WO2015051903A1

WO2015051903A1 - A novel process for the preparation of chiral cyclopentanone intermediates

Info

Publication number: WO2015051903A1
Application number: PCT/EP2014/002711
Authority: WO
Inventors: V. Theocharis Koftis; Efstratios Neokosmidis; Efi Gioti; Stefanos KOTOULAS; Theodoros TSATSAS; Aristotelis Menisiou; Thanos Andreou; Anastasia-Aikaterini Varvogli
Original assignee: Pharmathen SA
Current assignee: Pharmathen SA
Priority date: 2013-10-08
Filing date: 2014-10-06
Publication date: 2015-04-16
Anticipated expiration: 2016-04-08

Abstract

The present invention relates to a process for the preparation of chiral cyclopentanone derivatives, using easily accessible starting materials.

Description

A NOVEL PROCESS FOR THE PREPARATION OF CHIRAL CYCLOPENTANONE INTERMEDIATES

TECHNICAL FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

The cyclopentane core is frequently present in a series of biologically active and pharmaceutically interesting compounds. The observed substitution patterns of this core, and the resulting stereochemical configuration, grant each of these compounds significant structural and chemical complexity. Their challenging preparation has inspired synthetic efforts since the late 70s, in a field of organic chemistry eventually termed "carba-sugar synthesis".

There are numerous examples in the scientific literature which demonstrate the use of cyclopentane-core intermediates in the synthesis of organic molecules with significant biological interest.

Prostaglandins, for example, are an interesting class of compounds characterized by their optically active cyclopentane core. Prostaglandin derivatives are utilized in a wide range of clinical uses. A few examples involve induction of labor (dinoprostone), prevention and treatment of ulcer (misoprostol), pulmonary hypertension (epoprostenol), glaucoma treatment (bimatoprost).

As a consequence, they have been a popular synthetic target, since the early 80s. The scheme below shows the preparation of natural prostaglandin PGEi from an achiral diketocyclopentene {Tetrahedron Letters 1983, 24, 4103). The optically active carbon of the cyclopentane moiety is created with the aid of asymmetric reductive reagent

BINAL.

PGE1

A very common starting material for prostaglandin synthesis is the Corey lactone diol. In WO2006112742A2, latanoprost is prepared from a suitably protected Corey lactone derivative.

0₂Ph

Apart from prostaglandin derivatives, the cyclopentane core is found in other pharmaceuticals, such as entecavir (treatment for hepatitis B). Corey's lactone may again be used as a precursor of the functionalized cyclopentane core. In WO2012006964A1, entecavir is prepared according to the following scheme.

In Tetrahedron Letters 2012, 53, 502 entecavir is synthesized from optically inactive 1 ,3-propanediol. Chirality is introduced with the aid of a Sharpless asymmetric epoxidation.

EtOOC 1. DIBALH

OH OH OPMB 2. Sharpless

Mitsunobu

reaction cone. HCI

entecavir

TBSd NH₂

In patent application WO2010074534A2 entecavir is synthesized form a cyclopentenone starting material. Chirality, in this case, is introduced with the use of (R)-methyl-CBS-oxaz0borolidihe catalyst, in the first step of the process. The other two stereocenters are formed once more with the use of an optically active reagent, diisopinocampheylborane (Ipc₂BH). The overall process is shown in the below scheme.

i) p-TsOH

ii) TBAF

iii) 2N HCI entecavir

In all the above examples, the issue of multifunctionalization and introduction of chirality to the cyclopentane core is dealt with the use of highly elaborate reagents and conditions. Some of these methodologies significantly hamper the cost-efficiency of the manufacturing process, whereas others involve dangerous or toxic chemicals.

It is therefore an object of the present invention to provide a method for the preparation of chiral multifunctionalized cyclopentane precursors. These precursors would then give access to compounds such as entecavir or prostaglandins, such as PGF_2a. Non-limiting examples of PGF_2a are latanoprost, bimatoprost, travoprost, carboprost. SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation of chiral multi- functionalized cyclopentanone derivatives. These compounds are useful building blocks for the synthesis of compounds, which consist of an optically active cyclopentane core and are biologically active molecules.

The invention provides a process for the preparation of compound of formula III or its enantiomer and comprises of the following key steps: a) intramolecular cycloaddition (INOC reaction) of compound of formula A or its enantiomer, to form compound of formula B or its enantiomer,

wherein Ri is selected from hydrogen or a hydroxyl protecting group and R₂ represents a hydroxyl protecting group, or R_! and R₂ are taken together to form a cyclic hydroxyl protecting group; b) optional protection of the free hydroxyl group, when Ri is hydrogen, and ring opening (isoxazoline ring opening), to form compound of formula C or its enantiomer;

c) protection of the primary hydroxyl group of compound of formula C or its enantiomer and optional protection of the secondary hydroxyl group, when R\ is hydrogen, to form compound of formula III or its enantiomer;

, wherein R₃ and R4 represent a hydroxyl protecting group or R₃ and R4 are taken together to form a cyclic hydroxyl protecting group.

The process described above provides also compounds of formulae A, B and C.

DEFINITIONS

The term "hydroxyl protecting group" refers to protecting groups known in the art and exemplified such as in Greene's Protective Groups on Organic Synthesis 4^th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541. Preferred hydroxyl protecting groups are alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates. More preferred hydroxyl protecting groups are allyl (All), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), 2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl (THP), 2,4- dinitrobenzyl, diphenylmethyl (DPM), trityl (Tr), p-methoxyphenyldiphenylmethyl (MMTr), benzyl (Bn), naphthyl (NAP), p-methoxybenzyl (PMB), p-nitrobenzyl, formyl, acyl (Ac), chloroacyl, methoxyacyl, pivaloyl (Piv), benzoyl (Bz), p- nitrobenzoyl, p-phenylbenzoyl, p-methoxybenzoyl, p-bromobenzoyl, trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPDMS), triisopropylsilyl (TIPS) tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyldiphenylsilyl, thexyldimethylsilyl (TDS), methyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), allyl carbonate (Alloc), 9-(Fluoromethyl) carbonate (Fmoc), benzyl carbonate (Cbz), t-butyl carbonate (Boc), sulfate, allylsulfonate, methanesulfonate, benzylsulfonate, tosylate.

The term "cyclic hydroxyl-protecting group" refers, also, to protecting groups exemplified in the textbook mentioned above. Preferred cyclic hydroxyl protecting groups are cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic carbonate, silyl derivatives. More preferred cyclic hydroxyl-protecting group are ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p-methoxybenzylidene, naphthylidene, 4-phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, l,3-(l,l,3,3-tetraisopropyl)disiloxanediyl (TIPDS - Markiewicz), di-tert- butylsilylenediyl (DTBS). DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a novel process for the preparation of trisubstituted cyclopentanones of Formula III and its enantiomer (ent-IU) starting from oximes of Formula A and ent-A, respectively.

ent-A ent- ent-C enf-lll

They key features of this novel process are the intramolecular nitrile oxide-olefin cycloaddition (INOC) reaction (step a) and the cleavage of the resulting 2-isoxazoline ring (step b).

Step a: The INOC reaction

The first step of the process is an intramolecular 1,3-dipolar cycloaddition reaction between a dipolarophile and a nitrile oxide. The nitrile oxide reactive species may be prepared in situ from the previously undisclosed oximes of Formula A, directly or through the hydroximoyl chloride intermediates, then performs an intramolecular 1,3- dipolar cycloaddition with the terminal alkene dipolarophile to form a fused 2- isoxazoline compound of Formula B.

The experimental conditions for the INOC transformation have been extensively studied in the relevant literature and a recent review (Curr. Org. Synth. 2011, 8, 628) provides further insight on the potential of the INOC reaction as a carbon-carbon bond-forming methodology. Typical conditions described include reagent combinations such as, among others, N-chloro-succinimide (NCS), sodium hypochlorite (NaOCl), t-butoxy iodide {in situ 'BuOI), (diacetoxyiodo)benzene (PhI(OAc)₂), 1-chlorobenzotriazole, Chloramine-T, bromous acid sodium salt (NaBr0₂) with tributyltin chloride/dibutyltin dichloride/trimethylsilyl chloride (Bu₃SnCl/Bu₂SnCl₂/TMSCl), bis(tributyltin) oxide [(BU_jSn^O] with t-butoxy chloride/N-chloro-succinimide/N-bromo-succinimide ('BuOCl/ NCS/NBS), potassium or sodium fluoride (KF or NaF), silver acetate (AgOAc), butyl lithium (BuLi), ethylmagnesium bromide (EtMgBr), diethyl zinc (Et₂Zn). Most suitable conditions are the ones using N-chloro-succinimide, sodium hypochlorite and Chloramine-T.

The undesired oximolactone formation, observed when R, is hydrogen, may be controlled by a buffered acidic medium using, for example, silica gel as additive. The experimental conditions, such as reaction solvent, order of addition, reaction time and temperature, and reagent equivalents, may be optimized to enhance the conversion, the yield and the diastereoselectivity of the transformation.

Step b: 2-isoxazoline ring opening

The robust chemistry of the INOC and the variety of structural complexity which may derive from the 2-isoxazoline moiety, have inspired numerous approaches for the cleavage of this ring. As summarized in Curr. Org. Synth. 2011, 8, 659, the respective jS-hydroxy-ketones may be obtained by several methodologies and reagents, such as hydrogenolysis with nickel or palladium and acidic additives, samarium iodide or low-valent titanium species, peracids, iron pentacarbonyl [Fe(CO)₅] or cobalt hexacarbonyl [Co(CO)₆] -assisted cleavage, ozonolysis. Other suitable conditions include homolytic conditions, such as the ones used for pinacol condensations, and the use of copper nanoparticles and surfactants in aqueous media (Green Chem. 2012, 14, 1589). Most suitable conditions are the ones using nickel, palladium, titanium and copper. Side reactions have been frequently observed in the relevant isoxazoline opening literature, such as over-reduction to the amine, racemization of vicinal stereocenters and elimination. Advantageously, they may be suppressed or altogether avoided after suitable optimization of the experimental conditions. Adequate optimizations may refer to the metal or metal complex nature and loading, the hydrogen gas and ozone pressure and delivery device, the equivalents of the samarium, titanium and boron species, the reaction time and temperature, and also the nature and acidity of the reaction medium to ensure the fast hydrolysis of the imine intermediate. The ring opening reaction is best carried out while monitoring and adjusting the pH of the reaction medium. This may be achieved using one or more adequate additives, optionally in solution, such as organic and inorganic acids, bases or salts. Advantageously, the pH of the reaction medium may be controlled by the presence of an aqueous buffer, either as part of the reaction medium or as an additive after completion of the reaction.

When R, is hydrogen, the free hydroxyl group may be optionally protected before the ring opening is performed. Advantageously, these two transformations may be carried out in a single reaction sequence, optionally in a single chemical step, or may be performed sequentially without isolation of the intermediate. Suitable protection conditions are the ones found in the relevant literature for the respective hydroxyl protecting groups.

Step c: Protections

The primary alcohol resulting from the ring opening of the previous step may be protected as detailed in the relevant literature, to provide an OR₄ primary group. When the compound of Formula C has no free secondary alcohol moiety (Ri in Formula C is not hydrogen), no further protection is required at this step and R₃ is the same as R_\. When the compound of Formula C is a 1 ,3-diol (Ri in Formula C is hydrogen), the primary and the secondary alcohols may be protected sequentially, using suitable reagents and conditions, as described in the relevant prior art, usually in the context of sugar chemistry. Therefore, R4 and R₃ may be the same or different. They may also together form a cyclic hydroxyl protecting group, also a common protection pattern for this type of 1 ,3-diols.

The preferred hydroxyl protecting groups are esters, alkyl and aryl ethers, silyl ethers, acetate.

Silyl ethers may be alkyl silyl ethers, aryl silyl ethers, mixed alkyl aryl silyl ethers or allyl silyl ethers.

Esters may be alkyl or aryl esters, including benzoate and substituted benzoate esters, as detailed in the relevant definitions.

More preferred are the ether and acetal-type protecting groups allyl (All), trityl (Tr), tetrahydropyranyl (THP), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), the arylmethyl ether groups benzyl (Bn), p-methoxybenzyl (PMB), p-nitrobenzyl, the silyl ethers trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPDMS), triisopropylsilyl (TIPS) tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyldiphenylsilyl, thexyldimethylsilyl (TDS), the acetyl-type groups acyl (Ac), chloroacyl, methoxyacyl, pivaloyl (Piv), the benzoyl (Bz) and substituted benzoyl groups p-phenylbenzoyl, p-nitrobenzoyl, p-methoxybenzoyl and p- bromobenzoyl.

The preferred cyclic hydroxyl protecting groups are acetals, carbonates and silyl- based groups, as detailed in in the relevant definitions.

More preferred are the cyclic acetal groups ethylidene, isopropylidene, hexylidene, benzylidene, p-methoxybenzylidene, and the cyclic silyl-based groups 1,3-(1,1,3,3- tetraisopropyl)disiloxanediyl (TIPDS - Markiewicz), di-tert-butylsilylenediyl (DTBS).

Suitably, steps b) and c) of the process may be performed sequentially, without isolation of any intermediates. If required, the resulting compound of Formula III may be purified by known methods, such as column chromatography or crystallization. Protecting group strategy

As usually the case in multi-step synthesis, the final protecting group strategy is the product of compromise between i) the accessibility of the starting materials, ii) the constraints of the employed chemical transformations and iii) the purpose of the targeted intermediate.

In this case, the starting oximes A and ent-A may be easily prepared with hydroxylamine from the respective aldehydes, either free or masked as lactols. The hidden C₂-symmetry of these two aldehydes was first observed and exploited by Nicolaou during the synthesis of amphoteronolide B (J Am. Chem. Soc. 1988, 110, 4672) and later enabled their preparation from a single chiral pool precursor by Furstner (Tetrahedron 1993, 38, 8541). Building on this precedent, a combined approach leading to the oximes A and ent-A from a common 3-deoxy-D- glucofuranose precursor is one among several other pathways that have been reported in the prior art with varying protecting group configurations.

The conditions employed during the main steps of the process may be adjusted to accommodate several types of protecting groups. For example, it has been found that typical INOC conditions (step a) using N-chlorosuccinimede (NCS), sodium hypochlorite (NaOCl) or t-butoxy iodide (^lBuOI) are adequate for the cyclization of diol-protected oximes (Formula A when Ri is an ether, silyl-ether or ester group), but also that methodologies using Chloramine-T are advantageous when a free hydroxyl group is present (Formula A when Ri is hydrogen). Accordingly, hydrogenolysis under buffered conditions at step b) performs well when R_\ is a silyl or other ether protecting group, but also that low-valent titanium-mediated cleavage is advantageous when Ri is hydrogen or an ester protecting group. In terms of intermediate properties, fully protected compounds B may be isolated by column chromatography, but also by crystallization when suitable protecting groups are employed as Ri and/or R₂, such as the p-nitrobenzoyl and p-phenylbenzoyl groups.

As a result of this flexibility, Ri, R₂, R₃ and R4 moieties selected from a variety of ethers, silyl-ethers and esters, as detailed above, are compatible with the employed chemical transformations in the synthetic scheme. Consequently, the process of the present invention features significant tolerance towards the actual choice of protecting groups. It may, therefore, be adjusted efficiently to the protecting group strategy requirements of specific cyclopentanone targets of Formula III.

One of these specific targets is the cyclopentanone fragment Ilia, which may be used for the preparation of entecavir, as disclosed in our co-pending application.

A specific type of compound of Formula III, prepared with a different synthetic approach, is also used in patent application WO2010074534A2 for the synthesis of entecavir.

The suitable oxime precursor Al may be prepared from a widely available derivative of D-glucose, according to transformations common in the chemistry of sugars.

3. aq.AcOH

diacetone-D-glucose

A1

The previously undisclosed oxime intermediate Al may be further elaborated into the entecavir precursor Ilia accordingjo the process .of ..the present invention. - Step a: The INOC reaction

Suitable conditions for the cyclization reaction may be selected from the ones described in the relevant prior art, as summarized above. It has been found advantageous to perform the reaction using Chloramine-T, Sodium hypochlorite or N- Chloro-succinimide as a means to generate the reactive nitrile-oxide species. The solvent of the reaction may be selected from polar solvents, including water, alcohols, such as methanol, ethanol, isopropanol or similar, ethers, such as diethylether, methyl t-butyl ether, tetrahydrofuran, methyl-tetrahydrofuran or similar, chlorinated solvents, such as dichloromethane, dichloroethane, chloroform or similar, as well as mixtures thereof. The preferred solvents are alcohols, ethers dichloromethane or mixtures thereof.

The temperature of the reaction may range from -40°C to the boiling point of the solvent, preferably from -20 to 40 °C. Optionally, an additive, such as silica gel, an organic ion-pair compound, such as tetra-alkylammonium halide or hydroxide or an ion exchange resin or polymer, may be added during or after the reaction.

The reaction is monitored by TLC and is quenched and submitted to extractive work up according to standard procedures. The product is optionally purified by methods known in the art, such as column chromatography. The crude residue may also be used without any further treatment for the next reaction.

As it is known from the literature such cycloaddition reaction could also afford another stereoisomer product which can be easily converted to the desire more stable product under suitable conditions. Step b: Protection and ring opening

The free alcohol may be protected using the conditions described in the prior art for similar compounds. Advantageously, imidazole is used as a base and TBSC1 as the source of the silyl protection. The protected intermediate is then subjected with or without further treatment to ring opening conditions. Suitably, hydrogenolysis conditions using Pd on carbon or Raney-Ni catalysts are used for this reaction, along with an additive selected from boric acid, boronate esters or acetic acid, as described in the prior art. Preferably, boric acid or acetic acid may be used as additives. The solvent of the reaction may be selected from water, alcohols, ethers or hydrocarbons and mixtures thereof. Preferably, the solvent contains water and an alcohol, such as methanol or ethanol, or an ether, such as tetrahydrofuran, methyl- tetrahydrofuran or methyl t-butyl ether. The reaction temperature may range from -10 °C to the boiling point of the solvent, preferably between -5 °C and 40 °C.

Standard workup procedures, including filtration and optional extraction, provide the target compound, which may be used directly in the next step or purified according to known methods.

Alternatively, the ring opening reaction may be carried out using a Ti(III) species, optionally generated in situ. Among the suitable conditions described in the prior art, the preparation of titanium triisopropoxide [Ti(0'Pr)₃] has been found advantageous for this transformation. The reactive species is generated by treating a solution of ethylmagnesium bromide with titanium tetraisopropoxide, according to standard procedures. The isoxazoline is then added to the mixture and stirred at a suitable temperature until full consumption of the starting material.

The reaction may be selected from ethereal solvents, such as diethylether, tetrahydrofuran, methyltetrahydrofuran, methyl t-butyl ether or similar, chlorinated solvents, such as dichloromethane, dichloroethane, chloroform or similar, or mixtures thereof.

The reaction mixture may be directly subjected to the following protection step after adequate displacement of the metal.

Alternatively, an aqueous solution is added to the reaction to provide the targeted aldol compound. Suitably, the acidity of this solution may be adjusted with adequate additives, such as inorganic acids, bases, salts or combinations thereof. Preferably, the aqueous solution is neutral or acidic.

Standard workup procedures, including filtration and extraction, provide the target compound, which may be purified with known methods, or, preferably, directly used in the next step of the process.

Ste c: Primary protection

n

Suitable conditions for the TBS protection of a primary alcohol have been extensively described in the prior art. Preferably, typical conditions using t-butyldimethylsilyl chloride and imidazole in dichloromethane may be employed. Standard quench and workup conditions provide the target compound in high yield. The crude residue may be purified by known methods, such as column chromatography.

Additionally, with small modifications, the previously undisclosed oxime intermediate A2 may also be prepared. Oxime A2 may be further elaborated into the entecavir precursor Illb according to another process of the present invention.

The preparation of compound of formula Illb from oxime A2 is shown in the below scheme. The conditions described above for the preparation of compound of formula Ilia may also apply here.

The process of the present invention will be demonstrated in more details with reference to the following examples, which are provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner.

EXPERIMENTAL

3. aq.AcOH

diacetone-D-glucose

Add a stirred solution of 10 g diacetone-D-glucose and 0.011 g (0.004 eq) imidazole in 80 ml tetrahydrofuran, to a slurry solution of 23.1 g (1.5 eq) sodium hydride 60% dispersion in mineral oil in 40 ml tetrahydrofuran, slowly, while keeping temperature at 25-30 °C (during 30 minutes). Further stir for 20 minutes and then add 6.95 ml (3 eq) carbon disulfide. Further stir for 30 minutes, add 4.2 ml (1.8 eq) methyl iodide and further stir for 15 minutes. Add 1.9 ml acetic acid, stir for 30 minutes, filter solids and wash with 5 ml tetrahydrofuran. Evaporate filtrate, wash residue three times, each with 40 ml diethyl ether, wash combined diethyl ether washings twice, each with 40 ml aqueous saturated sodium bicarbonate solution and once with 40 ml water. Dry and evaporate organic solvent. Add to the residue 40 ml toluene, 19.3 ml (5.5 eq) 1- butanol and 11.4 ml (5 eq) poly(methylhydrosiloxane). Heat at 135 °C. In another flask mix 2.2 ml toluene, 1.64 ml (0.16 eq) tributyltin hydride and 3.1 ml (0.16 eq) bistributyltin oxide and add, from that solution, four equal doses to reaction mass during 20 h. Cool reaction mass at 20-30 °C, add 100 ml tetrahydrofuran, cool further at 0-10 °C, add 100 ml 8% w/v aqueous solution of sodium hydroxide during 15 minutes, heat reaction mass for 60 minutes at 55-60 °C, cool again at room temperature. Add 45 ml ethyl acetate, take organic layer, extract aqueous layer twice, each with 45 ml ethyl acetate, wash combined extracts with 40 ml 20% w/w aqueous solution of sodium chloride. Dry organic layer with 4 g sodium sulfate, evaporate solvent to get crude residue (17 g). Add to the residue (17g) 120 ml process water, 48 ml glacial acetic acid and stir overnight at room temperature. Cool at 0-5 °C, add 73 ml 50% w/v aqueous solution of sodium hydroxide and let temperature rise at room temperature. Evaporate solvent completely, add to the residue 450 ml dichloromethane, filter to remove solids, 225 ml dichloromethane wash of solids, dry filtrate with 2 g sodium sulfate and evaporate solvent completely to get crude residue. Add to the residue 150 ml acetonitrile and 150 ml n-hexane, separate layers and collect acetonitrile layer. Evaporate solvent completely to get residue (6.7 g) which is used in the next reaction.

Dissolve the residue (6.7 g) in 140 ml dichloromethane, cool at 0-5 °C, add 14 ml (5.17 eq) triethylamine and, dropwise, 5 ml (3.3 eq) mesyl chloride. Stir for 1 h at that temperature, add 60 ml process water, separate layers, extract aqueous layer twice, each with 100 ml dichloromethane. Combine organic extracts and wash with 100 ml saturated aqueous solution of sodium bicarbonate, followed by 100 ml 20% w/v aqueous solution of sodium chloride. Dry with 2 g sodium sulfate, evaporate solvent completely to get residue (9.5 g). Dissolve the residue (9.5 g) in 160 ml glyme, add 15.7 g (5 eq) Nal, 8.6 g (5 eq) activated zinc (Zn) and heat at 80-85 °C for 5 h. Cool at room temperature, filter to remove solids, wash solids with 400 ml dichloromethane, wash filtrate with 200 ml process water and 200 ml of saturated aqueous solution of sodium thiosulfate. Dry organic layer with 2 g sodium sulfate, evaporate solvent to get residue (4.7 g). Dissolve the crude residue (4.7 g) in 60 ml methanol, add 0.3 ml cone, sulfuric acid and heat for 4 h at 65-70 °C. Cool at room temperature, add 30 ml sat. aqueous solution of sodium bicarbonate, distil methanol, extract aqueous layer four times, each with 40 ml ethyl acetate. Combine organic extracts, dry with 2 g sodium sulfate, evaporate solvent to get the crude unprotected methylglucoside [(3R,5S)-2-methoxy- 5-vinyltetrahydrofuran-3-ol] (3.38 g).

Dissolve crude unprotected methylglucoside (2.83 g) in 157 ml tetrahydrofuran, cool at 0-5 °C, add 0.94 g (1.2 eq) sodium hydride 60% dispersion in oil, stir for 1 h at 0-5 °C, add slowly 3.5 ml (1.5 eq) benzyl bromide. Let temperature rise at 25 °C and heat at 65-70 °C for 6 h. Cool at room temperature add 25 ml aqueous sat. solution of ammonium chloride and 75 ml ethyl acetate, separate layers. Extract aqueous layer twice, each with 25 ml ethyl acetate, dry organic layer with 2 g sodium sulfate, evaporate solvent completely to get crude benzylated compound (6.28 g). Add 97 ml 60% aqueous solution of acetic acid and 0.5 ml cone, sulfuric acid to 5.85 g of the above residue and heat for 24 h at 70-75 °C. Cool at 0-5 °C, add 60 ml 50% w/v sodium hydroxide aqueous solution, add 140 ml ethyl acetate, separate layers, extract aqueous layer three times, each with 80 ml ethyl acetate, combine organic extracts, wash them with 150 ml aqueous sat. solution of sodium bicarbonate, dry with 2 g sodium sulfate, evaporate solvent completely to get residue, 5 g of crude masked aldehyde. Dissolve this crude mass in 225 ml methanol, add 3.8 g (2 eq) sodium bicarbonate and 2.5 g (1.5 eq) hydroxylamine hydrochloride and stir for 2 h at rt. Evaporate solvent completely and add 140 ml ethyl acetate. Filter to remove solid and evaporate filtrate to get the crude oxime (4.95 g), which may be used in the next reaction without further purification.

1H NMR (300 MHz, CDC1₃, as mix of E/Z isomers) 5 7.35 (dd, J= 13.1, 5.9 Hz, 5H), 7.23 (d, J= 5.3 Hz, 0.4H), 6.82 (d, J= 6.4 Hz, 0.16H), 5.90 - 5.74 (m, 0.85H), 5.30 - 5.13 (m, 1H), 5.09 (d, J= 10.4 Hz, 0.85H), 5.00 - 4.89 (m, 0.2H), 4.62 (dd, J= 11.6, 3.4 Hz, 0.85H), 4.44 (t, J= 10.2 Hz, 0.85H), 4.32 (s, 0.85H), 4.26 - 4.17 (m, 0.6H), 2.92 (s, 0.2H), 2.75 (s, 0.6H), 2.10 - 1.70 (m, 2.4H)

Example 2: Preparation of compound Al

Treat a solution of 1.12 g of starting material in 86 ml of methanol, consecutively with 1.45 g sodium bicarbonate and 0.9 g hydroxylamine hydrochloride. After stirring at room temperature for 2 hours, evaporate the solvent and add to the residue 50 ml ethyl acetate, filter to remove solids and evaporate to provide 1.24 g of the target oxime.

Method A: INOC with Chloramine-T

Dissolve Al (4.95 g) in 210 ml ethanol, add 19.8 g (4 w/w) silica gel, cool at 8-10 °C, add solution of 8.89 g (1.5 eq) chloramine-T-trihydrate in 100 ml ethanol, dropwise, during 2 h. Let temperature rise at room temperature, evaporate solvent completely and separate residue by column chromatography to get Bl as oil.

Method B: INOC with NaOCl

Dissolve 50 mg of Al in 5.1 ml tetrahydrofuran and cool at 0 °C. Add 5 ml of a 5% aqueous solution of sodium hypochlorite in portions, under stirring, until the starting material is consumed. Add ethyl acetate and separate layers, then wash the organic layer with 10% w/v aqueous solution of sodium hydroxide, water and brine. Dry over sodium sulfate, filter and evaporate then purify using column chromatography.

1H NMR (500 MHz, CDC1₃) δ 7.46 - 7.26 (m, 5H), 4.67 (t, J= 9.8 Hz, 2H), 4.50 (d, J = 11.6 Hz, 1H), 4.44 (s, 1H), 4.03 (t, J= 9.1 Hz, 1H), 4.00 - 3.90 (m, 2H), 2.82 - 2.72 (m, 1H), 2.29 (s, 1H), 2.18 (d, J = 14.3 Hz, 1H)

¹³C NMR (126 MHz, CDC1₃) δ 165.67, 137.12, 128.65, 128.30, 128.18, 74.32, 72.79, 71.68, 70.52, 60.10, 45.52

Dissolve Bl (10.4 g) in 93 ml dichloromethane, add 6.073 g (2 eq) imidazole, 10.08 g (1.5 eq) t-butyl dimethylsilyl chloride and stir at room temperature for 3 h. Add 40 ml process water, separate layers, extract aqueous layer with 40 ml dichloromethane, combine organic extracts, dry with 2 g sodium sulfate, evaporate solvent and separate residue by column chromatography to get 12.7 g of residue. 1H NMR (500 MHz, CDC1₃) δ 7.37 - 7.27 (m, 5H), 4.68 (d, J= 11.7 Hz, 1H), 4.60 (dd, J= 10.0, 8.1 Hz, 1H), 4.50 (d, J= 11.7 Hz, 1H), 4.38 (ddd, J= 7.2, 5.0, 1.0 Hz, 1H), 4.04 (dd, J= 10.3, 8.1 Hz, 1H), 4.00 - 3.93 (m, 1H 3.89 (dd, J= 15/7, 7.8 Hz, 1H), 2.82 (dt, J= 14.5, 7.4 Hz, 1H), 2.22 - 2.16 (m, 3H), 0.91 - 0.82 (m, 9H), 0.05 - 0.01 (m, 6H)

¹³C NMR (126 MHz, CDC1₃) δ 206.99, 164.72, 137.48, 128.57, 128.22, 127.98, 74.17, 73.45, 71.41, 69.70, 60.27, 46.19, 31.04, 25.80, 18.03, -4.57, -4.61

Method C: Hydrogenolysis with palladium on activated carbon and boric acid

Dissolve 5 g of the residue in 455 ml methanol, add 90 ml process water, 13.52 g (15.2 eq) boric acid and 0.5 g 10% palladium on activated carbon (50% wet). Stir under hydrogen atmosphere at 20 - 25 °C. After end of reaction filter through celite pad and wash pad with 350 ml cyclohexane, merging filtrates. To the biphasic system add 113 g sodium chloride, cool at 8 - 10 °C and add 365 ml water maintaining constant internal temperature. Separate aqueous layer and wash it with 215 ml cyclohexane, separate and combine organic layers, wash them with 100 ml sodium bicarbonate (sat.aq. sol.), dry organic layer with 5 g sodium sulfate and evaporate solvent to get crude residue (4 g).

Method D: Homolytic cleavage with in situ titanium triisopropoxide

Dissolve 5.86 ml titanium tetraisopropoxide in 43.6 ml dichloromethane and add dropwise a Grignard solution prepared from 525 mg magnesium turnings and 1.66 ml ethylbromide in 26 ml diethylether. After the addition, stir for 20 min at room temperature and another 20 min at 50 °C. Add to the reaction mixture a solution of 3 g of the protected isoxazoline residue in 14.6 ml dichloromethane and keep stirring at this temperature until consumption of the starting material. Cool the reaction mass and add 7.2 ml water, stir for 15 min and filter through celite. Wash the celite pad with 30ml dichloromethane, separate layers, dry the organic layer and evaporate the solvent to get the crude residue.

Ή NMR (500 MHz, CDC13) δ 7.42 - 7.27 (m, 5H), 4.85 (d, J = 11.8 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H), 4.23 (dd, J = 15.8, 9.1 Hz, 1H), 4.02 (dd, J = 10.9, 2.6 Hz, 1H), 3.75 (ddd, J = 14.8, 11.1, 5.7 Hz, 2H), 2.63 - 2.55 (m, 1H), 2.39 - 2.33 (m, 1H), 1.83 (dd, J = 22.3, 11.3 Hz, 1H), 0.90 (s, 10H), 0.10 (d, J = 7.2 Hz, 6H) 13C NMR (126 MHz, CDC13) δ 214.64, 137.58, 128.58, 128.51, 128.07, 128.04, 79.83, 77.41 , 77.16, 76.91 , 72.56, 65.95, 59.09, 58.75, 37.92, 25.81 , 18.03, -4.32, - 4.71

n

Dissolve crude CI (5.5 g) in 28.5 ml dichloromethane, add 1.961 g (2 eq) imidazole, add 3.256 g (1.5 eq) t-butyl dimethylsilyl chloride and stir at room temperature for 1 h. Add 70 ml aqueous sat. solution of ammonium chloride and 70 ml dichloromethane, separate layers, extract aqueous layer three times, each with 70 ml dichloromethane. Dry organic layer with 1 g sodium sulfate and evaporate solvent to get residue, then separate by column chromatography to get 1.1 g of Ilia as oil.

1H NMR (500 MHz, CDC1₃) δ 7.39 - 7.31 (m, 4H), 7.31 - 7.26 (m, 1H), 4.87 (d, J= 1 1.8 Hz, 1H), 4.69 (d, J= 1 1.8 Hz, 1H), 4.38 (ddd, J= 10.1, 8.0, 6.4 Hz, 1H), 4.02 (dd, J= 9.9, 2.2 Hz, 1H), 3.74 - 3.66 (m, 2H), 2.55 (ddd, J= 1 1.7, 7.8, 6.5 Hz, 1H), 2.16 (dt, J= 8.1 , 2.2 Hz, 1H), 1.85 - 1.76 (m, 1H), 0.89 (s, 9H), 0.81 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.02 (s, 3H), -0.01 (s, 3H)

¹³C NMR (126 MHz, CDC1₃) δ 213.75, 137.75, 128.56, 128.1 1 , 127.97, 127.91 , 80.75, 72.46, 65.28, 59.22, 58.75, 37.80, 25.90, 25.89, 18.27, 18.1 1 , -4.33, -4.63, - 5.51 , -5.57

R?=benzvl)

Compound Bl may be converted to the respective aldol using either method described in Example 4. Protection of both hydroxy groups may be carried out by treating a dichloromethane solution of the resulting diol with catalytic 4- dimethylaminopyridine, triethylamine and 3 eq of t-butyl dimethylsilyl chloride. Acidic quench and workup with dichloromethane provides the target compound.

The analytical data for the compound of Formula Ilia were identical to the ones obtained in Example 5.

To a cooled (0 °C) solution of isoxazoline Bi (1 g) and 4-dimethylaminopyridine (5 mg) in dry dichloromethane (11.6 ml), add triethylamine (0.84 ml) and a solution of p-nitrobenzoyl chloride (955 mg) in dry dichloromethane (5.1 ml) successively and dropwise. Allow temperature to rise to rt and continue stirring until complete consumption of the starting material (2 hours approximately). Add saturated aqueous ammonium chloride solution (13 ml) carefully and continue stirring for 15 minutes. After separating the organic layer, wash it with water (10 ml), dry over anhydrous sodium sulfate and concentrate under reduced pressure. Further purification with flash column chromatography affords the target compound (1.4 g).

The target compound may also be prepared according to the INOC-Method B, as described in Example 3, starting from (3S,5R)-5-(benzyloxy)-6-(hydroxyimino)hex-l- en-3-yl 4-nitrobenzoate.

1H NMR (300 MHz, CDC1₃) δ 8.36 - 8.26 (m, 1H), 8.24 - 8.14 (m, 1H), 7.43 - 7.29 (m, 2H), 5.05 - 4.94 (m, 1H), 4.83 - 4.67 (m, 1H), 4.62 - 4.52 (m, 1H), 4.42 - 4.30 (m, lH), 4.14 (tt, J = 1 1.0, 5.6 Hz, 1H), 3.09 (dt, J = 15.1, 6.5 Hz, 1H), 2.61 - 2.48 (m, 1H).

To a mixture of 495mg Bi, pyridine (14 ml) and 4-dimethylaminopyridine (7 mg) add tritylchloride (1.42 g) successively under inert atmosphere. Stir the resulting suspension overnight at elevated temperature (100 °C). Allow the reaction mass to cool to room temperature and add water (20 ml). After stirring for 10 minutes, extract the desired compound twice with ethyl acetate each with 25 ml. Combine organic layers, dry over anhydrous sodium sulfate and concentrate to dry under reduced pressure. Purification with flash column chromatography affords 570 mg of the title compound.

1H NMR (300 MHz, CDC1₃) δ 7.45 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 4.3 Hz, 1H), 7.30 (dd, J = 10.0, 5.1 Hz, 1H), 7.27 - 7.22 (m, 1H), 4.62 (d, J = 11.7 Hz, 1H), 4.45 - 4.41 (m, 1H), 4.17 (dd, J = 6.6, 4.1 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.86 (dd, J = 14.1, 6.8 Hz, 1H), 3.28 (dd, J = 10.5, 7.4 Hz, 1H), 2.30 - 2.19 (m, 1H).

To a solution of 146 mg BI in 6 ml dichloromethane add 0.48 ml methoxymethyl chloride and 2.15 ml diisopropylethylamine and stir at room temperature until consumption of the starting material. Acidic quench and workup with dichloromethane provides 110 mg of the target compound, after column purification. The target compound may also be prepared according to the INOC-Method B, as described in Example 3, starting from (2R,4S)-2-(benzyloxy)-4- (methoxymethoxy)hex-5-enal oxime.

1H NMR (500 MHz, CDC1₃) δ 7.38 - 7.27 (m, 2H), 4.69 (d, J = 11.7 Hz, 1H), 4.67 - 4.62 (m, 1 H), 4.60, (d, J = 7.0 Hz, 1 H), 4.51 (d, J 1 1.7 Hz, 1 H), 4.40 (ddd, J = 7.1 , 4.7, 1.0 Hz, 1H), 4.11 (dd, J= 11.0, 8.6 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.74 (q, J= 8.0 Hz, 1H), 3.35 (s, 1H), 2.93 (dt, J= 14.8, 7.6 Hz, 1H), 2.27 (ddd, J= 14.4, 8.3, 4.7 Hz, 1H). 1³C NMR (126 MHz, CDC1₃) δ 164.79, 137.34, 129.68, 128.60, 128.27, 128.04, 127.33, 96.53, 78.29, 74.77, 71.46, 69.19, 58.67, 55.69, 43.31.

Example 10: Preparation of compound B-; (Ri=t-butyldiphenylsilyl. R?=benzyl)

The target compound may be prepared according to the INOC-Method B, as described in Example 3, starting from (2R,4S)-2-(benzyloxy)-4-((tert- butyldiphenylsilyl)oxy)hex-5-enal oxime. It may also be prepared by treating 146 mg of Bi in 6ml dichloromethane with 128 mg imidazole, a catalytic quantity of 4-dimethylaminopyridine and 0.25 ml of t-butyl- diphenylsilyl chloride at room temperature. When the reaction is complete, acidic quench and workup with dichloromethane affords 232 mg of the target compound. 1H NMR (500 MHz, CDC1₃) δ 7.54 (d, J= 6.7 Hz, 4H), 7.36 (dd, J= 14.7, 7.3 Hz, 2H), 7.31 (t, J= 8.1 Hz, 8H), 7.27 (d, J= 4.5 Hz, 4H), 7.22 (d, J= 4.2 Hz, 1H), 4.56 (d, J= 11.7 Hz, 1H), 4.38 (d, J= 11.7 Hz, 1H), 4.22 - 4.14 (m, 1H), 4.07 - 3.96 (m, 2H), 3.92 (dd, J= 18.3, 10.3 Hz, 1H), 3.81 (dd, J= 15.3, 7.6 Hz, 1H), 3.25 - 3.16 (m, 1H), 2.69 (dt, J= 14.6, 7.5 Hz, 1H), 2.32 - 2.22 (m, 1H), 0.99 (s, 9H).

0-5 °C, add a solution of 6.0 g biphenyl-4-carbonyl chloride in 32 ml dichloromethane, dropwise at 0-5 °C, under argon atmosphere. Stir for 30 min at 0-5 °C. Let temperature rise at 20-25 °C, add 40 ml sodium bicarbonate saturated solution, separate layers and keep organic layer aside. Extract the aqueous three times with 40 ml dichloromethane each. Combine the organic extracts and wash them with 40 ml brine. Extract the aqueous layer five times, each with 40 ml dichloromethane. Combine all organic extracts, dry over sodium sulfate, filter and evaporate solvents completely to get solid product. Add 16ml of ethyl acetate and 50 ml of cyclohexane, stir for 15 min, filter the solids and discard. Evaporate filtrate, add cyclohexane, stir for 15 min then filter solids to obtain pure product.

Dissolve 1.4 g of the above prepared compound in 28 ml tetrahydrofuran, add 16 ml 60% aqueous solution of acetic acid, 0.9 ml cone, sulfuric acid and heat for 16-18 hrs at 50-55 °C. Cool at 25-30 °C, add 100 ml dichloromethane and adjust pH at 9-10 with ~80 ml of 10% aqueous sodium hydroxide solution. Separate layers, extract the aqueous four times with 35ml dichloromethane each. Wash the combined organic extracts with 70 ml water, dry over sodium sulfate and filter through Buchner funnel under vacuum. Evaporate solvents off completely to get oily residue. Purify the solid residue with chromatography column eluting with cyclohexane : ethyl acetate 8 :2. Dissolve 0.425 g of the above prepared compound (1.37 mmol) in 20 ml methanol, add 0.23 g sodium bicarbonate (2.0 eq) and 0.17 g hydroxylamine hydrochloride (1.5 eq) and stir for ~lh at 20-25 °C. Evaporate solvent completely and wash the solid twice with 15 ml ethyl acetate. Filter through Buchner funnel under vacuum to remove solid, spray wash the solid on the funnel with 5 ml ethyl acetate and collect the filtrates. Evaporate solvents completely to get crude oxime A2.

1H-NMR (500MHz, d6-DMSO, as mixture of E/Z isomers): δ 11.23 (br, 0.3H), 11.08 (br, 1H), 8.06-8.02 (m, 2.4H), 7.83-7.81 (m, 2.4H), 7.73-7.70 (m, 2.4H), 7.50-7.48 (m, 3.2H), 7.43-7.39 (m, 1.3H), 6.86 (d, J= 5.0 Hz, 0.3H), 6.00-5.97 (m, 0.3H), 5.91- 5.81 (m, 1.3H), 5.66-5.62 (m, lH)m, 5.17-5.00 (m, 3.6H), 4.18-4.11 (m, 1.3H), 2.07- 1.93 (m, 2.4H)

Example 12: Preparation of compound B_fi (Ri=hydrogen, Ri=p-phenyl-benzoyl)

Dissolve 0.46g of oxime A₂ (1.41 mmol) prepared in Example 11, in 14.2 ml ethanol, add 1.33 g silica gel, cool at 8-10 °C, add a suspension of 0.6 g chloramine-T- trihydrate in 6.9 ml ethanol dropwise during 2.5 hrs. Let temperature rise at 20-25 °C. Filter the solids through Buchner funnel under vacuum and spray wash the solids on the funnel with 5 ml ethanol. Collect the filtrates and evaporate the solvents completely. Purify the residue by chromatography column eluting with cyclohexane:ethyl acetate 5:5.

1H NMR (500 MHz, CDC1₃) δ 8.10 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 8.3 Hz, 2H), 7.65 - 7.56 (m, 2H), 7.47 (t, J= 7.5 Hz, 2H), 7.40 (dd, J= 10.6, 4.1 Hz, 1H), 5.83 - 5.76 (m, 1H), 4.75 (dd, J= 10.1, 8.6 Hz, 1H), 4.14 (tdd, J= 17.8, 10.4, 8.2 Hz, 3H), 3.18 (dt, J= 14.7, 7.3 Hz, 1H), 2.31 (ddd, J= 14.7, 7.4, 4.7 Hz, 1H)

¹³C NMR (126 MHz, CDC1₃) δ 165.43, 163.48, 146.21, 139.76, 130.32, 129.73, 128.96, 128.30, 127.90, 127.29, 127.15, 77.28, 77.23, 77.03, 76.77, 74.66, 72.77, 66.01, 59.70, 45.49, 29.70

phenyl-benzovO

Dissolve 0.110 g of oxazolidinone B₇ prepared in example 12 (0.34mmol) in 5 ml dichloromethane, add 0.070 g imidazole (3.0 eq), 0-102 g t-butyldimethy 1 si lylchloride - (2.0 eq) and 0.020 g 4-dimethylaminopyridine (cat.). Stir overnight at 20-25 °C. Add 5ml water and separate layers. Extract the aqueous layer twice with 5 ml dichloromethane. Dry over sodium sulfate and filter through buchner funnel under vacuum. Evaporate solvents off completely to get semi-solid residue. Purify the residue by chromatography column eluting with Cyclohexane:EtOAc/l 5 : 1

'H NMR (500 MHz, CDCI3) δ 8.11 (dd, J= 8.2, 2.5 Hz, 2H), 7.75 - 7.58 (m, 4H), 7.44 (ddd, J= 11.8, 9.7, 5.9 Hz, 3H), 5.75 (s, 1H), 4.70 (dd, J= 12.7, 5.4 Hz, 1H), 4.14 (dd, J= 12.9, 5.5 Hz, 1H), 4.12 - 3.91 (m, 2H), 3.12 (ddd, J= 14.1, 7.0, 4.3 Hz, 1H), 2.39 - 2.16 (m, 1H), 1.61 (s, 1H), 1.26 (s, 1H), 0.88 (d, J= 2.8 Hz, 9H), 0.08 (d, J= 16.4 Hz, 6H)

¹³C NMR (126 MHz, CDC1₃) δ 165.43, 163.39, 146.11, 139.84, 130.32, 128.94, 128.25, 128.06, 127.29, 127.10, 74.55, 73.26, 65.74, 60.14, 46.26, 25.65, 17.90, -4.72, -4.77

Claims

1. A process for the preparation of compound of formula III or its enantiomer, comprising:

a) intramolecular cycloaddition of compound of formula A or its enantiomer, to form compound of formula B or its enantiomer;

wherein Ri represents hydrogen or a hydroxyl protecting group and R₂ represents a hydroxyl protecting group, or Ri and R₂ are taken together to form a cyclic hydroxyl protecting group;

b) optional protection of the free hydroxyl group, when R_\ is hydrogen, and ring opening, to form compound of formula C or its enantiomer;

c) protection of the primary hydroxyl group of compound of formula C or its enantiomer, and optional protection of the secondary hydroxyl group, when Ri is hydrogen, to form compound of formula III or its enantiomer;

wherein R₃ and R represent a hydroxyl protecting group or R₃ and R₄ are taken together to form a cyclic hydroxyl protecting group.

2. A process according to claim 1 , wherein:

- Ri represents hydrogen, R₂ represents a hydroxyl protecting group, R₃ and R₄ represent a hydroxyl protecting group or R₃ and R4 taken together form a cyclic hydroxyl protecting group, or - Ri, R₂₎ R₃ and R4 represent hydroxyl protecting groups and R₃ is the same as R_\,

- Ri and R₂ taken together form a cyclic protecting group, R3 is the same as R_\ and R4 represents a hydroxyl protecting group;

wherein the protecting group is selected from alkyl and aryl ethers, esters and silyl ethers and the cyclic hydroxyl protecting group is selected from acetals, silyl groups and cyclic carbonates.

A process for the preparation of compound of formula C or its enantiomer, wherein Ri represents hydrogen or a hydroxyl protecting group and R₂ represents a hydroxyl protecting group, or R_\ and R₂ are taken together to form a cyclic protecting group, comprising:

b) ring opening of compound of formula B or its enantiomer, to form compound of formula C or its enantiomer, wherein R_\ and R₂ are as defined above

A process for the preparation of compound of formula B or its enantiomer, comprising the intramolecular cycloaddition of compound of formula A or its enantiomer, wherein R_\ represents hydrogen or a hydroxyl protecting group and R₂ represents a hydroxyl protecting group or R_\ and R₂ are taken together to form a cyclic protecting group.

A process, according to claims 1-5, wherein the intramolecular cycloaddition reaction is performed under conditions comprising N-chlorosuccinimide, sodium hypochlorite or chloramine-T.

A process, according to claims 1-4, wherein the ring opening reaction is performed under conditions comprising palladium, nickel or copper catalysis, or titanium (III) compounds, such as titanium trifluoride (TiF₃), titanium trichloride (T1CI₃) and titanium isopropoxide (Ti(0'Pr)₃), which is optionally generated in situ.

A process, according to claims 3 to 7, wherein the hydroxyl protecting groups are selected from alkyl and aryl ethers, silyl ethers and esters and the cyclic hydroxyl protecting group is selected from acetals, silyl groups and cyclic carbonates. 8. Compound of formula III or its enantiomer, wherein R_1? R₂, R₃ and R4 are defined as in claim 1 or 2, with the proviso that R₂ is not hydrogen, alkylsilyl or allylsilyl.

Compound of formula C or its enantiomer, wherein R_\ and R₂ are defined as in claim

10. Compound of formula B or its enantiomer, wherein Rj and R₂ are defined as in claim 1 or 2.

11. Compound of formula A or its enantiomer, wherein R_\ and R₂ are defined as in claim

12. A process for the preparation of compound of formula Ilia or its enantiomer, comprising:

a) intramolecular cycloaddition of compound of formula Al or its enantiomer, to form compound of formula Bl or its enantiomer;

b) protection of the free hydroxyl group of compound of formula Bl or its enantiomer, to form compound of formula B2 or its enantiomer and ring opening, to form compound of formula CI ;

c) protection of the primary hydroxyl group of compound of formula CI

enantiomer, to form compound of formula Ilia or its enantiomer;

A process for the preparation of compound of formula Illb or its enantiomer, comprising:

a) intramolecular cycloaddition of compound of formula A2 or its enantiomer, to form compound of formula B7 or its enantiomer;

b) protection of the free hydroxyl group of compound of formula B7 or its enantiomer, to form compound of formula B8 or its enantiomer and ring opening, to form compound of formula C2;

c) protection of the primary hydroxyl group of compound of formula C2

enantiomer, to form compound of formula Illb or its enantiomer;

14. Compound of formula Ilia, as defined in claim 12.

15. Compound of formula Illb, as defined in claim 13

16. Use of compound of formula III, or its enantiomer, as defined in claim 1 or 2, as an intermediate in the synthesis of a compound.

17. Use of compound of formula III, or its enantiomer, as defined in claim 1 or 2, for the preparation of entecavir or prostaglandins.

18. Use of compound of formula III as defined in claim 1 or 2 for the preparation of entecavir. Use of compound of formula Ilia as defined in claim 12 for the preparation of entecavir.

Use of compound of formula Illb for the preparation of entecavir.