AU2015202722A1 - A method of producing ingenol-3-angelate - Google Patents

Abstract

The present invention relates to methods of producing ingenol-3-angelate (I) from ingenol (II). O ,,'H "', 0 H - HO 20 OH HO 2 0 OH 5 (I) (II) Furthermore, the invention relates to intermediates useful for the synthesis of ingenol-3 angelate (I) from ingenol (II) and to methods of producing said intermediates.

Description

P/0101 1i Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: A method of producing ingenol-3-angelate The following statement is a full description of this invention, including the best method of performing it known to us: 1A A METHOD OF PRODUCING INGENOL-3-ANGELATE FIELD OF THE INVENTION 5 The present invention relates to methods of producing ingenol-3-angelate (2 methyl-2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a-dihydroxy-4 (hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a-octahydro 1H-2,8a-methanocyclopenta[a]cyclopropa[ejcyclodecen-6-yl ester; PEP005, Ingenol mebutate) from ingenol. The present invention further provides novel 10 intermediates and methods for the synthesis of the intermediates useful for producing ingenol-3-angelate. BACKGROUND OF THE INVENTION 15 Ingenol-3-angelate (PEP005, ingenol mebutate) is a protein kinase C activator in phase III clinical development for the treatment of actinic keratosis. The drug candidate is also in phase II trials for non-melanoma skin cancer [Ogbourne, S. M.; Anti-cancer Drugs, (2007), 18, 357-62]. 20 The compound ingenol-3-angelate (PEP005) [Sayed, M.D. et.al.; Experienta, (1980), 36, 1206-1207] can be isolated from various Euphorbia species, and particularly from Euphorbia peplus [Hohmann, J. et. al; Planta Med., (2000), 66, 291-294] and Euphorbia drummondii by extraction followed by chromatography as described in US 7449492. According to this procedure, extraction of 17 kg of 25 fresh Euphorbia peplus affords 7 g of a crude oil, which subsequently must be purified by HPLC to afford pure ingenol-3-angelate. The purification method is not ideally suited for larger scale production, as chlorophyll, which otherwise would co-migrate with ingenol-3-angelate, must be removed from the extract before the final purification step. Thus, the yield of ingenol-3-angelate by 30 extraction from Euphorbia pep/us and subsequent chromatography is extremely low. Therefore an alternative process for the production of ingenol-3-angelate which is also suitable for larger scale production would be desirable.

2 Ingenol is a natural product which is easily extracted from the readily available seeds of Euphorbia lathyris [Appendino, G. et. al., J. Nat. Prod. (1999), 62, 76 79]. As part of the extraction procedure the various ingenol esters present are hydrolysed and thus the amount of isolated ingenol is increased, making ingenol 5 more readily available than ingenol-3-angelate [Appendino, G. et, al., J. Nat. Prod. (1999), 62, 76-79; Girin, M.A. et. al., J. Chromatogr., (1993), 637, 206 208]. Ingenol or ingenol esters may also be found in other Euphorbia species, for example ingenol or ingenol esters have also been found in E. acrurensis, E. 10 antiquorum, E. biglandulosa, E. canariensis, E. cooper, E. cotinifolia, E. deightonil, E. desmondi, E. drupifera, E. ebracteolata, E. esula, E. helioscopia, E. hermentiana, E. iberica, E. ingens, E. jolkini, E. kamerunica, E. kansui, E. leuconeura, E. matabe/ensis, E. megalantha, E. mili, E. myrsinites, E. nematocypha, E. nubica, E. palustris, E. peptus, E. petiolata, E. pilosa, E. 15 quadrialata, E. quinquecostata, E. resinifera, E. royleana, E. seguierana, E. serrata, E. sieboldiana, E. tirucalli, E. triangularis, E. trigona. Furthermore, ingenol is commercially available, for example from LC Laboratories, 165 New Boston Street, Woburn, MA 01801, USA. Ingenol has previously been used as a starting point for the semi-synthetic 20 preparation of ingenol-3-esters [Sorg, B. et. al, Z. Naturforsch., (1982), 37B, 748-756] and ingenol-3-ester derivatives [Appendino et. al., Eur. J. Org. Chem. (1999), 3413; Opferkuch et.al., Z. Naturforschung, (1981), 36B, 878]. However, the preparation of ingenol-3-angelate and ingenol-3-angelate derivatives from ingenol has not been described. The preparation of angelate esters is not 25 straightforward as angelic acid and angelate esters are prone to isomerisation of the double bond to form the tiglate ester, both with and without the presence of base [Beeby, P., Tetrahedron Lett. (1977), 38, 3379-3382, Hoskins, W.M., J. Chem. Soc. Perkin Trans. 1, (1977), 538-544, Bohlmann, F. et. al., Chem. Ber. (1970), 103, 561-563]. Furthermore, ingenol derivatives are known to degrade 30 in the presence of acid [Appendino et. al., Eur. 3. Org. Chem. (1999), 3413]. Also, ingenol-3-esters are readily rearranged to afford the ingenol-5-esters and ingenol-20-esters. This is particularly the case for esters of short-chain carboxylic acids [Sorg, B. et. al, Z. Naturforsch., (1982), 37B, 748-756]. The purification method previously described for the purification of ingenol-3-esters 3 to avoid the rearranged side-products [Sorg, B. et. al, Z. Naturforsch., (1982), 37B, 748-756] is not suitable for large scale production of ingenol-3-angelate. SUMMARY OF THE INVENTION 5 One or more embodiments of this invention may provide a scalable process for the synthesis of ingenol-3-angelate (PEP005) starting from ingenol. The present invention provides novel processes to produce ingenol-3-angelate from ingenol. The present invention further provides novel intermediates for the 10 preparation of ingenol-3-angelate. Thus, in one aspect, the invention relates to methods of producing ingenol-3 angelate (I) from ingenol (II). 15 In another aspect, the invention relates to a method of producing ingenol-3 angelate (2-Methyl-2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl ester) (I) from ingenol (II) 20 H H 0 H 0 H 03 / 3 / OHO 5 HOHO ~ HO 20 OH HO 20 OH (I) (II) comprising the steps of: 25 (a) reacting one or both hydroxyl groups in positions 5 and 20 of ingenol with suitable hydroxyl protecting agents, same or different, to obtain a compound of the general formula (III) or (IV), i.e. protecting one or both hydroxyl groups in 4 HH "' O -'H 0n - 'H H H 3H HO HO / HOHO

R

2 0 20 OR 1 (III) (I V) D-O wherein R 1 represents hydrogen or a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group, or R 1 represents a hydroxyl 5 protective group and R 2 represents hydrogen or a hydroxyl protective group, or wherein D represents a dihydroxyl protective group (b) esterifying compounds (III) or (IV) to obtain compounds of the general formula (V) or (VI), i.e. esterifying the hydroxyl group at the 3-position of 10 compounds (III) or (IV) to obtain compounds of the general formula (V) or (VI) r O H ". H 0 -H 0' 11H H / H 0 3 0 OHO OHO - R20 5 OR 2 20 1qD (V) (VI) wherein R 1 , R 2 and D are as described above, and 15 (c) removing the hydroxyl protective groups R 1 , or Ri and R 2 , or D from compounds (V) or (VI) to obtain ingenol-3-angelate (I). In another aspect, the invention relates to a method of producing ingenol-3 angelate (2-Methyl-2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a 20 dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[ecyclodecen-6-y ester) (I) from ingenol (II) 5 0 '1H "o O 'H H / H 03 / 3 OHO 5 HO 5 - HO 20 OH HO 2 0 OH (I) (II) comprising the steps of: 5 (d) esterifying ingenol (II) to obtain a compound of the formula (VII) O H 0 / H HOH 34 0O 5 R 0 0 (VII) 2Z O wherein R 3 represents hydrogen or angeloyl, i.e. esterifying the 3- and the 20 10 hydroxyl group and optionally esterifying the 5-hydroxyl group of ingenol (II) to obtain a compound of the formula (VII) and (e) cleaving the angelate ester(s) in position 20 or in position 5 and 20 of compound (VII) to obtain ingenol-3-angelate (I). 15 In a further aspect, the invention relates to a method of producing ingenol-3 angelate (2-Methyl-2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a octahydro-1H-2,8a-methanocyclopenta[ajcyclopropa[e]cyclodecen-6-yI ester) 20 (I) from ingenol (II) 6 H H / H 03 / 3 / OHO 5 HOHO 5 HO 20 OH HO 2 OH (I) (II) comprising the step of: (f) selective esterification of the 3-hydroxy group of compound (II) to obtain 5 ingenol-3-angelate (I). In another aspect, the invention relates to a compound of general structure (V) wherein R 1 represents hydrogen or a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group; 10 with the proviso that not both R 1 and R 2 represent hydrogen: and with the proviso that R 1 and R 2 do not represent acetyl; and with the proviso that R 1 and R 2 do not represent 2-[(2 aminobenzoyl)amino]benzoyl; and with the proviso that R 1 does not represent decanoyl; 15 and with the proviso that R 1 does not represent 3-phenyl-2-propenoyl. In another aspect the invention relates to a compound of general structure (VI) wherein D represents a dihydroxyl protective group; with the proviso that D does not represent isopropylidene. 20 In another aspect, the invention relates to a compound of general formula III wherein R 1 and R 2 independently represents hydrogen or an ether, acetal, ketal, silylether, or a sulfenate derived hydroxyl protective group; with the proviso that not both R 1 and R 2 represent hydrogen; 25 and with the proviso that R 1 does not represent triphenylmethyl; and with the proviso that R 1 does not represent t-butyldimethysilyl. In another aspect, the invention relates to a compound of general formula IV wherein D represents a dihydroxyl protective group; 7 with the proviso that D does not represent isopropylidene. DETAILED DESCRIPTION OF THE INVENTION 5 Definitions All terms are intended to be understood as they would be understood by a person skilled in the art. 10 The term "hydroxyl protecting agent" is intended to mean a reagent which under suitable reaction conditions reacts with a hydroxyl group to form a hydroxyl protective group. The term "hydroxyl protective group" is intended to include any group which 15 forms a derivative of the hydroxyl group that is stable to the projected reactions wherein said hydroxyl protective group subsequently optionally can be selectively removed. Said hydroxyl derivative can be obtained by selective reaction of a hydroxyl protecting agent with a hydroxyl group. 20 The term "hydroxyl protecting group" is intended to have the same meaning as the term "hydroxyl protective group". Ether derivatives, such as allyl ether, prenyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 2-trimethylsilylethyl ether, tert-butyl ether, cinnamyl 25 ether, propargyl ether, p-methoxyphenyl ether, benzyl ether, 3,4 dimethoxybenzyl ether, 2,6-dimethoxybenzyl ether, o-nitrobenzyl ether, p nitrobenzyl ether, 4-(trimethylsilylmethyl)-benzyl ether, 2-naphthylmethyl ether, diphenylmethyl ether, (4-methoxyphenyl)-phenylmethyl ether, (4-phenyl phenyl)-phenylmethyl ether, p,p'-dinitrobenzhydryl ether, 5-dibenzosuberyl 30 ether, tris(4-tert-butylphenyl)methyl ether, (a-naphthyl)-diphenylmethyl ether, p-methoxyphenyldiphenylmethyl ether, di(p-methoxyphenyl)phenylmethyl ether, tri(p-methoxyphenyl)methyl ether or 9-(9-phenyl)xanthenyl ether are examples of hydroxyl protecting groups.

8 Ether derived hydroxyl protective groups also include alkoxyalkylethers (acetals and ketals) such as 1-ethoxyethyl ether, 1-methyl-1-methoxyethyl ether, [(3,4 dimethoxybenzyl)oxy]methyl ether, guaiacolmethyl ether, 2 methoxyethoxymethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, 5 tetrahydropyranyl ether, tetrahydrofuranyl ether, methoxymethyl ether benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, p nitrobenzyloxymethyl ether, o-nitrobenzyloxymethyl ether, (4 methoxyphenoxy)methyl ether, tert-butoxymethyl ether, 4-pentenyloxymethyl ether, siloxymethyl ether, 1-methoxycyclohexyl ether, 4 10 methoxytetrahydropyranyl ether, 1-[(2-chloro-4-methyl)phenyl]-4 methoxypiperidin-4-yl ether, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl ether, 1-(4-chlorophenyl)-4-methoxypiperidin-4-y ether or 1-methyl-1-benzyloxyethyl ether. 15 Ether derived hydroxyl protective groups also include thioacetals and thio ketals such as tetrahydrothiopyranyl ether, 4-methoxytetrahydrothiopyranyl ether, tetrahydrothiofuranyl ether or 1,3-benzodithiolan-2-yl ether. Hydroxyl protective groups also include silyl ether derivatives, such as 20 trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert butyldimethylsilyl ether, dimethylisopropylsilyl ether, diethylisopropylsilyl ether, diphenylmethylsilyl ether, triphenylsilyl ether, dimethylthexylsilyl ether, 2 norbornyldimethylsilyl ether, tert-butyldiphenysilyl ether, (2 hydroxystyryl)dimethylsilyl ether, (2-hydroxystyryl)diisopropylsilyl ether, tert 25 butylmethoxyphenylsilyl ether or tert-butoxydiphenylsilyl ether. Hydroxyl protective groups also include esters of hydroxyl groups such as acetate ester, chloroacetate ester, trifluoroacetate ester, phenoxyacetate ester, formate ester, benzoylformate ester, dichloroacetate ester, trichloroacetate 30 ester, methoxyacetate ester, p-chlorophenoxyacetate ester, phenylacetate ester, 3-phenylpropionate ester, 4-pentenoate ester, 4-oxopentanoate ester, pivaloate ester, crotonate ester, 4-methoxycrotonate ester, angelate ester, benzoate ester or p-phenylbenzoate ester.

9 Hydroxyl protective groups also include carbonates of hydroxyl groups such as methoxymethyl carbonate, 9-fluorenylmethyl carbonate, methyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, vinyl carbonate, allyl carbonate or p-nitrophenyl carbonate. 5 Hydroxyl protective groups also include sulfenates of hydroxyl groups such as 2,4-dinitrophenylsulfenate. 10 A dihydroxyl protective group is any group which forms a derivative of a diol which is stable to the projected reactions wherein said dihydroxyl protective group subsequently optionally can be selectively removed. Said dihydroxyl derivative can be obtained by selective reaction of a dihydroxyl protecting agent with a diol. 15 Ketal derivatives, such as isopropylidene ketal (acetonide), cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzophenone ketal, 1-tert butylethylidene ketal or 1-phenylethylidene ketal, 3-pentylidene ketal, 2,4 dimethyl-3-pentylidene ketal, 2,6-dimethyl-4-heptylidene ketal, 3,3-dimethyl-2 20 butylidene ketal; and acetal derivatives such as benzylidene acetal, 2,4 dimethoxybenzylidene acetal, 4-nitrobenzylidene acetal, 2,4,6 trimethylbenzylidene acetal, 2,2-dimethyl-1-propylidene acetal, methylene acetal, ethylidene acetal, p-methoxybenzylidene acetal, tert-butylmethylidene acetal, 3-(benzyloxy)propylidene acetal, acrolein acetal, 2-nitrobenzylidene 25 acetal, mesitylene acetal or 2-naphthaldehyde acetal, are examples of dihydroxyl protective groups. Other dihydroxyl protective groups include cyclic ortho esters or ortho esters, such as methoxymethylene acetal, ethoxymethylene acetal, 2 30 oxacyclopentylidene ortho ester or isopropoxymethylene acetal. Other dihydroxyl protective groups include bisacetal derivatives such as butane 2,3-bisacetal or cyclohexane-1,2-diacetal; or dispiroketals such as octahydro [2,2']-bipyranyl ketal.

10 Other dihydroxyl protective groups include bisacetal derivatives such as butane 2,3-bisacetal or cyclohexane-1,2-diacetal; or dispiroketals such as octahydro [2,2']-bipyranyl ketal. 5 Other dihydroxyl protective groups include silyl derivatives such as di-tert butylsilylene, dialkylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), 1, 1,3,3-tetra-tert-butoxydisiloxanylidene, methylene-bis-(diisopropylsilanoxanylidene, or 1,1,4,4-tetraphenyl-1,4 disilanylidene derivatives. 10 Dihydroxyl protective groups also include cyclic carbonates. Other dihydroxyl protective groups include cyclic boronates such as phenyl boronate, methyl boronate or ethyl boronate. 15 Hydroxyl protective groups and dihydroxyl protective groups also include solid phase supported protective groups. Solid phase supported reagents for the introduction of solid phase supported protective groups may include for example polymer-bound 2-Chlorotrityl chloride for the introduction of a solid phase 20 supported trityl protective group, or Acetylpolystyrene resin or 4-(4 Hydroxyphenyl)butan-2-one-based resins for the preparation of solid phase supported ketal-protective groups. Non-limiting examples of hydroxyl protective groups and dihydroxyl protective 25 groups all included in the scope of this invention, can for example be found in "Protective Groups in Organic Synthesis", 4 th ed. P.G.M. Wuts; T.W. Greene, John Wiley, 2007, page 16-366, and in P.J. Kocienski, "Protecting Groups", 3 rd ed. G. Thieme, 2003, which are hereby incorporated by reference 30 Angelic acid is 2-methyl-2(Z)-butenoic acid. Tiglic acid is 2-methyl-2(E)-butenoic acid.

11 alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl. The term "alkenyl" is intended to indicate a radical obtained when one hydrogen 5 atom is removed from a hydrocarbon containing at least one C=C double bond. Said alkenyl comprises 3-12, preferably 3-6 carbon atoms, e.g. allyl. The term alkyl halide is intended to indicate a molecule of the general formula R-X, wherein R is an optionally substituted alkyl group as defined above, and X 10 is any halogen substituent such as chloro, bromo or iodo. The term alkenyl halide is intended to indicate a molecule of the general formula R-X, wherein R is an optionally substituted alkenyl group as defined above, and X is any halogen substituent such as chloro, bromo or iodo.The term "alkoxy" is 15 intended to indicate a radical of the formula -OR', wherein R' is alkyl as indicated above, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, etc. The term "alkoxyalkyl" is intended to indicate an alkyl radical as defined above, which is substituted with an alkoxy radical as defined above, i.e. R'-0-R'-, 20 wherein each R' is alkyl same or different, as indicated above, e.g. methoxymethyl, ethoxymethyl. The term "alkoxyalkyl halide" is intended to indicate a molecule of the general formula R'-O-R'-X wherein each R' is alkyl, same or different, as indicated 25 above, and X is any halogen substituent such as chloro, bromo or iodo, e.g. methoxymethyl chloride, ethoxymethyl chloride. The term "alkylcarbonyl" is intended to indicate a radical of the formula -C(O) R', wherein R' is alkyl as indicated above, e.g. acetyl. 30 The term "alkenylcarbonyl" is intended to indicate a radical of the formula -C(O) R', wherein R' is alkenyl as indicated above, e.g. angeloyl.

12 The term "aryl" is intended to indicate a radical of the formula Ar-, obtained when one hydrogen atom is removed from a cyclic carbon containing compound with a delocalised (4n+2) nc-electron system. n is an integer >0, preferably 1 or 2. Examples of Ar- are phenyl, 2,4,6-trichlorophenyl, 4-nitrophenyl. 5 The term "arylalkyl" is intended to indicate a radical of the formula Ar-R"-, wherein Ar-R"- is an alkyl radical as indicated above substituted with an aromatic radical, e.g. benzyl. 10 The term "acid halide" is intended to indicate a molecule of the general formula R'-C(0)-X or Ar-C(O)-X wherein R' is optionally substituted alkyl or alkenyl as defined above, Ar is optionally substituted aryl as defined above and X is halogen such as chloro, bromo or lodo, as defined herein. Examples of acid halides are acetyl chloride, chloroacetyl chloride, phenoxyacetyl chloride, 15 benzoyl chloride, 2,4,6-trichlorobenzoyl chloride, 4-nitrobenzoyl chloride or angeloyl chloride. The term "acid anhydride" is intended to indicate a molecule of the general formula R'-C(O)-O-C(O)-R' or Ar-C(O)-O-C(O)-Ar wherein R' is optionally 20 substituted alkyl or alkenyl as defined above and Ar is optionally substituted aryl as defined above. Examples of acid anhydrides are acetic anhydride, angelic anhydride, benzoic anhydride or 2,4,6-trichlorobenzoic anhydride. The term "mixed anhydride" is intended to indicate a molecule of the general 25 formula R-C(O)-O-C(O)-R" or Ar-C(O)-0-C(O)-R' wherein R- and R'- are different and R' and R" are optionally substituted alkyl or alkenyl as defined above and Ar is optionally substituted aryl as defined above. Examples of "mixed anhydrides" are angeloyl 2,4,6-trichlorobenzoyl anhydride or angeloyl 4 nitrobenzoyl anhydride. 30 The term "alkoxycarbonyl" is intended to indicate a radical of the formula R'-O C(0)-, wherein R' is alkyl as indicated above, e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl etc.

13 The term "arylsulfenyl" is intended to indicate a radical of the formula Ar-S(O) wherein Ar- is as defined above, e.g. 2,4-dinitrophenylsulfenyl. 5 The term "diol" is intended to indicate a molecule containing two or more hydroxyl groups, in which the two hydroxyl groups are not attached to the same carbon atom. In general diol protecting groups are used for protection of 1,2-diols and/or 1,3-diols. Examples of "diols" are ingenol or ingenol-3-angelate. 10 The term "activated acid derivative" is intended to indicate a derivative of an acid, which under the chosen reaction conditions will react more readily than the corresponding acid with an alcohol to form an ester. Examples of "activated acid derivatives" are acid halides, acid anhydrides, "mixed anhydrides", methyl angelate or vinyl angelate. 15 The term "coupling reagent" is intended to indicate a reagent, which will facilitate the formation of an ester from an acid and an alcohol by the formal binding of water. Examples of "coupling reagents" are dicyclohexylcarbodiimide (DCC), 1-methyl-2-chloro-pyridinium iodide, HBTU (O-(benzotriazol-1-yl) 20 N,N,N'N-tetramethyluronium hexafluorophosphate), DMTMM (4-(4,6 dimethoxy-1,3,5-triazin-2-yl)-4-methymorpholinium chloride), HATU (N,N,N',N' Tetramethyl-O-(7-azabenzotriazol- 1-yl)uronium hexafluorophosphate), EDCI (N (3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride). 25 The term "activator" is intended to indicate a reagent, which will facilitate the formation of an ester from an acid or an activated acid derivative and an alcohol by the removal of acid from the reaction mixture. Examples of "activators" are triethylamine, NN-diisopropylethylamine, pyridine or lutidine. 30 The term "catalyst" is intended to indicate a compound, which in substoichiometric or stoichiometric amount, or in excess, will accelerate the reaction without being consumed itself. Examples of a catalyst is DMAP (4-(NN dimethylamino)pyridine) or 1-hydroxybenzotriazole..

14 The term "enzymatic catalysis" is intended to indicate catalysis of chemical reactions by specialised proteins called enzymes. Examples of enzymes are lipases, esterases, proteases or cutinases. 5 The term "esterase" is intended to indicate an enzyme which is capable of catalysing the cleavage of an ester into acid and alcohol. The term "lipase" is intended to indicate an enzyme which is capable of catalysing the hydrolysis of lipids. Lipases are often capable of hydrolysing 10 esters that are not lipids. An example of a lipase is Candida antarctica Lipase B. The term "angelate" is intended to indicate an ester of angelic acid. The term "esterify" is intended to indicate a reaction in which a hydroxyl group 15 is combined with a suitable reactant, i.e. combined with a carboxylic acid or a carboxylic acid derivative under suitable reaction conditions, to form an ester. The term "ether derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of 20 an ether group. The term "ester derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of an ester group. 25 The term "acetal derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of an acetal group. 30 The term "ketal derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of a ketal group.

15 The term "silylether derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of a silylether group. 5 The term "sulfenate derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of a sulfenate group. The term "boronate derived hydroxyl protective group" is intended to indicate a 10 hydroxyl protecting group in which the hydroxyl group to be protected is part of a boronate group. The term "carbonate derived hydroxyl protective group" is intended to indicate a hydroxyl protecting group in which the hydroxyl group to be protected is part of 15 a carbonate group. Embodiments In one embodiment, the invention relates to methods of producing ingenol-3 20 angelate (I) from ingenol (II), in which one or more hydroxyl groups are protected by hydroxyl protective groups or dihydroxyl protective groups. In one embodiment the invention relates to a method of producing ingenol-3 angelate (2-Methyl-2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a 25 dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yI ester) (I) from ingenol (II) '"'0 H " 0 H H / H 03 / 3 OHO HOHO S HO20 OH HO 2 0 OH (I) (II) 16 comprising the steps of: (a) protecting one or both hydroxyl groups in positions 5 and 20 of ingenol with 5 a protective group to obtain a compound of the general formula (III) or (IV) '" -O'H 0n O 1'H 3 H / H 3 // HO HO 5 HO HO

R

2 0 20

OR

1 HO (III) (I V) D-0 wherein R 1 represents a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group, or wherein D represents a dihydroxyl protective 10 group (b) esterifying compounds (III) or (IV) to obtain compounds of the general formula (V) or (VI) " O 'H "". 0 H / H / H 03 0 / OHO 'OHO - R 2 0 5 20 OR 1 -- , 15 (V) (VI) wherein R 1 , R 2 and D are as described above, and (c) removing the hydroxyl protective groups R 1 , or R, and R 2 , or D from compounds (V) or (VI) to obtain ingenol-3-angelate (I). 20 In another embodiment the invention relates to a method of producing ingenol 3-angelate (2-Methyl-2(Z)-butenoic acid (1aR,2S,5R,5aS,6S,8aS,9R,1OaR) 5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo- 17 1a,2,5,5a,6,9, 10, lOa-octahydro-1H-2,8a methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yI ester) (I) from ingenol (II) O ' H H 7 H 03 / 3 / OHO 5 HOHO 5 HO 20 OH HO 20 OH (I) (II) 5 comprising the steps of: (d) esterifying Ingenol (II) to obtain a compound of the formula (VII) H 0 3 H O

R

3 O 2 0 (VII) 2 0 10 wherein R 3 represents hydrogen or angeloyl, and (e) cleaving the angelate ester(s) in position 20 or in position 5 and 20 of 15 compound (VII) to obtain ingenol-3-angelate (I). In another embodiment the invention relates to a method of producing ingenol 3-angelate (2-Methyl-2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR) 5,5a-dihydroxy-4-(hydroxymethyl)- 1,1, 7,9-tetramethyl- 11-oxo 20 la,2,5,5a,6,9,10,10a-octahydro-1H-2,8a methanocyclopenta[a]cyclopropa[e]cyclodecen-6-y ester) (I) from ingenol (II) 18 " 0 -,H ""' 1H H / H 03 / 3 OHO 5 HOHO 5 HO 2 0 OH HO 20 OH (I) (II) comprising the step of: (f) selective esterification of the 3-hydroxy group of compound (II) to obtain 5 ingenol-3-angelate (I). In one embodiment, R 1 may represent hydrogen or R 1 may represent an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group and R 2 may represent hydrogen or an ether, acetal, ketal, 10 silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group. For example, R 1 may be selected from the group consisting of hydrogen, [(3,4 dimethoxybenzyl)oxy] methyl, guaiacolmethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 15 allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, acetyl, chloroacetyl, phenoxyacetyl or angeloyl. 20 R 2 may for instance be selected from the group consisting of hydrogen or [(3,4 dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, 25 diethylisopropylsilyl, tert-butyldiphenylsilyi, triphenylsilyl, acetyl, chloroacetyl, phenoxyacetyl or angeloyl. In another embodiment, D may represent an acetal, ketal, diacetal, diketal, ortho ester, silyl, boronate or a carbonate derived dihydroxyl protective group.

19 For example, D may be selected from the group consisting of isopropylidene, cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yi, 1,2 dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2']-bipyran-2,2'-di-yl, di-tert 5 butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3 pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3 dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4 dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2 dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene.. 10 In a specific embodiment, R 1 represents a hydroxyl protective group, and R 2 represents hydrogen. In another specific embodiment, R 3 represents hydrogen. 15 In another embodiment the invention relates to a method wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above with angelic acid in the presence of a coupling reagent or an enzyme. 20 In another embodiment the invention relates to a method wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above with angelic acid in the presence of a coupling reagent. In an embodiment the coupling reagent is selected from the group consisting of 25 DCC, HATU, EDCI or 2-chloro-1-methyl-pyridinium iodide In another embodiment the invention relates to a method wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above, with an activated derivative of angelic acid. 30 In an embodiment the activated derivative of angelic acid is selected from the group consisting of methyl angelate, angeloyl chloride, angelic acid anhydride, [(Z)-2-methylbut-2-enoyl] 2,4,6-trichlorobenzoate or angeloyl 4-nitrobenzoyl anhydride.

20 In another embodiment the invention relates to a method wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above, with an angelic acid halide or with angelic acid anhydride or with a mixed 5 angelic acid anhydride. In an embodiment angelic acid halide is angeloyl chloride. In an embodiment a mixed angelic anhydride is [(Z)-2-methylbut-2-enoyl] 10 2,4,6-trichlorobenzoate or angeloyl 4-nitrobenzoyl anhydride. In an embodiment the invention relates to a compound of general formula (V) wherein R 1 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group, and R 2 represents 15 hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group; In an embodiment the invention relates to a compound of general formula (V) wherein R, and R 2 independently represents hydrogen or [(3,4 20 dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, chloroacetyl or 25 phenoxyacetyl. In an embodiment the invention relates to a compound of general formula (V) wherein R, represents a hydroxyl protective group and R 2 represents hydrogen; 30 In an embodiment the invention relates to a compound chosen from the group consisting of Ingenol-20-(tert-butyldimethylsilyl)-ether-3-angelate.

21 In an embodiment the invention relates to a compound of general formula (VI) wherein D represents an acetal , ketal , diacetal , diketal , ortho ester, silyl, boronate or a carbonate dihydroxyl protective group. 5 In an embodiment the invention relates to a compound of general formula (VI) wherein D represents cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2 dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2']-bipyran-2,2'-di-yl, di-tert butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3 10 pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3 dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4 dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2 dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene. 15 In an embodiment the invention relates to a compound chosen from the group consisting of ingenol-5,20-(di(tert-butyl)silylene)-ether-3-angelate In an embodiment the invention relates to a compound of general formula(IV) 20 wherein D represents an acetal , ketal , diacetal , diketal , ortho ester, silyl, boronate or a carbonate derived dihydroxyl protective group. In an embodiment the invention relates to a compound of general formula(IV) wherein D represents cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, 25 methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2 dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2']-bipyran-2,2'-di-yl, di-tert butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3 pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3 dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4 30 dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2 dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene. In an embodiment the invention relates to a compound chosen from the group consisting of 22 Ingenol-5,20-(3-pentylidene)-ketal, Ingenol-5,20-(2,4-dimethyl-3-pentylidene)-ketal, Ingenol-5,20-(2,6-dimethyl-4-heptylidene)-ketal, Ingenol-5,20-cyclopentylidene-ketal, 5 Ingenol-5,20-cyclohexylidene-ketal, Ingenol-5,20-(3,3-dimethyl-2-butylidene)-ketal, Ingenol-5,20-(1-phenyl-1-ethylidene)-ketal, Inge nol - 5,20- benzyl id en e- acetal, Ingenol-5,20-(4-methoxybenzylidene)-acetal, 10 Ingenol-5,20-(2,4-dimethoxybenzylidene)-acetal, Ingenol-5,20-(4-nitrobenzylidene)-acetal, Ingenol-5,20-(2,4,6-trimethylbenzylidene)-acetal, Ingenol-5,20-(2,2-dimethyl- 1-propylidene)-acetal, Ingenol-5,20-methyl-orthoformate, 15 Ingenol-5,20-ethyl-orthoformate, Ingenol-5,20-(prop-2-yf)-orthoformate, or Ingenol-5,20-(di(tert-butyl)silylene) -ether. In an embodiment the invention relates to a compound a compound of general 20 structure (VII) wherein R 3 represents hydrogen or angeloyl. In an embodiment the invention relates to the use of a compound of general formula (III), (IV), (V) or (VI) as an intermediate in the manufacture of ingenol 3-angelate. 25 Synthetic Methods The compounds of the general formula (III) and (IV) can for example be 30 synthesised by reacting compound (II) with a hydroxyl protecting agent or a dihydroxyl protecting agent according to methods well known to a person skilled in the art, such as methods described in "Protective Groups in Organic Synthesis", 4 th ed. P.G.M. Wuts; T.W. Greene, John Wiley, 2007 or in P.J.

23 Kocienski, "Protecting Groups", 3 rd ed. G. Thieme, 2003 and references cited therein. For example, compound (III) wherein R 1 is triphenylmethyl and R 2 is hydrogen 5 or triphenylmethyl, can be synthesised by reacting compound (II) with a triphenylmethyl reagent such as triphenylmethylpyridinium fluoroborate or triphenylmethyl chloride in a suitable solvent such as pyridine, NN dimethylformamide or dichloromethane in the presence or in the absence of base [eg. Opferkuch et.al., Z. Naturforschung, (1981), 368, 878]. 10 Compound (III) wherein R, is arylalkyl or alkenyl such as p-methoxybenzyl or allyl and R 2 is hydrogen or arylalkyl or alkenyl, can for example be synthesised by reacting compound (11) with an alkyl halide or alkenyl halide such as p methoxybenzyl halide or allyl halide in a suitable solvent such as NN 15 dimethylformamide or tetrahydrofuran optionally in the presence of a suitable base such as potassium carbonate. Compound (III) wherein R, is alkoxyalkyl such as methoxymethyl or 2 methoxyethoxymethyl and R 2 is hydrogen or alkoxyalkyl such as methoxymethyl 20 or 2-methoxyethoxymethyl, can for example be synthesised by reacting compound (II) with an alkoxyalkyl halide such as methoxymethyl chloride or 2 methoxyethoxymethyl chloride in a suitable solvent such as tetrahydrofuran or dichloromethane optionally in the presence of a suitable base such as NN diisopropylethylamine. 25 Compound (III) wherein R, is 2-tetrahydropyranyl and R 2 is hydrogen or 2 tetrahydropyranyl, can for example be synthesised by reacting compound (II) with dihydropyran in a suitable solvent such as dichloromethane or acetonitrile in the presence of a suitable acid such as p-toluenesulfonic acid. 30 Compound (III) wherein R, is silyl and R 2 is hydrogen or silyl, can for example be synthesised by reacting compound (II) with a silyl chloride such as tert butyldimethylsilyl chloride, tert-butydiphenylsilyl chloride or triisopropylsilyl chloride in a suitable solvent such as NN-dimethylformamide, pyridine, 24 dichloromethane, tetrahydrofuran or acetonitrile optionally in the presence of a suitable base such as imidazole, triethylamine, NN-diisopropylethylamine, 4 (N,N- dimethylamino)pyridine or 2,6-lutidine, or by reacting compound (II) with a silyl triflate such as tert-butyldimethylsilyl trifluoromethanesulfonate in a 5 suitable solvent such as dichloromethane optionally in the presence of a suitable base such as triethylamine. Compound (III) wherein R 1 is alkylcarbonyl or alkenylcarbonyl such as acetyl, chloroacetyl or phenoxyacetyl or angeloyl and R 2 is hydrogen or alkylcarbonyl or 10 alkenylcarbonyl, can for example be synthesised by reacting compound (II) with the corresponding acid chloride such as acetyl chloride, chloroacetyl chloride or phenoxyacetyl chloride or angeioyl chloride or by reacting compound (II) with an acid anhydride such as acetic anhydride, chloroacetic anhydride or phenoxyacetic anhydride or angelic acid anhydride in a suitable solvent such as 15 pyridine or dichloromethane optionally in the presence of a suitable base such as N,N-diisopropylethylamine or 4-(NN-dimethylamino)pyridine, or by reacting compound (II) with an acyl donor such as vinyl acetate or chloroacetic anhydride or vinyl angelate optionally in the presence of an enzyme as catalyst. 20 Compound (III) wherein R, is alkoxycarbonyl such as methoxycarbonyl or 9 fluorenylmethoxy carbonyl and R 2 is hydrogen or alkoxycarbonyl such as methoxycarbonyl or 9-fluorenylmethoxy carbonyl, can for example be synthesised by reacting compound (II) with the corresponding alkylchloro formate in a suitable solvent such as pyridine or dichloromethane optionally in 25 the presence of a suitable base such as triethylamine or N,N,N',N' tetra methylenediamine. Compound (III) wherein Ri is an arylsulfenyl such as 2,4-dinitrophenylsulfenyl and R 2 is hydrogen or an arylsulfenyl such as 2,4-dinitrophenylsulfenyl can for 30 example be synthesised by reacting compound (II) with an optionally substituted sulfenylchloride such as as 2,4-dinitrophenysulfenyl chloride in a suitable solvent such as dichloromethane optionally in the presence of a suitable base such as pyridine.

25 Compound (IV) wherein D represents an acetal such as benzylidene acetal can for example be synthesised by reacting compound (II) with an aldehyde such benzaldehyde or a dimethoxy acetal such as benzaldehyde dimethyl acetal in a suitable solvent such as dichloromethane or NN-dimethylformamide or THF in 5 the presence of a suitable acid such as p-toluenesulfonic acid; or a benzylidene acetal can for example be prepared by reacting compound (II) with an a,a-di halo-toluene derivative such as for example a,a-dibromotoluene or a,a (bispyridinium)toluenedibromide in a suitable solvent such as pyridine, DMF or THF in the presence of a suitable base such as K 2

CO

3 or LIHMDS. 10 Compound (IV) wherein D represents a ketal such as isopropylidene ketal can for example be synthesised by reacting compound (II) with a ketone such as acetone or a dimethoxy ketal such as 2,2-dimethoxy propane in a suitable solvent such as dichloromethane or NN-dimethylformamide or THF in the 15 presence of a suitable acid such as p-toluenesulfonic acid or methanesulfonic acid. Acetone and 2,2-dimethoxy propane can also act as solvents. Compound (IV) wherein D represents a bis-acetal such as butane 2,3-bisacetal or cyclohexane-1,2-diacetal or a dispiroketals such as octahydro-[2,2']-bipyranyl 20 ketal can be prepared by reacting compound (II) with 2,2,3,3 tetramethoxybutane or cyclohexane-1,2-dione and trimethyl orthoformate in the presence of a suitable acid such as p-toluenesulfonic acid in a suitable solvent such as methanol or by reacting with bisdihydropyran in the presence of a suitable acid such as p-toluenesulfonic acid in a suitable solvent such as 25 dichloromethane. Compound (IV) wherein D represents a cyclic ortho ester such as methoxymethylene acetal or 2-oxacyclopentylidene ortho ester can for example be synthesised by reacting compound II with an ortho ester such as trimethyl 30 orthoformate in a suitable solvent such as dichloromethane in the presence of an acid such as p-toluenesulfonic acid; or by reacting compound II with a dihalomethylalkoxyether, such as for example dichloromethyl methy( ether,in a suitable solvent such as DMF or THF in the presence of a suitable base such as LiHMDS or K 2 C0 3

.

26 Compound (IV) wherein D represents silyl such as di-tert-butylsilylene can for example be synthesised by reacting compound II with a dialkylsilyl dichloride or a dialkylsilyl ditriflate such as di-tert-butylsilyl ditriflate in a solvent such as 5 acetonitrile,dichloromethane or NN-dimethylformamide optionally in the presence of a base such as triethylamine or 2,6-lutidine. Compound (IV) wherein D represents carbonyl can for example be synthesised by reacting compound (II) with phosgene or N,N'-carbonyldiimidazole in 10 pyridine. Compound (IV) wherein D represents a boronate such as phenyl boronate can for example be synthesised by reacting compound (II) with phenylboronic acid in pyridine. 15 The synthesis of compounds of general formula (III) and (IV) from compound (II) may be performed both in a batch reactor and in a flow reactor, such as for example an Alfa Laval ART® Plate Reactor 37 20 The reagents for introducing the hydroxyl protective groups R1, R2 or D may be solid phase supported reagents such as for example polymer bound 2 Chlorotrityl chloride, acetylpolystyrene resin or 4-(4-Hydroxyphenyl)butan-2 one-based resins. 25 The compounds of the general formula (III) and (IV) can be esterified in the 3 position to obtain the compounds of the general formula (V) and (VI) by reaction of compound (III) or (IV) with angelic acid in the presence of a coupling reagent or with activated angelic acid derivatives. Compound (II) can be esterified to 30 obtain compounds of the general formula (VII) by reaction of compound (II) with angelic acid in the presence of a coupling reagent or with activated angelic acid derivatives. The compounds may be prepared according to, but not limited to, methods for esterification described in "Esterification" by J. Otera, Wiley- 27 VCH, 2003, which is hereby incorporated by reference, and references cited therein. For example compound (V), (VI) or (VII) can be synthesised by reacting 5 compound (III), (IV) or (II) with an activated angelic acid derivative such as angeloyl halide such as angeloyl chloride. The esterification by reaction with angeloyl chloride can take place without an activator, or it can take place in the presence of a base such as pyridine or triethylamine, LiHMDS or DMAP, in a suitable solvent such as for example pyridine or THF. Examples of the synthesis 10 of angelic acid esters using angeloyl chloride can for example be found in Beeby, P.J., Tetrahedron Lett., (1977), 38, 3379-3382. Compound (V), (VI) or (VII) can for example be synthesised by reacting compound (III), (IV) or (II) with an activated angelic acid derivative such as 15 angelic anhydride. The esterification by reaction with angelic anhydride can take place without a catalyst, or in the presence of an acidic catalyst using an acid such as perchloric acid or a Lewis acid such as scandium (III) triflate or bismuth (III) triflate, or in the presence of a base such as sodium hydrogencarbonate or triethylamine, LiHMDS, NaHMDS, KHMDS, pyridine, cesium carbonate or DMAP, 20 in a suitable solvent such as for example THF, MeCN, pyridine or MTBE. Examples of the synthesis of angelic acid esters using angelic acid anhydride can for example be found in Hartmann, B. et. a/.; Tetrahedron Lett., (1991), 32, 5077-5080 or in JP2008127287. 25 Compound (V), (VI) or (VII) can for example be synthesised by reacting compound (III), (IV) or (II) with an activated angelic acid derivative such as a mixed anhydride such as angeloyl trichlorobenzoyl anhydride, such as angeloyl 2,4,6-trichlorobenzoyl anhydride. The esterification by reaction with a mixed anhydride can take place without a catalyst, or in the presence of an acidic 30 catalyst using an acid such as perchloric acid or a Lewis acid such as scandium (III) triflate or bismuth (III) triflate, or in the presence of a base such as sodium hydrogencarbonate or triethylamine, in a suitable solvent such as for example toluene. Examples of the synthesis of angelic acid esters using angeloyl trichlorobenzoyl anhydride can for example be found in Hartmann, B. et. a!.; 28 Tetrahedron Lett. (1991), 32, 5077-5080, or in Ball, B., Org. Lett., (2007), 9, 663-666. Compound (V), (VI) or (VII) can for example be synthesised by reacting 5 compound (III), (IV) or (II) with angelic acid in the presence a coupling reagent. Angelic acid can be esterified in the presence of a coupling reagent such as a carbodiimide such as dicyclohexylcarbodiimide or EDCI (N-(3 Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) with or without catalysts such as 1-hydroxybenzotriazole. Examples of the synthesis of angelic 10 acid esters using dicyclohexylcarbodiimide with or without catalysts can for example be found in H oskins, W.M., J. Chem. Soc. Perkin Trans. 1, (1977), 538 544. Other coupling reagents for esterification can for example be 2-halo-1 alkylpyridinium salts such as 1-methyl-2-chloro-pyridinium iodide, or hydroxy benzotriazol derivatives such as HBTU (O-(benzotriazol-1-yl)-N,N,N',N' 15 tetramethyluronium hexafluorophosphate), or HATU (N,N,N',N'-Tetramethyl-O (7-azabenzotriazol-1-yl)uronium hexafluorophosphate), or triazine derivatives such as DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride. Suitable solvents can be methylene chloride, toluene, DMF or THF. Solid-supported coupling reagents can also be used in the 20 esterification step [Nam, N.-H., Journal of Combinatorial Chemistry, (203), 5, 479-545, or "Esterification" by J. Otera, Wiley-VCH, 2003] which are hereby incorporated by reference, Compound (V), (VI), (VII) or (I) can for example be synthesised by reacting compound (III), (IV) or (II) with an angeloyl donor such as angelic acid 25 anhydride, angelic acid ester such as vinyl angelate, or angelic acid thioester in the presence of an enzyme such as a lipase or an esterase. Examples of esterification of an ingenol derivative catalysed by lipase can be found in Teng, R.W., Fitoterapia, (2009), 80, 233-236 which is hereby incorporated by reference 30 The synthesis of compounds of general formula (V) and (VI) from compound of general formula (III) and (IV) may be performed both in a batch reactor and in a flow reactor.

29 The reagents for the synthesis of compounds of general formula (V) and (VI) from compound of general formula (III) and (IV) may be solid phase supported reagents. 5 Ingenol-3-angelate (I) can be synthesised by selective removal of the protective groups, R, and R 2 or D, from the compounds of the general structure V or VI, according to methods well known to a person skilled in the art for deprotection of hydroxyl or dihydroxyl protective groups, such as methods described in "Protective Groups in Organic Synthesis", 4 th ed. P.G.M. Wuts; T.W. Greene, 10 John Wiley, 2007 or in P.J. Kocienski, "Protecting Groups", 3 rd ed. G. Thieme, 2003 which are hereby incorporated by reference and references cited therein. Ingenol-3-angelate (I) can be synthesised by selective removal of the angefoyl groups from the 20-position or from the 5- and the 20-positions of the 15 compound of the general structure (VII). For example compound (I) can be synthesised from compound (V) wherein R 1 represents hydrogen or alkyl such as triphenylmethyl and R 2 represents hydrogen or triphenylmethyl by reacting compound (V) with a suitable acid such 20 as formic acid or trifluoroacetic acid in a suitable solvent such as ether, methanol or dichloromethane. Compound (I) can for example be synthesised from compound (V) wherein R 1 represents hydrogen or alkyl such as p-methoxybenzylmethyl or allyl and R 2 25 represents hydrogen or p-methoxybenzylmethyl or allyl by reacting compound (V) with 2,5-dichloro-5,6-dicyano-p-benzoequinone (DDQ) in dichloromethane. The allyl group can also be removed by isomerisation of the olefin to a vinyl ether by reaction with a transiton metal catalyst such as Wilkinson's catalyst (Rhodium(I) tris(triphenylphosphine) chloride), followed by cleavage of the vinyl 30 ether in the presence of water. Compound (I) can for example be synthesised from compound (V) wherein R 1 represents hydrogen or alkoxyalkyl such as 2-methoxyethoxymethyl and R 2 represents hydrogen or alkoxyalkyl such as 2-methoxyethoxymethyl by cleaving 30 the acetal moiety of Ri and/or R 2 , for example by acid catalysed cleavage with a Lewis acid such as zinc (II) bromide or titanium (IV) chloride in a suitable solvent such as dichloromethane. 5 Compound (I) can for example be synthesised from compound (V) wherein R 1 represents hydrogen or alkoxyalkyl such as 2-tetrahydropyranyl and R 2 represents hydrogen or alkoxyalkyl such as 2-tetrahydropyranyl by cleaving the acetal moiety of Ri and/or R 2 , for example by acid catalysed cleavage in the presence of a suitable acid such as p-toluenesulfonic acid in a suitable solvent 10 such as methanol. Compound (I) can for example be synthesised from compound (V) wherein R 1 represents hydrogen or silyl such as tert-butyldimethylsilyl and R 2 represents hydrogen or silyl such as tert-butyldimethylsilyl by reacting compound (V) with a 15 suitable acid such as hydrogen chloride in a suitable solvent such as methanol or by reacting with a fluoride source such as tetra n-butylammonium fluoride or tetrafluorosilane in a suitable solvent such as tetrahydrofuran or acetonitrile. Compound (I) can for example be synthesised from compound (V) wherein R 1 20 represents hydrogen or alkylcarbonyl such as acetyl or chloroacetyl and R 2 represents hydrogen or alkylcarbonyl such as acetyl or chloroacetyl by hydrolysing the ester moiety of R 1 and/or R 2 by enzymatic catalysis utilising an enzyme such as a lipase, or by hydrolysing the ester moiety of R 1 and/or R 2 in a suitable solvent such as methanol or water in the presence of a suitable base 25 such as potassium carbonate or in the presence of a suitable acid such as hydrogen chloride. Compound (I) can for example be synthesised from compound V wherein R 1 represents hydrogen or alkoxycarbonyl such as 9-fluorenylmethoxycarbonyl and 30 R 2 represents hydrogen or alkoxycarbonyl such as 9-fluorenylmethoxycarbonyl by cleaving the carbonate moiety of R 1 and/or R 2 by cleavage in the presence of a suitable base such as triethylamine in a suitable solvent such as pyridine.

31 Compound (I) can for example be synthesised from compound (V) wherein R, represents hydrogen or 2,4-dinitrophenylsulfenyl and R 2 represents hydrogen or 2,4-dinitrophenylsulfenyl by cleavage of the sulfenate moiety of R 1 and/or R 2 with a nucleophile such as sodium cyanide in a suitable solvent such as 5 methanol. Compound (I) can for example be synthesised from compound (VI) wherein D represents an acetal such as benzylidene acetal by cleaving the acetal moiety in the presence of a suitable acid such as acetic acid, trifluoroacetic acid or p 10 toluenesulfonic acid in a suitable solvent such as water, dichloromethane or methanol. Compound (I) can for example be synthesised from compound (VI) wherein D represents a ketal such as isopropylidene ketal by cleaving the ketal moiety in 15 the presence of a suitable acid such as aqueous hydrogen chloride, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, solid supported p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid or formic acid, in a suitable solvent such as methanol, THF or isopropanol . 20 Compound (I) can for example be synthesised from compound (VI) wherein D represents a cyclic ortho ester such as methoxymethylene acetal by cleaving the orthoester moiety in the presence of a suitable acid such as aqueous hydrogen chloride or acetic acid in a suitable solvent such as dioxan or water. 25 Compound (I) can for example be synthesised from compound (VI) wherein D represents silyl such as di-tert-butylsilylene by reacting compound (VI) with fluoride source such as tetra n-butylammonium fluoride or tetrafluorosilane in a suitable solvent such as tetrahydrofuran or acetonitrile. 30 Compound (I) can for example be synthesised from compound (VI) wherein D represents carbonyl by cleaving the carbonate moiety in the presence of a suitable base such as pyridine in a suitable solvent such as water or by enzymatic catalysed hydrolysis in the presence of an enzyme such as a lipase or an esterase.

32 Compound (I) can for example be synthesised from compound (VI) wherein D represents a boronate such as phenyl boronate by transesterification with a diol such as 1,3-propanediol. 5 The synthesis of compound (I) from compounds of general formula (V) and (VI) may be performed both in a batch reactor and in a flow reactor, The reagents for the synthesis of compound (I) from compound of general formula (V) and (VI) may be solid phase supported reagents. 10 Compound (I) can for example be synthesised from compound (VII) wherein R3 represents angeloyl or hydrogen by enzymatic catalysed hydrolysis of the ester moiety in the 20-position or in the 5- and 20-positions in the presence of an 15 enzyme such as a lipase or an esterase. In a still further aspect, the present invention relates to a compound of general structure (V), wherein R 1 represents a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group, or a compound of general 20 structure (VI), wherein D represents a dihydroxyl protective group, or a compound of general structure (VII), wherein R 3 represents hydrogen or angeloyl. EXAMPLES 25 General All the starting materials used are commercially available, unless otherwise described. For proton nuclear magnetic resonance ( 1 H NMR) spectra, chemical shift values (8) (in ppm) are quoted relative to the internal standard 30 tetramethylsilane (8 = 0.00). The value of a multiplet, either defined doublet (d), triplet (t), quartet (q) or a range (m) is given. All organic solvents used were anhydrous, unless otherwise specified.

33 Flash chromatography was performed on silica gel. Appropriate mixtures of ethyl acetate, dichloromethane, methanol, petroleum ether (bp. 40-60 *C), and heptane were used as eluents unless otherwise noted. 5 Abbreviations Bu 3 N: Tributylamine CDI: 1,1'-Carbonyldiimidazole Cs 2

CO

3 : Cesium carbonate 10 DCC: N,N'-Dicyclohexylcarbodiimide DIPEA: N,N-Diisopropylethylamine DMAP: 4-(Dimethylamino)pyridine EDCI: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HATU: N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium 15 hexafluorophosphate HCI: Hydrochloric acid HOAt: 3H-[1,2,3]-Triazolo[4,5-bjpyridin-3-o

K

2

CO

3 : Potassium carbonate KHMDS: Potassium hexamethyldisilazide 20 LiHMDS: Lithium hexamethyldisilazide MSA: Methanesulfonic acid NaHMDS: Sodium hexamethyldisilazide TEA: Triethylamine CDC1 3 : Deuterochloroform 25 DCM: Dichloromethane DMF: N,N-Dimethylformamide IPA: 2-Propanol (isopropyl alcohol) MeCN: Acetonitrile MeTHF: 2-Methyltetrahydrofuran 30 MTBE: Methyl tert-butyl ether PhMe: Toluene TFA: Trifluoroacetic acid THF: Tetrahydrofuran I: Ingenol 34 I-3-Ang: Ingenol-3-angelate I-3-Tig: Ingenol-3-tiglate I-3,4-A: Ingenol-3,4-acetonide I-5,20-A: Ingenol-5,20-acetonide 5 I-3,4:5,20-A: Ingenol-3,4:5,20-diacetonide I-5,20-A-3-Ang: Ingenol-5,20-acetonide-3-angelate I-5,20-A-3-Tig: Ingenol-5,20-acetonide-3-tiglate I-3,4-X: Ingenol-3,4-acetal/ketal I-5,20-X: Ingenol-5,20-acetal/ketal 10 I-3,4:5,20-X: Ingenol-3,4:5,20-diacetal/diketal AngOH: Angelic acid Ang 2 0: Angelic anhydride AngOMe: Methyl angelate AngCl: Angeloyl chloride 15 AngIm: Angeloyl imidazolide AngOAt: Angeloyl HOAt ester AngOTig: Angeloyl tiglate TigOH: Tiglic acid Tig 2 0: Tiglic anhydride 20 TigOMe: Methyl tiglate TigCl: Tigloyl chloride 'H NMR: Proton nuclear magnetic resonance TLC: Thin layer chromatography Equiv.: Equivalents 25 N/A: Not applicable H 3 4 5 " HOHO O 2H HOHO 35 Preparation of ingenol-5,20-acetonide (Compound 1) Example 1 Ingenol (1.00 g, 2.30 mmol) was dissolved in a solution of p-toluenesulphonic acid monohydrate in acetone (0.47 mg/mL, 22.5 mL). The solution was stirred 5 at room temperature for 25 min. To this solution was added saturated aqueous solution of sodium hydrogencarbonate (0.2 mL). The obtained mixture was concentrated in vacuo. The residue was taken up in brine and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography 10 (heptane/ethyl acetate 19:1 -+ heptane/ethyl acetate 0:1), giving the title compound as a white solid (616 mg, 69%). Also see: Opferkuch, H. J. et al., Z. Naturforsch. 1981, 36b, 878-887 (compound 4) 'H NMR (300 MHz, CDCl 3 ) 6 5.91 (q, 3 = 1.5 Hz, 1H), 5.82-5.77 (m, 1H), 4.25 15 (d, 3 = 4.5 Hz, 1H), 4.20 - 4.07 (m, 3H), 3.93 (s, 1H), 3.51 (s, 1H), 2.57 - 2.41 (m, 2H), 2.25 (ddd, 3 = 15.7, 8.4, 2.9 Hz, 1H), 1.85 (d, 3 = 1.5 Hz, 3H), 1.77 (dt, 3 = 15.8, 5.9 Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H), 1.13 (s, 3H), 1.05 (s, 3H), 1.00 - 0.87 (m, 4H), 0.70 (td, 3 = 8.4, 6.4 Hz, 1H). 20 Example 2 Ingenol (7.0 g, 20.1 mmol) was dissolved in a solution of p-toluenesulfonic acid monohydrate in acetone (0.2 mg/mL, 200 mL). The solution was stirred at room temperature for 1.5 h (TLC control). To this solution was added saturated aqueous solution of sodium hydrogencarbonate (2.0 mL). The obtained mixture 25 was filtered. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate (20 mL). To this solution was added petroleum ether (40 mL). The mixture was let stand for 2 h. The crystals were filtered and dried, giving 4.5 g of the title compound. The mother liquor was purified by chromatography (petroleum ether/ethyl acetate 2:1 to 0:1), giving further 1.2 g of the title 30 compound and 0.6 g of unreacted ingenol. The total yield was 73 o, or 81 /o based on recovered ingenol. Example 3 36 Dry ingenol (15.00 g, 90 %, 38.75 mmol) was dissolved in acetone (630 mL) with stirring, and the solution was heated to 45 *C. A solution of methanesulfonic acid (0.745 g, 7.75 mmol) in acetone (10 mL) was added during 5 seconds. The solution was stirred at 45 *C for an additional 95 5 seconds, before a solution of triethylamine (1.35 mL, 0.98 g, 9.69 mmol) in acetone (10 mL) was added during 5 seconds. The mixture was cooled to 20 *C, and ethyl acetate (500 mL) was added. Most of the reaction solvent (650 mL) was distilled off under vacuum. Water (200 mL) was added to the remaining solution, and the mixture was agitated for 2 minutes. The water layer was 10 removed, and the water wash was repeated once before the organic phase was concentrated under vacuum. The crude product contained 84 % of the title compound as determined by 1H NMR spectroscopy. The residue was dissolved in toluene (75 mL) by heating to reflux temperature followed by slow cooling to 5 *C. After 4 hours standing, the formed crystals were filtered off, rinsed with 5 15 *C toluene (2 x 5 mL) and dried under vacuum at 20 *C until constant weight. After 18 hours, ingenol-5,20-acetonide (8.97 g) was obtained. ci o 0 C, 0 C4 C, 20 Example 4 Preparation of [(Z)-2-methylbut-2-enoyl) 2,4,6-trichlorobenzoate Angelic acid (601 mg, 6.0 mmol) was dissolved in dichloromethane (3.0 mL) under argon. Diisopropylethylamine (1.23 mL, 7.20 mmol) was added at 5-10 OC in a period of I min. To this solution was added 2,4,6-trichlorobenzoyl 25 chloride (1.12 mL, 7.20 mmol) at 3-6 0 C in a period of 4 min. After the reaction solution had been stirred at 2 OC for 45 min, petroleum ether (9.0 mL) was added. The obtained suspension was purified by flash chromatography (petroleum ether/dichloromethane 3:1), giving the title compound as a white solid (605 mg, 33 %). 30 'H NMR (300 MHz, CDCI 3 ) 6 7.40 (s, 2H), 6.42 (qq, J = 7.4, 1.5 Hz, 1H), 2.09 (dq, J = 7.4, 1.5 Hz, 3H), 1.97 (p, J = 1.5 Hz, 3H ('H NMR data: see also Matthew, B et al.; Org Lett. 2007, 9, 663-666).

37 00 Example 5 5 Preparation of angelic anhydride To a solution of angelic acid (5 g, 50 mmol) in dichloromethane (100 mL) was added NN'-dicyclohexylcarbodiimide (8.6 mL, 60 % in xylene, 25 mmol) at room temperature, The reaction mixture was stirred at this temperature for 1 h. The precipitate was filtered off. The filtrate was concentrated in vacuo. The 10 residue was purified by chromatography (petroleum ether/ethyl acetate 10:1), giving 4.3 g of the title compound as an oil (94 %). 'H NMR (300 MHz, CDC1 3 ) 6 6.37 - 6.25 (m, 2H), 2.06 (dq, 3 = 7.4, 1.5 Hz, 6H), 1.97 - 1.93 (m, 6H). 15 H 0 3 4 OHO 0 20 ,,X0 Preparation of ingenol-5,20-acetonide-3-angelate (compound 2) Example 6A mixture of ingenol-5,20-acetonide (233 mg, 0.60 mmol), [(Z)-2 20 methylbut-2-enoyl] 2,4,6-trichlorobenzoate (231 mg, 0.75 mmol), and sodium hydrogencarbonate* (75.6 mg, 0.90 mmol) in toluene (2.5 mL) was stirred at 100 OC for 22 h. The mixture was then filtered and washed with toluene. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 19:1 -+ heptane/ethyl acetate 3:2), 25 giving the title compound as a white solid (215 mg, 76 % yield).

38 * In the absence of sodium hydrogencarbonate, the product obtained contained 2-3 % of ingenol-5,20-acetonide-3-tiglate. 'H NMR (300 MHz, CDCl 3 ) 6 6.13 - 6.03 (m, 2H), 5.81 - 5.75 (m, 1H), 5.66 (s, 1H), 4.27 - 4.08 (m, 3H), 4.02 (s, 1H), 3.19 (s, 1H), 2.68 - 2.53 (m, 1H), 2.27 5 (ddd, J = 15.8, 9.1, 3.0 Hz, 1H), 2.02 - 1.95 (m, 3H), 1.94 - 1.87 (m, 3H), 1.81 - 1.68 (m, 4H), 1.47 (s, 3H), 1.43 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.98 (d, J = 7.1 Hz, 3H), 0.90 (dd, J = 11.9, 8.4 Hz, 1H), 0.69 (td, J = 8.7, 6.4 Hz, 1H). 10 Example 7 A mixture of ingenol-5,20-acetonide (1.32 g, 3.40 mmol), angelic anhydride (0.72 g, 3.94 mmol), and cesium carbonate (1.66 g, 5.10 mmol) in acetonitrile (26 mL) was stirred at room temperature for 2 h. The mixture was taken up in dichloromethane (30 mL) and washed with water. The aqueous phase was 15 extracted three times with dichloromethane (3 x 4 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 8:1), giving 1.46 g of the title compound (91 O/) as a white solid. 20 Example 8 Ingenol-5,20-acetonide (10.00 g, 25.74 mmol) was dissolved in tetrahydrofuran (100 mL) with stirring, and the solution was cooled to 10-15 *C. A solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 29.6 mL, 29.6 mmol) was added over a period of 10 minutes. Then a solution of angelic anhydride 25 (5.51 mL, 5.62 g, 30.8 mmol) in tetrahydrofuran (70 mL) was added during 15 minutes. Ethyl acetate (200 mL) was added, and most of the reaction solvent (200 mL) was distilled off under vacuum. Water (75 mL) was added to the remaining solution, and the mixture was agitated for 2 minutes. The water layer was removed, and the water wash was repeated once before the organic phase 30 was concentrated under vacuum, The residue was dissolved in methanol (61 mL) by heating to reflux temperature followed by slow cooling to 5 *C. After 4 hours standing, the formed crystals were filtered off, rinsed with 5 *C methanol (2 x 5 mL) and dried under vacuum at 20 *C until constant weight. After 18 hours, ingenol-5,20-acetonide-3-angelate (8.78 g) was obtained.

39 H H 3 4 0 HO HO 20 HO Preparation of ingenol-3-angelate (compound 3) 5 Example 9 Ingenol-5,20-acetonide-3-angelate (7 mg, 0.015 mmol) in methanol, which contained 1 O/ of concentrated aqueous hydrochloric acid solution, was stirred at room temperature for 1 h. The solution was diluted with ethyl ether. Water was 10 added. After phase separation, the aqueous phase was extracted with ethyl ether. The combined organic phases were dried and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 1:1), furnishing the product (4 mg, 63 /b yield). 'H NMR (300 MHz, CDCI 3 ) 6 6.17 (qq, J = 7.3, 1.4 Hz, 1H), 6.08-6.02 (m, 2H), 15 5.54 (s, 1H), 4.29 (d, J = 4.5 Hz, 1H), 4.22 - 4.01 (m, 4H), 3.48 (s, 1H), 2.60 2.46 (m, 1H), 2.40 - 2.17 (m, 2H), 2.02 (dq, J = 7.2, 1.4 Hz, 3H), 1.95-1.91 (m, 3H), 1.83 - 1.68 (m, 4H), 1.09 (s, 3H), 1.05 (s, 3H), 1.01 - 0.82 (m, 4H), 0.77 - 0.61 (m, 1H). 20 Example 10 A solution of ingenol-5,20-acetonide-3-angelate (1.46 g, 3.10 mmol) in methanol (30 mL), which contained 0.5 % of concentrated aqueous hydrochloric acid solution, was stirred at room temperature for 1 h. The solution was then diluted with toluene and washed with water. The aqueous phase was extracted 25 with ethyl ether. The combined organic phases were dried and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 1:1 to 0:1), giving the product (1.20 g, 90 %), which contained 2 % of ingenol-3-tiglate. Separation of ingenol angelate and ingenol tiglate by Preparative HPLC/MS: 40 Preparative HPLC/MS was performed on a Dionex APS-system with two PP150 preparative pumps and a Thermo MSQ Plus mass spectrometer. Column: XTerra C-18, 150 x 19 mm, 5 pm; Loading: 50 mg of ingenol angelate in 0.35 mL of acetonitrile; 5 Solvent system: eluent A: solution of 0.1 /a HCOOH in H 2 0, eluent B: solution of 0.1 /b HCOOH in acetonitrile Flow rate: 18 mL/min; Run: 40 /b A/60 b B; isocratic for 20 min. The fractions were collected based on ion traces of relevant ions (MS-detector: MSQ from Dionex) and PDA signal (240-400 nm; detector: UVD 340 U from 10 Dionex) Example 11 Ingenol-5,20-acetonide-3-angelate (47.1 mg, 0.10 mmol) was dissolved in tetrahydrofuran (0.47 mL) under argon. An aqueous solution of hydrochloric 15 acid (4 M, 4.7 pL) was added under ice-cooling. The solution was stirred at room temperature for 24 h. The solution was concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 5:1 -+ heptane/ethyl acetate 1:1), furnishing the title compound (30.8 mg, 72 % yield) besides starting material (6.1 mg, 13 /b). 20 Example 12 Ingenol-5,20-acetonide-3-angelate (6.00 g, 12.75 mmol) was suspended in 2 propanol (152 mL) and stirred at 20 *C. A solution of phosphoric acid (15.00 g, 153 mmol) in water (8 mL) was added, and the suspension was heated to 30-35 25 *C. The resulting clear solution was stirred for 7 days. The reaction mixture was cooled to 20 OC and diluted with methyl tert-butyl ether (500 mL), Water (100 mL) was added, and the mixture was agitated for 2 minutes. The water layer was removed, and the water wash was repeated four times before the organic phase was concentrated under vacuum. Methyl tert-butyl ether (200 30 mL) was added followed by concentration. The crude product contained > 95 % ingenol-3-angelate. The residue was dissolved in acetonitrile (20 mL) by heating to reflux temperature. The solution was cooled to 5 *C. After 24 hours standing at 5 OC, the precipitated product was filtered off, rinsed with 5 *C acetonitrile (2 41 x 5 mL) and dried under vacuum at 20 *C until constant weight, After 18 hours, ingenol-3-angelate (3.91 g) was obtained. Preparation of compounds of general formula (IV) from ingenol: 5 Example 13 Preparation of symmetrical ketals The procedure described in Example 1 for the synthesis of ingenol-5,20 acetonide was used for the preparation of symmetrical ketals, replacing acetone with 3-pentanone, 2,4-dimethyl-3-pentanone, 2,6-dimethyl-4-heptanone, 10 cyclopentanone or cyclohexanone, on a scale of 25-50 mg ingenol. Product distribution is shown in table 1A Products are shown in table 1B 15 Table 1A Synthesis of symmetrical ketals - acid catalyzed Reagent and solvent Product distributiona 1-5,20-A (70-75 %) 1-3,4-A (5-10 %/) Propanone (acetone) 1-3,4-A (10 %) I-3,4:5,20-A (10-15 % 1(5-10 %) I-5,20-X (70-75 %) 3-Pentanone I-3,4-X (5-10 %) I-3,4:5,20-X (10-15 %) I (5-10 %) I-5,20-X (0-5 %) I-3,4-X (0-5 %) 2,4-Dimethyl-3-pentanone 1-3,4-5,(0-5 ) 1-3,4:5,20-X (0-5 % I (90-95 %) I-5,20-X (15-20 %) I-3,4-X (15-20 %/) 2,6-Dimethyl-4-heptanone I-3,4-X ( -5 ) I-3,4:5,20-X (0-5 I1(60-65 %) 42 I-5,20-X (70-75 %) I-3,4-X (5-10 %) I-3,4:5,20-X (10-15 %) I (5-10 %) I-5,20-X (70-75 %) I-3,4-X (5-10 %) Cyclohexanone I-3,4:5,20-X (10-15 %) 1I(5-10 %) 8 The product distributions were estimated from 1H NMR and/or TLC data. Table 1B H H 0 $ H I'' H 7H 0 H /H 3 434 H 3 4 345/ 3-4 45/ HOHO 5 / O S 200 R14- 'O 20 0 R14- H 4 20 R134O R12ko R13 HO R12> R11 R11 Ingenol-5,20-ketal Ingenol-3,4-ketal Ingenol-3,4:5,20-diketal R" = R1 = R = R1 = = RR = Methyl = R = Methyl Methyl Ingenol-5,20-acetonide Ingenol-3,4-acetonide Ingenol-3,4:5,20 diacetonide R" = R" = Ethyl 13 14 Ethyl = Rl2 = R 3 = R1 = Ingenol-5,20-(3- ingenol-3,4-(3- Ethyl pentylidene)-ketal Ingenol-3,4:5,20-di[(3 (Compound 4) pentylidene)-ketal] R" = R" = Prop-2-yl " = Prop-2-yl = R 12 = R1 3 = R 4 = Ingenol-5,20-(2,4- Ingenol-3,4-(2,4- Prop-2-yl dimethyl-3-pentylidene)- dimethyl-3-pentylidene)- Ingenol-3,4:5,20 ketal di[(2,4-dimethyl-3 ketal (Compound 5) pentylidene)-ketal] Ru = R 2 = 2- R 13 = R 14 = 2- R" = R 2 = R 3 = R" = 43 Methylprop-1-yl Methylprop-1-yl 2-Methylprop-1-yl Ingenol-5,20-(2,6- Ingenol-3,4-(2,6- Ingenol-3,4:5,20 dimethyl-4-heptylidene)- dimethyl-4-heptylidene)- di[(2,6-dimethyl-4 ketal ketal heptylidene)-ketal] (Compound 6)

R'

1

R

1 = R 13

R'

4 = R"R12 = CH2CH2CH2CH2 134R13R4 Ingen5 2 0 C CR 1

R

1 4 = CH 2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2 Ingeno[-5,20 cyclopentylidene-ketal Ingenol-3,4- Ingenol-3,4:5,20 (Compound 7) cyclopentylidene-ketal di(cyclopentylidene ketal)

RR

13

R

4 =R"R1 = R1 3

R

1 4 =

CH

2

CH

2

CH

2

CH

2

CH

2 CH 2

CH

2

CH

2

CH

2

CH

2 CH 2

CH

2

CH

2

CH

2

CH

2 Ingenol-5,20 cycolden-kt Ingenol-3,4- Ingenol-3,4:5,20 (Comouent cyclohexylidene-ketal di(cyclohexylidene-ketal) (Compound 8) Example 14 Preparation of non- symmetrical ketals 5 The general procedure described in Example 15 was used for the preparation of non-symmetrical ketals, replacing the acetal/aldehyde with 3,3-dimethyl-2 butanone, acetophenone or (1,1-dimethoxyethyl)benzene, on a scale of 25-50 mg ingenol. 10 Product distribution is shown in table 2A Products are shown in table 2B Table 2A Synthesis of non-symmetrical ketals - acid catalyzed Reagent in THF Product distributiona I-5,20-X (20-30 %) 3,3-Dimethyl-2-butanone I-3,4-X (20-30 %) I-3,4:5,20-X (10-20 %) 44 I (30-40 %) Several other products observed by TLC Acetophenone No conversion I-5,20-X (10-20 %) I-3,4-X (30-40 %) Di methoxyethyl) benzene I-3,4:5,20-X (10-20 %) I (30-40 %) Several other products observed by TLC a The product distributions were estimated from 'H NMR and/or TLC data. Table 2B H H H 0 0'~ " H 0 H 4 H 45/ 3 4 5 / HOHO 0O 0 20 O 2 R14- 0 20 0 R14 H O 20 O R12 V HO R12 Ingenol-5,20-ketal Ingenol-3,4-ketal Ingenol-3,4:5,20-diketal R1 = 1,1-Dimethylethyl R1 2 = R14 = 1,1 Ingenol-5,20-(3,3- = 1,1-ehly Dimethylethyl dimehyl--butlidee)- Ingenol-3,4-(3,3 dimethyl-2-butylidene)- dimethyl-2-butylidene)- Ingenol-3,4:5,20 ketal di[(3,3-dimethyl-2 (Compound 9) butylidene)-ketal]

R

12 = Phenyl R 2 = R14 = Phenyl Ingenol-5,20-(-pheny- henyl Ingenol-3,4:5,20-di[(1 Ingeol-520-(-pheyl- Ingenol-3,4-(1-phenyl-1-phnl-ehldn) 1-ethylidene)-ketal ethylidene)-ketal phenyl-1-ethylidene) (Compound 10) ketal) 5 Example 15 (general procedure) Preparation of acetals Ingenol (25 mg, 72 Lmol) was dissolved in tetrahydrofuran (622 pL) at 20 *C. A solution of p-toluenesulfonic acid monohydrate in tetrahydrofuran (50 mg/mL, 45 0.26 M, 96 pL, 25 pmol) was added with stirring. The aldehyde/acetal (86 Lmol) was added, and the progress of the reaction was monitored by TLC. The data provided were obtained after 21 hours of reaction time. Product distribution is shown in table 3A 5 Products are shown in table 3B Table 3A Synthesis of Acetals - acid catalyzed Reagent in THF Product distributiona 1-5,20-X (65-70 %) (One epimer) I-3,4-X (5-10 %) Benzaldehyde I-3,4:5,20-X (10-15 %) 1 (10-15 %) No epimers observed by TLC and 'H NMR I-5,20-X (45-50 %) (One epimer) I-3,4-X (5-10 %) Benzaldehyde dimethylacetal I-3,4:5,20-X (10-15 ) I (30-35 %) No epimers observed by TLC Several other products observed by TLC I-5,20-X (10-20 %) I-3,4-X (10-15 %) 4-Methoxybenzaldehyde I-3,4:5,20-X (5-10 %) I (60-70 %) No epimers observed by TLC I-5,20-X (10-15 %) 1-3,4-X (5-10 %) 2,4-Dimethoxybenzaldehyde 1-3,4:5,20-X (5-10 %) I (70-75 %) One other product observed by TLC I-5,20-X (15-20 %) 4-Nitrobenzaldehyde I-3,4-X (5-10 %) I-3,4:5,20-X (5-10 %) 46 I (65-70 %) No epimers observed by TLC I-5,20-X (15-20 %) I-3,4-X (0-5 %) 2,4,6-Trimethylbenzaldehyde I-3,4:5,20-X (10-15 %) I (65-70 %) No epimers observed by TLC I-5,20-X (45-50 %) I-3,4-X (10-15 %) Trimethylacetaldehyde I-3,4:5,20-X (10-15 %) I (25-30 %) No epimers observed by TLC The product distributions were estimated from 'H NMR and/or TLC data. Table 3B H H S - H ''.. O "H " " " O ' H ' . . O ' H/H 0 H H / H 5/ 45/3 4 O O HOHO R14-I' 0 20 0 20 R 0 2 R R12O H HO H H Ingenoj-5,20-acetal Ingenol-3,4-acetal Ingenol-3,4:5,20 diacetal

RR

2 = Phenyl = Phenyl R1 2 = R 4 = Phenyl Ingenol-5,20- Ingenol-3,4-benzylidene- Ingenol-3,4:5,20 benzyl idene-acetal acetal di(benzylidene-acetal) (Compound 11) R1 2 = 4-Methoxyphenyl R = R 4 = 4 Ingenol-5,20-(4- R' 4 = (4 Methoxyphenyl methoxybenzylidene)- Ienol-3,4-(4- Ingenol-3,4:5,20-di[(4 acetal met b d methoxybenzylidene) acetal (Compound 12) acetal] 47 R1=2,- R" = 2,4- R12 = R 1 = 2,4

R

12 = 2,4 Dimethoxyphenyl Dimethoxyphenyl DiDimethoxyphenyl Ingenol-5,20-(2,4- imeoxyphenyl Ingenol-3,4:5,20 dimethoxybenzylidene)- inenol-3,4-(2,4- di[(2,4 acetal dimethoxybenzylidene) acetal (Compound 13) acetal]

R

2 = henyl R 14 = 4R = R4 = 4 Ingenol-5,20-(4- = 4-Nitrophenyl Nitrophenyl nitrobenzylidene)-acetal ngenli3,4-(- Ingenoi-3,4:5,20-di[(4 (Compound 14) nitrobenzylidene)-aceta] R " = 2,4,6- 14 = 2,4,6- R = = 2,4,6 Trimethylphenyl Trimethyiphenyl Trimethylphenyl Ingenol-5,20-(2,4,6- Ingenol-3,4-(2,4,6- Ingenol-3,4:5,20 trimethylbenzylidene)- trimethylbenzylidene)- di[(2,4,6 n trimethylbenzylidene) a cetalI (Compound 15) acetal] R1 2 = 1,1-Dimethylethyl R 2 = R1 = 1,1 Ingenol-5,20-(2,2- = 1,1-mhlh Dimethylethyl dimethyl- 1-propylidene)- Ingenol-3,4:5,20 aci etl I -1 -pro Iid -dimethyl- 1-propylidene)- Ingenol-3,4:5,20 acetal di[(2,2-dimethyl-1 (Compound 16) acetal propylidene)-acetal] Example 16 (general procedure) Synthesis of benzylidene acetal 5 Ingenol (25 mg, 72 pmol) was dissolved in the solvent (622 pL) at 20 *C with stirring. For reactions conducted in pyridine, no further base was added. For reactions conducted in acetone or N,N-dimethylformamide, potassium carbonate (158 pmol) was added. For reactions conducted in tetrahydrofuran or 2 methyltetrahydrofuran, lithium hexamethyldisilazide (158 pmol) was added as a 10 solution in tetrahydrofuran (1.0 M). A solution/suspension of the reagent (79 imol) in the solvent (96 pL) was added dropwise. The progress of the reaction was monitored by TLC. For slow reactions, the temperature was increased from 20 *C to 50 *C and eventually to the boiling point of the solvent. The reaction of 48 ingenol with a,a-dibromotoluene in pyridine was conducted at 100 *C for 3 hours. The reaction of ingenol with a,a-bis(pyridinium)toluene dibromide in tetrahydrofuran was conducted at 50 OC for 1 hour. Product distribution is shown in table 4A 5 Products are shown in table 4B Table 4A Synthesis of benzylidene acetal - base promoted Reagent Solvent Base Product distribution

K

2

CO

3 (in Pyridine or a,a- acetone and acetone or Dichlorotolu- DMF or DMF) or No conversion ene MeTHF LIHMDS (in MeTHF) I-5,20-X (85-90 %) (One epimer) a,a- I-3,4-X (0-10 %) Dibromotolu- Pyridine Pyridine -3,4:2 (010 ) I-3,4:5,20-X (0-10 %/) ene 1(0-5 %) 1-5,20-X (20-30 %) I-3,4-X (20-30 %) a,a-Bis(pyridi- I-3,4:5,20-X (20-30 % ) nium)toluene THF LiHMDS dibromideb 1(20-30%) Several other products observed by TLC a, a- 85(4-

K

2

CO

3 (in (dimethyl- Pyridine or DMF) or amino)pyridi- No conversion DMF or THF LiHMDS (in nium)toluen e TH F) dibromid ec a The product distributions were estimated from 'H NMR and/or TLC data. b Preparation: cf. Acta Chem. Scand. 1972, 26, 3895-3901 and J. Org. Chem. 10 2007, 72, 9854-9856 (compound 1 in Scheme 2).

49 c Prepared by treatment of a,a-dibromotoluene (10 g, 0,04 mmol) with 4 (dimethylamino)pyridine (10.78 g, 0.088 mmol) in acetone (20 mL) at reflux for 1 hour. 5 Example 17 Synthesis of orthoformates The general procedure described in Example 15 was for the preparation of orthoformates, replacing the aldehyde/acetal with trimethyl orthoformate, triethyl orthoformate or tri(prop-2-yl) orthoformate, on a scale of 25-100 mg 10 ingenol. Product distribution is shown in table 5A Products are shown in table 5B Table 5A Synthesis of orthoformates - acid catalyzed Reagent in THF Product distribution' I-5,20-X (75-80 %, 60:40 mixture of epimers) Trimethyl orthoformate I-3,4-X (0-10 %) 1-3,4:5,20-X (0-10 %) I (10-15 %) I-5,20-X (75-80 %, 60:40 mixture of epimers) Triethyl orthoformate 1-3,4-X (0-10 %) I-3,4:5,20-X (0-10 %) I (10-15 %) I-5,20-X (75-80 %, 60:40 mixture of epimers) Tri(prop-2-yl) orthoformate 1-3,4-X (0-10 %) 1-3,4:5,20-X (0-10 %) 1I(10-15 %) 15 The product distributions were estimated from IH NMR and TLC data. Table 5B 50 H H H 0 H 3 H / H H 3 5 / 34 4 5/ HOHO 5 / 0 0 20 O 0 R240 0 20 0 R24OV H 20 H O R220 H HO R220H H H Ingenol-5,20- Ingenol-3,4- Ingenol-3,4:5,20 orthoformate orthoformate diorthoformate R" = Methyl

R

24 = Methyl

R

22 = R 24 = Methyl Ingenol-5,20-methyl- Ingenol-3,4-methyl- Ingenol-3,4:5,20 orthoformate (Compound 17) orthoformate di(methyl-orthoformate) R = Ethyl R24 = Ethyl

R

22 = R 24 = Ethyl Ingenol-5,20-ethyl- Ingenol-3,4-ethyl- Ingenol-3,4:5,20 orthoformate (Compound 18) orthoformate di(ethyl-orthoformate)

R

22 = Prop-2-yl R = R 24 = Prop-2-yl

R

24 = Prop-2-yl Ingenol- 5,20- (prop- 2- Ingenol-3,4:5,20 yl)-orthoformate Ineol3-p -2) di[(prop-2-yl) o rth ofo rm ate (Compound 19) orthoformate] Example 18 Synthesis of Methyl orthoformate (methoxymethylene acetal) 5 The procedure described in Example 16 was employed using dichloromethyl methyl ether as the reagent, and using lithium hexamethyldisilazide in tetrahydrofuran. The reaction was conducted in tetrahydrofuran at 20 OC for 30 minutes. 10 Table 6A Methyl orthoformate (methoxymethylene acetal) - base promoted Reagent Solvent Base Product distribution 51 I-5,20-X (10-15 %) Dichloro- I-3,4-X (10-15 %) methyl THF LiHMDS I (50-60 O/) methyl ether Several other products observed by TLC a The product distribution was estimated from TLC data. Synthesis of compounds of general formula (VI) 5 Synthesis of ingenol-5,20-acetonide-3-angelate using Angelic acid (AngOH) Example 19A (general procedure) 10 Ingenol-5,20-acetonide (10.0 mg, 26 pmol) and angelic acid (2.6 mg, 26 pmol) were dissolved in the solvent (175 pL) at 20 *C with stirring. For reactions conducted in the presence of base, either 4-(dimethylamino)pyridine (6.3 mg, 52 pmol) or N,N-diisopropylethylamine (9 pL, 6.7 mg, 52 pmol) was added 15 before the dropwise addition of a solution/suspension of the coupling reagent (26-52 pmol) in the solvent (75 pL). The progress of the reaction was monitored by TLC and 'H NMR spectroscopy. Example 19B 20 Ingenol-5,20-acetonide (25.0 mg, 64 pmol), angelic acid (6.4 mg, 64 pmol) and 2-chloro-1-methyl-pyridinium iodide (19.7 mg, 77 pmol) (Mukaiyama's reagent) were suspended in toluene (108 pL). Tributylamine (37 pL, 29 mg, 155 pmol) was added, and the mixture was stirred at 60 OC for 18 hours. The progress of the reaction was monitored by TLC and 'H NMR spectroscopy. 25 Product distribution and reaction conditions for examples 19A and 19B are shown in table 7A Products are shown in table 7B The (E)/(Z) ratio is the Tiglate/Angelate ratio.

52 Table 7A Synthesis of ingenol-5,20-acetonide-3-angelate usingAngelic acid (AngOH) Reagent Solvent Products formed (crude yield)" (E)/(Z)b EDCI CDC1 3 Ang 2 0 N/A I-5,20-A-3-Tig (50-60 %) and Ang 2 0, EDCI/DMAP DCM 96:4 AngOTig and Tig 2 O DCC CDCl 3 I-5,20-A-3-Ang (2 %) and Ang 2 0 1:99 DCC PhMe No conversion N/A DCC/DIPEA PhMe No conversion N/A DCC/DMAP CDC1 3 I-5,20-A-3-Tig (75 %) 85:15 Initial formation of AngOAt (100 %) HATU/DIPEA DMF Subsequent formal hydrolysis to AngOH and N/A HOAt 2-Chloro-1 methyl- I-5,20-A-3-Tig (30-40 %) and Ang 2 0, pyridinium PhMe 90:10 iodide /AngOTig and Tig 2 O iodide/ Bu 3 N a,b The yields and (E)/(Z) ratios of were estimated from 'H NMR and TLC data. b (E)/(Z) > 1:99 due to a content of 0.5-1 % TigOH in AngOH. 5 The (E)/(Z) ratio is the I-5,20-A-3-Tig/I-5,20-A-3-Ang ratio Table 7B H H O 3 4 3 4 OHOQ / OHO 2 20 O 0 0 2 H ..A- H Ingenol-5,20-acetonide- Ingenol-5,20-acetonide 3-angelate 3-tiglate 53 Synthesis of ingenol-5,20-acetonide-3-angelate using Angelic anhydride Example 20A The procedure for the synthesis of ingenol-5,20-acetonide-3-angelate 5 described in Example 8 was used for lithium hexamethyldisilazide in methyl tert butyl ether, lithium hexamethyldisilazide in tetrahydrofuran, sodium hexamethyldisilazide in tetrahydrofuran and potassium hexamethyldisilazide in tetrahydrofuran on a scale of 25 mg - 10 g ingenol-5,20-acetonide. 10 Example 20B The experimental procedure for the synthesis of ingenol-5,20-acetonide-3 angelate using cesium carbonate is described in Example 7. Example 20C (general procedure) 15 Ingenol-5,20-acetonide (15.0 mg, 39 tmol) was dissolved in pyridine (386 I) or tetrahydrofuran (386 pL) at 20 *C with stirring. For the reaction conducted in pyridine, angelic anhydride (10.6 mg, 58 pLmol) was added. For the reaction conducted in tetrahydrofuran, 4-(dimethylamino)pyridine (7.1 mg, 58 ptmol) was added before the addition of angelic anhydride (10.6 mg, 58 pmol). The 20 progress of the reaction was monitored by TLC and 'H NMR spectroscopy. Product distribution and reaction conditions for examples 20A, 20B and 20C are shown in table 8A Products are shown in table 7B 25 The (E)/(Z) ratio is the I-5,20-A-3-Tig/I-5,20-A-3-Ang ratio. Table 8 Synthesis of ingenol-5,20-acetonide-3-angelate usingAngelic anhydride (Ang 2 0) Reagent Solvent Products formed (crude yield)a (E)/(Z)b I-5,20-A-3-Ang (> 95 /a) LIHMDS MTBE Slower conversion in MTBE than in THF due 2:98 to low solubility 54 Rapid and clean conversion into I-5,20-A-3 LiHMDS THF 2:98 Ang (> 95 /b) I-5,20-A-3-Ang (> 95 %) NaHMDS THF Slower conversion than with LiHMDS 2:98 requiring larger excess of reagents I-5,20-A-3-Ang (> 90 0 %b) KHMDS THF Slower and less clean conversion than with 2:98 LiHMDS and NaHMDS Cs 2

CQ

3 MeCN I-5,20-A-3-Ang (> 95 %) 2:98 Pyridine Pyridine I-5,20-A-3-Tig (55 0/) 96:4 DMAP THF I-5,20-A-3-Tig (55 /o) 96:4 a,b The yields and (E)/(Z) ratios were estimated from 1H NMR and TLC data. b (E)I(Z) 2: 2:98 due to a content of 1.5-2 /b AngOTig in Ang 2 0. The (E)/(Z) ratio is the I-5,20-A-3-Tig/I-5,20-A-3-Ang ratio 5 Synthesis of ingenol-5,20-acetonide-3-angelate using Angeloyl chloride Example 21A The procedure described in Example 8 for angelic anhydride was employed for the reaction between angeloyl chloride and ingenol-5,20-acetonide using lithium 10 hexamethyldisilazide in tetrahydrofuran. The experiment was conducted on a scale of 25 mg ingenol-5,20-acetonide. Example 21B The procedure described in Example 20C for angelic anhydride was employed, 15 replacing angelic anhydride with angeloyl chloride, for the reaction between angeloyl chloride and ingenol-5,20-acetonide in ethyl ether without base, in tetrahydrofuran without base, in pyridine and in tetrahydrofuran with 4 (dimethylamino)pyridine (1.5 equiv.) added. The experiments were conducted on a scale of 15-50 mg ingenol-5,20-acetonide. 20 Product distribution and reaction conditions for examples 21A and 21B are shown in table 9 Products are shown in table 7B 55 The (E)/(Z) ratio is the I-5,20-A-3-Tig/1-5,20-A-3-Ang ratio. Table 9 Synthesis of ingenol-5,20-acetonide-3-angelate using Angeloyl chloride (AngCl)c Reagent Solvent Products formed (crude yield)a (E)/(Z)b LiHMDS THF I-5,20-A-3-Ang (60 %) and 1-5,20-A (30 %) 3:97 and other impurities (10 %) None Ethyl No conversion, low solubility N/A ether None THF No reaction N/A Pyridine Pyridine I-5,20-A-3-Tig (60-70 %) and impurities (30 96:4 %/) DMAP THF I-5,20-A-3-Tig (50-60 /a) 96:4 a,b The yields and (E)/(Z) ratios were estimated from 1 H NMR and TLC data. 5 b (E)/(Z) 3:97 due to isomerization of AngCl to TigCl during storage. The (E)/(Z) ratio is the I-5,20-A-3-Tig/I-5,20-A-3-Ang ratio c Preparation: cf. Tetrahedron Letters 1977, 38, 3379-3382 (compound 2). Synthesis of inoenol-5,20-acetonide-3-angelate using Methyl angelate 10 Example 22 The procedure described in Example 8 for angelic anhydride was employed for the reaction between methyl angelate and ingenol-5,20-acetonide using lithium hexamethyldisilazide in tetrahydrofuran. The experiment was conducted on a 15 scale of 25 mg ingenol-5,20-acetonide. Table 10 Synthesis of ingenol-5,20-acetonide-3-angelate using Methyl angelate (AngOMe)c Reagent Solvent Product formed (crude yield) 8 (E)I(Z)b LiHMDS THF I-5,20-A-3-Ang (7 /b) 1:99 a,b The yield and (E)/(Z) ratio were estimated from 'H NMR and TLC data. b (E)/(Z) = 1:99 due to a content of 0.5-1 /b TigOMe in AngOMe, 56 The (E)/(Z) ratio is the I-5,20-A-3-Tig/I-5,20-A-3-Ang ratio c Prepared by dropwise addition of a solution of (trimethylsilyl)diazomethane in ethyl ether (2.0 M, 18.8 mL, 38 mmol) over a period of 175 minutes at 20 *C to a stirred solution of angelic acid (3.0 g, 30.0 mmol) in 5 dichloromethane/methanol = 3:2 (30 mL). The reaction mixture was concentrated, and methyl angelate was purified by vacuum distillation. Also see J. Org. Chem. 1950, 15, 680-684. 'H NMR (300 MHz, CDCl 3 ) 5 6.06 (qq, 1H), 3.74 (s, 3H), 1.98 (dq, 3H), 1.89 (quintet, 3H). 10 Example 23 (general procedure) Preparation of ingenol-3-angelate from ingenol-5,20-acetonide-3-angelate 15 Ingenol-5,20-acetonide-3-angelate (15 mg, 35 pmol) was dissolved/suspended In the organic solvent (331 pL) at 20 *C. A solution of the catalyst in water (17 pL) was added with stirring resulting in a concentration of 0.1 M with respect to ingenol-5,20-acetonide-3-angelate. For formic acid/water (95:5), acetic acid/water (95:5) and trifluoroacetic acid/water (95:5), ingenol-5,20-acetonide 20 3-angelate was dissolved in the solvent mixture. The progress of the reaction was monitored by TLC and 'H NMR spectroscopy. Product distribution and reaction conditions for examples 23 is shown in table 11A Products are shown in table 11B 25 Table 11A (E)/(Z)a (E)/(Z)a Cata- pK Solvent Temp at complete after n Com lyst ratio 0 C conversion days ment (days) (days)

THF/H

2 0 5:95 19:81 HCI -8.0 1 20 Clean 95:5 (4) (11) 57 MeOH/H 2 0 3:97 6:94 HCI -8.0 1 20 Clean 95:5 (< 1) (2)

IPA/H

2 0 3:97 14:86 HCI -8.0 1 20 Clean 95:5 (3) (11) TH F/H 2 0 2:98 2:98 MSA -2.6 2 20 Clean 95:5 (3) (4)

IPA/H

2 0 2:98 3:97 MSA -2.6 2 20 Clean 95:5 (2) (10) AG 50WX2

IPA/H

2 0 2:98 3:97 cation -2.6 2 20 Clean exch. 95:5 (2) (13) resin

IPA/H

2 0 3:97 3:97 Esterifi TFA -0.25 6.5 20 95:5 (> 4) (4) cationc TFA -0.25 124 TFA/H 2 0 20 N/A N/A Dec.d 95:5

IPA/H

2 0 2:98 2:98

H

3

PO

4 2.12 12 30 Clean 95:5 (7) (10) HCOOH 3.77 252 HCOOH/H 2 0 20 N/A N/A Dec.d 95:5 AcOH/H 2 0 2:98 2:98 Esterifi AcOH 4.76 166 20 95:5 (> 4) (4) cationc a The (E)/(Z) ratios were estimated by 'H NMR spectroscopy. a (E)/(Z) 2 2:98 due to a content of 1-2 /b 1-5,20-A-3-Tig in I-5,20-A-3-Ang. b Number of moles catalyst relative to I-5,20-A-3-Ang. c Ester formation between catalyst and the ingenol 20-position. 5 d Decomposition. The (E)/(Z) ratio is the I-3-Tig/I-3-Ang ratio Table 11B 58 / H H H 0H H 0 / H 0 34 H HO~ OHO OHO HO 20 HO 20 -- iZ HOHO20H Ingenol-3-angelate Ingenol-3-tiglate H 0 H 34 H 45 / HOHO O 20 5 Example 24 Ingenol-5,20-(di(tert-butyl)silylene)-ether (Compound 20) To a solution of ingenol (50.4 mg, 0.145 mmol) and 2,6-lutidine (46.7 mg, 0.436 mmol) in N,N-dimethylformamide (0.25 mL) was added di(tert-butyl)silyl bis(trifluoromethanesulfonate) (76.6 mg, 0.174 mmol) at 0 *C. The obtained 10 solution was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous solution of sodium hydrogencarbonate. The mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash 15 chromatography (heptane/ethyl acetate 1:0-+1:1), giving the title compound (35.7 mg, 50%) as a white foam. 'H NMR (300 MHz, CDC1 3 ) 5 6.02 (d, J = 5.1 Hz, 1H), 5.96 (q, J = 1.5 Hz, 1H), 4.47 (d, 3 = 12.5 Hz, 1H), 4.33 - 4.18 (m, 4H), 3.89 (s, 1H), 2.57 - 2.30 (m, 2H), 1.87 (d, J = 1.5 Hz, 3H), 1.76 (ddd, 3 = 15.8, 6.3, 3.9 Hz, 1H), 1.11 (s, 59 3H), 1.05 (s, 3H), 1.02-0.95 (m, 22H), 0.90 (dd, J = 11.8, 8.4 Hz, 1H), 0.75 0.61 (m, 1H).

C

2 8

H

44 0 5 Si 0 'H H 0 3 4 OHO 0 20 5 Example 25 Ingenol-5,20-(di(tert-butyl)silylene)-ether-3-angelate (Compound 21) A mixture of ingenol -5,20-(di(tert-butyl)silylene)-ether (35.5 mg, 0.073 mmol), [(Z)-2-methylbut-2-enoyll 2,4,6-trichlorobenzoate (29.7 mg, 0.097 mmol), and 10 sodium hydrogencarbonate (10.2 mg, 0.12 mg) in toluene (0.3 mL) was stirred under argon atmosphere at 100 *C for 20 h. After being cooled to room temperature, the reaction mixture was filtered and washed with toluene. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 1:0-+4:1), giving the title compound as 15 a white foam (23.4 mg, 5 6%). 1H NMR (300 MHz, CDCI 3 ) 6 6.10 - 5.96 (m, 3H), 5.67 (s, 1H), 4.49 (d, J = 12.5 Hz, 1H), 4.35 - 4.21 (m, 3H), 3.64 (s, 1H), 2.64-2.52 (m, 1H), 2.46 - 2.27 (m, 1H), 2.01 - 1.93 (m, 3H), 1.91 (dq, J = 3.0, 1.5 Hz, 3H), 1.82 - 1.65 (m, 4H), 1.10-1.04 (m, 15H), 1.03 - 0.95 (m, 12H), 0.94 - 0.84 (m, 1H), 0.67 (ddd, 3 = 20 10.1, 8.4, 6.4 Hz, 1H).

C

33

H

50

O

6 Si H 0 H 3 4 0 5/ OHO HO 20 60 Example 26 Ingenol-3-angelate To a solution of lngenol-5,20-(di(tert-butyl)silylene)-ether-3-angelate (10.3 mg, 0.018 mmol) in tetrahydrofuran (0.1 mL) was added tetrabutylammonium 5 fluoride (1 M in tetrahydrofuran, 0.054 mmol) under argon atmosphere at -20 *C. The solution was stirred at the same temperature for 15 min. The reaction was quenched with saturated aqueous solution of ammonium chloride. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was 10 purified by chromatography (heptane/ethyl acetate 4:1-1:1), giving the title compound (2.2 mg, 29%). H 0 H 3 45 / HOHO HO 20 0Si Example 27 15 Ingenol-20-(tert-butyldimethylsilyl)-ether (Compound 22) To a solution of ingenol (66.2 mg, 0.15 mmol) and 2,6-lutidine (48.2 mg, 0.45 mmol) in N,N-dimethylformamide (0.25 mL) was added tert-butyldimethylsilyl chloride (27.1 mg, 0.18 mmol). The solution was stirred at the same temperature for 30 min. The reaction was not complete. 2,6-Lutidine (16.1 mg, 20 0.15 mmol) and tert-butyldimethylsilyl chloride (18.1 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 1 h, taken up in aqueous solution of sodium hydrogencarbonate, and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography 25 (heptane/ethyl acetate 3:1), providing an impure product. This impure product was subjected to a further chromatographic purification (dichloromethane/ethyl acetate 19:1-+10:1), giving the title compound as a white foam (65.8 mg, 95%).

61 Also see: Opferkuch, H. J. et al., Z. Naturforsch. 1981, 36b, 878-887 (compound 10) 'H NMR (300 MHz, CDCI 3 ) 6 6.11 - 5.94 (m, 1H), 5.96 - 5.84 (m, 1H), 4.44 (broad s, 1H), 4.32 (s, 1H), 4.29 - 4.07 (m, 3H), 4.01 (s, 1H), 3.86 (s, 1H), 5 2.57 - 2.39 (m, 1H), 2.32 (ddd, J = 15.6, 9.1, 3.0 Hz, 1H), 1.85 (d, J = 1.4 Hz, 3H), 1.75 (ddd, 3 = 15.7, 6.2, 4.8 Hz, 1H), 1.11 (d, J = 7.1 Hz, 3H), 1.06 (s, 3H), 0.96 (dd, 3 = 7.6, 5.3 Hz, 3H), 0.89 (s, 9H), 0.88 - 0.80 (m, 1H), 0.78 0.60 (m, 1H), 0.08 (d, J = 1.3 Hz, 6H).

C

36

H

42

Q

5 Si 10 H 0 H 0 3 45 / O H HO 20 0 Si Example 28 Ingenol-20-(tert-butyldimethylsilyl)-ether-3-angelate (Compound 23) 15 A mixture of ingenol-20-(tert-butyldimethylsilyl)-ether (61.6 mg, 0.133 mmol), [(Z)-2-methylbut-2-enoyl] 2,4,6-trichlorobenzoate (54.4 mg, 0.177 mmol), and sodium hydrogencarbonate (16.8 mg, 0.20 mmol) in toluene (0.55 mL) was stirred under argon atmosphere at 100 *C for 17 h. After being cooled to room temperature, the reaction mixture was filtered and washed with toluene. The 20 filtrate was concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 89:11-*78:22), giving the title compound as a white foam (14.4 mg, 23%). 'H NMR (300 MHz, CDCI 3 ) 6 6.08 (qd, 3 = 7.2, 1.4 Hz, 1H), 6.03 (q, J = 1.5 Hz, 1H), 5.96 (d, J = 4.6 Hz, 1H), 5.69 (s, 1H), 4.76 (s, 1H), 4.29 - 4.07 (m, 3H), 25 4.01 (s, 1H), 3.65 (s, 1H), 2.69 - 2.51 (m, 1H), 2.33 (ddd, J = 15.6, 9.6, 3.0 Hz, 1H), 2.03 - 1.95 (m, 3H), 1.97 - 1.85 (m, 3H), 1.82 - 1.65 (m, 4H), 1.07 (s, 3H), 1.03 (s, 3H), 0.96 (d, J = 7.2 Hz, 3H), 0.93 - 0.80 (m, 10H), 0.67 (td, 3 = 9.4, 6.4 Hz, 1H), 0.07 (s, 6H).

62

C

31

H

48

O

6 Si H H 7' H 3 4 o5 / OHO HO 20 HO Example 29 5 Ingenol-3-angelate Ingenol-20-(tert-butyldimethylsilyl)-ether-3-angelate (14.4 mg, 0.026 mmol) was dissolved in tetrahydrofuran (0.07 mL). To this solution was added hydrochloric acid in methanol (12.5 mM, 0.07 mL) at 0 OC. The solution was stirred at room temperature for 6.5 h and then subjected to flash 10 chromatography (heptane/ethyl acetate 2:1-+1:1), giving the title compound (4.6 mg, 40%) and the starting material (4.4 mg). The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be 15 taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 20 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 25

Claims (33)

1. Methods of producing ingenol-3-angelate (I) from ingenol (II). - H H 0 -H 0 -0 H H 3 / 3 OHO 5 HOHO 5 H 2 0 OH H 2 0 OH (I) (II) 5

2. A method according to claim 1 of producing ingenol-3-angelate (2-Methyl 2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a-dihydroxy-4 (hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a-octahydro 1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-y ester) (I) from ingenol (II) 10 H H 0 H / H 03 / 3 H OHO 5 HOHO 5 HO 2 0 OH HO 20 OH (I) (II) comprising the steps of: 15 (a) reacting one or both hydroxyl groups in positions 5 and 20 of ingenol with suitable hydroxyl protecting agents, same or different, to obtain a compound of the general formula (III) or (IV) H . O H 0 H H H 3 HOOHO o HOO5 HO HO R 2 0 20 R 1 HO (III) (I V) D-0 64 wherein R 1 represents hydrogen or a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group, with the proviso that not both Ri and R 2 represent hydrogen, 5 or wherein D represents a dihydroxyl protective group (b) esterifying the hydroxyl group at the 3-position of compounds (III) or (IV) to obtain compounds of the general formula (V) or (VI) n, O H ' O H 7 H / H 0 3 0 OHO OHO - R 2 0 5 20 R 1 -- O0 10 (V) (VI) D-O wherein R 1 , R 2 and D are as described above, and (c) removing the hydroxyl protective groups R 1 or R 2 , or Ri and R 2 , or D from compounds (V) or (VI) to obtain ingenol-3-angelate (I). / H / H 03 / 3 / OHO 5 HOHO 5 HO 20 OH HO 2 0 OH 15 () (11)

3. A method according to claim 1 of producing ingenol-3-angelate (2-Methyl 2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a-dihydroxy-4 (hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a-octahydro 1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yI ester) (I) from 20 ingenol (II) 65 ' , O .H o , O H 0 -H III.. 0 -H1. H / H 0 3 / 3 OHO 5 HOHO 5 HO 20 OH HO 20 OH (I) (II) comprising the steps of: 5 (d) esterifying the 3- and the 20-hydroxyl group and optionally esterifying the 5 hydroxyl group of ingenol (II) to obtain a compound of the formula (VII) H 3 / 0 HO O R 3 0 20 0 (VII) 20 10 wherein R 3 represents hydrogen or angeloyl, and (e) cleaving the angelate ester(s) in position 20 or in position 5 and 20 of compound (VII) to obtain ingenol-3-angelate (I). 15

4. A method according to claim 1 of producing ingenol-3-angelate (2-Methyl 2(Z)-butenoic acid (laR,2S,5R,5aS,6S,8aS,9R,lOaR)-5,5a-dihydroxy-4 (hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-la,2,5,5a,6,9,10,10a-octahydro 1H-2,8a-methanocyclopenta(a]cyclopropa[e]cyclodecen-6-yl ester) (I) from ingenol (II) 20 66 0 -H . O H H / H 03 / 3 OHO 5 HOHO 5 HO 20 OH HO 2 OH (I) (II) comprising the step of: 5 (f) selective esterification of the 3-hydroxy group of compound (II) to obtain ingenol-3-angelate (I).

5, A method according to claim 2 wherein R 1 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl 10 protective group, and R 2 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group.

6. A method according to claim 2, wherein D represents an acetal , ketal , diacetal , diketal , ortho ester, silyl, boronate or a carbonate derived dihydroxyl 15 protective group,

7. A method according to claim 2 or 5 wherein R 1 is selected from the group consisting of hydrogen or [(3,4-dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2 methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1 20 methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2 (trimethylsilyl)ethoxymethyl, triethylsilyl, trilsopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butydiphenylsilyl, triphenylsilyl, acetyl, chloroacetyl,phenoxyacetyt or angeloyl. 25

8. A method according to claim 2, 5 or 7 wherein R 2 is selected from the group consisting of hydrogen or [(3,4-dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2 methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1 methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2 (trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, 67 dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, acetyl, chloroacetyl,phenoxyacetyl or angeloyl.

9. A method according to claim 2 or 6, wherein D is selected from the group 5 consisting of isopropylidene, cyclopentylidene, cyclohexylidene, p methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3 dimethoxybutane-2,3-di-yl, 1,2-dimethoxycyclohexan-1,2-di-yl, octahydro [2,2']-bipyran-2,2'-di-yl, di-tert-butylsilylene, 1,3-(1,1,3,3 tetraisopropyldisiloxanylidene), phenyl boronate, 3-pentylidene, 2,4-dimethyl-3 10 pentylidene, 2,6-dimethyl-4-heptylidene, 3,3-dimethyl-2-butylidene, 1-phenyl 1-ethylidene,benzylidene, 2,4-dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6 trimethylbenzylidene, 2,2-dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene. 15

10. A method according to claim 2, 5 or 7 wherein R 1 represents a hydroxyl protective group and R 2 represents hydrogen.

11. A method according to claim 3 wherein R 3 represents hydrogen. 20

12. A method according to claim 2, 5, 6, 7, 8, 9 or 10 wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above with angelic acid in the presence of a coupling reagent or an enzyme.

13. A method according to claim 2, 5, 6, 7, 8, 9, 10 or 11 wherein step (b) 25 comprises reacting compound (III) or (IV), wherein R 1 , R2 and D are as defined above with angelic acid in the presence of a coupling reagent.

14. A method according to claim 2, 5, 6, 7, 8, 9, 10, 12 or 13 wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined 30 above, with angelic acid in the presence of N,N'-Dicyclohexylcarbodiimide, N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate , N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N-(3 Dimethylaminopropyl)-N'-ethylcarbodiimide or 2-chloro-1-methyl-pyridinium iodide. 68

15. A method according to claim 2, 5, 6, 7, 8, 9 or 10 wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above, with an activated derivative of angelic acid. 5

16. A method according to claim 2, 5, 6, 7, 8, 9, 10 or 15 wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above, with methyl angelate, angeloyl chloride, angelic acid anhydride, [(Z)-2 methylbut-2-enoyl] 2,4,6-trichlorobenzoate or angeloyl 4-nitrobenzoyl 10 anhydride.

17. A method according to claim 2, 5, 6, 7, 8, 9 or 10 wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above, with an angelic acid halide or with angelic acid anhydride or with a mixed 15 angelic acid anhydride.

18. A method according to claim 2, 5, 6, 7, 8, 9, 10 or 17 wherein step (b) comprises reacting compound (III) or (IV), wherein R 1 , R 2 and D are as defined above, with angeloyl chloride, angelic acid anhydride, [(Z)-2-methylbut-2-enoyl] 20 2,4,6-trichlorobenzoate or angeloyl 4-nitrobenzoyl anhydride.

19. A compound of general formula (V) wherein R 1 represents hydrogen or a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group; 25 with the proviso that not both R 1 and R 2 represent hydrogen: and with the proviso that R 1 and R 2 do not represent acetyl; and with the proviso that R 1 and R 2 do not represent 2-[(2 aminobenzoyl)amino]benzoyl; and with the proviso that R 1 does not represent decanoyl; 30 and with the proviso that R 1 does not represent 3-phenyl-2-propenoyl.

20. A compound according to claim 19 wherein R 1 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl 69 protective group, and R2 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group;

21. A compound according to claim 18 or 20 wherein R, and R2 independently 5 represents hydrogen or [(3,4-dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2 methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1 methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2 (trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenysilyl, triphenylsilyl, 10 chloroacetyl or phenoxyacetyl.

22. A compound according to claim 19, 20 or 21 wherein R 1 represents a hydroxyl protective group and R 2 represents hydrogen; 15

23. A compound according to claim 19, 20, 21 and 22 chosen from the group consisting of Ingenol-20-(tert-butyldimethylsilyl)-ether-3-angelate

24. A compound of general formula (VI) wherein D represents a dihydroxyl 20 protective group; with the proviso that D does not represent isopropylidene.

25. A compound according to claim 24 wherein D represents an acetal , ketal , diacetal , diketal , ortho ester, silyl, boronate or a carbonate dihydroxyl protective group. 25

26, A compound according to claim 24 or 25 wherein D represents cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2 dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2']-bipyran-2,2'-di-yl, di-tert 30 butylsilylene, 1,3-(1,1,3,3-tetrasopropyldisiloxanylidene), phenyl boronate, 3 pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3 dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4 dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2 dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene. 70

27. A compound according to claim 24, 25 or 26 chosen from the group consisting of ingenol-5,20-(di(tert-butyl)silylene)-ether-3-angelate 5

28. A compound of general formula (III) wherein R 1 and R 2 independently represents hydrogen or an ether, acetal, ketal, silylether, or a suffenate derived hydroxyl protective group; with the proviso that not both R 1 and R 2 represent hydrogen; 10 and with the proviso that R 1 does not represent triphenylmethyl; and with the proviso that R 1 does not represent t-butyldimethylsilyl.

29. A compound of general formula IV wherein D represents a dihydroxyl protective group; 15 with the proviso that D does not represent isopropylidene.

30. A compound according to claim 29 wherein D represents an acetal , ketal diacetal , diketal , ortho ester, silyl, boronate or a carbonate derived dihydroxyl protective group. 20

31. A compound according to claim 29 and 30 wherein D represents cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2 dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2']-bipyran-2,2'-di-yl, di-tert 25 butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3 pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3 dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4 dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2 dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene. 30

32, A compound according to claim 29, 30 and 31 chosen from the group consisting of Ingenol-5,20-(3-pentylidene)-ketal, Ingenol-5,20-(2,4-dimethyl-3-pentylidene)-ketal, 71 I ngenol- 5,20- (2,6-d! methyl-4-heptyl idene)-ketal, Ing en o I-5,20 -cyclope ntyliid ene- ketal1, Inge nolI- 5,20 -cycfohexylIiden e- keta 1, Ing en ol -5,2 0 -(3,3-d im ethyl- 2- butyl id ene) -keta 1, 5 1Ingenol -5,20 -(1 -phenyl -I-ethyl idene)-ketal, Ingenol -5,20-benzyl id ene-acetal1, Ingenol-5,20-(4-methoxybenzylidene)-acetal, In genol -5,20-(2,4-dimethoxybenzyl idene)-acetal, Ing en oI- 5,2 0 -(4-nitrobenzyl iden e) -acetal1, 10 Ingenol-5,20-(2,4,6-trimethylbenzylidene)-acetal, Ingenol- 5,20- (2,2-dimethyl- I-propyi idene)-acetal, Ingenol-5,20-methyl-orthoformate, Inge nol- 5,20 -ethyl -o rthofo rmate, Ingenol-5,20-(prop-2-yi)-orthoformate, 15 Ing en ol -5,20- (d i(tert- butyl)silyle ne) -ether.

33. A compound of general structure (VII) wherein R 3 represents hydrogen or angeloyl. 20