.4 Hz), 1.86 (2H, m), 1.78 (3H, dd, J=6.8 and 1.7 Hz), 1.70 (3H, d, J=0.9 Hz), 1.61 (3H, s)

¹³ C NMR (CDCI ₃ ) δ 155.3, 141.3, 133.3, 122.7, 110.1, 85.2, 84.2, 68.6, 55.1, 35.2, 25.9, 23.8, 18.8, 17.9. Example 7

Methyl 6-benzyl-2,8-nonadien-3-yn-5-yl carbonate

'

Step 1 : 4-benzyl-hepten-l-yn-3-ol

OH

Bn

To a solution of methyl 2-(benzyl)-4-pentenoate (8.6 g, 42 mmol) in dry CH ₂ C1 ₂ (120 mL) at -78°C under N ₂ atmosphere DIBALH (42 mL, 42 mmol, 1M in heptane) was added dropwise. After 2.5 h ethynyl magnesium bromide (84 mL, 0.5 M, 42 mmol) was dropped in at the wall of the vessel and stirred for 30 minutes at -78°C before allowed to reach room temperature over night. The reaction mixture was diluted with Et ₂ 0 and washed with tartrate (sat. sol.), NaHC0 ₃ (sat.) and brine and dried over Na ₂ S0 ₄ before concentrated. Analytical sample was prepared by flash chromatography (Heptane: EtOAc, 100:5) before crude (9.6 g) was reacted further.

Major isomer

1H NMR (CDC1 ₃ ) 5 7.28 (2H, m), 7.21 (3H, m), 5.83 (IH, m), 5.11 (2H, m),

4.38 (IH, m), 2.74 (2H, dd, J,=7.4 Hz and J ₂ =4.2 Hz), 2.57 (IH, d, J,=2.2 Hz), 2.43 (IH, m), 2.15 (IH, m), 2.06 (IH, m), 1.91 (IH, dd, J,=6.3 Hz and J ₂ =2.2 Hz)

¹³ C NMR (CDC1 ₃ ) δ 137.1, 129.3, 129.2, 128.5, 128.4, 126.2, 117.3, 74.7, 64.4, 45.9, 36.3, 33.7

Minor isomer

1H NMR (CDC1 ₃ ) δ 7.28 (2H, m), 7.21 (3H, m), 5.83 (IH, m), 5.11 (2H, m), 4.42 (IH, m), 2.93 (IH, dd, J,=13.8 Hz and J ₂ =7.1 Hz), 2.66 (IH, dd, J,=13.7 Hz and J ₂ =7.6 Hz), 2.52 (IH, d, J,=2.2 Hz), 2.23 (2H, m), 2.05 (IH, m), 1.77 (IH, dd, J,=6.2 Hz and J ₂ =2.4 Hz)

1 ³ C NMR (CDC1 ₃ ) δ 136.4, 129.3, 129.2, 128.5, 128.4, 126.2, 117.1, 74.5,

64.1, 45.9, 35.4, 34.1. Step 2: 6-benzyl-2,8-nonadien-3-yn-5-ol

4-benzyl-hepten-l-yn-3-ol (9.6 g) was dissolved in Et ₃ N and cooled to 0°C under N ₂ atmosphere. Vinylbromide (59 mL, 59 mmol, 1M in THF) added before PdCl ₂ (PPh ₃ ) ₂ (296 mg, 0.4 mmol) and activated Cul (31.1 mg, 0.2 mmol). Icebath removed after 30 minutes and reaction allowed to stirr at room temperature over night. NaHC0 ₃ (sat.) added and extracted with EtOAc. Washed with Na ₂ S ₂ 0 ₃ (sat.) and brine, dried over Na ₂ S0 ₄ before filtered through a plug of celite and concentrated. Analytical sample was prepared by flash chromatography (Heptane: EtOAc, 100:5) before crude (9.9 g) was reacted further.

Major isomer

1H NMR (CDC1 ₃ ) δ 7.29 (2H, m), 7.21 (3H, m), 5.85 (2H, m), 5.68 (1H, m),

5.52 (1H, m), 5.11 (2H, m) 4.49 (1H, m), 2.73 (2H, m), 2.41 (1H, m), 2.14 (1H, m), 2.06 (lH, m), 1.89 (1H, d, J,=5.8)

¹³ C NMR (CDCI3) δ 140.2, 137.1, 129.2, 128.4, 127.4, 126.1, 117.1, 116.6, 89.0, 85.3, 64.9, 46.3, 36.4, 34.0

Minor isomer

1H NMR (CDCI3) δ 7.28 (2H, m), 7.21 (3H, m), 5.83 (1H, m), 5.11 (2H, m), 4.42 (1H, m), 2.90 (1H, dd, J,=13.6 Hz and J ₂ =7.1 Hz), 2.65 (1H, dd, J,=13.8 Hz and J ₂ =7.6 Hz), 2.23 (2H, m), 2.05 (1H, m), 1.76 (1H, d, J,=5.8 Hz)

¹³ C NMR (CDCI3) δ 140.4, 136.6, 129.3, 128.4, 127.4, 126.1, 117.0, 116.6, 89.0, 85.3, 64.6, 46.2, 35.6, 34.2

HRMS calc δ for Ci ₆ Hi ₉ 0 [M+l]: 127.1412, found 127.1399.

Step 3 : Methyl 6-benzyl-2,8-nonadien-3-yn-5-yl carbonate

6-benzyl-2,8-nonadien-3-yn-5-ol (9.9 g) was dissolved in dry CH ₂ CI ₂ (200 mL) and cooled to -10°C under N ₂ atmosphere before DMAP (6.7 g, 54.9 mmol) was added. Mixture was allowed to warm to room temperature for 30 minutes and then cooled to - 10°C before methyl chloroformate (5.87 mL, 76.0 mmol) was added dropwise. Reaction was allowed to reach room temperature over night. NaHC0 ₃ (sat.) was added and mixture extracted with EtOAc. Washed with brine, dried over Na ₂ S0 ₄ before consentrated. Purification by flash chromatography gave clear oil (7.24 g, 25 mmol, 60% yield from ester)

Major isomer

1H NMR (CDC1 ₃ ) δ 7.29 (2H, m), 7.20 (3H, m), 5.83 (2H, m), 5.71 (1H, dd,

J =7.3 Hz and J ₂ =2.2 Hz), 5.55 (1H, dd, J,=10.9 Hz and J ₂ =2.2 Hz), 5.31 (1H, dd, Hz and J ₂ =1.7 Hz), 4.80 (2H, m), 3.86 (3H, s), 2.79 (2H, m), 2.29 (2H, m), 2.17 (lH, m)

¹³ C NMR (CDC1 ₃ ) δ 183.4, 154.8, 139.6, 135.8, 129.3, 129.1, 128.5, 128.3, 126.3, 117.5, 116.3, 70.2, 55.0, 44.5, 36.0, 33.7

Minor isomer

1H NMR (CDC1 ₃ ) δ 7.29 (2H, m), 7.20 (3H, m), 5.83 (2H, m), 5.71 (1H, dd, J =7.3 Hz and J ₂ =2.2 Hz), 5.54 (1H, dd, J,=10.9 Hz and J ₂ =2.2 Hz), 5.36 (1H, dd, Hz and J ₂ =1.7 Hz), 4.80 (2H, m), 3.80 (3H, s), 2.79 (2H, m), 2.29 (2H, m), 2.17 (1H, m)

¹³ C NMR (CDC1 ₃ ) δ ¹³ C NMR (CDC1 ₃ ) δ 183.4, 154.8, 139.6, 135.7, 129.3, 129.1, 128.5, 128.3, 126.3, 117.5, 116.3, 70.2, 55.0, 44.5, 35.5, 33.9.

Below follows non-limiting examples on methods or processes for the production, preparation or synthesis of compounds of formula (I) or (la) from compounds of formula (II) or (Ha) by Pd-catalyzed carbonylation assisted

intramolecular Diels- Alder reaction. General procedure for the synthesis of a bicyclic compound of formula (I )or (la) by Pd-catalyzed carbonylation assisted intramolecular Diels-Alder reaction of a compound of formula (II)or (Ha) (scheme 3, example 8)

Scheme 3

The palladium catalyst (0.2 eq) and the phosphine ligand (0.2 eq) were weighed into a suitable reaction vessel and suspended in toluene (1 mL/mmol substrate). The carbonate (1 eq) in 2: 1 MeOH/toluene (1.5 mL per mmol substrate) was added after which CO was bubbled though the solution. In entry 4 only MeOH was used. The CO pressure was adjusted to the desired pressure (1-10 bar). Heating, thermal or microwave, was applied for entries 1-5 and 7. The reactions of entry 6 and 8 were run at ambient temperature (approximately 22 °C). The mixture was stirred until the reaction was complete (typically over night) after which it was diluted with EtOAc and filtered through a plug of Celite. The filtrate was concentrated and the crude product purified through column chromatography on silica gel (heptane/Et ₂ 0 1000: 1).

Example 8

Methyl 2,2,6-trimethyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylate

The general procedure as described above was employed for the synthesis of methyl 2,2,6-trimethyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylate. The yield of methyl 2,2,6-trimethyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylate varied as dependant on the factors: type of catalyst, type of ligand, reaction temperature, pressure of CO and type of solvent, as depicted in the table below (entry 1 to 8).

1H NMR (CDCI3) δ 6.86 (IH, d, J=5.4 Hz), 6.09 (IH, d, J=2.1 Hz), 3.77 (3H, s), 2.90 (IH, m), 2.59 (IH, m), 1.92 (IH, dd, J=12.0 and 6.7 Hz), 1.75 (IH, ddd, J=12.7, 4.6 and 1 Hz), 1.42 (IH, dt, J=12.9 and 5.9 Hz), 1.26 (IH, dd, J=l 1.7 and 9.7 Hz) 1.15 (3H, s), 1.12 (3H, d, J=7.3 Hz), 1.07 (3H, s)

¹³ C NMR (CDCI3) δ 167.3, 145.9, 138.1,134.4, 126.3, 51.7, 46.8, 44.7, 38.2, 35.9, 31.2, 29.7, 27.2, 20.0

HRMS calcd for C14H19O2 [M-l]: 219.1385, found: 219.1386

Entry Catalyst Ligand Temp. (°C) / CO Solvent Yield (%)

pressure (bar)

1 Pd ₂ (dba) ₃ DPPP 60 / 1.0 MeOH/ 7-10

Toluene

2 Pd(OAc) ₂ DPPP 60 / 1.0 MeOH/ 10-15

Toluene

3 Pd(OAc) ₂ DPPP 100 / 5.0 MeOH/ trace

Toluene amounts

4 Pd(OAc) ₂ DPPP 100 / 18 MeOH 0

5 Pd(OAc) ₂ Xantphos 60 / 1.0 MeOH/ 43

Toluene

6 Pd(OAc) ₂ DPPP 22 / 5.0 MeOH/ 73

Toluene

7 Pd(OAc) ₂ DPPP 60 / 5 MeOH/ 17

Toluene

8 Pd(OAc) ₂ DPPP 22 / 10 MeOH/ 3

Toluene

General procedure for the synthesis ofbicyclic compounds of formula (I) or (la) by Pd-catalyzed carbonylation assisted intramolecular Diels-Alder reaction of compounds of formula (II)or (Ha) (scheme 4, examples 9 to 11)

Scheme 4 Pd(OAc) ₂ (0.2 eq) and DPPP (0.2 eq) were weighed into a pre-dried autoclave vessel and suspended in toluene (1 mL/mmol substrate of formula [II] or [Ila]). A solution of the carbonate (1.0 eq), in MeOH/toluene 2: 1 (1.5 mL per mmol substrate of formula [II] or [Ila]), was added after which CO was bubbled though the solution. The autoclave was sealed and the atmosphere replaced by repeatedly filling with 1-2 bar of CO, followed by a final fill and release to obtain a final CO pressure of 5 bar. The mixture was stirred at ambient temperature until the reaction completes (typically over night) after which it was diluted with EtOAc and filtered through a plug of Celite. The filtrate was concentrated and the crude product purified through column

chromatography on silica gel (heptane/Et ₂ 0 1000: 1).

Examples 9 to 14 The general procedure as described above was employed for the synthesis of the bicyclic compounds of formula (I) depicted below in examples 9 to 14.

Methyl 6-methyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylate

Obtained after flash chromatography as a colourless oil in 36% yield.

1H NMR (CDC1 ₃ ) δ 6.85 (IH, d, J=5.4 Hz), 6.29 (IH, dd, J=5.2 and 2.7 Hz), 3.79 (3H, s), 2.77 (IH, m), 2.60 (IH, m), 2.43 (2H, m), 2.15 (IH, qdt, J=7.2 and 4.0 Hz), 1.80 (IH, ddd, J=12.8, 4.5 and 1.0 Hz), 1.43 (IH, dt, J=12.8 and 5.8 Hz), 1.36 (IH, dt, J=6.7 and 2.3 Hz), 1.12 (3H, d, J=7.3 Hz)

¹³ C NMR (CDCI3) δ 167.4, 145.5, 137.4, 127.8, 126.4, 51.8, 39.4, 35.9, 32.4, 31.4, 31.3, 20.2

HRMS calcd for C12H17O2 [M+l]: 193.1229, found: 193.1229 Methyl 6-methyl-2-phenyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylat e

Obtained after flash chromatography as a diastereomeric mixture in the form of a clear oil in 46% yield.

Major isomer trans:

1H NMR (CDCI ₃ ) δ 7.31 (2H, m), 7.22 (3H, m), 6.97 (IH, d, J=5.4 Hz), 6.34 (IH, m), 4.01 (IH, m), 3.79 (3H,s ), 2.87 (IH, m), 2.67 (IH, m), 2.62 (IH, dt, J=12.6 and 7.2 Hz), 1.99 (IH, dt, J=12.7 and 9.5 Hz), 1.88 (IH, m), 1.55 (lH, m), 1.37 (IH, t, J=10.1 Hz), 1.16 (3H, d, J=7.3 Hz)

1 ³ C NMR (CDCI ₃ ) δ 167.2, 146.5, 146.1, 138.2, 131.2, 129.0, 128.6, 127.6,

126.3, 51.8, 51.3, 42.5, 39.5, 35.8, 31.3, 20.0

Minor isomer cis: 1H NMR (CDCI3) δ 7.31 (2H, m), 7.22 (3H, m), 6.97 (1H, d, J=5.4 Hz), 6.42 (1H, t, J=2.5 Hz), 4.01 (1H, m), 3.80 (3H,s), 3.00 (1H, m), 2.67 (1H, m), 2.62 (1H, dt, J=12.6 and 7.2 Hz), 2.15 (1H, ddd, J=12.6 and 7.2 Hz), 1.83 (1H, m), 1.55 (1H, m), 1.37 (1H, t, J=10.1 Hz), 1.16 (3H, d, J=7.3 Hz)

1 ³ C NMR (CDCI3) δ 167.2, 146.7, 145.8, 138.1, 130.2, 129.0, 128.6, 127.4,

126.3, 51.3, 50.4, 40.1, 38.2, 36.0, 31.5, 20.0

HRMS calcd for Ci ₈ Hi ₉ 0 ₂ [M-l]: 267.1385, found: 267.1375

Methyl 2-benzyl-6-methyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylat e

Obtained after flash chromatography as a diastereomeric mixture in the form of a clear oil in 60% yield.

Major isomer (cis-cis)

1H NMR (CDCI3) δ 7.28 (2H, m), 7.21 (3H, m), 6.88 (1H, d, J=5.3 Hz), 6.23 (1H, m), 3.78 (3H, s), 3.01 (1H, m), 2.82 (1H, m), 2.75 (1H, dd, J=13.5 and 6.7 Hz), 2.60 (1H, m), 2.59 (1H, m), 1.92 (1H, dd, J=12.7 and 7.0 Hz), 1.76 (1H, dt, J=12.9 and 4.4 Hz), 1.51 (1H, dt, J=12.8 and 9.0 Hz) 1.40 (lH, m), 1.10 (3H, d, J=7.5 Hz)

¹³ C NMR (CDCI3) δ 167.0, 145.8, 141.4, 137.0, 131.2, 129.0, 128.1, 126.1,

125.7, 51.5, 46.5, 40.8, 37.1, 35.8, 35.7, 31.1, 19.8

Minor isomer (cis-trans)

1H NMR (CDCI3) δ 7.28 (2H, m), 7.21 (3H, m), 6.88 (1H, d, J=5.3 Hz), 6.28 (1H, m), 3.77 (3H, s), 3.09 (1H, m), 2.85 (1H, dd, J=13.4 and 7.0 Hz), 2.74 (1H, m), 2.64 (lH, m), 2.60 (lH, m), 2.21 (1H, dt, J=12.1 and 6.8 Hz), 1.77 (lH, m), 1.44 (2H, m), 1.10 (3H, d, J=7.5 Hz), 1.05 (1H, m)

1 ³ C NMR (CDCI3) δ 167.0, 145.8, 141.2, 137.1, 131.3, 128.8, 128.2, 126.0,

125.8, 51.5, 47.2, 42.3, 38.9, 38.6, 35.7, 31.0, 19.8

HRMS calcd for Ci ₉ H ₂ i0 ₂ [M-l]: 281.1542, found: 281.1529. Example 12

Methyl 6-methyl-l-phenyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylat es

Obtained as a 3: 1 diastereomeric mixture as a clear oil in 35% yield after flash chromatography.

Major isomer

1H NMR (CDC1 ₃ ) δ 7.33 (3H, m), 7.24 (2H, m), 6.90, (IH, d, J=5.4 Hz), 6.34 (IH, dd, J=4.9 and 2.4 Hz), 3.82 (3H, s), 2.98 (IH, td, J=8.4 and 10.0 Hz), 2.87 (2H, m), 2.65 (IH, m), 2.65 (IH, m), 1.80 (IH, ddd, J=12.8, 4.4 and 1.0 Hz), 1.51 (IH, td, J=12.8 and 5.8 Hz), 1.05 (3H, d, J=7.3)

¹³ C NMR (CDCI3) δ 167.3, 145.8, 144.3, 136.3, 128.7, 128.4, 128.2, 127.9, 127.3, 52.8, 51.9, 46.8, 41.4, 34.4, 31.3, 20.1

Minor isomer

1H NMR (CDCI3) δ 7.33 (3H, m), 7.15 (2H, m), 6.84 (IH, d, J=5.5 Hz), 6.53 (IH, dd, J=5.2 and 2.6 Hz), 3.81 (3H, s), 3.55 (IH, t, J=7.8 Hz), 3.16 (IH, m), 3.09 (2H, m), 2.75 (IH, m), 2.75 (IH, m), 2.49 (IH, m), 1.07 (3H, d, J=7.3 Hz)

¹³ C NMR (CDCI3) δ 167.3, 145.6, 144.5, 135.6, 126.5, 126.5, 126.3, 126.2, 126.0, 52.8, 51.8, 45.7, 43.4, 41.0, 29.3, 19.9

HRMS calcd for Ci ₈ H ₂ i0 ₂ [M+l]: 269.1542, found: 269.1548

Example 13

ethyl-2,6,7,7a-tetrahydro-lH-indene-4-carboxylate

Obtained as clear oil in 28% yield after flash chromatography using

heptane/EtO Ac ( 100 : 1 ) as eluent.

1H NMR (CDCI3) δ 6.84 (IH, d, J=5.8 Hz), 6.35 (IH, dd, J=5.1 and 2.5 Hz), 3.78 (3H, s), 2.69 (IH, m), 2.44 (2H, m), 2.16 (IH, m), 1.86 (IH, m), 1.55 (IH, m), 1.00 (3H, d, J=7.3 Hz), 0.90 (3H, s), 0.70 (3H, s)

¹³ C NMR (CDCI3) δ 167.2, 145.7, 136.3, 128.8, 125.6, 51.7, 48.5, 44.0, 34.0, 32.5, 25.1, 23.9, 22.7, 15.7 HRMS calcd for C14H19O2 [M-l]: 269.1542, found: 269.1548 Example 14

Obtained after flash chromatography (heptane: EtOAc, 10:1) as a 2: 1 diastereomeric mixture of yellow oil with 56 % yield.

Major isomer

1H NMR (CDCI3) δ 7.28 (3H, m), 7.19 (2H, m), 6.92, (1H, m), 6.21 (1H, m),

3.76 (3H, s), 3.07 (1H, m), 2.84 (2H, m), 2.61 (1H, m), 2.37 (1H, m), 2.21 (1H, t, J=6.9 Hz), 1.94 (lH, m), 1.54 (lH, m), 1.29 (lH, m), 1.08 (1H, t, J=9.9 Hz)

¹³ C NMR (CDCI3) δ 166.9, 141.4, 130.9, 129.2, 129.0, 128.9, 128.2, 126.4,

125.7, 51.6, 46.4, 42.2, 40.8. 38.6, 35.8, 29.2, 27.1

Minor isomer

1H NMR (CDCI3) δ 7.28 (3H, m), 7.19 (2H, m), 6.92, (1H, m), 6.26 (1H, m),

3.77 (3H, s), 2.99 (1H, m), 2.73 (2H, m), 2.55 (1H, m), 2.37 (1H, m), 2.21 (1H, t, J=6.9 Hz), 1.98 (lH, m), 1.52 (lH, m), 1.24 (lH, m), 1.05 (1H, t, J=9.9 Hz)

¹³ C NMR (CDCI3) δ 166.9, 141.4, 130.9, 129.2, 129.0, 128.9, 128.2, 126.4,

125.8, 51.5, 46.4, 42.2, 40.8. 38.6, 35.8, 29.2, 26.9

HRMS calc for Ci ₈ H ₂ i0 ₂ [M+l]: 269.1542, found 269.1540

In the claims, the term "comprises/comprising" does not exclude the presence of other species or steps. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms "a", "an", "first", "second" etc do not preclude a plurality.