WO2009030733A1 - Method for the synthesis of 4-alkoxy-, 4-hydroxy- and 4-aryloxy-substituted tetrahydro-furo[3,4-b]furan-2(3h)-one compounds - Google Patents

Abstract

The present invention relates to a method for the synthesis of enantiomerically and diastereomerically enriched 4-alkoxy-, 4-hydroxy- or 4-aryloxy- substituted tetrahydro-furo[3,4-b]furan-2(3H)-ones by aldol coupling of a suitable hydroxyl-protected hydroxy-acetaldehyde and 4-oxobutanoic acid or an ester thereof, and subsequent removal of the protecting group from the aldol compound and (optionally simultaneous) cyclizations and acetal formation under acidic conditions in the presence of an alcohol, followed by optional isolation of the desired compounds. The invention also relates to compounds according to formulae [Xl] and [XII].

Description

METHOD FOR THE SYNTHESIS OF 4-ALKOXY-. 4-HYDROXY- AND 4-ARYLOXY- SUBSTITUTED TETRAHYDRO-FUROr3.4-BlFURAN-2(3HVONE COMPOUNDS

The present invention relates to a method for the synthesis of 4-alkoxy-, 4-hydroxy- and 4-aryloxy-substituted tetrahydro-furo[3,4-b]furan-2(3H)-one compounds and in particular to the synthesis of (3aS,4S,6aR)-4-methoxy-tetrahydro- furo[3,4-b]furan-2(3H)-one and its enantiomer (3aR,4R,6aS)-4-methoxy-tetrahydro- furo[3,4-b]furan-2(3H)-one and 4-aryloxy, 4-hydroxy and other 4-alkoxy analogs of the same stereogeometry. 4-Alkoxy-, 4-hydroxy- or 4-aryloxy-substituted (3aS,6aR)-tetrahydro- furo[3,4-b]furan-2(3H)-ones of the formula [I], wherein R represents a hydrogen atom, an (optionally substituted) alkyl or an (optionally substituted) aryl group, are convenient precursors for (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol (of formula [II]).

[I] [II]

The latter compound is an important building block for HIV protease inhibitors. Of particular interest is the protease inhibitor TMC114 of formula [III] which was developed (see, for instance, Surleraux et al. in J. Med. Chem. 2005, 48, 1813) and recently launched by Tibotec Pharmaceuticals Ltd. The molecule possesses a bis- tetrahydrofuranyl moiety, which is introduced into TMC1 14 using a mixed carbonate of compound [II] as described by Ghosh et al. in J. Med. Chem. 1996, 39, 3278.

Several approaches for the synthesis of the building block of formula [II] are known. In the most efficient approach to the synthesis of the compound of formula [II], as disclosed by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920, S-2,3-O-isopropylidene-glyceraldehyde of formula [V] is used as the source of chirality. This aldehyde can, for instance, be prepared from L-ascorbic acid of formula [IV] in 3 steps (see EP 1673364 A1 ). In one variant of this approach (see also EP 1448567 A1 ) the key step is a diastereoselective Michael addition of nitromethane to the dimethylmalonate adduct of S-2,3-O-isopropylidene- glyceraldehyde which is subsequently transformed to (3aS,4S,6aR)-4-methoxy-

Scheme 1

VII tetrahydro-furo[3,4-b]furan-2(3H)-one (which is a compound according to formula [I], wherein R = CH₃) in 5 steps. In an improved variant of this approach (see also WO 2005095410 to Quaedflieg et al.), as shown in Scheme 1 , the key step is a diastereoselective Michael addition of nitromethane to the Wittig adduct (of formula [Vl]). This Wittig adduct is obtained by reaction of triethyl phosphonoacetate with S-2,3-O-isopropylidene-glyceraldehyde of formula [V]. The diastereoselective Michael addition of nitromethane to the Wittig adduct gives the nitro compound of formula [VII]. This nitro compound is subsequently transformed to (3aS,4S,6aR)-4-methoxy- tetrahydro-furo[3,4-b]furan-2(3H)-one (according to formula [I], wherein R = CH₃) in 2 steps representing a multi-step process, i.e. a Nef reaction and acid-catalyzed isopropylidene deprotection followed by cyclization to the lactone and cyclic hemi- acetal and transformation of the latter moiety to a methoxy acetal due to use of methanol as the solvent. Compounds of formula [I] can be conveniently converted to the desired building block of formula [II] by reduction, for instance with LiBH₄, followed by acid-catalyzed cyclization in a one-pot process. Although the process disclosed by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920 gives the building block of formula [I] in high enantiomeric (> 99%), diastereomeric (> 99%) and chemical purity and although the process can be conveniently scaled up to ton scale and has relatively little raw material costs, it has the disadvantage, however, that the synthesis of the precursor (3aS,4S,6aR)-4-methoxy- tetrahydro-furo[3,4-b]furan-2(3H)-one (a compound according to formula [I], wherein R = CH₃) is linear and requires many chemical steps so that the production costs of the building block of formula [II] are still significant.

Since the building block of formula [II] is a pharmaceutical intermediate to be produced on large scale, there is a great need for a more simple synthetic route to the precursor (3aS,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan- 2(3H)-one (of formula [I], R = CH₃) and to 4-hydroxy- or 4-aryloxy- or other 4-alkoxy- substituted (3aS,6aR)-tetrahydro-furo[3,4-b]furan-2(3H)-one derivatives of formula [I].

The present invention relates to a method for the synthesis of a 4- alkoxy, 4-hydroxy or 4-aryloxy-substituted (3aS,6aR)-tetrahydro-

[I] [VIII] furo[3,4-b]furan-2(3H)-one of the formula [I] or a 4-alkoxy, 4-hydroxy or 4-aryloxy- substituted (3aR,6aS)-tetrahydro-furo[3,4-b]furan-2(3H)-one of the formula [VIII], wherein R represents a hydrogen or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group, by: i) an aldol reaction in the presence of a catalyst of a hydroxyl-protected hydroxy- acetaldehyde of the general formula [IX] and 4-oxo-butanoic acid or a 4-oxo- butanoic acid ester of the general formula [X], respectively,

wherein P₁ represents a hydroxyl-protecting group and P₂ represents a hydrogen atom or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group, giving an aldol product of formula [Xl], which may spontaneously (partially) lactonize to a product of formula [XII], followed by - A -

ii) cleavage of the hydroxyl protecting group P₁ from the compound of formula [Xl] or [XII] or a mixture thereof, and cyclization to a cyclic acetal or hemi-acetal and optional (further) lactonization which latter two steps may optionally occur simultaneously, in an alcohol solvent of the formula ROH, wherein R is as defined above.

R is hydrogen or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group. If substituted, the alkyl, and aryl groups may be substituted with alkyl groups of 1-6 C-atoms or aryl groups of 1-6 C-atoms or protected functional groups comprising one or more heteroatoms such as oxygen, sulphur and nitrogen or unprotected functional groups comprising one or more heteroatoms such as oxygen, sulphur and nitrogen. Additionally, the alkyl groups may be interrupted by one or more heteroatoms such as oxygen, sulphur and nitrogen, whereas the aryl groups may comprise within their ring system one or more heteroatoms such as oxygen, sulphur and nitrogen.

The term hydroxyl-protecting group refers to a substituent which protects hydroxyl functions against undesirable reactions during synthetic procedures. Examples of hydroxyl-protecting groups are disclosed in Greene and Muts, "Protective Groups In Organic Synthesis" (John Wiley & Sons, New York, 3^rd edition, 1999). Suitable hydroxyl protecting groups P₁ for the present invention for example comprise methyl and substituted methyl groups (such as methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl); ethyl and substituted ethyl groups (such as 1-ethoxyethyl, terf-butyl, allyl, 1-methoxy-1-methyl- ethyl); benzyl and substituted benzyl groups (such as p-methoxybenzyl, 3,4- dimethoxybenzyl, triphenylmethyl); aryl and substituted aryl groups such as p-methoxy- phenyl; silyl groups (such as trimethylsilyl, triethylsilyl, terf-butyldimethylsilyl, tert- butyldiphenylsilyl, tri-isopropylsilyl, diethylisopropylsilyl, terf-hexyldimethylsilyl, triphenylsilyl, di-terf-butylmethylsilyl); acyl- or aroyl groups (such as formyl, acetyl, benzoyl, pivaloyl, methoxyacetyl, chloroacetyl, levulinoyl, 1-adamantoyl); alkoxycarbonyl or aryloxycarbonyl groups (such as benzyloxycarbonyl, p- nitrobenzyloxycarbonyl, te/t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2- (trimethylsilyl)ethyloxycarbonyl, allyloxycarbonyl) and sulfate and sulfonyl groups (such as allylsulfonyl, methanesulfonyl, benzylsulfonyl and tosyl). The term alkyl refers to saturated monovalent hydrocarbon radicals having straight or branched hydrocarbon chains or, in the case that at least 3 carbon atoms are present, cyclic hydrocarbons or combinations thereof and contains typically 1 to 20 carbon atoms (Ci_-2oalkyl), suitably 1 to 10 carbon atoms (Ci-i_Oalkyl), preferably 1 to 8 carbon atoms (Ci_-8alkyl), more preferably 1 to 6 carbon atoms (Ci_-6alkyl), and even more preferably 1 to 4 carbon atoms

Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term aryl refers to an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen from the aromatic moiety, and includes monocyclic and polycyclic radicals, such as phenyl, biphenyl and naphthyl.

The problem addressed by the present invention is the provision of a process for the synthesis of formula [I] or [VIII] which requires less chemical steps than the process known from prior art. The advantage of the method according to the present invention is that it provides a more simple synthetic route to the precursor (3aS,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one (of formula [I], R = CH₃) and to 4-hydroxy- or 4-aryloxy- or other 4-alkoxy-substituted (3aS,6a/?)-tetrahydro- furo[3,4-b]furan-2(3H)-one derivatives of formula [I]. Additional advantages of this route are that it involves few chemical steps and uses readily available and non-chiral starting compounds. It should be noted that side-reactions may occur, wherein both the aldehydes of formula [Xl] or [XII] may be (partially) transformed into acetal or hemi- acetal forms with the alcohol functionality (of another molecule) of the compound of formula [Xl] or with any other alcohol present in the reaction mixture for instance as a solvent. In a further embodiment the invention relates to a method as given above, wherein step ii) is followed by subsequent isolation of the compound of formula [I] Or [VIII].

In another embodiment the invention relates to a method as given above, wherein the isolation of the compound of formula [I] or [VIII] follows a preceding upgrading of the diastereomeric purity of the resulting compound of formula [I] or [VIII] using an aqueous work-up step comprising an aqueous alkaline quench reaction.

In yet another embodiment the invention relates to a method a given above, wherein the isolation of the compound of formula [I] or [VIII] follows a preceding upgrading of the diastereomeric purity and optionally also the enantiomeric purity of the resulting compounds of formula [I] or [VIII] using an aqueous work-up step followed by a crystallization step.

In a preferred embodiment of the present invention P₁ is an acid labile hydroxyl-protecting group, because this facilitates simultaneous reactions at the end of the process. More preferably Pi is a sterically large and acid labile hydroxyl-protecting group. The presence of a sterically large hydroxyl-protecting group on the aldehyde hinders reactions and more specifically hinders reactions with the same aldehydes also comprising a sterically large hydroxyl-protecting group. Even more preferably P₁ is an electron donating, sterically large and acid labile hydroxyl-protecting group. Even more preferably P₁ is an acid labile hydroxyl-protecting silyl group. Most preferably P₁ is a terf-butyldimethylsilyl group.

P₂ represents a hydrogen atom or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group. The substituent can be any possible substituent, provided that the substituent is not reactive towards any of the starting materials, intermediates and/or products of the reaction. In view of fast lactonisation at lower costs, P₂ preferably is a substituted or an unsubstituted alkyl group, more preferably an alkyl group with 1-6 carbon atoms, most preferably a methyl group.

Some of the aldehydes of formula [IX] may be obtained from commercial sources or synthesized by various methods described in the literature. For instance, aldehydes of formula [IX] may be obtained by mono-O-protection of 1 ,2- ethanediol followed by oxidation of the remaining alcohol functionality. Suitable oxidation methods may be TEMPO based oxidation methods or Swern type oxidation methods like using pyridine. SO3 as described for instance in March's Advanced Organic Chemistry, 5^th edition, Ed. M. B. Smith and J. March, John Wiley & Sons, 2001. Alternatively, aldehydes of formula [IX] may be obtained by protection of both hydroxyl functionalities of 2-butene-1 ,4-diol followed by oxidative cleavage of the double bond. 4-Oxobutanoic acid or esters thereof of formula [X] may be obtained from commercial sources or synthesized by various methods described in the literature. For instance 4-oxobutanoic acid methylester may be obtained by ring opening of γ- butyrolactone with methanol using an acidic or alkaline catalyst, followed by oxidation of the resulting γ-hydroxybutyric acid methylester. Preferably, 4-oxobutanoic acid methylester may be obtained by hydroformylation of methyl acrylate.

In the present invention the aldehydes according to formula [IX] and [X] may be used without further purification but preferably they may be distilled or crystallized prior to use in the aldol reaction.

With respect to step i) in the method according to the invention, the aldol reaction between aldehydes of formula [IX] and aldehydes of formula [X] in the method according to the present invention is carried out in the presence of a catalyst. Preferably the reaction is carried out in the presence of a chiral catalyst such as a chiral base, a chiral Lewis acid, a chiral metal containing homogeneous catalyst, an enzyme or a chiral organocatalyst. More preferably the reaction is carried out in the presence of an organocatalyst. The term "organocatalyst", as used herein, refers to a catalyst consisting of an organic compound which does not contain a metal atom. Preferred catalysts are chiral organocatalysts, in particular chiral amines, such as L- or D-proline or L- or D-O-methyl-prolinol. The catalyst may also be employed on a solid support.

For the production of the compound of formula [I] a suitable catalyst of the aldol reaction is L-proline, whereas for the production of a compound of formula [VIII] D-proline can be used. The use of chiral organocatalysts such as L-proline for enantioselective and diastereoselective aldol reactions between two aldehydes is known in the art, e.g. in WO03/089396 (to D. MacMillan et al.) and as disclosed by D. MacMillan et al. in Angew. Chem. Int. Ed. 2004, 43, 2152-2154. However, according to the present invention it was found that these chiral organocatalysts surprisingly can also be applied for the enantioselective and diastereoselective synthesis of 4-alkoxy-, 4-hydroxy- or 4-aryloxy-substituted tetrahydro-furo[3,4-b]furan-2(3H)-ones of the formulae [I] and [VIII]. Using enantiomerically pure proline as the organocatalyst, the enantiomeric excess (e.e.) of the aldol reaction products of the formula [Xl] and [XII] is usually > 95%. On the other hand, the diastereoselectivity of the aldol reaction is much lower. Surprisingly, the diastereomeric ratio depends largely on the steric size and electronic properties of the hydroxyl protecting group P₁: the more electron donating or the larger P₁ the higher the diastereomeric ratio. If, for instance, enantiomerically pure proline is used as the organocatalyst and P₁ is an acetyl group, the diastereomeric ratio is only approximately 1 :1 , i.e. the diastereomeric excess (d.e.) is 0%. The diastereomeric ratio increases to a value of approximately 3:1 (corresponding to a d.e. of 50%) if Pi is a terf-butyldimethylsilyl group. In contrast, the properties of P ₂ do not seem to influence the diastereomeric ratio of the aldol product. Furthermore, increasing the ratio between aldehydes [IX] and [X] leads to higher yields of aldol product but does not seem to have a significant impact on the diastereomeric ratio. Additionally, by proper selection of the reaction conditions the diastereomeric ratio, yield en e.e. may be improved significantly.

Aldehydes of formula [IX] and formula [X], respectively, may for example be applied in a molar ratio of at least 0.5:1 in order to optimize the aldol reaction, preferably in a molar ratio of at least 1 :1 , more preferably in a molar ratio of at least 1.2:1 and most preferably in a molar ratio of at least 1.3:1. An upper limit of the molar ratio of the aldehydes of formula [IX] and formula [X], respectively, is typically 10:1 in order to maintain the process at an efficient cost level, preferably 5:1 , more preferably 3:1 , most preferably 2:1. The amount of catalyst used in the process according to the invention is generally at least 0.001 mol equivalent to minimize reaction times required for an acceptable yield, preferably at least 0.005 mol equivalent and most preferably at least 0.01 mol equivalent, and generally not more than 1 mol equivalent in order to maintain the process at an efficient cost level, preferably not more than 0.5 mol equivalent and more preferably not more than 0.2 mol equivalent, all based on the aldehyde which amongst the two aldehydes (of formulae [IX] and [X]) is added in the lowest molar amount.

The aldol reaction is typically carried out in an organic solvent like for example toluene, dichloromethane, ethyl acetate, dioxane, acetonitrile, dimethylsulfoxide, N-methylpyrrolidinone, N,N-dimethyl formamide, sulfolane or tetrahydrofuran (THF) and others or mixtures thereof. Polar aprotic solvents are preferred since they do not disturb the catalytic mechanism. More preferably the organic solvent is dimethylsulfoxide, N-methylpyrrolidinone, N,N-dimethyl formamide, sulfolane or THF. Most preferably the aldol reaction is carried out in THF. Suitably the aldol reaction is carried out at temperatures above -50⁰C to minimize reaction times required for an acceptable yield, preferably above -10⁰C and most preferably above 0°C. As an upper limit the temperature typically is kept below 100⁰C for high results on enantiomeric excess and diastereomeric excess, preferably below 40⁰C, most preferably below 30°C. The total weight % of aldehydes in relation to the total of aldehydes, solvents and catalyst may be at least 0.1 weight % for the reaction to proceed at an acceptable speed, preferably at least 1 weight % and most preferably at least 10 weight %. On the other hand the total weight % of aldehydes may not exceed 70 weight % to prevent the presence of too many side reactions, preferably not exceed 50 weight % and most preferably not exceed 30 weight %.

The reaction time is not critical and will be preferably chosen such that the aldehyde which amongst the two aldehydes is added in the lowest molar amount is almost completely or completely consumed. During the aldol reaction the primarily formed aldol product of the formula [Xl] may spontaneously partly or fully lactonize to the lactone congener [XII]. The extent to which this lactonization occurs largely depends on the properties of the P₂ group and on the reaction conditions. For instance, if the P₂ group is smaller in steric size or more electron withdrawing, the electrophilicity of the ester function increases and the extent to which lactone formation occurs during the aldol reaction increases. Additionally, if the temperature of the reaction is higher, the extent of lactone formation during the aldol reaction will also be higher. The extent to which lactonization occurs during the aldol reaction has no or no significant effect on the final result of the reaction cascade towards the desired compounds of formula [I] or [VIII]. The present invention also relates to compounds of the general formula [Xl] or [XII], wherein P₁ represents a hydroxyl-protecting group and P₂ represents a hydrogen atom or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group, and wherein the asterisks (^*) indicate chiral centers. Suitable hydroxyl-protecting groups Pi are a methyl, substituted methyl, ethyl, substituted ethyl, benzyl, substituted benzyl, silyl, acyl, aroyl, alkoxycarbonyl, aryloxycarbonyl, sulfate or sulfonyl group. Preferably Pi is a tert- butyldimethylsilyl group. Preferably P₂ is an alkyl group with 1-6 C-atoms. More preferably P₂ is a methyl group. Most preferably Pi is a te/t-butyldimethylsilyl group and P₂ is a methyl group. The reaction product as shown in formula [Xl] or [XII] or a mixture thereof can be isolated using methods known to any person skilled in the art, such as aqueous work-up and extraction. Further purification of the reaction product of formula [Xl] or [XII] or a mixture thereof can be performed by using methods known to any person skilled in the art, such as by chromatography or crystallization. Compounds [Xl] and [XII] obtained from the aldol reaction can be characterized by ¹H NMR spectroscopy. Compounds [Xl] and [XII] can be used in the preparation of pharmaceutical ingredients. The invention also relates to use of the compounds of formulae [Xl] or [XII] or a mixture thereof in the synthesis of compounds of formulae [I] and/or [VIII]. Furthermore, the invention relates to use of the compounds of formulae [Xl] Or [XII] or a mixture thereof in the synthesis of the compound of formula [III].

With respect to step ii) in the method according to the invention, the reaction product as shown in formula [Xl] or [XII] or a mixture thereof, which may be (partly) in the form of a acetal or hemi-acetal, can be further converted to compounds of formula [I] or [VIII]. This conversion entails cleavage of the hydroxyl protecting group Pi from the compound of formula [Xl] or [XII] or a mixture thereof, and cyclization to a cyclic acetal or hemi-acetal and optional (further) lactonization which latter two steps may optionally occur simultaneously in an alcohol solvent of the formula ROH, wherein R is as defined above. These reactions may be performed in many different sequences provided that the removal of the hydroxyl-protecting group P₁ precedes the cyclization to a cyclic acetal or hemi-acetal. Therefore, we can discern many different combinations, of which some are described below without being limited thereto.

In an embodiment of step ii) in the method according to the invention the Pi protecting group may be removed under non-acidic conditions, which may lead to the (partial) formation of a cyclic (hemi-) acetal and subsequently, the reaction mixture may be subjected to acidic conditions in the presence of an alcohol ROH, wherein R is as defined above, leading to (further) lactonization and simultaneous formation of the desired cyclic acetal or hemi-acetal.

In another embodiment of step ii) in the method according to the invention the Pi protecting group may be removed under non-acidic conditions, which may lead to the (partial) formation of a cyclic acetal or hemi-acetal and subsequently, the reaction mixture may be subjected to acidic conditions in the absence of an alcohol ROH, wherein R is as defined above, leading to (further) lactonization and (further) cyclic acetal or hemi-acetal formation and subsequently, the resulting cyclic acetal or hemi-acetal may be transformed to the desired acetal or hemi-acetal under acidic conditions in the presence of ROH.

In yet another embodiment of step ii) in the method according to the invention the P₁ protecting group may be removed under acidic conditions in the absence of an alcohol ROH and simultaneously lactonization and cyclic acetal or hemi- acetal formation may occur and subsequently, under acidic conditions in the presence of ROH, wherein R is as defined above, the resulting cyclic (hemi-acetal) may be transformed into the desired cyclic acetal or hemi-acetal.

In yet another embodiment of step ii) in the method according to the invention, which is the preferred embodiment, the Pi protecting group may be removed under acidic conditions in the presence of an alcohol ROH, wherein R is as defined above, and simultaneously lactonization may occur as well as formation of the desired cyclic acetal or hemi-acetal.

In yet another embodiment of step ii) in the method according to the invention - which may be effectuated if the Pi protecting group has no or little acid lability, acid labile being defined as cleavable by an acid under the chosen conditions, i.e. in the presence of this acid under the chosen conditions the free OH-group is formed - the (further) lactonization may be performed under acidic conditions. Subsequently, the P₁ protecting group may be removed and subsequently the desired cyclic acetal or hemi-acetal may be obtained upon cyclization under acidic conditions in the presence of ROH, wherein R is as defined above.

In yet another embodiment of step ii) in the method according to the invention - which may also be effectuated if the P₁ protecting group has no to little acid lability - the (further) lactonization may be performed under acidic conditions. Subsequently, the P₁ protecting group may be removed and subsequently a cyclization to a cyclic acetal or hemi-acetal may be effectuated under acidic conditions in the absence of ROH. Then, under acidic conditions and in the presence of ROH, wherein R is as defined above, the transformation of the first obtained cyclic acetal or hemi- acetal to the desired cyclic acetal or hemi-acetal may be effectuated.

In yet another embodiment of step ii) in the method according to the invention - which may also be effectuated if the P₁ protecting group has little acid lability - the (further) lactonization may be performed under acidic conditions. Subsequently, the P₁ protecting group may be removed under (strong) acidic conditions in the absence of ROH and simultaneously a cyclization to a cyclic acetal or hemi-acetal may occur. Then, under acidic conditions and in the presence of ROH, wherein R is as defined above, the transformation of the first obtained cyclic acetal or hemi-acetal to the desired cyclic acetal or hemi-acetal may be effectuated.

In yet another embodiment of step ii) in the method according to the invention - which may also be effectuated if the P₁ protecting group has little acid lability - the (further) lactonization may be performed under acidic conditions. Subsequently, the P₁ protecting group may be removed under (strong) acidic conditions in the presence of ROH, wherein R is as defined above, and simultaneously the desired cyclic acetal or hemi-acetal may be formed.

Removal of the Pi protecting group can be accomplished by any suitable method known to a person skilled in the art. For instance, if Pi is a benzyloxycarbonyl (Z) group, this can be removed for instance using hydrogenolysis with Pd/C and H₂. Preferably, Pi is acid labile so that the Pi deprotection, (further) lactonization and cyclic acetal or hemi-acetal formation may be performed simultaneously. It has been established that if the Pi deprotection, (further) lactonization, and cyclic acetal or hemi-acetal formation are performed simultaneously in the presence of an acid, the overall yield of the compounds of formula [I] or [VIII] is high. If the acid-mediated reactions are furthermore conducted in the presence of an alcohol ROH, wherein R is as defined above, the desired cyclic acetal or hemi-acetal may be formed directly. It has been established that if the P₁ deprotection, (further) lactonization, and cyclic acetal or hemi-acetal formation are performed simultaneously under acidic conditions in the presence of an alcohol ROH, the yield of the compounds of formula [I] or [VIII] is even higher.

It is advantageous when the R group in the formula ROH is identical to P₂. If the R group in the formula ROH and P₂ are not identical, part of the acetal in the resulting end product of the formula [I] or [VIII] may be based on the alcohol of the formula P₂OH and not, as desired, fully on the alcohol of formula ROH. In case the R group in the formula ROH and P₂ are not identical, it may therefore be advantageous to use a large excess of ROH in the cyclic acetal or hemi-acetal formation step. In case the R group in the formula ROH and P₂ are not identical it may alternatively be advantageous to promote lactonization during or after the aldol reaction step and subsequently remove the expelled alcohol P₂OH prior to the cyclic acetal or hemi- acetal formation step, for instance by distillation. Alternatively, the mixture of cyclic acetals or hemi-acetals may, as such or after isolation from the reaction mixture, be transformed into the desired cyclic acetal or hemi-acetal based on the alcohol of the formula ROH by reacting the mixture of cyclic acetals or hemi-acetals with an excess of the alcohol of the formula ROH under acidic conditions.

Preferably, the R of the formula ROH is a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group. If substituted, the alkyl, and aryl groups may be substituted with optionally protected, functional groups comprising one or more heteroatoms such as oxygen, sulphur and nitrogen. Additionally, the alkyl groups may be interrupted by one or more heteroatoms such as oxygen, sulphur and nitrogen, whereas the aryl groups may comprise within their ring system one or more heteroatoms such as oxygen, sulphur and nitrogen. More preferably, the R of the formula ROH is an alkyl group with 1-6 C-atoms or an aryl group with 1-14 C-atoms. Even more preferably R of the formula ROH is a substituted or unsubstituted alkyl group. Most preferably, the R of the formula ROH is methyl, since the resulting compound of formula [I] or [VIII] can then be efficiently purified by crystallization as will be described below.

The acid used for the lactonization and cyclic acetal or hemi-acetal formation reactions (and optionally also for the Pi deprotection), if any, may be any Brønsted acid, preferably an inorganic Brønsted acid like hydrochloric acid, sulfuric acid or phosphoric acid. Most preferably the inorganic Brønsted acid is sulfuric acid or hydrochloric acid. The amount of the acid is at least 0.01 molar equivalents based on the total amount of aldehydes, preferably it is at least 0.1 molar equivalents based on the total amount of aldehydes, and most preferably it is at least 0.25 molar equivalents based on the total amount of aldehydes. The upper limit of the amount of the acid used is at most 50 molar equivalents based on the total amount of aldehydes, preferably it is at most 10 molar equivalents based on the total amount of aldehydes, and most preferably it is at most 5 molar equivalents based on the total amount of aldehydes.

In the case that the Pi deprotection, lactonization and cyclic acetal or hemi-acetal formation reactions of step ii) are performed simultaneously under acidic conditions, the temperature is at least -40⁰C, more preferably at least -20⁰C and most preferably at least -10°C. As an upper limit the temperature is preferably at most 70⁰C, preferably at most 50⁰C and most preferably at most 30⁰C. In the case that the acid lability of the hydroxyl-protecting group Pi is low, and the Pi deprotection, lactonization and cyclic acetal or hemi-acetal formation are performed simultaneously, it may be advantageous to vary the temperature during the reaction. For instance, in the first stage of the reaction a high temperature may be applied to completely cleave the hydroxyl-protecting group Pi, and in the later stage of the reaction a lower temperature may be applied in order to increase the relative amount of the diastereomers which are represented by formula [XIII] or [XIV]. Increase of the relative amount of the diastereomers of formula [XIII] or [XIV] may be advantageous because in some cases (depending on the nature of the R group) these diastereomers have been found to be crystallizable. For instance, (3aS,4S,6a/?)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)- one (corresponding to the compound of formula [XIII] with R = Me) and its enantiomer (3aR,4/?,6aS)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one (corresponding to the compound of formula [XIV] with R = Me) can be efficiently purified by crystallization.

[XIII] [XIV]

The reaction times for the Pi deprotection, lactonization and cyclic acetal or hemi-acetal formation reactions are not critical and will be preferably chosen such that the yield of compounds of formula [I] or [VIII] is highest and/or in case the 4α-substituted diastereomer is crystallizable, the relative amount of the diastereomer of formula [XIII] or [XIV] is highest. 4α-Substituted diastereomers are the diastereomers of the formula [XIII] or [XIV]. 4β-Substituted diastereomers are the diastereomers with opposite 4-OR stereogeometry.

Isolation of the formed compound of formula [I] or [VIII] may be performed by methods known to the person skilled in the art. For instance, the reaction mixture may be concentrated by evaporation and the resulting product may subsequently be purified such as by chromatography or crystallization. Preferably, any excess of acid may be first neutralized by the addition of a base such as a tertiary amine, a hydroxide or an alkoxide, and then the product may be purified such as by chromatography or crystallization. Optionally, the formed salt after the addition of the base may be removed prior to the purification such as by chromatography or crystallization.

Alternatively, in a further embodiment of the invention, subsequent upgrading of the diastereomeric purity of the formed compounds of formula [I] and [VIII] may be performed using an aqueous work-up step. As indicated above, the diastereoselectivity of the aldol reaction is usually much lower than the enantioselectivity. Usually, the diastereomeric ratio is < 20:1 , meaning that without precautions a significant amount of the wrong diastereomer would end up in the final product of compound [I] or [VIII] and thus also building block [II] would be contaminated with the wrong diastereomer. It has now been found, as clarified in Scheme 2, that after the Pi deprotection, lactonization and cyclic acetal or hemi-acetal formation reactions, th e undesired diastereomer remains in one of the monocyclic structures of the formula [XV] or [XVI]. This might be due to the trans-configuration of the substituents on the tetrahydrofuran ring of formula [XV] or on the tetrahydrofuranone ring of formula [XVI]. As a result of the fact that the undesired diastereomers remain in the monocyclic form they are more polar than the fully cyclized diastereomers of the formulae 4α-[l] or 4β-[l] and they may therefore be removed by an aqueous work-up which is preferably extractive.

Scheme 2

Hence, for the isolation of compounds of formula [I] or [VIII], an aqueous work-up may be used to remove the undesired diastereomer and the organocatalyst. A base may be applied to neutralize the acid, used for the lactonization and cyclic acetal or hemi-acetal formation reactions (and optionally also for the P₁ deprotection) reaction, since acidic aqueous conditions - except for the case that R is a hydrogen atom - would cause hydrolysis of the acetal functionality in the compounds of formula [I] or [VIII] to the hemi-acetal congener, thus resulting in product loss. Therefore, isolation of compounds of formula [I] or [VIII] is preferably carried out by an aqueous alkaline quench reaction followed by extraction of compounds of formula [I] or [VIII] with a water-immiscible solvent. Water-immiscible solvents are the solvents that form a separate layer within 24 hours after having been mixed with water at the temperature at which the separation is desired to be performed. The undesired diastereomers of the formula [XV] and [XVI] and optionally the organocatalyst (such as for instance proline) predominantly remain in the aqueous phase. Even more preferably the aqueous alkaline quench reaction is conducted by adding the acidic mixture resulting from the deprotection, lactonization and (cyclic) acetal formation reactions to the alkaline aqueous solution.

Preferably, during the aqueous alkaline quench reaction the pH of the aqueous phase of the reaction mixture resulting from the aqueous alkaline quench reaction is kept between 2 and 9, more preferably between 3 and 8, most preferably between 3.5 and 7.5. Also advantageously, at the end of the aqueous alkaline quench reaction the pH is set between 3.5 and 6, preferably between 3.5 and 5, most preferably between 3.8 and 4.5. These pH ranges may be accomplished by the use of carbonates and bicarbonates as the base. Optionally, additional base or acid may be used to set the pH at a certain value at the end of the quench reaction. Within the preferred pH range, the alcohol of the formula ROH may be evaporated from the reaction mixture after the alkaline quench and before the extractions with solvent. Removal of the alcohol of the formula ROH before the extractions with solvent may have the advantage that the extraction efficiency of compounds of the formula [I] and [VIII] thus increases leading to higher yields.

Suitable water-immiscible solvents are for example any ester, hydrocarbon, ether, halogenated hydrocarbon, or aromatic solvent. These include, but are not limited to toluene, xylene(s), te/t-butyl methyl ether, dichloromethane, ethyl acetate, isopropyl acetate or isobutyl acetate. Preferably, ethyl acetate or toluene is used.

Furthermore, in yet another embodiment of the invention, subsequent upgrading of the diastereomeric purity and optionally also the enantiomeric purity of compounds of formula [I] and [VIII] may be performed using an aqueous work-up step followed by a crystallization step. To further isolate compounds of the formula [I] or [VIII] in pure form, it is advantageous to perform a crystallization. Surprisingly, it appeared that in some cases the 4α-diastereomers, which are usually more predominantly present than the 4β-diastereomers, may be crystallized from the extraction phase of the aqueous workup of the reaction mixtures of the Pi deprotection, lactonization and cyclic acetal or hemi-acetal formation steps. In case the 4α-diastereomers can be crystallized this can be done from an organic solvent or a mixture of an organic solvent with one or more other organic solvents and/or water. It may be attractive to use the same solvent for extraction as well as crystallization, but this is not required. For purification by crystallization of the compound [I] or [VIII] the R group of the compound of formula [I] or [VIII] is preferably not hydrogen. In case the R group of the compound of formula [I] or [VIII] is methyl, purification by crystallization of the compound [I] or [VIII] is particularly effective, since in that case almost exclusively the 4α-diastereomers crystallize with high enantiomeric (> 98% e.e.) and diastereomeric (> 95%) purity. Suitable solvents for the crystallization of these compounds, i.e. (3aS,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one or (3aR,4/?,6aS)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one include for example isopropanol, terf-amyl alcohol, terf-butanol, ethylacetate, methylisobutylketone, toluene and mixtures thereof. More preferably isopropanol, te/t-amyl alcohol, terf-butanol, toluene and mixtures thereof are used as they produce a high crystallization yield. Even more preferably isopropanol or terf-amyl alcohol are used, most preferably isopropanol.

To increase the yield of the 4α-diastereomers of compounds of formula [I] or [VIII] with R = CH₃, the corresponding 4β-diastereomers may be epimerized into the 4α-diastereomers using an acid, for instance an organic or inorganic acid, preferably in the absence of water and in the presence of methanol. Epimerization is preferably performed with MeSO₃H in methanol, or any comparable acid with a similar acidic strength. Preferably, the amount of MeSO₃H in methanol employed ranges between about 0.05 and about 1.5 equivalents, based on compounds of [I] or [VIII], more preferably between about 0.1 and about 0.3 equivalents. The temperature for carrying out the epimerization is preferably between 10⁰C and reflux temperature, preferably between 20⁰C and reflux temperature, even more preferably between 40⁰C and reflux temperature, most preferably at reflux temperature.

Several alternatives may exist to include an epimerization step of the 4β-diastereomers. In the first alternative, after obtaining a mixture of compound 4α-[l] and 4β-[l], the compound of formula 4α-[l] is crystallized and further converted to building block [II]. In a second alternative, after obtaining a mixture of compound 4α-[l] and 4β-[l], the compound of formula 4α-[l] is crystallized and the mother liquor, which contains a relatively large amount of the undesired 4β-[l], is subjected to epimerization to obtain a mixture with a relatively large amount of 4α-[l], and apply a second crystallization of 4α-[l]. In a third alternative, after obtaining a mixture of compound 4α- [I] and 4β-[l], the compound of formula 4α-[l] is crystallized and the mother liquor, containing a relatively large amount of the undesired 4β-[l] is subjected to a simultaneous crystallization of the 4α-[l] and epimerization of 4β-[l] to 4α-[l]. In a fourth and preferred alternative, after obtaining a mixture of compound 4α-[l] and 4β-[l], this mixture may be directly transformed in one step into (almost) 100% 4α-[l] in (almost) 100% yield, so without by-product formation, via a direct crystallization of 4α-[l] and simultaneous epimerization of 4β-[l] to 4α-[l]. This alternative is preferable since only one step is needed for the transformation of the mixture of 4α-[l] and 4β-[l] to solely 4α-[l] which has lower production costs and since only one batch of 4α-[l] is obtained with homogeneous quality.

Furthermore, the present invention relates to a method for further conversion of compounds of formula [I] obtained according to the invention into the building block of formula [II] by reduction, for instance with LiBH₄, followed by acid- catalyzed cyclization preferably in a one-pot process, as disclosed by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920 (see also EP 1448567 A1 or WO 2005/095410 A1 ). This building block of formula [II] can then be further converted into TMC114 of formula [III] using a mixed carbonate of compound [II] as described by Ghosh et al. in J. Med. Chem. 1996, 39, 3278 in Scheme 7 on page 3280 column 2, which reaction sequence is incorporated herein by reference.

The invention is now illustrated by way of the following examples, without however being limited thereto. The invention also relates to the process according to all possible combinations of the process according to the invention and one or more of the preferred embodiments, features and ranges as described herein above.

EXAMPLES Materials and methods Solvents and reagents were used as received without further purification. Terf-butyldimethylsilyloxy-acetaldehyde ([IX], with P₁ = Tert- butyldimethylsilyl (TBDMS)) was purchased from Aldrich and distilled under reduced pressure prior to use in order to remove the trimeric form of the aldehyde. 4- Oxobutanoic acid methylester was purchased from Aldrich and used as received. ¹H and ¹³C NMR spectra were recorded at 300 MHz and 75 MHz, respectively, in CDCI₃ or DMSO-CZ₆ on a Bruker Avance Ultrashield™ 300 NMR spectrometer. Quantitative ¹H NMR spectroscopy was performed using p-nitrotoluene as internal standard. The course of reactions was monitored by ¹H NMR, TLC or GC.

The enantiomeric excess (e.e.) of (3aS,4S,6a/?)-4-methoxy- tetrahydro-furo[3,4-b]furan-2(3H)-one compound of formula [I] (R= CH₃) was determined by GC using an Agilent 6890 GC (EPC) and a Betadex 120 column of 60 m and an internal diameter of 0.25 mm and with a film thickness of 0.25 μm using a column head pressure of 195 kPa, a column flow of 1.0 mL/min, a split flow of 50 mL/min and an injection temperature of 200 ⁰C. The used ramp was: initial temperature 150 ⁰C (40 min), rate 20 °C/min, final temperature 220 ⁰C (6 min). Detection was performed with an FID detector at a temperature of 250 ⁰C. The retention times were as follows: (3aR,4R,6aS)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one 26.4 min, (3aS,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one 27.0 min. Racemic material was prepared according to the procedure as reported by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920.

Example 1. Synthesis of acetoxy-acetaldehvde ([IXI, Pi = Ac)

NMO cat. K₂OsO₄. H₂O

To a stirred solution of 20.5 ml. (0.25 mol) but-2-ene-1 ,4-diol and 105 ml. (0.75 mol) triethylamine in 400 ml. tetrahydrofuran (THF) was added 60 ml. (0.63 mol) acetic anhydride at ambient temperature. After 16 h stirring, 300 ml. saturated aqueous sodium bicarbonate solution and 300 ml. diethylether were added. The aqueous layer was extracted with 200 ml. diethylether and the combined organic phase was washed with 300 ml. brine, dried (Na₂SO₄) and concentrated in vacuo. The resulting residue was purified by vacuum distillation (3 mbar, 80-82⁰C) to give 39.3 g of 1 ,4-diacetoxybut-2-ene, corresponding to a yield of 91 % based on but-2-ene-1 ,4-diol. To a stirred solution of 17.2 g of 1 ,4-diacetoxybut-2-ene (100 mmol) in a mixture of 150 ml. acetone and 50 ml. water were added 26 g N-methylmorpholine-N-oxide (NMO, 200 mmol) and 270 mg K₂OsO₄-H₂O (0.75 mmol) at ambient temperature. After 3 h stirring, TLC showed complete conversion of the diacetate and 300 ml. saturated aqueous sodium hydrogen sulfite solution and 300 ml. ethylacetate were added. The aqueous layer was extracted with 600 ml. ethylacetate and the combined organic phase was washed with 400 ml. brine, dried (Na₂SO₄) and concentrated in vacuo to give 18.5 g of the diol as white crystals, corresponding to a yield of 90% yield based on 1 ,4-diacetoxybut-2-ene. To a stirred solution of 8.2 g diol (40 mmol) in 150 mL dichloromethane was added 80 g sodium periodate on silica (55 mmol) at ambient temperature. After VA h stirring, TLC showed complete conversion. The silica was removed by filtration and rinsed with 100 mL dichloromethane. The combined filtrate was concentrated in vacuo and the residue purified by distillation to give 4.1 g of the aldehyde, corresponding to 50% yield based on the diol. ¹H NMR (CDCI₃): δ 9.62 (s, 1 H), 4.68 (s, 2H), 2.20 (s, 3H). ¹³C NMR (CDCI₃): δ 196.0, 173.1 , 69.0, 20.7.

Example 2. Synthesis of benzoyloxy-acetaldehvde ([IXl, Pi = Bz)

NMO cat K₂OsO₄ H₂O

To a stirred solution of 20.5 mL (0.25 mol) but-2-ene-1 ,4-diol and 105 mL (0.75 mol) triethylamine in 500 mL THF was added 72.6 mL (0.625 mol) benzoyl chloride at ambient temperature. After 4V_- h stirring at ambient temperature, the reaction mixture was partitioned between 300 mL saturated aqueous NaHCO₃ solution and 300 mL diethylether. The aqueous layer was extracted with 2 x 200 mL diethylether and the combined organic phase was washed with 300 mL brine, dried (Na₂SO₄) and concentrated in vacuo giving 51.7 g 1 ,4-dibenzoyloxybut-2-ene as white crystals, corresponding to a yield of 70% based on but-2-ene-1 ,4-diol. ¹H NMR (CDCI3): δ 8.05-8.08 (m, 2H), 7.57 (dt, J = 1.2, 7.5 Hz, 1 H), 7.42-7.47 (m, 2H), 5.97 (t, J = 4.7 Hz, 2H), 5.02 (d, J = 4.7 Hz, 4H). To a stirred solution of 29.6 g (100 mmol) 1 ,4-dibenzoyloxybut-2-ene in a mixture of 210 ml. acetone and 70 ml. water were added 25.8 g N- methylmorpholine-N-oxide (NMO, 220 mmol) and 270 mg K₂OsO₄-H₂O (0.75 mmol) at ambient temperature. After 5 h stirring at ambient temperature, the reaction mixture was partitioned between 300 ml. saturated aqueous sodium bisulfite solution and 300 ml. ethyl acetate. The aqueous layer was extracted with 3 x 300 ml. ethylacetate and the combined organic phase was washed with 300 ml. brine, dried (Na₂SO₄) and concentrated in vacuo to give 32.0 g of 1 ,4-dibenzoyl-erithritol as a white powder, corresponding to a yield of 97% based on 1 ,4-dibenzoyloxybut-2-ene. ¹H NMR (CDCI₃): δ 8.01-7.95 (m, 2H), 7.52 (dt, J = 1.2, 7.5 Hz, 1 H), 7.36-7.41 (m, 2H), 4.57 (bs, 4H), 3.93 (bs, 2H), 2.68 (bs, 2H).

To a stirred suspension of 1.65 g (5 mmol) of 1 ,4-dibenzoylerithritol in 60 ml. dichloromethane was added 10 g sodium periodate on silica gel at ambient temperature. After 21 h stirring at ambient temperature, the periodate on silica gel was removed by filtration and rinsed with 20 ml. dichloromethane. The combined filtrate was concentrated in vacuo giving 1.48 g of benzoyloxy-acetaldehyde as a colorless liquid, corresponding to 90% yield based on 1 ,4-dibenzoyl-erythritol. ¹H NMR (CDCI₃): δ 9.74 (s, 1 H), 8.12 (d, J = 8.7 Hz, 2H), 7.60 (t, J = 8.7 Hz, 1 H), 7.49 (t, J = 8.7 Hz, 2H), 4.91 (s, 2H).

Example 3. Synthesis of p-methoxybenzyloxy-acetaldehyde ([IXI, P^= PMB)

To a stirred suspension of 14.0 g (125 mmol) potassium te/t-butoxide in 75 ml. THF were added, under nitrogen, 4.2 ml. (50 mmol) but-2-ene-1 ,4-diol. After 5 h stirring at ambient temperature, 17.0 ml. p-methoxybenzylchloride and a catalytic amount of tetrabutylammonium iodide were added. After 64 h stirring at 5O⁰C, the reaction mixture was partitioned between 150 ml. saturated aqueous NaHCO₃ solution and 150 ml. diethylether. The aqueous layer was extracted with 2 x 150 ml_ diethylether and the combined organic phase was washed with 150 ml. brine, dried (Na₂SO₄) and concentrated in vacuo giving 17.0 g 1 ,4-di-p-methoxybenzyloxy-but-2- ene as a colorless oil. ¹H NMR (CDCI₃): δ 7.26 (d, J = 8.9 Hz, 4H), 6.89 (d, J = 8.9 Hz, 4H), 5.78 (t, J = 4.7 Hz, 2H), 4.43 (s, 4H), 4.04 (d, J = 4.7 Hz, 4H), 3.82 (s, 6H).

NMO cat K₂OsO₄ H₂O

To a stirred solution of 17.0 g (50 mmol) 1 ,4-di-p-methoxybenzyloxy- but-2-ene in a mixture of 120 ml. acetone and 40 ml. water were added 13.0 g

N-methylmorpholine-N-oxide (NMO, 110 mmol) and 129 mg K₂OsO₄-H₂O (0.35 mmol) at ambient temperature. After 5 h stirring at ambient temperature, the reaction mixture was partitioned between 200 ml. saturated aqueous sodium bisulfite solution and 200 ml. ethylacetate. The aqueous layer was extracted with 3 x 200 ml. ethylacetate and the combined organic phase was washed with 200 ml. brine, dried (Na₂SO₄) and concentrated in vacuo to give 19.0 g 1 ,4-di-p-methoxybenzyl-erythritol as a white powder, corresponding to a yield of 100% based on 1 ,4-di-p-methoxybenzyloxy-but-2- ene. ¹H NMR (CDCI₃): δ 7.26 (d, J = 8.9 Hz, 4H), 6.89 (d, J = 8.9 Hz, 4H), 4.48 (s, 4H), 3.81 (s, 6H), 3.80 (bs, 2H), 3.62 (bs, 4H), 2.68 (bs, 2H). To a stirred suspension of 18.0 g (50 mmol) 1 ,4-di-p-methoxybenzyl- erythritol in 250 ml. dichloromethane were added 10O g sodium periodate on silica gel at ambient temperature. After 4 h stirring at ambient temperature the periodate on silica gel was removed by filtration and rinsed with 50 ml. dichloromethane. The combined filtrate and wash layer was concentrated in vacuo giving 13.7 g p-methoxybenzyloxy- acetaldehyde as a colorless liquid, corresponding to 76% yield based on 1 ,4-di-p- methoxybenzyl-erythritol. ¹H NMR (CDCI₃): δ 9.63 (s, 1 H), 7.22 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 4.49 (s, 2H), 4.00 (s, 2H), 3.74 (s, 3H).

Example 4. Aldol reaction between aldehydes [IXl (Pi_= Ac) and [Xl (P? = Me) with riXl:rXl = 1 :1 A mixture of 23 mg L-proline (0.2 mmol), 204 mg (2.0 mmol) acetoxy- acetaldehyde ([IX], Pi = Ac), 232 mg 4-oxobutanoic acid methylester (2.0 mmol) and 5 ml. dry THF was stirred for 22 h in a closed flask at 20⁰C. The reaction mixture was partitioned

cat. L-Pro THF

between 20 ml. saturated aqueous NaHCO₃ and 20 ml. ethylacetate. The aqueous phase was extracted with 2 x 20 ml. ethylacetate and the combined organic phase was washed with 20 ml. brine, dried (Na₂SO₄) and concentrated in vacuo giving a residue which was purified by flash chromatography over silica gel using n-heptane/ethyl acetate (2/3, v/v) as the eluent. This gave 180 mg of a pure 1 :1 mixture of the two {R,Sy and (S,S)-isomers of the Aldol product of formula [Xl] (Pi = Ac, P₂ = Me) corresponding to an overall yield of 41 % based on the starting aldehydes.

Example 5. Aldol reaction between aldehydes [IXI (Pi_= Bz) and [XI (P? = Me) with riXl:rXl = 1 :1

cat L-Pro THF

A mixture of 23 mg L-proline (0.2 mmol), 328 mg (2.0 mmol) benzoyloxy-acetaldehyde ([IX], P₁ = Bz), 232 mg 4-oxobutanoic acid methylester (2.0 mmol) and 5 mL dry THF was stirred for 64 h in a closed flask at 20⁰C. The reaction mixture was partitioned between 20 mL saturated aqueous NaHCOs and 20 mL ethylacetate. The aqueous phase was extracted with 2 x 20 mL ethylacetate and the combined organic phase was washed with 20 mL brine, dried (Na₂SO₄) and concentrated in vacuo giving a residue which was purified by flash chromatography over silica gel using n-heptane/ethyl acetate (3/2, v/v) as the eluent. This gave 240 mg of a 2:1 mixture of the two {R,S)- and (S,S)-isomers of the Aldol product of formula [Xl] (P₁ = Bz, P₂ = Me) corresponding to an overall yield of 43% based on the starting aldehydes.

Example 6. Synthesis of (3aS,6a/?)-4-methoxy-tetrahvdro-furo[3,4-b1furan-2(3H)-one (Ml. R = Me) using aldehydes NXl (Pi = TBDMS) and [Xl (P? = Me) with NXUXl = 1 :1.5

cat L- Pro THF

major

H₂SO₄, MeOH

A mixture of 345 mg L-proline (3.0 mmol), 4.36 g (25.0 mmol) tert- butyldimethylsilyloxy-acetaldehyde ([IX], Pi = TBDMS), 4.35 g 4-oxobutanoic acid methylester (37.5 mmol) and 30 mL THF was stirred for 16 h in a closed flask at 20⁰C. Then, 50 mL methanol was added and the mixture was concentrated in vacuo. The volatiles were further removed by coevaporation with 2 x 50 mL methanol. ¹H NMR spectroscopy showed that the R, S- and S,S-isomers of the Aldol product with formula [Xl] (P₁ = TBDMS, P ₂ = Me) were present as the main products in a ratio of 3:1. The crude product was taken up in 50 mL methanol, cooled to O⁰C and 2.0 mL (37.5 mmol) sulfuric acid was added. After stirring at O⁰C for 3 h the reaction mixture was, slowly and under vigorous stirring, poured into a solution of 7.6 g KHCO₃ in 50 mL water. The slightly alkaline solution was acidified to pH = 4 with 10 wt% aqueous sulfuric acid. The salts were removed by filtration and rinsed with 100 mL ethyl acetate. The methanol was removed from the filtrate by evaporation in vacuo and the resulting aqueous phase was extracted with 5 x 100 mL ethylacetate. The combined extracts and wash layer were dried (Na₂SO₄) and concentrated in vacuo giving a residue. According to quantitative ¹H NMR spectroscopy this contained 0.80 g of (3aS,4S,6aR)-4-methoxy- tetrahydro-furo[3,4-b]furan-2(3H)-one as the main compound and (3aS,4/?,6a/?)-4- methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one as the minor compound, corresponding to an overall crude yield of 20% based on te/t-butyldimethylsilyloxy-acetaldehyde ([IX], P₁ = TBDMS). It is of interest to note that the corresponding (3aS,6aS)-isomers were not detected in the end product, which means that the diastereomeric purity has clearly improved as compared to before the aqueous work-up. The NMR data were all in line with the ones reported by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920. GC indicated that the e.e. of the (3aS,4S,6a/?)-isomer was > 98%.

Example 7. Synthesis of (3aS,4S,6a/?)-4-methoxy-tetrahvdro-furo[3,4-b1furan-2(3H)- one (Ml. R = Me) using aldehydes [IXl (P₁= TBDMS) and [Xl (P₂ = Me) with NXl=FXl = 2:1

cat L-Pro THF

major

1 aqueous work-up

2 crystallization

(3aS,4S,6aR)- (3aS,4R,6aR)- (3aS,6aS)-ιsomers (3aS,4S,6aR)- ^lsomer isomer (minor) isomer

(major) _(mlnor) (pure)

A mixture of 0.63 g L-proline (5.47 mmol), 9.53 g (54.7 mmol) tert- butyldimethylsilyloxy-acetaldehyde ([IX], P₁ = TBDMS), 3.18 g 4-oxobutanoic acid methylester (27.4 mmol) and 43 ml. THF was stirred for 94 h in a closed flask at 4°C. Then, a 1.25 M HCI solution in methanol (66 ml.) was added and the reaction mixture was stirred for another 22 h at 4°C and subsequently poured slowly under vigorous stirring into a solution of 15.2 g KHCO₃ in 100 ml. water at ambient temperature. The resulting slurry was acidified to pH 4 with 10 wt% aqueous sulfuric acid. The salts were removed by filtration and rinsed with 200 ml. ethylacetate. THF and methanol were removed from the aqueous filtrate by evaporation in vacuo and the resulting aqueous phase was extracted with 4 x 200 ml. ethylacetate. The combined extracts and wash layer were dried (MgSO₄) and concentrated in vacuo giving a yellow oil containing 3.68 g of (3aS,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one as the main compound as determined by quantitative ¹H NMR spectroscopy, corresponding to a yield of 52% based on te/t-butyldimethylsilyloxy-acetaldehyde ([IX], Pi = TBDMS). Besides this main (3aS,4S,6aR)-isomer, also a minor amount of the (3aS,4/?,6aR)- isomer was present in the mixture as well as minor amounts of the (3aS,6aS)- and (3a/?,6a/?)-isomers (in the lactone-opened form).

Subsequently, the oil was seeded with a crystal of (3aS,4S,6aR)-4- methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one (as prepared according to the method reported by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920). This resulted in crystallization which was allowed to proceed overnight at 4 ⁰C. Subsequently, 200 ml_ n-pentane was added and the suspension stirred for 1 Y₂ h at 3O⁰C and at 4⁰C overnight. After decanting the n-pentane the (3aS,4S,6a/?)-4-methoxy-tetrahydro- furo[3,4-b]furan-2(3H)-one was recrystallized from methyl-terf-butylether/n-pentane (20 ml_, 1/1 , v/v). To the resulting yellow sticky solid was added isopropanol (1.5 ml.) turning it into a white crystalline solid which was isolated by filtration yielding 1.2 g of stereoisomerically pure (3aS,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one with a chemical purity of 92% as determined by quantitative ¹H NMR spectroscopy. This corresponds to an overall yield of 26% based on terf-butyldimethylsilyloxy- acetaldehyde ([IX], P₁ = TBDMS). GC indicated that the e.e. was > 98%. All physical data were in line with the ones reported by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920.

Example 8. Synthesis of (3aS,6a/?)-4-methoxy-tetrahvdro-furo[3,4-b1furan-2(3l-0-one (Ml. R = Me) using aldehydes NXl (P₁= PMB) and [Xl (P₂ = Me) with riX1:fXl = 1 :1.5

A mixture of 345 mg L-proline (3.0 mmol), 4.51 g (25.0 mmol) p- methoxybenzyloxy-acetaldehyde ([IX], Pi = PMB), 4.35 g 4-oxobutanoic acid methylester (37.5 mmol)

cat L-Pro THF

major

H₂SO₄/ MeOH

(3aS,4S,6aR)- isomer

(major)

and 30 ml. THF were stirred for 16 h in a closed flask at 20⁰C. Then, 50 ml. methanol was added and the mixture was concentrated in vacuo. The volatiles were further removed by coevaporation with 2 x 50 ml. methanol. ¹H NMR spectroscopy showed that the R,S- and S,S-isomers of the Aldol product with formula [Xl] (Pi = PMB, P₂ = Me) were present as the main products in a ratio of 2.5:1. To a solution of the crude product in 50 ml. methanol was added 5.3 ml. (0.10 mol) sulfuric acid and the mixture was stirred at 2O⁰C for 3 h and subsequently, slowly and under vigorous stirring, poured into a solution of 20 g KHCO3 in 80 ml. water. The slightly alkaline solution was acidified to pH = 4 with 10 wt% aqueous sulfuric acid. The salts were removed by filtration and rinsed with 150 ml. ethyl acetate. The methanol was removed from the filtrate by evaporation in vacuo and the resulting aqueous phase was extracted with 5 x 150 ml. ethylacetate. The combined extracts and wash layer were dried (Na₂SO₄) and concentrated in vacuo giving a residue. According to quantitative ¹H NMR spectroscopy this contained 0.71 g of (3aS,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one as the main compound and (3aS,4/?,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)- one as the minor compound, corresponding to an overall crude yield of 18% based on p-methoxybenzyloxy-acetaldehyde ([IX], P₁ = PMB). The NMR data were in line with the ones reported by Quaedflieg et al. in Org. Lett. 2005, 7(26), 5917-5920. GC indicated that the e.e. of the (3aS,4S,6a/?)-isomer was > 98%.

Claims

Method for the synthesis of compounds of a 4-alkoxy, 4-hydroxy or 4-aryloxy- substituted (3aS,6a/?)-tetrahydro-furo[3,4-b]furan-2(3H)-one of the formula [I] or a 4-alkoxy, 4-hydroxy or 4-aryloxy-substituted (3aR,6aS)-tetrahydro-furo[3,4- b]furan-2(3H)-one of the formula [VIII], wherein R represents a hydrogen or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl

group or an unsubstituted aryl group, by i) an aldol reaction in the presence of a catalyst of a hydroxyl-protected hydroxy-acetaldehyde of the general formula

[IX] and 4-oxo-butanoic acid or a 4-oxo-butanoic acid ester of the general formula [X], respectively, wherein P₁ represents a hydroxyl-protecting group

and P₂ represents a hydrogen atom or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group, giving an aldol product of formula [Xl], which may spontaneously (partially) lactonize to a product of formula [XII],

followed by ii) cleavage of the hydroxyl protecting group P₁ from the compound of formula [Xl] or [XII] or a mixture thereof, and cyclization to a cyclic acetal or hemi-acetal and optional (further) lactonization, which latter two steps may optionally occur simultaneously, in an alcohol solvent of the formula ROH, wherein R represents a hydrogen or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group.

2. Method according to claim 1 , wherein step ii) is followed by subsequent isolation of the compound of formula [I] or [VIII].

3. Method according to claim 2, wherein the isolation follows a preceding upgrading of the diastereomeric purity of the resulting compound of formula [I] or [VIII] using an aqueous work-up step comprising an aqueous alkaline quench reaction.

4. Method according to claim 2, wherein the isolation follows a preceding upgrading of the diastereomeric purity and optionally also the enantiomeric purity of the resulting compounds of formula [I] or [VIII] using an aqueous work-up step followed by a crystallization step.

5. Method according to any one of claims 1-4, wherein the catalyst is an organocatalyst.

6. Method according to claim 5, wherein the catalyst is a chiral amine which is L- proline or D-proline.

7. Method according to any one of claims 1-6, wherein P₁ is an acid labile hydroxyl-protecting group.

8. Method according to claim 7, wherein P₁ is an acid labile hydroxyl-protecting silyl group.

9. Method according to claim 8, wherein P₁ is a terf-butyldimethylsilyl group.

10. Method according to any one of claims 1-9, wherein P₂ is a methyl group.

1 1. Method according to any one of claims 1-10, wherein R is a substituted or unsubstituted alkyl group.

12. Method according to claim 1 1 , wherein R is a methyl group.

13. Method according to any one of claims 1-12 wherein both P₂ and R are a methyl group.

14. Method according to any one of claims 1-13, wherein the ratio of aldehydes with the formulae [IX] and [X], respectively, is between 1 :1 and 5:1.

15. Method according to any one of claims 1-14, wherein the temperature of the aldol reaction is between -1 O⁰C and 3O⁰C.

16. Method according to any one of claims 1-15, wherein the aldol reaction is performed in tetrahydrofuran.

17. Method according to any one of claims 1-16, wherein the removal of the P₁ group, the lactonization and the cyclization are performed simultaneously in the presence of an acid.

18. Method according to claim 17, wherein the acid is an inorganic Brønsted acid.

19. Method according to claim 18, wherein the inorganic Brønsted acid is hydrochloric acid or sulfuric acid.

20. Method according to any one of claims 3-19 comprising an aqueous work-up step, wherein the aqueous work-up step comprises an extraction of compounds [I] and/or [VIII] with a water-immiscible solvent from a reaction mixture resulting from an aqueous alkaline quench reaction.

21. Method according to claim 20 wherein the pH of the aqueous phase of the reaction mixture resulting from the aqueous alkaline quench reaction at the end of the aqueous alkaline quench reaction is between 3.5 and 6.

22. Method according to any one of claims 4-21 comprising a crystallization step, wherein the crystallization is performed from an organic solvent or a mixture of organic solvents.

23. Method according to claim 22, wherein the crystallization is performed from isopropanol, te/t-amyl alcohol, te/t-butanol or toluene or mixtures thereof.

24. Compounds according to formulae [Xl] and [XII] wherein P₁ represents a

[Xl] [XII] hydroxyl-protecting group and wherein P₂ represents a hydrogen atom or a substituted alkyl group or an unsubstituted alkyl group or a substituted aryl group or an unsubstituted aryl group.

25. Use of the compounds of formulae [Xl] and/or [XII] according to claim 24 in the synthesis of compounds of formulae [I] and/or [VIII].

26. Use of the compounds of formulae [Xl] and/or [XII] according to claim 24 in the synthesis of the compound of formula [III].

27. Method in which compounds of formula [I] obtained according to any one of claims 1-23 are converted by reduction.

28. Method according to claim 27, characterized in that the reduction is carried out with LiBH₄.

29. Method according to claim 28, characterized in that the reduction is followed by acid-catalyzed cyclization, preferably in a one-pot process.

30. Method according to claim 29, characterized in that the compound of formula [II] is synthesized.

31. Method according to claim 30, characterized in that the compound of formula

[II] is converted to a mixed carbonate.

32. Method according to claim 31 , characterized in that further conversion using a mixed carbonate of the compound of formula [II] is carried out.

33. Method according to claim 32, characterized in that the compound of formula

[III] is synthesized.