AU2003215422B2 - Anomeric derivatives of monosaccharides - Google Patents

Description

WO 03/082846 PCT/AU03/00384 Anomeric Derivatives of Monosaccharides FIELD OF THE INVENTION This invention relates to methods for the preparation of combinatorial libraries of potentially biologically active mainly monosaccharide compounds. These compounds are variously functionalized, with a view to varying lipid solubility, size, function and other properties, with the particular aim of discovering novel drug or drug-like compounds, or compounds with useful properties. The invention provides intermediates, processes and synthetic strategies for the solution or solid phase synthesis of monosaccharides, variously functionalised about the sugar ring, including the addition of aromaticity and charge, and the placement of amino acid and peptide side chain units or isosteres thereof.

BACKGROUND OF THE INVENTION From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar represents a three-dimensional scaffold to which a variety of substituents can be attached, usually via a scaffold hydroxyl group, although occasionally a scaffold carboxyl or amino group may be present for substitution. By varying the substituents, their relative position on the sugar scaffold, and the type of sugar to which the substituents are coupled, numerous highly diverse structures are obtainable. An important feature to note with carbohydrates, is that molecular diversity is achieved not only in the type of substituents, but also in the three dimensional presentation. The different stereoisomers of carbohydrates that occur naturally (examples include glucose, galactose, mannose etc,Fig offer the inherent structural advantage of providing alternative presentation of substituents.

WO 03/082846 PCT/AU03/00384 2 OH OH OH HO 1 0 HO 0 HOV I OH OH OH OH HO OH c,P-D-Galactose a,p-D-Glucose c,13-D-Mannose Fig. 1 The first example of a combinatorial approach employing carbohydrate chemistry, was a symposium report on the design and synthesis of a peptidomimetic using a glucose scaffold in the early 1990's 1 The results, revealed that the glucose based structures designed as mimetics of a potent somatostatin (SRIF) agonist acted as agonists at low concentration, and at high concentration became the first known antagonists of SRIF. Although hardly the production of a library, the results were unique.

Continuing in part the work commenced in the early 1990's, Nicolaou and coworkers began developing carbohydrate based peptido-mimetics targeting integrins. Many integrins recognize an Arg-Gly-Asp (RGD) sequence in ligands such as fibronectin, vitronectin and fibrinogen, each binding with different affinities to the individual integrin receptors. Through a process of rational design a number of carbohydrate based RGD mimetics were synthesized. The chemical synthesis of nine different compounds by this group with very few common intermediates required a considerable amount of chemical effort. It was evident from such results, that in order to generate a number of different structures in a facile manner new chemistries needed to be developed to streamline and enable what at this stage was unfortunately a protracted and arduous methodology.

Since 1998 researchers in the group of Kunz 2 have been developing a number of carbohydrate building blocks with a similar purpose in mind. In general the building blocks that they have developed are coupled to a solid support to effect the desired chemical transformations. The chemistry developed can be employed to achieve, like the work of Hirschmann and co- WO 03/082846 PCT/AU03/00384 3 workers 3 the introduction of peptidomimetic side chains to carbohydrate scaffolds in an effort to produce glyco-based mimetics of cyclic peptides.

Admittedly, with the chemistry they have developed, there are inherent limitations in the types of functional groups that they are able to introduce and the range of stereoisomeric building blocks that they are able to employ.

It is now becoming reasonably established in the art that relates to the solid phase production of combinatorial carbohydrate based libraries, that one of five protecting groups on a carbohydrate scaffold is a protecting group modified as a linker, so as to allow coupling of the block to a solid support.

The strategy that then follows is simple, remove a protecting group and effect coupling at the freed functionality with a peptidomimetic or other reagent.

Remove another protecting group and couple with the next reagent, and so on.

Following this generally accepted principle, a system has been developed that allows the chemical synthesis of highly structurally and functionally diverse derivatised carbohydrate and tetrahydropyran structures, of both natural and unnatural origin. The diversity accessible is particularly augmented by the juxtaposition of both structural and functional aspects of the molecules. In order to access a wide range of diverse structures, stereo-center inversion chemistry is required, so as to achieve non-naturally occurring and hard to get sugars in a facile manner. Other chemistries are also required that provide unnatural deoxy or deoxy amino derivative which impart greater structural stability to the drug-like target molecules. With a suite of reagents to effect a suitable range of chemistries on a solid support, allowing such things as; wide functional diversity, highly conserved intermediates, a limited number of common building block to be required, and with suitable chemistry to allow access to unusual carbohydrate stereo-representations and including access to deoxy and deoxy amino analogues, a methodology is then established that can create focused libraries for a known target, or alternatively diversity libraries for unknown targets for random screening.

WO 03/082846 PCT/AU03/00384 4 Many of the traditional methods of carbohydrate synthesis have proved to be unsuitable to a combinatorial approach, particularly because modern highthroughput synthetic systems require that procedures to be readily automatable. The compounds and processes described herein are particularly suited to the solid and solution phase combinatorial synthesis of carbohydrate-based libraries, and are amenable to automation. The methods of the invention yield common intermediates that are suitably functionalized to provide diversity in the structure of the compounds so generated. In this way the technology described can produce many and varied compounds around the basic structure shown in Figure 1. Using this method, it is possible to introduce varied functionality in order to modulate both the biological activity and pharmacological properties of the compounds generated.

Thus the compounds and methods disclosed herein provide the ability to produce random or focused combinatorial-type libraries for the discovery of other novel drug or drug-like compounds, or compounds with other useful properties in an industrially practical manner.

It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

WO 03/082846 PCT/AU03/00384 SUMMARY OF THE INVENTION In a first aspect, the invention provides a compound of formula I R6

R

formula I Wherein, n is 0 or 1; the ring may be of any configuration and the anomeric center may be of either the a or 3 configuration; R6 and R7 are hydrogen, or together form a carbonyl oxygen; R1 is selected from the group consisting of hydrogen; -N(Z)Y and C(Z)Y wherein; When R1 is then: Y is selected from hydrogen, or the following, where G denotes the point of connection to the nitrogen atom in N(Y)Z; 0 G W

O

GS

0 0 G I

G/SW

0

IO

OH

0 G NW

Q

WO 03/082846 PCT/AU03/00384 6 Z is selected from hydrogen or X1; Q is selected from hydrogen or W; The groups W are independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2

F,

nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; The groups X1 are independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; When R1 is then: Y is selected from hydrogen, double bond oxygen to form a carbonyl, or triple bond nitrogen to form a nitrile.

Z may be optionally absent, or is selected from hydrogen or U, Wherein U is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents WO 03/082846 PCT/AU03/00384 7 include but are not limited to OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid;, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.

Suitably, When R1 is H, at least two of the groups R2, R3, R4 and R5 are selected from the group consisting of-OX2 or and the others are independently selected from hydrogen, -OH, -OX2, wherein Y is as defined above, T is selected from hydrogen or X2; and X2 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms, When R1 is N(Z)Y or C(Z)Y, at least one of the groups R2, R3, R4 and R5 are selected from the group consisting of -OX2 or and the others are independently selected from hydrogen, -OH, -OX2, -N(T)Y, wherein Y is as defined above, T is selected from hydrogen or X2; and X2 is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms, It is understood that the rules of molecular stoichiometry will be upheld by the default addition of hydrogens atoms as required.

The groups Z and Y may be combined to form a monocyclic or bicyclic ring structure of 4 to 10 atoms. This ring structure may be further substituted with X groups; The groups R2, R3, R4 and R5 are independently selected from hydrogen, OH, NHDde, NHDTPM and other vinylogous amines, N(Z)Y, wherein N(Z)Y is as defined above, OX and X is independently selected from WO 03/082846 PCT/AU03/00384 8 alkyl, alkenyl, alkynyl, heteroalkyl, aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, acyl, arylacyl, heteroarylacyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO 2

NH

2

N

3 halogen, CF3, CHF 2

CH

2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; With the proviso that when R2 is N(Z)Y, R6 and R7 are hydrogen, and R4 and R5 are OH or together form a benzylidene or substituted benzylidene, then R1 cannot be N(Z)Y.

A preferred embodiment of the first aspect provides for compounds of formula I in which R1 is H and R4 is N(Z)Y; In a particularly preferred embodiment R1 is H and R4 is N(Z)Y wherein Z is hydrogen; A further embodiment of the first aspect provides for compounds of formula I in which R1 and R4 are independently N(Z)Y; Another embodiment provides for compounds of formula I in which R1 is H and both R2 and R4 are N(Z)Y; In a preferred embodiment provides for compounds of formula I in which the ring is of the gluco, galacto or allo configuration; A further embodiment provides for compounds of formula I in which R1 is N(Z)Y and R2 is N(Z)Y; WO 03/082846 PCT/AU03/00384 9 A further embodiment provides for compounds of formula I in which R1 is P(Z)Y and R2 is N(Z)Y, wherein P is carbon and Y is hydrogen.

A further embodiment provides for compounds of formula I in which R1 is P(Z)Y and R4 is N(Z)Y, wherein P is carbon and Y is hydrogen.

A further embodiment provides for compounds of formula I in which R1 is N(Z)Y and R5 is N(Z)Y and the ring is of the furan form.

In a second aspect, the invention provides for a method of synthesis of compounds of formula I in which R1 is hydrogen, comprising the step of reducing a synthetic intermediate of formula II, in which the substituent V is either bromine or chlorine, R6 and R7 are as defined in the first aspect, R4, R3, and R2 are independently selected from OH, O-acyl, N 3 NHDde, NHDTPM, NHZ, NHBOC, phthalimide, 0-protecting group or when R6 and R7 together for a carbonyl oxygen, R5 may additionally be optionally substituted O-alkyl, O-arylalkyl or O-aryl. Where the protecting groups may be chosen from any suitable oxygen protecting groups known in the art, including acetals and ketals which protect two adjacent oxygens.

R6 R7 0 V

R

4 R2 R3 formula II In a third aspect, the invention provides for a method of synthesis of compounds of formula I in which R1 is N(Z)Y comprising the step of reacting a compound of formula II with and azide nucleophile, in which the substituents for formula II are as described in the second aspect.

WO 03/082846 PCT/AU03/00384 In a fourth aspect, the invention provides for a method of combinatorial synthesis of compounds of the formula I comprising the step of immobilizing a compound of formula III onto a support. Said support may be soluble or insoluble. Non-limiting examples of insoluble supports include derivatised polystyrene, tentagel, wang resin, MBHA resin, aminomethylpolystyrene, rink amide resin etc. Non-limiting examples of soluble supports include DOXmpeg, polyethylene glycol etc.

R6 R7 formula III Wherein R1 is as defined in the first aspect, R2, R3, R4, R5, R6 and R7 are as defined in the second aspect, and the linkage between the compound of formula Illand the support is through any of positions R2, R3,R4 or In a fifth aspect, the invention provides for a method of synthesis of compounds of formula I in which R1 is N(Z)Y, comprising the step of reacting a compound of formula IV in the presence of a lewis acid with an azide source.

formula IV in which the substituent V is -OAcyl, R6 and R7 are as defined in the first WO 03/082846 PCT/AU03/00384 11 aspect, R4, R3, and R2 are independently selected from OH, O-acyl, N 3 NHDde, NHDTPM, NHZ, NHBOC, phthalimide, O-protecting group or when R6 and R7 together for a carbonyl oxygen, R4 may additionally be optionally substituted O-alkyl, O-arylalkyl or O-aryl. Where the protecting groups may be chosen from any suitable oxygen protecting groups known in the art, including acetals and ketals which protect two adjacent oxygens.

In a sixth aspect, the invention provides for a method of synthesis of compounds of formula I in which R1 is H, comprising the step of reducing a compound of formula IV in which the substituents for formula II are as described in the fifth aspect.

In a seventh aspect, the invention provides for a method of combinatorial synthesis of compounds of formula I comprising the step of immobilizing a compound of formula V onto an support. Said support may be soluble or insoluble. Non-limiting examples of insoluble supports include derivatised polystyrene, tentagel, wang resin, MBHA resin, aminomethylpolystyrene, rink amide resin etc., Non-limiting examples of soluble supports include DOXmpeg, polyethylene glycol etc.

R6 R4 R7 R1 R3 R2 formula V Wherein R1 is as defined in the first aspect, R2, R3, R4, R6 and R7 are as defined in the fifth aspect, and the linkage between the compound of formula V and the support is through any of positions R2, R3, or R4.

WO 03/082846 PCT/AU03/00384 12 In a eighth aspect, the invention provides for a method of solution phase combinatorial synthesis of compounds of formula I comprising the step of alkylating a free hydroxyl on a compound of formula III, wherein R1 is as defined in the first aspect, R2, R3, R4, R5, R6 and R7 are as defined in the second aspect and any one of the protecting substituents may be removed prior to alkylation.

Compounds of the invention are useful in screening for biological activity.

For the purposes of this specification it will be clearly understood that the word "comprising" means "including but not limited to", and that the word "comprises" has a corresponding meaning.

WO 03/082846 PCT/AU03/00384 13 General Solution and Solid Phase Methods For Examples 1-21 General Method 1: Formation of a Glycosyl Bromide To a solution of the anomeric-acetate compound (100 mmol) in dichloromethane (250 mL) at 0 C, was added a solution of 33% HBr in acetic acid (100mL). The solution was then stirred for 2 h at room temperature. At this time chloroform was added to the suspension and the resulting solution poured onto ice/water. The chloroform layer was then collected and washed with cold water, saturated sodium hydrogen carbonate, brine, dried (MgSO4), and the solvent removed to leave a foam. This foam was trituated with ether mL) for 30 min and the resulting solid filtered to give the glycosyl bromide as a white solid. Yield typically greater than General Method 2: Reduction at the Anomeric Centre to Form a Glycitol To a suspension of glycosyl bromide (100 mmol) in dry toluene 200 mL was added tributyltin hydride (110 mmol) and the whole refluxed under nitrogen for 3 h. The suspension was concentrated to dryness and the residue redissolved in a 2:1 dichloromethane/chloroform (250 mL) mixture. To the residue was then added potassium fluoride (20 g) in water (100 mL), and the heterogeneous solution stirred vigorously for 45 min. The resulting suspension was filtered through a pad of celite and washed several times with dichloromethane. The combined filtrates were then washed with water, brine, dried (MgSO 4 and solvent removed in vacuo to leave a solid in typically quantitative yield.

General Method 3: Solution Phase Zemplen To a suspension of the acetylated compound (100 mmol) in dry methanol (125 mL) at 0°C was added a solution of sodium methoxide (0.33 mmol) in dry methanol (125 mL) and the mixture was stirred under nitrogen for 2 h.

Amberlite IR 120 H' was added until pH 5 was reached, the solution was filtered and the resin washed several times with a 2:1 WO 03/082846 PCT/AU03/00384 14 methanol/dichloromethane mixture. The combined filtrates were then concentrated to dryness to leave a solid. Typically quantitave yield.

General Method 4: Solution Phase Benzylidene Protection To a solution of the triol (-100 mmol) in dry N,N-dimethylformamide (325 mL)/acetonitrile (200 ml) was added 4-methoxybenzaldehyde dimethyl acetal (180 mmol) and p-toluene sulfonic acid (2.5 mmol). This solution was then heated at 60°C on a rotary evaporator at 300 mmHg for 30 min and then over the course of 4 h the pressure was reduced to 80 mmHg and approximately 200 mL of solvent collected. After this time a second batch of reagent mmol) and acetonitrile (125 mL) was added and the evaporation process repeated over 2 h. All solvent was then removed under reduced pressure and the residue re-dissolved in an 8:1 chloroform/triethylamine mixture, washed with dilute sodium hydrogen carbonate, dried (MgSO 4 and the solvent removed under reduced pressure to leave a oil. The oil was typically loaded onto a pad of silica and eluted with -10% ethyl acetate in light petroleum (40-60oC), to provide a white solid.

General Method 5: Solution Phase Benzovlation The sugar (100 mmol) was partially suspended in pyridine (400 mL) and pchlorobenzoyl chloride (46 mL, 120 mmol) added dropwise at 0°C and the resulting reaction mixture stirred at room temperature for 2 h. After this time cold water (30 mL) was added and the solution stirred for a further 1 h at room temperature. All solvents were then removed under reduced pressure and any traces of pyridine azeotropically removed with toluene. The residue solid was then redissolved in chloroform and washed with water, 10% citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO 4 and concentrated under reduced pressure to leave a foam. This foam was trituated with ether and the resulting solid filtered to give the benzoylated compound as a solid, typical yield General Method 6: Solution Phase Nucleophilic Inversion of a Carbon Centre To a solution of the sugar (100.0 mmol) in dry chloroform (300 mL) cooled to WO 03/082846 PCT/AU03/00384 was added pyridine (180.0 mmol) and trifluoromethane sulfonic anhydride (115 mmol) and the whole stirred for 1 h at this temperature. The reaction was then diluted with chloroform, and the resulting solution washed with cold water, cold 10% hydrochloric acid, cold water, dried (MgSO4), and the solvent removed in vacuo. The resulting residue was then redissolved in N,N-dimethylformamide (600 mL), and sodium azide (500 mmol) was added at 0°C in portions. The suspension stirred overnight at room temperature.

The reaction was diluted with chloroform and the resulting solution then washed with water, 10% citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO 4 and the solvent removed in vacuo, followed by azeotroping with toluene to leave the product, typically 95% yield.

General Method 7: Solution Phase Alkylation To a suspension of sodium hydride (100 mmol) in dry N,N,dimethylformamide (360 mL) at 0°C under nitrogen was added a solution of the sugar (63.2 mmol) in dry N, N-dimethylformamide (30 mL). The mixture was stirred at 0°C for 15 min and then warmed to room temperature and stirred for a further 30 min. The suspension was again cooled to 0°C, the alkylating agent (85 mmol) added dropwise over a period of 5 min, after which the suspension was warmed to room temperature and stirred for 16 h. The suspension was then cooled to 0°C and the reaction quenched with ammonium chloride solution, chloroform added, and the organic layer washed with saturated sodium hydrogen carbonate, water, dried (MgSO 4 and all solvent removed to leave an oil. Crude products were purified by column chromatography (typically: silica, 50% ethyl acetate in light petroleum 600C)) to give the desired product as a solid, in yields of 55-95%.

General Method 8: Solution Phase DTPM Removal To a solution of the DTPM derivatised sugar (100 mmol) in a 3:1 mixture of dry methanol/N,N,-dimethylformamide (500 mL), was added hydrazine monohydrate (350 mmol) and the mixture stirred for 3 h. After this time the mixture was filtered and the filtrate was then concentrated under reduced pressure. The residue was redissolved in dichloromethane, washed with WO 03/082846 PCT/AU03/00384 16 saturated sodium chloride, dried (MgSO 4 and all solvent removed under reduced pressure to leave a solid, typically in quantitative yield.

General Method 9: Solution Phase HBTU Coupling To a solution of the acylating agent (10 mmol) and HBTU (12 mmol) in dry N,N,-dimethylformamide (60 mL) was added diisoproplyethylamine (25 mmol) and the mixture stirred for 10 min. A solution of the sugar building block (9.4 mmol) in dry N,N,-dimethylformamide (8 mL), was then added and the mixture further stirred for 16 h. Chloroform was then added and the reaction mixture was washed with water, 10% citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO4) and the solvent removed under reduced pressure to leave an oil. Purification of the products was by column chromatography (typically, silica; 50% ethyl acetate in light petroleum or alternatively by trituation with diethyl ether to give clean products in typical yields of 55-85%.

General Method 10: Solution Phase Reaction with an Isocyanate To a solution of the sugar derivative (10 mmol) in dry dichloromethane (100 mL) was added dropwise ethyl isocyanatoacetate (10.7 mmol). The resulting solution stirred for 3 h. In the case of a precipitate occuring, the solid was filtered after 3 h and washed with dichloromethane to give a white solid.

Alternatively if no precipitate formed, chloroform was added and the reaction mixture washed with water, dried (MgSO 4 and the solvent removed in vacuo to typically leave an oil. Purification of oils was achieved by column chromatography. Products were typically formed in yields of 65-90%.

General Method 11: Solution Phase Reaction with an Anhydride To a solution of the sugar derivative (10 mmol) in dry dichloromethane mL) was added dropwise acetic anhydride (11 mmol). The resulting solution stirred for 16 h. In the case of a precipitate occuring, the solid was filtered after and washed with dichloromethane to yield a white solid. Alternatively if no precipitate occured, chloroform was added and reaction mixture washed with water, 10% citric acid, saturated sodium hydrogen carbonate, brine, dried WO 03/082846 PCT/AU03/00384 17 (MgSO 4 and the solvent removed under reduced pressure to leave an oil.

Oils were purified by column chromatography. Products were typically formed in yields of 50-99%.

General Method 12: Solution Phase Reaction with an Acid Chloride To a solution of the sugar derivative (10 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (12 mmol) and an acid chloride (11.6 mmol), and the solution then stirred for 16 h. Chloroform was then added and the reaction mixture washed with water, 10% citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO 4 and the solvent removed under reduced pressure to give an oil. Purification was by either column chromatography (typically: silica; 50% ethyl acetate in light petroleum 0 or by trituation with diethyl ether. Products were typically formed in yields of 70-80%.

General Method 13: Solution Phase Reduction of an Azide To a stirred solution of the sugar derivative (10 mmol) in methanol (90 mL) was a solution of ammonium chloride (50 mmol) in water (18 mL). Added to the reaction mixture was zinc dust (300 mmol) and the resulting suspension stirred for 3 h. The reaction mixture was then filtered through a pad of celite and washed with ethyl acetate. The organic layer was then collected, washed with saturated sodium hydrogen carbonate, dried (MgSO 4 and all solvent removed under reduced pressure to leave a white solid. Products were typically formed in yields of 60-75%.

General Method 14: Solution Phase Removal of p-Methoxvbenzvl Group Sugar derivative (~2mmol) was dissolved in a solution of 70% chloroform, trifluoroacetic acid, 5% anisole, 5% water, and the resulting reaction mixture stirred for 6 h. All solvent was then removed under reduced pressure to leave a dark oil. Products were purified by HPLC-MS General Method 15: Solution Phase Base Catalysed Hydrolysis Sugar derivative mmol) was dissolved in methanol mL). To this WO 03/082846 PCT/AU03/00384 18 solution was 1M sodium hydroxide (0.42 mL) and the resulting reaction mixture agitated for 16h. Amberlite resin (400 mg) was added, the suspension was then stirred for 30sec, filtered, and resin washed with methanol. The resulting solutions were collected and freeze dried, and the residues then purified by HPLC-MS.

General Method 16: Simultaneous Removal of Benzoate and DTPM Sugar derivative (1 mmol) was stirred at room temperature in a 1 molar NaOH/methanol solution (6 mL, 1.5 mmol) in DMF (1.5 ml) until complete consumption for (12 hrs). Hydrazine monohydrate (0.3 ml) was added and the stirring continue for 2hr. The volatile solvents were removed in vacuo and the residue was taken up in EtOAc and washed with saturated bicarbonate solution, dried over MgSO 4 and evaporated to dryness. Products were typically formed in yields of 85-90%.

General Method 17: Solution Phase Diazotransfer To a solution of the sugar derivative (1 mmol) and CuSO 4 .5H 2 0 (0.02 mmol) in methanol/water 10 mL), was added drop-wise the TfN 3 solution mmol). The reaction mixture was stirred at room temperature for 20hr and more TfN 3 mmol) was added. After additional 16hr, concentrated

NH

4 0H solution was added to quench excess TfN 3 and the stirring continued for 72hr. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated bicarbonate solution, dried over MgSO 4 and evaporated to dryness.

The residue was evaporated to afford the desired product in quantitative yield.

General Method 18: Solution Phase Benzylidene Removal To a solution of the sugar derivative (1 mmol) in acetonitrile/methanol/water was added TsOH.H 2 0 (~100micromol). The resulting reaction mixture was stirred at 500C for 1.5 hrs. The volatile solvents were then removed in vacuo and the residue purified by flash chromatography. The desired product was typically obtained in 70-80% yield..

WO 03/082846 PCT/AU03/00384 19 General Method 19: Solution Phase Silvl Protection.

To a solution of the sugar derivative (1 mmol) in pyridine (1ml), was added DMAP (1 mmol) and TBDPSCI (1.5 mmol). The resulting reaction mixture was stirred at 120°C for 45min, then the solvent removed in vacuo. The residue was taken up in dichloromethane washed with 1N HCI solution, dried over MgSO 4 and evaporated to dryness. The residue was chromatographed to afford the desired product in typically 85-95% yield.

General Method 20: Coupling of Building Block to Resin The Trichloroacetimidate derivatised resin (IRORI Wang resin ~1 mmol) was weighed into the reaction vessel and washed with THF. The derivatised building block (1.86 mmol) was dissolved in anhydrous DCM (1.2ml), added to the resin and shaken for 3 mins. BF 3 'Et20 (-100l) was added and the reaction vessel shaken continuously for 10 mins. The reaction mixture was filtered under vacuum and the resin washed with THF, DCM, and dried.

General Method 21: Solid Phase Debenzovlation The resin bound sugar was shaken in a solution of THF/MeOH and NaOMe (0.02 Molar) overnight. The reaction was drained and washed with anhydrous THF and repeated as described above. The reaction solvent was drained and the resin washed with THF, a solution of THF: CH 3 COOH: MeOH 8:1:1, THF, and DCM. The resin was dried overnight.

General Method 22: Solid Phase Alkylation The resin was reacted with a 0.25 molar solution of tert-butoxide in DMF min) and then the alkylating agent, (0.25 molar in DMF, 20 min) was reacted with the resin. The resin was washed with DMF and again treated with the two solutions, this procedure was repeated a further four times. The final wash of the resin was performed as above; with DMF, THF/MeOH/ CH 3

CO

2

H

THF, DCM and MeOH. The resin was then dried overnight.

General Method 23: Solid Phase Silyl Deprotection A solution of PSHF (proton sponge hydrogen fluoride) (0.5 Molar in WO 03/082846 PCT/AU03/00384 DMF/Acetic Acid, 95:5) was prepared. The resin was added to the solution and the reaction was stirred at 65 0 C for 24 hours. The resin was then washed with DMF, MeOH/CH 3 COOH/THF, 1:1:8, THF and DCM, and then dried under high vacuum General Method 24: Solid Phase Azide Reduction Resin was placed in a round bottom flask. A solution of tert-Butoxide (0.2 molar) in anhydrous DMF was prepared. DTT (0.2 molar) was added to the tert-Butoxide solution and stirring continued until all DTT dissolved. The solution was poured into the Buchner flask containing the Kans. The reactor was degassed by applying vacuum (15 mbar) and filled with nitrogen. This technique was repeated twice and the reactor shaken at room temperature for 6 hr, allowing the evolved N 2 gas to escape. The reaction solvent was removed from the flask and the Kans washed with DMF, THF, and MeOH before being dried under high vacuum for 12 hours.

General Method 25: Solid Phase N-Acvlation Method 1 Acids were weighed into round bottom flask and DIC (diisopropylcarbodiimide) (0.25 molar) in DMF was added to make a molar solution of the acid. The resultant solution was stirred at room temperature for 1 hour and DMAP (to 0.05 molar) was added. The solution was poured into a reactor containing the Kans and shaken vigorously. The reactor was degassed by applying vacuum (15 mbar) and filled with nitrogen.

This technique was repeated twice and the reactor shaken at room temperature over night. The reaction solvent was removed from the flask and the Kans washed with DMF, MeOH, THF, MeOH, DCM and MeOH.

Method 2: Acids were weighed into round bottom flask and DMF was added to make a M solution, followed by addition of DIPEA (to make 0.5 The solution was stirred until homogeneous and HBTU (to make 0.5 M) was added.

Stirring was continued for additional 30 minutes and the solution was poured WO 03/082846 PCT/AU03/00384 21 into a reactor containing the Kans and shaken vigorously. The reactor was degassed by applying vacuum (15 mbar) and filled with nitrogen. This technique was repeated twice and the reactor shaken at room temperature for overnight. The reaction solvent was removed from the flask and the Kans washed with DMF, MeOH, THF, MeOH, DCM and MeOH.

General Method 26: Solid Phase Nitro Group Reduction A solution of tin(ll) chloride (1 Molar) in a mixture of DMF and water was prepared, filtered, the solution was poured into a reactor containing the Kans and shaken vigorously. The reactor was degassed by applying vacuum mbar) and filled with nitrogen. This technique was repeated twice and the reactor shaken at room temperature for 24 hour. The Kans were washed with DMF, THF, DCM, MeOH and DCM and dried under high vacuum.

General Method 27: Solid Phase Fmoc Removal A 20% v/v solution of piperidine in DMF was prepared and the solution was poured into a reactor containing the Kans and shaken vigorously. The reactor was degassed by applying a vacuum (15 mbar) and then was filled with nitrogen. This technique was repeated twice and the reactor shaken at room temperature for one hours. After one hour the solvent was removed, the Kans were washed with DMF and the deprotection was repeated as above.

The reaction solvent was removed, the Kans washed with DMF, MeOH, THF, MeOH, DCM and MeOH and dried under high vacuum.

General Method 28: Solid Phase Guanylation A solution of 3,5-dimethylpyrazolyl formamidinium nitrate (0.2 molar) in anhydrous DMF was prepared, and DIPEA (to 1 molar) added. The resin in Kans were pooled, added to the solution, and the reaction was stirred at for 24 hours. The reaction solvent was removed from the flask via a vacuum line and the flask shaken to release further solvent from the Kans. The Kans were washed with DMF, THF and DCM and dried under high vacuum.

General Method 29: Cleavage from Resin WO 03/082846 PCT/AU03/00384 22 Cleaving solutions were prepared from DCM triethylsilane TFA The Kans were opened and the resins poured into reactors in the MiniBlock, 0.7 ml of the above cleaving solution was added to each reactor and the reactors were shaken at room temperature for 3 hours. The solutions were collected into test tubes (12x75mm). The resins were washed with DCM.

The washings were combined with the cleavage in the test tubes and the volatile solvents were removed by beta RVC. The residues were dried in the vacuum oven for 48 hours. Analytical samples were obtained by washing the remaining resins with acetonitrile (0.5ml), collected in 96-wells plate and evaporated in alpha RVC. The samples were re-dissolved in acetonitrile and analysed.

General Method 30: DTPM Protection of an Amine To a stirred solution of the amino compound (20 mmol) dissolved in MeOH (150mL) at room temperature was added a solution of DTPM reagent mmol) in MeOH (50mL). After 10 min the product started to crystallise and after 40mins the reaction mixture was filtered. The crystalline residue was washed with ether and dried under vacuum to yield the DTPM protected product in typically 90% yield.

General Method 31: N-Acyl formation using Diisoproplycarbodiimide A solution of the starting material (0.62mmol) in dry DCM was added to a solution of the acid (0.76mmol) and DIC (0.76mmol) in DCM (5 mL). The reaction was stirred for 3h and the reaction mixture then diluted with DCM.

The reaction mixture was washed with 10% citric acid, satd. sodium bicarbonate solution, filtered over cotton and the solvents evaporated.

Column chromatography of the resulting residue provided the product, typically in 90% to near quantitative yields.

General Method 32: Solid Phase Cleavage of the DTPM Protecting Group.

A 5% solution of hydrazine hydrate in DMF was prepared. The cleavage solution was added to resin in a reactor (approx. 1 mL per 100mg of resin) and left to react for four hours. The resin was filtered, and washed with DMF, WO 03/082846 PCT/AU03/00384 23 MeOH, THF, MeOH, DCM and MeOH and then dried under high vacuum.

General Method 33: Selective Benzylidene Ring Opening to the 6-Position.

The benzylidene protected compound (50 mmol) was dissolved in dry N, Ndimethylformamide (400 mL) and added to a flask containing pre-activated 3A molecular sieves (120 To this suspension was added sodium cyanoborohydride (300 mmol) and the resulting reaction mixture stirred for min under nitrogen. The suspension was then cooled to 0°C, and a solution of TFA (650 mmol) in dry N,N-dimethylformamide (80 mL) added in portions, and the suspension then heated at 55°C for 16 h. The suspension was then filtered through a bed of celite and washed several times with chloroform.

These combined washings were then washed with water, 10% citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO4), and the solvent removed in vacuo to leave a yellow foam, which was azeotropically dried with toluene. Typical yields were in the order of 85-95%.

General Method 34: Formation of a Glycosyl Azide.

From the anomeric acetate derivative the glycosyl bromide was prepared as described in General Method 1. To a solution of the bromosugar (50 mmol) in acetonitrile (200 mL) was added TMS-azide (100 mmol) followed by TBAF (100 mmol). The reaction mixture was left to stir for 2 hours at which time the solvent was removed in vacuo, the residue taken up in chloroform, and the resulting solution washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), and the solvent removed in vacuo to leave a solid, typically in 85-95% yield.

WO 03/082846 PCT/AU03/00384 24 Example 1: Synthesis of 1, 5-anhydro-4-azido-3-0-(4-chlorobenzol)-2, 4dideoxv-2-h1, 3-dimethyl-2 (1H, 3H, methvlamino-6-O-(4-methoxybenzl)--qafactitoL.

1-a AcO 1-b O 0 I-C 0HO ACO 0 ACO 0-j AcO--- HO NH OAc ACO AcO- 1 '7HO NHHHN BrI HN

HHN

0 0 0- N

N

J1 20 3 MeOPh-VO0 0 CBzO-' 0 6 0 MeOPh 0~ 0 HO-37

HN

I-e

H

0 CIZ HN HN H H H 0 0 0 N-0 I-a. Synthesis of 2-deoxV-2-[(1 ,3-dimethyl-2,4,6- (I H, 3H, methylaminol-3 ,4,6-O-triacetyl-cc-D-qlucopyranosy bromide Compound 2 was synthesized according to the procedure described in General Method 1. Compound 2, as a white solid. Rf (product) 0.75 in ethyl acetate; 8H (400 MHz; CDCI 3 2.00 (3 H, 2.05 (3 H, 2.09 (3 H, s), 3.29 (3 H, 3.30 (3 H, 3.78 (1 H, dt, J 9.9 Hz and J 3.6 Hz), 4.13 (1 H, dd, J 13.4 Hz and J 3.0 Hz), 4.35 (2 H, in), 5.19 (1 H, t, J 9.8 Hz), 5.46 (1 H, t, WO 03/082846 PCT/AU03/00384 J 9.8 Hz), 6.50 (11 H, d, J 4.0 Hz), 8.13 (1 H, d, J 13.6 Hz) and 10.30(11 H, br t, J 11.6 Hz); LCMVS [M+Hf=534.

1-b. Synthesis of 1, 5-anhyd ro-2-deoxV-2-r(1 ,3-dimethVl-2 (11H, 3H, trioxopyrimidin-5-ylidene) methylaminol-3,4,6-0-triacetyl-D-glucitoI Compound 3 was synthesized according to the procedure described in General Method 2. Compound 3, quantitative yield; Rf (product) Z 0.65 in ethyl acetate., 8H (400 MHz; CDC13) 2.03 (3 H, 2.04 (3 H, 2.09 (3 H, s), 3.28 (3 H, 3.30 (3 H, 3.53 (11 H, t, J 11.2 Hz), 3.68 (2 H, in), 4.14 (2 H, in), 4.25 (1 H, dd, J 12.6 Hz and J 5.0 Hz), 5.04 (1 H, t, J 9.4 Hz), 5.16 (11 H, t, J 9.6 Hz), 8.13 (1 H, d, J 13.6 Hz) and 10. 10 (1 H, br t, J 11.4 Hz); 5c (400 MHz; ODC1 3 21.04 (OH 3 x 21.17 (CH 3 27.63 (OH 3 28.33 (CH 3 60.36 62.32 (CHA) 68.29 68.62 (OH 2 73.98 76.97 92.65 151.97 158.84 162.65 164.91 169.57 170.36 (C) and 170.65 LCIMS [M+H]+=456.

1-c. Synthesis of I .5-anhyd ro-2-deoxy-2-[(1 ,3-dimethyl-2,4,6- (1 H, 3H, trioxopyrimid in-5-ylidene) methylaminol-D-cducitOl Compound 3 was treated as described by General Method 3 to provide 4; Rf (product) 0.00 in 1:1 ethyl acetate/light petroleum (40-600C), (S.M 5-0.4).

When system changed to 9:1 acetonitrilefinethanol, Rf (product) P 0.4. (S.M 8H (400 MHz; DMSO) 3.13 (3 H, 3.14 (3 H, 3.47 (3 H, mn), 3.65 (3 H, dd), 3.85 (1 H, d, J 6. 0 Hz), 4.52 (1 H, t, J 5.8 Hz), 5.11 (1 H, d, J 4.8 Hz), 5.28 (1 H, d, J 5.6 Hz), 8.18 (11 H, d, J 14.4 Hz) and 10.03 (1 H, br t, J 8.4 Hz); 80 (400 MHz; DMS0) 27.63 (OH 3 28.29 (OH 3 62.00 (OH 2 62.90 (OH), 67.68 (OH 2 71.37 75.42 82.22 152.18 (C x 160.18 162.71 and 164.37 LOMS [M+H]=330.

1 Synthesis of 1, 5-anhydro-2-deoxy-2-[(1I,3-dimethyl-2,4,6- (1H, 3H. 3 0 trioxopjyrimidin-5-ylidene) m ethyl am ino-4,6-0-(4-m ethoxvybenzyjlide ne)-Dcilucitol Compound 4 was treated as described by General Method 4, to give the desired product 5 as a solid Rf (product) z0. 1 in 1: 1 ethyl acetate/light WO 03/082846 PCT/AU03/00384 26 petroleum (40-601C), 5H (400 MHz; CDCI 3 3.29 (3 H, 3.30 (3 H, 3.48 H, in), 3.70 (1 H, t, J 10.2 Hz), 3.81 (3 H, 3.83 (1 H, in), 4.11 (1 H, in), 4.32 (1 H, dd, J 10.4 Hz and J 4.8 Hz), 5.51 (1 H, 6.90 (2 H, d, J 8.8 Hz), 7.40 (2 H, d, J 8.4 Hz), 8.24 (1 H, d, J 13.6 Hz) and 10.20 (1 H, br t, J 11.5 Hz); LOMS [M+H]+=448.

I Synthesis of 1 ,5-anhyd ro-3-O-(4-ch lorobenzoyl)-2-deoxv-2-F(l 1 3dimethvl-2 (11H, 3H, 5H)-trioxopyrimidin-5-vlidene) methylaminol-4,6-O- (4-methoxybenzlidene)-D-llucitoI Compound 5 was treated according to General Method 5, to give the product 6 as a off-white solid Rf (product) 0.33 in 1:1 ethyl acetate/light petroleum (40-601,C). (S.Mz; 0.17); 5H (400 MHz; CDC1 3 3.24 (3 H, 3.25 (3 H, 3.72 (8 H, rn), 4.14 (1 H, t, J 5.5 Hz), 4.35 (11 H, t, J 5.4 Hz), 5.50 (11 H, 5.57 (1 H, t, J 9.6 Hz), 6.82 (2 H, dd, J 6.6 Hz and J 2.2 Hz), 7.30 (2 H, dd, J 6.8 Hz and J 2.0 Hz), 7.38 (2 H, dd, J 6.8 Hz and J 2.0 Hz), 7.93 (2 H, dd, J 6.6 Hz and J 2.2 Hz), 8.12 (1 H, d, J 13.6 Hz), and 10.20 (11 H, br t, J 11.6 Hz); LOMS [M+Hf=586.

1-f. Synthesis of 1, 5-a n hydro-3-O-(4-ch lo robe nzoyl)-2-d eox-2-Y1 ,3-d imethl- 2,4,6- (1 H, 3H, 5H)-trioxopyrimidin-5-vlidene) methylaminol-6-O-(4methoxybenzl)-D-ci Iucitol Compound 6 was treated according to the procedure described in General Method 33 to give the product 7 as an off-white foam Rf (product) 0.26 in 1:1 ethyl acetate/light petroleum (40-601C). (S.M z0.33); 5H (400 MHz; CDCI 3 3.23 (3 H, 3.24 (3 H, 3.51 (2 H, in), 3.80 (8 H, in), 4.13 (1 H, dd, J 11.4 Hz and J 5.4 Hz), 4.52 (2 H, q, J 11.2 Hz), 5.27 (1 H, t, J 9.6 Hz), 6.87 (2 H, d, J 8.8 Hz), 7.26 (2 H, in), 7.40 (2 H, d, J 8.8 Hz), 7.93 (2 H, d, J 8.8 Hz), 8.11 (1 H, d, J 13.6 Hz), and 10.30 (1 H, br t, J 11.5 Hz); LOMVS [M+HI+=588.

I-g. Synthesis of 1,5-an hydro-4-azidc-3-O-(4-ch lorobenzovl)-2 .4-d ideoxv-2- ,3-diinethyl-2,4,6- (I H, 3H, 5H)-trioxopyriiidin-5-ylidene) iethylaminol-6- O-(4-methoxybenzyl)-D-galactitoI WO 03/082846 PCT/AU03/00384 27 Compound 7 was treated according to the procedure described in General Method 6 to give compound 8, Rf (product) 0.62 in 1:1 ethyl acetate/light petroleum. Product recrystallised from isopropanol; LOMVS [M+H]=61 3.

1-h. Synthesis of 1, ,5-anhyd ro-4-azid o-3-O-(4-cho robe nzovl)- 2 ,4-d ideoxy-2- 1,3-dimethyl-2,4,6- (1 H, 3H, 5H)-trioxopyrimidin-5-Vlidene) methVlamingL-Dcialactitol Compound 8 was reacted according to General Method 3, to give the desired product 9 as a white foam, 8H (400 MHz; COC13) 3.25 (3 H, 3.26 (3 H, 3.65 (5 H, in), 3.80 (3 H, 4.09 (3 H, in), 4.50 (2 H, q, J 9.5 Hz and J 3.6 Hz), 6.89 (2 H, d, J 8.8 Hz), 7.26 (2 H, d, J 8.8 Hz), 8.21 (1 H, d, J 13.6 Hz), and 10. 15 (1 H, br t, J 11.4 Hz); LOMS [M+H]1*475.

WO 03/082846 PCT/AU03/00384 28 Example 2: Synthesis of a Galactitol Library Preparation of Intermediates; General Procedures for Alkylation of the C-3 Position and Removal of the DTPM Group

N

3 OBnOMe

HOJ:X

9 NHDTPM 2-a I 2-a 2 a 2-a 2-a. Alkylation of the C-3 Position: Preparation of compounds 10,11 and 12.

Compounds 10, 11, and 12 were prepared according to General Method 7.

Analytical Data Compound No. 10 11 12 503 1589 1 589 2-b. Removal of the DTPM Group at the C-2 Position. Preparation of Compounds 13, 14, 15 and 16.

Compounds 13, 14, 15, and 16 were prepared according to General Method 8.

Analytical Data.

Compound 13 14 15 16 337 423 309 423 Data for 5-Azido-4-ethoxy-6-(4-methoxy-benzyloxymethyl)-tetrahydro-pyran-3 ylamine (13) Yellow oil, yield (100 8H (400 MHz; CDCI 3 1.27 (3 H, t, J 7.0 Hz), 1.50 (2 H, br 3.06 (1 H, t, J 11.0 Hz), 3.21 (2 H, 3.52 (4 H, 3.78 (4 H, m), 3.93 (1 H, dd, J 10.8 Hz and J 4.6 Hz), 4.04 (1 H, d, J 3.2 Hz), 4.48 (2 H, q, J WO 03/082846 PCT/AU03/00384 29 14.8 Hz and J 11.6 Hz), 6.88 (2 H, d, J 8.4 Hz) and 7.26 (2 H, d, J 8.8 Hz); LOMVS [M+H]-=337.

2-c. Preparation of Intermediates: General Procedures from Preparation of Derivatives at the C-2 Position Compounds 17 to 51 were individually prepared according to one of General Methods 9, 10, 11 and 12.

N

3 OBnOMe

N

3 OBnOMe RJN42\ R20 -j

NH

2 NR1 13. R2 CH 2

CH

3 175 14. R2 CH 2

C(CH

3 2 C(O)OMe R2 H 16. R2 CH 2 C(O) t Bu Analytical Data: Example of a product of General Method 9: [3-A zido-5-(3-tertbutoxycarbonylminopropioylamino)2(4-methoxybezyloxymethy)tetrahydro-pyran-4-yloxy]-acetic acid tert-butyl ester (33) Sugar (16) (3.1 mmol) coupled to Boc-p-alanine (3.2 mmol) gave the title compound (33) as an off-white solid, in 69% yield after column chromatography (silica; 50% ethyl acetate in light petroleum (40-60 0 8H (400 MHz; CDCI 3 1.42 (9 H, 1.49 (9 H, 2.43 (2 H, t, J 6.4 Hz), 2.95 (1 H, t, J 10.2 Hz), 3.48 (6 H, in), 3.81 (3 H, 4.07 (4 H, mn), 4.47 (3 H, q, J 11.4 Hz and J 6.8 Hz), 5.24 (1 H, br. 6.89 (2 H, d, J 8.8 Hz), 7.25 (2 H, d, J 8.4 Hz) and 7.51 (1 H, br. d, J 5.2 Hz); LCMS [M+H]=594.

Example of a Product of General Method 9: Acetic acid [5-azido-4-hydroxy-6- (4-methoxy-benzyloxymethyl)-tetrahydrO-pyran7-3-Ylcarbamoyll-methyl ester Sugar (15) (4.2 mmol), was coupled to acetoxyacetic acid (4.3 minol) and after trituation with diethyl ether gave the title compound (45) as a white solid in 64%, 8H (400 MHz; CDCI 3 2.17 (3 H, 3.19 (1 H, t, J 10.8 Hz), 3.44 (1 H, WO 03/082846 PCT/AU03/00384 d, J 7.2 Hz), 3.60 (3 H, 3.76 (1 H, 3.80 (3 H, 4.06 (3 H, 4.49 (2 H, q, J 10.2 Hz and J 2.4 Hz), 4.56 (2 H, 6.04 (1 H, d, J 6.8 Hz), 6.89 (2 H, d, J 6.8 Hz) and 7.26 (2 H, d, J 8.8 Hz); LCMS [M+H+Na]+=431.

Example of a product of General Method 9: N-[5-Azido-4-hydroxy-6-(4methoxy-benzyloxymethyl)-tetrahydro-pyran-3-yl]-succinamic acid methyl ester (18) Sugar (15) (4.5 mmol), coupled to succinic acid mono methyl ester (4.8 mmol), after trituation with diethyl ether gave the title compound (18) as a white solid; 6 H (400 MHz; DMSO) 2.35 (2 H, dt, J 6.9 Hz and J 2.4 Hz), 2.47 (2 H, t, J 6.8 Hz), 2.89 (1 H, t, J 10.8 Hz), 3.43 (2 H, dd, J 5.8 Hz and 2.6 Hz), 3.56 (3 H, 3.64 (2 H, dd, J 11.0 Hz and J 5.0 Hz), 3.73 (3 H, 3.80 (3 H, 4.39 (2 H, q, J 10.9 Hz), 5.48 (1 H, d, J 4.4 Hz), 6.89 (2 H, dd, J 6.4 Hz and J 2.8 Hz), 7.23 (2 H, d, J 8.8 Hz) and 7.73 (1 H, d, J 8.0 Hz); 6c (400 MHz; DMSO) 29.65 (CH 3 30.80 (CH 3 48.62 (CH 2 52.12 (CH 2 55.86

(CH

2 63.92 (CH 2 68.56 69.85 72.18 72.76 76.20

(CH

2 114.30 (CH x 129.03 (CH x 130.68 159.32 171.73 (C) and173.35 LCMS [M+H+Na]f=423.

Example of a product of General Method 10; {3-[5-Azido-4-hydroxy-6-(4methoxy-benzyloxymethyl)-tetrahydro-pyran-3-yl]-ureido}-acetic acid ethyl ester (41) Compound 41, white solid, yield 66%; SH (400 MHz; DMSO) 1.17 (3 H, t, J6.8 Hz), 2.88 (1 H, t, J 10.6 Hz), 3.31 (2 H, 3.42 (2 H, 3.67 (9 H, 3.85 (1 H, dd, J 3.2 Hz and J 1.2 Hz), 4.06 (2 H, q, J 7.0 Hz), 4.39 (2 H, q, J 10.7 Hz), 5.56 (1 H, d, J 4.4 Hz), 6.09 (1 H, d, J 6.8 Hz), 6.28 (1 H, t, J 5.8 Hz), 6.89 (1 H, d, J 6.8 Hz) and 7.22 (1 H, d, J 6.8 Hz); 5c (400 MHz; DMSO) 15.03 (CH 3 42.28 (CH 2 x 49.30 (CH 3 55.88 61.00 (CH 2 64.13 69.47 (CH 2 69.84 (CH 2 72.74 76.06 114.30 (CH x 2), 129.03 (CH x 130.68 158.56 159.32 and 171.57 LCMS =438.

Example of a product of General Method 11: [5-Acetylamino-3-azido- 2 4 WO 03/082846 PCT/AU03/00384 31 methoxy-benzyoxy-methy-tetrahydrO-pyra-4-YIoxy-aCetic acid tert-butyl ester (36) Derivatisation of the t-butyl sugar (16) (3.1 mmol) gave the title compound 36 as a yellow oil, 89%, 8H (400 MHz; ODC1 3 1.43 (9 H, s, C(CH 3 1.94 (3 H, 2.88 (1 H, t, J 10.0 Hz), 3.45 (4 H, mn), 3.74 (3 H, 4.04 (4 H, m),4.40 (3 H, in), 6.82 (2 H, d, J 8.8 Hz), 7.19 (2 H, d, J 8.8 Hz) and 7.41 (1 H, br d, J 5.2 Hz); LOMS [M+H]"=465.

Example of a product of General Method 12: 3-[3-Azido-2-(4-methoXybenzyloxymethyl)-5-(2-methoxycarboflyl-acetYlamio)-terahydro-PYrafl- 4 yloxy]-2,2-dimethyl-propionic acid methyl ester (51) Derivatisation of the pivolate sugar (14) (3.6 mmol) gave the title compound as a brown oil (51) 75 8H (400 MHz; CDC1 3 1.16 (3 H, 1.24 (3 H, s), 3.35 (3 H, in), 3.57 (6 H, mn), 3.68 (3 H, 3.73 (3 H, 3.81 (3 H, 4.28 (3 H, in), 4.46 (2 H, q, J 12.0 Hz and J 11.6 Hz), 6.89 (2 H, d, J 6.4 Hz) and 7.26 (2 H, d, J 6.0 Hz); LOMS IM+H*523.

The table below represents all compounds made with derivatives at the 2position.

WO 03/082846 32 Table 1: Intermediates for synthesis of Galactitol Library.

PCTIAU03/00384 "'NHRi No. I1 I R2* 1Molecular Ion Molecular Ion 17 Ria _R2d [M+H]f=537 35 Rif R2a =508 18 Ria R2c [M+Na] 4 =423 36 Rig R2d =465 19 Ria R2a [M+H] 4 =451 37 R~g R2c [M+H] 4 Ria R2b [M+H]+=537 38 Rig R2a [M+H]+=379 21 Rib R2d [M+H +=565 39 Rig R2b [M+H]+=465 22 Rib R2c [M+H] 4 =451 40 Rih R2d [M+H]+=552 23 Rib R2a [M+H]'=479 41 Rlh R2c =438 24 Ric R2d [M+H ]=656 42 Rih R2a =466 Ric R2c [M-IH] 4 =542 43 Rlh R2b [M+H]+=552 26 Ric R2a _[M+Hf=570 44 Rh R2d [M+H +=523 26 Rid R2d [M+H] 4 =656 45 Ru R2c [M+Nal+=431 28 Rid R2c [M+Hf=542 46 Rh R2a [MjH]f=437 29 Rid R2a [M+H 4 570 47 Rli R2b [M1H] 4 523 Rie R2d [M+Hf=6i3 48 Rlj __R2d 1!YiH]+=523 31 Rie R2c [M+Hf=499 49 Rij __R2c [M+Hf409 32 Rie R2a [M+Hf=527 50 Rij__ R2a [M+Hf"=437 33 Rif R2d [M+H]+=594 51 Rlj R2b [M+H]f=523 34 Rif- R2c [M+Hf=480 *Sidearms for Tables 1 and 2 can be found at the end of Table 2.

2-d. Preparation of derivatives reduced at the C-4 Position Compounds 52 to 86 were prepared according to General Method 13.

NOBnOMe ~~2d R201

HR

17-51 1 H N OBnOMe 0NHRi 62-86 WO 03/082846 33 Table 2: Observed molecular ions of reduced azides PCT/AIJO3/00384 0R2 No. RI R2 Molecular [on No. RI R2 Molecular Ion 52 RIa R2d [M+H]=6ii 70 Rif R2a [M+H]r=482 53 Ria R2c [M+H]+=397 71 Rig R2d [Mi-H]+-439 54 Rla R2a fM+H]+=425 72 Rig R2c Na Data Ria R2b No Data 73 Rig R2a [M+Hj+=353 56 1Rib R2d [M+H]=539 74 Rig R2b [M+jH]E=439 57 RI b R2c [M+H]+=425 75 Ri h R2d =5 6 68 Rib R2a [M+Hl -453 76 Rih R2c [MjH]f-412 59 Rio R2d [M+Hl+=588 77 Rih R2a [M+H]+=440 RIc R2c [M+H]+=474 78 Rlh R2b 1M+H+=526 I (loss of acetate) '61 Ric R2a LM+H]=502 79 Ri R2d [M+H]=497 loss of acetate) 62 Rid Rd [M H]+=588 80 Rli R2c [M+H]+=383 63 Rid R2c [M+HI'474 81 Rli R2a [M+H]+=4i1 (___loss of acetate) 64 Rid R2a [M+H]+"544 82 Rli R2b _[M+H]=497 Rie R2d [M+Hlf=587 83 RiJ R2d _[M+HV=497 66 Rie R2c [M+H]+=43i 84 -Rij R2c [M+Hf383 loss of acetate) 67 Rie R2a [M+H]f=501 85 Rli R2a M+H]+=411 68 Rif R2d [M+H]f=568 86 RIh R2b =497 169 Rif R2c [M+H]=454 WO 03/082846 34 Sidearms for Example 2: Tables 1 and 2.

PCTIAU03/00384

H

3 O CH 3 MeOw-X

H

3 C-y o R2a R2b R2c 0 0 SS- OMe OMe 0 D4- 0

H

3 C 0

H

3 C>K

CH

3 0 R2d CAc

H

0 R~c 0 NyO0 OH 3 DAc Y -KH 0Rif O H 3 M~ IU Rie

OH

3 I-I Nk-OE 0Rig 0Rlh 0

OAN'CH

3 0 Rli 0OH 0 RIj 2-e. Final N-Acvlation of Galactitol Derivatives in the C-4 Position.

Compounds 87 to 416 were prepared in an automated fashion using chemistries according to General Method 9. As required, protecting groups on the sidearms, or the ring were hydrolytically cleaved in either a base or acid catalysed fashion, using either General Method 14 or

H

2 N Bn0Me 2-

NHRI

52-86 R3HN OH R20 0,

NHRI

87-416 WO 03/082846 Table 3: Library of I ,5-Anhydro-cialactitol Compounds PCTIAU03/00384 Compound No. RI R2 R3 Yield Rento TieHL (inL) Method 87 Ria R2a R3a 70 4.72 A 88 RIa R2a R3b 83 4.28 A 89 Ria R2a R3c 74 4.90 A Ria R2a R3d 38 4.44 A 91 Ria R2a R3e 10 4.73 A 92 Ria R2a R3f 44 4.53 A 92 Rib R2a R3b 54 4.73 A 94 Rib R2a R3g 77 4.35 A Rio R2a R3h 82 5.33 A 96 Rio R2a R3a 50 4.28 A 97 Rio R2a R3c 42 4.00 A 98 Rio R2a R3d 85 4.46 A 99 Rio R2a R3f 21 4.62; A 100 Rid R2a R3h 84 4.55 A 101 Rid R2@ R3a i00 4.56 A 102 Rid R2a R3b 91 4.72 A 103 Rid R2a R3o 70 4.64 A 104 Rid R2a RMd 92 5.27 A 105 Rid R2@ R3f 50 4.73 A 106 Rie R2a R3i 100 3.54 A 107 Rle R2a R3i 61 4.53 A 108 Rle R22 R3b- 97 5.74 A 109 Rie R2a RMd 93 6.02 A 110 Rie R2@ M~e 10 6.18 A 'I'l Rie R2a R3f 62 5.74 A 112 Rif R2a R3b 80 4.55 A 113 Rlf R2a RMd 36 5.17 A ___114 Rig_ R22 R3j 100 4.55 A 115 Rig R2a R3k 96 5.36 A 116 RIg R22 R31 100 16.66 A 117 Rig R2a R3m 100 7.01 A 118 Rig R2a R3n 100 6.39 A 119 Rig R22 R3o 97 4.44 A 120 Rig IR2a R3o 95 4.37 A 121 Rig R2a R3p 90 5.40 A 122 RIf R2a R3j 90 14.92 A 123 Rif R2a R3k 93 5.14 A 124 Rif R2a RUn 96 6.84 A 125 R~f R2a R3n 95 7.19 A 126 Rif R2a IR3o 72 6.48 A WO 031082846 WO 03182846PCT/AU03/00384 127 Rif R2a R3g 63 2.60 A)k 128 Rih R2a R31 79 4.07 A 129 Rlh R2a R3m 77 3.52 A 130 Rlh R2a R3n 100 4.09 A 131 Rih R2a R3o 54 5.36 A 132 Rih R2a R3g 74 5.50 A 133 Rlh R2a R3p 91 3.78 A 134 Rli R2a R3m 79 4.05 A 135 Rli R2a R3r 77.5 1.50 A 136 Rli R2a R3s 69 3.77 A 137 Rli R2a R3t 100 5.26 A 138 Rli R2a R3n 93 5.38 A 139 Rli R2a R3v 71 3.83 A 140 Rli R2a R3m 87 4.79 A 141 Rlj R2a R3n 95 5.65 A 142 Rlj R2a R3r 78 5.08 A 143 Rlj R2a R3s 81 5.65 A 144 Rlj R2a R3t 98 5.27 A 145 Rlj R2a R3n 93 5.08 A 146 Rli R2a R3v 99 4.92 A 147 Rib R2a R3m 90 4.92 A 148 Rlb R2a R3n 45 5.10 A 149 Rlb R2a R3r 97 5.17 A 150 Rlb R2a R3s 89 5.19 A 151 Rib R2a R3t 82 5.54 A 152 Rlb R2a R3n 95 5.63 A 153 Rlb R2a R3v 62 6.39 A 154 Ria R2b R3b 95 6.73 A 155 Rla R2b R3d 100 17.49 A 156 Rib_ R2b R3b 97 6.37 A ___157 Rib R2b RMd 97 5.00 A 158 Rio R2b R3w 16.5 7.47 A 159 Rio R2b R3b 98.5' 5.27 A 160 Rlc R2b R3d 99 5.01 A 161 Rio R2b R3g 40 4.09 A 162 Rid R2b R3b 70.5 4.72 A 163 Rid R2b RMd 69 5.74 A 164 Rid R2b R3g 95 5.19 A 165 Rie R2b R3w 80 4.62 A 166 Rie Rt R3b 100 4.28; A 167 Rie R2b RMd 100 4.62 A 168 Rie R2b R3g 63 14.28 A 169 Rif R2b R3d 97 14.44 A 170 Rlf R2b R3j 100 14.37 A 171 Rif R2b R3k 91 4.62 A 172 Rif R2b R31 97 4.18 A 173 Rif R2b R3m 65 4.07 A 174 Rif R2b R3x_ 91 4.64 A 175 Rif R2b R3g 54 4.99 A 176 Rlh R2b R3j 85 6.94 A 177 Rih R2b R3k 100 6.09 A 178 RIF R2b R31 100 4.92 A -l R2b IR3m 1 92 4.53 A 180 jRlh R2b RUx 90 15.19 181_ _3 m 1 14.61__ A_ 18I Rli R2b Rm 83 J46____ WO 03/082846 WO 03/82846PCT/AIJO3/00384 182 Rli R2b R3p 15 1.69- A 183 Rli R2b R3r 100 4.09 A 184 Rli R2b R3s 100 1.69; A 185 Rli R-ib R3t 96 4.18 A 186 Rli R2b R3u 100 4.46 A 187 Rli R2b R3v 100 4.94 A 188 Rlj R2b R3m 97 1.71 A 189 R14 R2b R3p 98 1.69 A 190 R1j R2b R3r 84 2.07 A 191 Rij R2b R3s 100 2.26 A 192 Rlj R2b R3t 100 1.69 A 193 Ri[ R2b R3u 70 2.26 A 194 R1IF R2b R3v 100 1.6 A 195 RI[ R2b Rg 100 3.00 A 196 Rla- R2c R3w 100 4.41 A 197 Ria R2c R3a 50 0.55 A 198 Rla R2c R3b 96 1.78 A 199 Ria R2c R3c 58 1.69 A 200 Ria R2c RMd 95 2.35 A 201 Ria R2c R3f 32 2.26 A 202 Ria R2c R3g 6 4.14 A 203 Rib R2c R3b 100 3.94 A 204 Rib R2c RMd 100 4.75 A 205 RIb R2c R3f 32 14.9 A 206 Rib R2c R3i 83 1.8 A 207 Ric R2c R3w 77 1.69 A 208 Ric R2c R3a 44 2.17 A 209 Ric R2c R3b 99 4.33 A 210 Rio R2c R3c 43 2.26 A 211 RIc R2c RMd 93 3.34 A 212 Rid R2c R3c 94 4.18 A 213 Rid R2c Rd 90 5.36 A 214 Rld R2c RMe 15 2.17 A 215 Rid R2c R3f 91 1.89 A 216 Rie R2c RNi 100 1.78 A 217 Rie R2c R3w 97 4.55 A 218 Rie R2c R3a 80 6.20 A 219 Rie R2c R3b 94 3.25 A 220 Rie R2o R3c 62 4.09 A 221 Rie R2c RMd 91 4.35 A 222 Rie R2c R3f 37 4.48 A 223 Rif R2c R3b 100 4.83 A 224 Rif R2o RMd 96 5.28 A 225 Rig R2c R3j 100 1.78 A 226 Rig R2c R3k 100 4.00 A 227 Rig R2c R31 100 4.00 A 228 Rig R2c R3m 100 5.74 A 229 Rig -R2c R3x 100 3.73 A 230 RIg Rc R3o 100 5.10 A 231 Rig R2c R3g 100 4.09 A 232 Rig R2c R3p 98 5.56 A 233 Rig R2c R3r 95 6.55 A 234 Rif [R2c R31 88 6.39A 235 Rif IR2cI R3k 85 5,13 A 236 Rif I~ R3I947

A

WO 03/082846 PCT/AU03/00384 237 Rif R2c R3m 94 3.82 A 238 Rlf R2c R3x 84 4.09 A 239 Rif R2c R3o 98 3.08 A 240 Rlf R2c R3q 98 3.54 A 241 Rlf R2c R3p 94 3.73 A 242 R1h R2c R3j 100 3.91 A 243 R1h R2c R3k 86 5.36 A 244 Rlh R2c R31 98 4.83 A 245 R1h R2c R3m 96 2.35 A 246 R1h R2c R3x 100 5.28 A 247 Rlf R2c R3r 88 5.13 A 248 R1h R2c R3o 97 4.78 A 249 Rih R2c R3q 98 4.88 A 250 Rlh R2c R3p 98 4.53 A 251 Rlh R2c R3q 100 4.68 A 252 Rli R2c R3m 91 4.73 A 253 Rli R2c R3p 100 4.88 A 254 Rli R2c R3s 98 4.73 A 255 Rli R2c R3t 82 5.37 A 256 Rli R2c R3u 100 6.50 A 257 Rli R2c R3v 52 5.18 A 258 Rlj R2c R3m 92 5.23 A 259 Rlj R2c R3p 98 5.03 A 260 Rlj R2c R3r 4 5.18 A 261 Rlj R2c R3s 100 5.28 A 262 Rlj R2c R3t 94 5.13 A 263 R1j R2c R3u 100 5.0;0 A 264 Rlj R2c R3v 100 6.39 A 265 R1 R2c R3g 71 4.99 A 266 Rib R2c R3m 100 4.83 A 267 R1b R2c R3p 98 6.50 A 268 Rib R2c R3r 100 4.92 A 269 Rib R2c R3s 63 5.14 A 270 R1b R2c R3t 95 6.84 A 271 Rlb R2c R3u 91 7.19 A 272 Rib R2c R3v 95 6.48 A 273 R1b R2d R3i 55 2.60 A 274 R1b R2d R3w 11 3.52 A 275 Rib R2d R3a 48 3.75 A 276 R1b R2d R3b 48 5.36 A 277 Rib R2d R3d 85 5.50 A 278 R1b R2d R3e 11 3.78 A 279 Rib R2d R3f 46 4.05 A 280 Rlf R2d R3i 73 1.50 A 281 Rlf R2d R3w 21 3.77 A 282 Rif R2d R3b 81 5.26 A 283 Rlf R2d R3d 91 5.38 A 284 Rif R2d R3f 78 3.83 A 285 R1g R2d R3j 100 4.79 A 286 R1g R2d R3k 100 5.65 A 287 Rig R2d R31 100 5.08 A 288 Rig R2d R3m 100 5.65 A 289 Rig R2d R3o 100 5.27 A 290 Rig R2d R3r 100 5.08 A 291 Rif R2d R3j 72 4.92 A WO 03/082846 WO 03/82846PCTIAU03/00384 292 Rif R2d R31 100 5.08 A 293 Rif R2d R3x 28 5.10 A 294 Rif R2d R3o 25 5.17 A 295 Rif ER2d R13r 100 5.19 A 296 Rlh R2d R3k 7 2 5.54 A 297 Rlj R2d R~ 56 5.63 A 298 Rlj R2d R3r 66 5.10 A 299 Rij R2d R3t 42 6.73 A 300 Rlj R2d R~U 100 7.49 A 301 Rlj R2d R3v 100 6.37 A 302 RIb R2d R3r 5 5.00 A 303 Rib R2d R3u 100 7.47 A 304 RIc R2a R3b 100 5.27 A 305 Rle R2a R3w 88 4.72 A 306 Rla R2a Ry 64 4.61 A 307 RIb R2a R3h 95 1.69 A 308 Rib R2a R3w 13 4.09 A 309 Rib R2a R3a 76 1.69 A 310 Rib Rk2a RYf 59 4.18 A 311 Ric R2a R3y 90 4.46 A 312 Rle R2a R3z 84 4.94 A 313 Rif Ra R1 100 1.71 A 314 Rif R2a -R3w 72 1.69 A 315 Rif R2a R3a 64 2.07 A 316 RIf Ra R3e 8 2.6A 317 Rif R2a R3f 98 1.69 A 318 Rli R2a R31 42 2.26 B 319 Rli R2a R2 78 1.60 B 320 RIh R2a R32 56 3.00 B 321 Rla R2b R33 70 4.41 A 322 Rla R2b R3f 90 0.55 A 323 Rib R2b R3w 94 1.78 __B 324 Rib R2b R3c 69 1.69 B 325 Rib R2b R3e 12 2.35 B 326 R 1d- R0 b R3l- -98 2.26 B 327 Rid R2b R 3z 78 4.14 A 328 Rid R2b R3w 82 2.33 B 329 Rle R2b R~ 6 4.75 A 330 Rle R2b R3c 81 4.9 B 331 Rif R2b R31 100 1.8 B 332 Rif R2b R3w 91 1.69 B 333 Rif R2b R3c 93 2.17 B 334 Ria R2c R3z 52 4.33 A 335 Rib R2 C R3i 98 2.26 B 336 Rib R2c R3a 28 3.34 B 337 Rid R 2c R 3z -60 -4.18 A 338 Rle R2c R3z 23 4.73 A 339 Rif R2c Ri 100 21 340 Rif R2c R3z 87 1.89 A 341 Rif R: c R3c 1100 2.35 B Rif I R2C I RY 148 4.55 B

A

343 Rib IR2d IR3s 150 F F F t

T

343 Rib I R2d I R3s 1 50 Ria I R2b IRli 3.25

A

A

A

I 345 1 I I-Ria I R2b FR3W 110 4.09 R12 IR9r~ R 3e 1 34 14.35 WO 03/082846 PCT/AU03/00384 347 Rib R2a R3e 53 4.48 A 348 Rlf R2a R3c 76 1.78 A 349 Rib R2b R3i 85 1.48 B 350 Rib R2b R3a 19 1.78 B 351 Ric R2a R3g 41 5.74 A 352 Rid R2a R3w 80 3.73 A 353 Rlh R2d R3x 46 5.13 A 354 Rib R2a R3d 62 5.00 A 355 Rli R2b R32 53 1.41 B 356 Rlj R2b R32 75 1.67 B 357 R1b R2b R32 41 1.72 B 358 Rib R2b R3m 52 4.88 A 359 R1b R2b R3r 84 4.49 A 360 Rlb R2b R3s 64 5.57 A 361 Rib R2b R3t 63 6.87 A 362 Rib R2b R3u 100 7.13 A 363 Rib R2b R3v 51 6.44 A 364 Rli R2c R32 100 59 B 365 Rlj R2c R32 42 3.36 B 366 R1b R2c R32 60 4.1 A 367 R1 R2d R32 7 4.14 A 368 R1b R2d R32 25 4.53 A 369 R1a R2e R3c 87 4.26 A 370 Rlc R2e R3a 85 4.46 A 371 R1h R2e R3o 53 4.73 A 372 R1i R2e R3v 100 5.57 A 373 Rik R2b R3b 25 5.19 A 374 R11 R2b R3b 95 5.28 A 375 R1l R2b R3d 100 5.38 A 376 Rim R2b R3d 50 4.73 A 377 R1n R2b R3k 53 4.55 A 378 R1k R2c R3b 72 5.36 A 379 R1k R2c R3d 54 5.56 A 380 Rik R2c R3u 74 7.68 A 381 R1b R2f R3i 47 4.48 A 382 R1b R2f R3b 90 5.68 A 383 Rib R2f R3d 84 5.78 A 384 Rlf R2f R3i 69 4.28 A 385 Rlf R2f R3b 83 5.58 A 386 Rif R2f R3d 89 5.68 A 387 R1g R2f R3m 45 5.68 A 388 Rif R2f R3o 66 5.48 A 389 Rlf R2f R3p 32 5.27 A 390 R1h R2f R3k 59 6.28 A 391 Rlh R2f R31 91 5.65 A 392 Rlh R2f R3p 97 5.82 A 393 Rlh R2f R3r 97 5.01 A 394 Rlj R2f R3m 81 5.28 A 395 Rlj R2f R3p 91 5.78 A 396 Rlj R2f R3t 92 6.78 A 397 R1j R2f R3u 99 7.33 A 398 Rlj R2f R3v 100 6.63 A 399 Rib R2f R3p 89 5.91 A 400 R1b R2f R3s 82 6.18 A 401 Rib R2f R3t 100 7.03 A WO 03/082846 PCT/AIJO3/00384 402 Rib R2f R3u 88 7.83 A 403 Rll R2b R3i ,54 4.4 A 404 Ric R2e R3i 70 3.82 A 405 Rll R2a R3c 39 4.46 B 406 Rlh R2c R3z 69 4.18 A 407 Rlf R2f R33 21 10.48 A 408 Rlh R2f R3m 58 5.58 A 409 Rlh R2f RNx 92 5.60 A 410 Rlj R2f R3g 73 6.2 A 411 Rlb R2f R3m 46 5.68 A 412 Rlk R2b R3r 50 5.14 A 413 Rik R2b R3s 54 6.05 A 414 Rlk R2b R3t 88.5 7.15 A 415 Rik R2b R3u 100 7.35 A 416 Rlk R2b RNv 100 6.79 A WO 03/082846 42 Functional Groups for Table 3 Galactitol Library PCT/AIJO3/00384 o 0 N 4

OH

00 RI d 0 RI b 0 0 Rl eOH 0 0 N *14 KII'iOH RI c 0 VkN

,,OH

H 0 Ri f 0 N OCH 3 Ri g 0 0

VAOH

RI h 0 Y NH 2 RI i 0

OH

NRlj 0

OCH

3 0 Rhl 0 Y N 00 OH 3 H 0 Rlm 0 N 00H 3 RI k 0 0 0 00 OH 3 RI n

H

3 C CH 3 0 00H 3 R2e

"OH

0 R2a R2b O 'H 3 R2c

H

3 0 CH 3 0

OH

R2d H0

N

N

R3a 0D R3e 0

HO

R3j R3b 0

H

N

N 0 HNP0 0 1 R3g R3d=Rle 0

H

2

N

R3h=Rl 0

NH

2 R31 0 R3k HOIC R31

HN

N~ 0 R3m 0 0

HN

HO&A

R3n=Rl a WO 03/082846 WO 03/82846PCT/AIJO3/00384 0 O N 1i 0 OH C R3r R3o R3q=Rlc R3u R3v 0

OH

R3w=Rlj 0 0

H

3 C N fl *H R3y 0 OY NH R H3z RUx

FEFO

HO V 1 0 F F R31 -0 0 R32=R1 b R33 WO 03/082846 PCT/AU03/00384 44 HPLC Methods for Compounds in Table 3.

Method A Time H 2 0% MeCN% Flow rate mi/min 0 100 0 2 2 100 0 2 40 60 2 12 0 100 1 2 Agilent SIB Zorbax C1 8 4.6 x 50mm (5Ltm, LC Mobile Phase: Acetonitrile Water 0.1% formic acid Method B Time H 2 0% MeCN% Flow rate mi/min 0 100 0 2 1 100 0 2 7 65 35 2 8 0 100 2 9 0 100 2 Agilent SIB Zorbax Phenyl 4.6 x 150mm LC Mobile Phase: Acetonitrile: Water 0.1 %formic acid WO 03/082846 1 H-NMR Data for Three Compounds of Final Library.

PCT/AU03/00384 Compound (238) 6H (400 MHz; CDCI3) 1.01 (3 H, t, J 7.0 Hz), 2.49 (2H expected), 2.95 (1 H, t, J 10.9 Hz), 3.30-3.80 (6 H expected), 3.90 (1 H, 4.00 (1 H, dd, J 10.6 Hz and J 5.4 Hz), 4.63 (1 H, br. 4.75 (1 H, dd, J 9.4 Hz and J 3.4 Hz), 6.00 (1 H, d, J 6.4 Hz), 6.16 (1 H, t, J 5.8 Hz), 7.55 (1 H, t, J 7.8 Hz), 8.02 (2 H, t, J 6.4 Hz), 8.25 (1 H, d, J 10.0 Hz) and 8.33 (1 H, d, J 1.2 Hz).

Compound 200 SH (400 MHz; CDCI 3 0.94 (3 H, t, J7.0 Hz), 1.07 (2 H, t, J 6.8 Hz), 2.30-2.40 (4 H expected), 2.49 (2 H expected), 2.60-3.00 (4 H expected), 3.30-3.85 (4 H expected), 3.91-4.10 (2 H, 4.44 (1 H, dd, J 9.8 Hz and J4.2 Hz), 4.49 (1 H, br. 6.57 (2 H, 6.75 (2 H, dd, J 8.6 Hz and J 1.8 Hz), 7.02 (1 H, t, J 7.7 Hz), 7.66 (2 H, d, J 8.4 Hz), 7.78 (2 H, dd, J 14.8 Hz and J 8.4 Hz), 8.22 WO 03/082846 PCT/AU03/00384 46 (1 H, q, J 11.6 Hz and J 5.6 Hz), 9.2 (1 H, s) and 9.94 (1 H, d, J 9.2 Hz).

Compound 159 6 H (400 MHz; CDCI 3 2.30-2.90 (6 H expected), 3.05-3.46 (7 H expected), 3.59 (2 H, 3.80 (2 H, 3.93 (1 H, 4.21 (1 H, dd, J 8.8 Hz and J 4.4 Hz), 4.49 (1 H, t, J 6.0 Hz), 4.77 (1 H, d, J4.8 Hz), 6.64 (1 H, dd, J6.4 Hz and J 2.0 Hz), 6.87 (1 H, 6.98 (2 H, dd, J 8.6 Hz and J 2.6 Hz), 7.20 (2 H, dt, J 5.4 Hz and J 2.2 Hz), 7.74 (1 H, dd, J 20.4 Hz and J 9.2 Hz), 8.34 (1 H, t, J 5.6 Hz), 9.11 (1 H, d, J 11.6 Hz) and 9.60 (1 H, br. s).

WO 03/082846 PCT/AU03/00384 47 Example 3: Synthesis of a 1, 5-anhydro-2-azido-3-0-benzovl-6-0-(tbut yldiphenvlsilyl)-2-deox V-D-cilUCitOL.

OH OH OH HO 0 3-a 2QHO .0 3-b k 4 NHDTPM 417 NH 2 3-c HO9 3-e Ph 9 O, 0 3-d Bzo- Bzo- HO 421 N 3 420 N 3 41 9 N 3 3-

OTBIDPS

HO-

Bzo_ 3-a. General Method 8; 3-b. General Method 17; 3-c. General Method 4; 3-d.

General Method 5; 3-e. General method 18; 3-f. General Method 19.

WO 03/082846 PCT/AU03/00384 48 Example 4: Synthesis of a 1,5-anhydro-2-azido-3-O-benzovl-6-O-(tbutvldiphenylsilyl)-2-deoxy-D-qlucitol.

MeOPh 0 4-a) MeOPh(O4\ MeOPh 0 0 4 0 CIBzO- I HO-^ O 6 NHDTPM 423 NH 2

N

3 (4-c) TBDPSO HO 0 HO

HO

BzO-

BZO

422 N 3 421 4-a. 0- and N- Deprotection of Glucitol Building Block 6 to form Glucitol 423.

Compound 423 was synthesised according to General Method 16, 87.2% yield (0.837g). 282.30; 98% Purity by ELSD.

4-b. Formation of 2-Deoxv-2-Azido Glucitol Building Block 5 from Building Block 423.

The formation of building block 5 was carried out according to the procedure described in General Method 17; 308.1; 98% purity by ELSD.

Rt 4.62 mins (Agilent SB Zorbax C18 4.6 x 50mm (5qm, 80A), LC Mobile Phase: Acetonitrile: Water 0.1% formic acid). Gradient as follows: Time (min) water% CH 3 CN% Flow ml/min 0.00 90.0 10.0 1.500 1.00 90.0 10.0 1.500 7.00 0.0 100.0 1.500 12.00 0.0 100.0 1.500 20.00 0.0 100.0 1.500 4-c. Preparation of Building Block 421 from Building Block 5 in Three Steps.

Compound 421 was subjected to conditions as described in General Method 18. Then the product of this reaction was directly subjected to the conditions as described in General Method 3. Finally the material was subjected to the conditions as described in General Method 19 to provide 5 as a white solid in WO 03/082846 PCT/AU03/00384 49 69% yield after purification; 294.6.

Rt 3.52 mins, (Agilent SB Zorbax C18 4.6 x 50mm (5Lm, 80A) LC Mobile Phase: Acetonitrile: Water 0.1% formic acid) Gradient as follows; Time(min) water% CH 3 CN% Flow mi/min 0.00 90.0 10.0 2.00 1.00 90.0 10.0 2.00 7.00 0.0 100.0 2.00 12.00 0.0 100.0 2.00 13.00 90.0 10.0 2.00 15.00 90.0 10.0 2.00 4-d. Silyl Protection of Building Block 421 to form Building Block 422 Compound 422 was formed according to the procedure described in General Method 19 in 87% yield, [M+H] 532.3; 100% purity by ELSD Rt 6.84 mins, (Agilent SB Zorbax C18 4.6 x 50mm (5qm, 80A) LC Mobile Phase: Acetonitrile Water 0.1% formic acid) Gradient as follows: Time(min) water% CH 3 CN% Flow mllmin 0.00 90.0 10.0 2.00 1.00 90.0 10.0 2.00 7.00 0.0 100.0 2.00 14.00 0.0 100.0 2.00 15.00 90.0 10.0 2.00 Spectral analysis for compound 422; 1 H-NMR (CDC3, 400MHz): 0.99 9 H), 2.99 J= 3.76Hz, 1 3.21 J= 11.1, 11.5 Hz, 1 3.31 3.34 1 H), 3.65-3.72 1 3.75-3.82 1 3.82 3.89 2 4.02 (dd, J 5.4, 11.5 Hz, 1 5.11 J 9.2, 9.7 Hz, 1 7.28-7.43 8 7.51-7.55 (m, 1 7.58-7.56 2 8.02-8.06 2 H).

WO 03/082846 PCT/AU03/00384 Example 5: General synthetic route for preparation of a Library of Glucitol Peptide Mimetics.

NH OTBDPS a OTBDPS 0 OTBDPS a 'N422 N 3 424 N 3 425 N 3

R

3 R3 H

OTBDPS

R20 R30 R 429 NH 428 N 3 427 426 N O.OR3 -OR3 Final Products O O HO Compounds 432 to 440 R2 R20- 430 HR1 431 NHR1 5-a. Coupling of Glucitol Building Block 422 to the Trichloroacetimidate Derivatised Wang Resin to provide 424.

Building Block-Resin Conjugate was prepared according to the procedure outlined in General Method 5-b. Removal of the Benzoyl Group to Form 425.

Compounds represented by no. 424 were prepared according to General Method 21.

Alkylation at position 3 of Coniugate 425 to Provide Resin-Building Block 426.

The compounds represented by no. 425 were subjected to the conditions as described in General Method 22 to provide compounds no. 426.

Removal of TBDPS group The resins designated by 426 were subjected to the conditions as described in General Method 23.

Alkylation at position 6 to provide WO 03/082846 PCT/AU03/00384 51 The resin bound compounds designated by 427 were alkylated in groups as described for General Method 22.

Reduction of Azido group to provide The resin bound compounds designated by 428 were subjected to the conditions as described in General Method 24.

N-Acvlations The resins designated by 429 were either subjected to the conditions as described in General Method 25: Method 1, or, were subjected to the conditions as described in General Method 22: Method 2.

Reduction of the Nitro Group If required, the substituent nitro group of a side-arm was reduced to the amine according to the procedure described in General Method 26.

Deprotection of the Fmoc Protecting Group If required, the Fmoc protecting group on side-arms was deprotected according to the procedure described in General Method 27.

Guanylation of amino group If required, amino group substituents of side-arms were guanylated according to the procedure described in General Method 28.

5-k. Cleavage of final products from the resins The final products were cleaved from resin according to the procedure described in General Methods 29. Final compounds were purified by HPLC- MS (See Table 4).

5-1. Hydrolysis of Me ester If required, the cleavage mixtures designated by 431 were individually treated with a solution of LiOH (0.5 molar) in MeOH/water (ph~14) for a week.

The solvents were removed in vacuo and the residue was purified by HPLC.

WO 03/082846 PCT/AU03/00384 Table 4: Library of Glucitol compounds Comp.

R1 No.

R3 M+H Purity Rt Yield mg 432 433 434 Rla R1c R1d R2a R2b R2b R3a R3b R3c 509.1 507.2 555.2 85.8

ELSD

63.6 UV 77.9UV 3.71 3.38 4.04 4.9 Yield 2 53.9 18.7 14.1 435 R1d R2b R3d 541.1 3.62 8.6 30.9 73.2 436 Rla R2c R3a 369.1 0.86 9.6 50.5

ELSD

437 R1b R2c R3c 453.2 80-UV 3.18 438 R1b R2c R3d 439.1 2.52 1.6 7.1 439 Rie R3b R3a 487.1 63.8-UV 2.55 12.9 51.6 440 Rlf R3b R3a 446.1 65-UV 2.39 3.6 15.7 'UV implies purity by Ulta-Violet detection, ELSD implies purity by Electron Light Scattering Detection.

2 Yield calculated for the whole solid phase sequence; 140mg of resin was used for preparation of each compound; the substitution was 0.368mmol/g, thus the amount of the starting material was 0.0515mmol.

WO 03/082846 PCT/AU03/00384 53 Side Chains for Table 4:

OH

a NH 2 N JNH 2 0 RaBr 0

H

RaR2a R3a Rib 0

OHNH

2 O Rico R3b 0 Rid Me OH

N

CH

3 f I H R3c NH 2 R3d R2c 0 Rif

NH

2 O RIf HPLC Method for Compounds in Table 4: (Agilent SB Zorbax 01 8 4.6 x 50mm (514m, 80A) LC Mobile Phase: Acetonitrile Water 0.1 formic acid) Gradient as follows: Time(min) water% CH3CN% Flow m~lmin 0.00 95.0 5.0 2.00 1.00 95.0 5.0 2.00 7.00 0.0 100.0 2.00 12.00 0.0 100.0 2.00 13.00 95.0 5.0 2.00 15.00 95.0 5.0 2.00 WO 03/082846 PCT/AU03/00384 54 Example 7: Allitol Building Block Synthesis SPho Ph0 HO. 419 N 3 441 N 3 Bz N3 442 (7-c)

OTBDPS

HO 0,

HO

O

0 BzO N Bz 444 443 7-a. Synthesis of a 3-O-Triflate Glucitol 441.

Compound 419 (300 mg, 1.08 mmol) and symmetric collidine (0.22 mL, 1.65 mmol) were dissolved in anhydrous DCM (7.0 ml) and the solution then cooled to -25 0 C. A solution of trifluoromethanesulphonic anhydride (0.27 ml, 1.65 mmol) in DCM (2.77 ml) was injected into the solution and the reaction allowed to proceed overnight. The Solution was reduced to dryness, the residue dissolved in DCM (15ml) and then washed with 0.5 molar HCI. The organic phase was dried over MgSO 4 filtered and the solvent removed in vacuo to provide the product 441 (399mg, 90.3%).

7b. Inversion at the C-3 position of a Glucitol Block to Form Allitol Block 442.

To a solution of compound 441 (4.089 mmol) in DMF (7 mL) was added a solution of LiOBz (1.794 mmol) in DMF (7 mL). The reaction was was allowed to proceed at room temperature overnight. The solvent was removed in vacuo and the resulting residue redissolved in EtOAc. The solution was then washed with H 2 0, the organic layer was collected, dried over MgSO 4 filtered and the solvent removed in vacuo to provide allitol block 442 (74.1% yield).

7c. Cleavage of the Benzylidene Ring System to Provide Allitol Block 443.

Compound 443 was prepared according to the procedure as described in General Method 18.

WO 03/082846 WO 03/82846PCT/AIJO3/00384 7d. Formation of the Differentially Protected 1,5-Anhydro Allitol Buildingj Block Compound 444 was prepared according to the procedure as described by General Method 19.

Table 5: Analytical Data for Intermediates and Final Compound in the Synthesis of Allitol Buildina Block 444.

R

4 4

_.J

R2 Comp. R1 R2 R3 R4 7R Observed.

IMass H 441 N 3 H OTf Benzylidene 410.13 442 N, OBz H Benz liene 382.15 443 N 3 06z H H H 294.12 444 N 3 OBz IH H TBDPS 532.15 WO 03/082846 PCT/AU03/00384 56 Example 8: Prototype Library using H-Allose Building Block OTBDPS OTBDPS OTBDPS HO O O 0 SN3 N 3

N

3 BzO N3BzO 444 445 446 (8-c) jOR 1 OH OTBDPS 0 (8-d)0Q_0 0

OR

1 ORI o Derivatised Wan Resin to provide 445. 8 447 0^ (8-ho^ k) HO HR2 4-CIBnO 2 4-CIBnO 452 450 4 5 1 8-a. Couplina of Allitol Building Block 444 to the Trichloroacetimidate Derivatised Wang Resin to provide 445.

Building Block-Resin Conjugate was prepared according to the procedure outlined in General Method 8-b. Removal of the Benzoyl Group to Form 446.

Compound 446 was prepared from precursor 445 according to General Method 21.

8-c. Alkylation at position 3 of Conjugate 446 to Provide Resin-Building Block 447.

The compound represented by 446 were subjected to the conditions as described in General Method 22 to provide compounds no. 447.

8-d. Removal of TBDPS group The resins designated by 447 were subjected to the conditions as described WO 03/082846 PCT/AU03/00384 57 in General Method 23.

8-e. Alkylation at position 6 The resin bound compounds designated by 448 were alkylated in groups as described for General Method 22.

8-f. Reduction of Azido group The resin bound compounds designated by 449 were subjected to the conditions as described in General Method 24.

8-g. N-Acylations The resins designated by 450 were either subjected to the conditions as described in General Method 25: Method 1, or, were subjected to the conditions as described in General Method 25: Method 2.

8-h. Reduction of the Nitro Group If required, the substituent nitro group of a side-arm was reduced to the amine according to the procedure described in General Method 26.

8-i. Deprotection of the Fmoc Protecting Group If required, the Fmoc protecting group on side-arms was deprotected according to the procedure described in General Method 27.

8-i. Guanylation of amino group If required, amino group substituents of side-arms were guanylated according to the procedure described in General Method 28.

8-k. Cleavage of final products from the resins (14-final product) The final products were cleaved from resin according to the procedure described in General Methods 29 to provide compounds designated by no.

452. Final compounds were purified by HPLC-MS.

Table 6: Structural and Analytical Data for Allitol Based Building Block WO 03/082846 58 Intermediates and Final Products PCTIAU03/00384 0R4 )"Ri OR2 Compound RI R2 R3 R4 Exp. Mol M-iH 453 N, Bz H TBDPS 532.27 454 N 3 H H TBDPS 428.20 455 N 3 p-Clbenzyl H TBDPS 552.25 456 N, p-Clbenzyl H H 314.1 457 N 3 p-Clbenzyl H p-CIBenzy No Data 458 N 3 p-Clbenzyl H 2-Napthyl 454.27 459 NH 2 p-Clbenzyl H p-CIBn 412.20 460 NH 2 p-Clbenzyl H 2-Napthyl 428.20 461 Ria p-Clbenzyl H p-CIBn 691.40 462 Rla p-Clbenzyl H 2-Napthyl 707.40 463 Rla p-Clbenzyl H 4-MeBiphenyl 733.42 464 Rib p-Clbenzyl H p-CIBn 719.40 465 Rib p-Clbenzyl H 2-Napthyl 735.50 466 RIb p-Clbenzyl H 4-MeBiphenyl 747.44 452a Ric p-Clbenzyl H p-ClBn 469.26 452b Ric p-Clbenzyl H 2-Napthyl 485.32 452c Rid p-Clbenzyl H p-CIBn 497.26 452d Rid p-Clbenzyl H 2-Napthyl 513.37 452f Rie p-Clbenzyl H p-ClBn 511.28 462g Rie p-Clbenzyl H [2-Napthyl 527.33 452h Ril f p-Clbenzyl H p-CIBn 539.31 452i Rif p-Clbenzyl H 2-Napthyl 555.38 452i Rig p-Clbenzyl H 4-Mebiphenyl 525.30 462k Ric p-Clbenzyl H 4-Mebiphenyl 511.20 WO 03/082846 PCT/AU03/00384 59 Sidearms for Table 6 0 0 0 NR.,NHFmoc A N NHFmoc A N A,,NH 2 H Ria H Rib H Rio N) NH, A, N.,N NH N N NH H Rid H Rie NH 2 H Rif NH 2 0 AN t NH 2 H Rig Example 9: Svnthesis of a 1, 5-anhyd ro-3-azido-6-O-(t-but VdimethVlsilyl)-2 ,3dideoxv-2-fI, 3-dimethyI-2A46- 3H, met!jyjaminppL-D-IROJ.

MeOh~\O~MeOPh TBDPS 0 9b HO- NHDTPM HO-; NHTMN 3 45 N NHDTPM 9-a. Formation of aAminoallitol Building Block From a Glucitol Precursor., Compound 5 was reacted according to the procedure described in General Method 6.

9-b. Formation of a Silyl Protected Building Block.

Compound 453 was reacted according to the procedure described in General Method 18. The product of this reaction was reacted according to the procedure described in General Method i9 to provide compound 454.

WO 03/082846 PCT/AU03/00384 Example 10: Synthesis of a 1, 5-anhvydr-.3-azido-4-O-benzoyl-2, 3-dideoxy-2f(1, 3-dimethyl-2,4, 6-(IH, 3H, 5H)-trioxopyrimidin-5-ylidefle) methvlaminol-6- O-(4-methoxvbenzli--D-IulitoL AcO OAc A AcO QAc OH OH MeC H HNBr -aL 0 AcO- 0 HO:(1 0 456 NHDTPM

NDTPM

458 NHDTPM 4550 OB~f nOMe HOOBnOMe MeOPh-, O (1 O-d) 0 .(10-e)0 WHDTPM N!.

3 NHDTPM N 3

HDTPM

461 460 459

JHDTPM

462 General Method 2; 10-b. General Method 3; 10-c. General Method 4; General Method 6; 10-e. General Method 33; 10-f. General Method 1 O-g. General Method 14.

WO 03/082846 PCT/AU03/00384 61 Example 11: Synthesis of a Library of Compounds by Solid Phase Techniques Using a Galactitol Building Block N OBnOMe (1-a) CIBzO- 43NDTPM 469 NHR2 468 NH 2 467 NHDTPM t0 (1-g) '?HN1) R3H[, RIO 0 RlOL RiO 470 NHR2 471 NHR2 466 11-a. General Method 14; 11-b. General Method 20; 11-c. General Method 21; 11-d- General Method 22; 11-e. General Method 32; 11-f. General Method 25; 11-g. General Method 24; 11-h. General Method 25; 11-i to I selected from General Methods 26-29 (as appropriate).

WO 03/082846 PCT/AU03/00384 62 Example 12: Solid Phase Synthesis of a 2, 5-Bis Amino-Allitol Libraiy.

NHDT1 'INHDTPM N 3 NHTMI

HDP

N3 464 N 3 4744 1 (12-c) oO R1 CR1 CR1 Q 0 12-e) 0 (1 2-d) 0 C NHR2 N NH 2

N

3

HTM

N

3 477 N3476 N 7 4(1 2-f) CR 1C R1 CR1 12g o (12-h1j k) HO0 N2NHR2 R3HN HR R3HN HR

NH

4 78 479 480 12-a. General Method 20; 12-b. General Method 23; 12-c. General Method 22; 12-d. General Method 32; 12-e. General Method 25; 12-f. General Method 24; 12-g. General Method 25; 12-h to k selected from General Methods 26-29 (as appropriate).

WO 03/082846 PCT/AU03/00384 63 Example 13: Synthesis of a Librar of Cornpound by Solid Phase Techni ues Using a Diamino Gulitol Based Buildinq Bloc BZ HBzO 0 HO 0R1 4 NDTPM FNH DTPM HTPM NHDTPM

N

3 42N 3 41N 3 482 N 3 483 (13-d) RIRCR~O RIO 0 0R VN1R2 NR2 NR2 N3 NH 2 R3HNAC NH 2 46N 3 N 8 487 486 48548 48 13-a. General Method 20; 13-b. General Method 21; 13-c. Generai Method 22; 13-d. General Method 31; 13-e. General Method 25; 13-f. General Method 24; 13-g. General Method 25; 13-h to k selected from General Methods 26-29 (as appropriate).

WO 03/082846 64 Example 14: Synthesis of an Exemplary Library 1 PCT/AU03/00384 PART 1: In this example three different mimetics of three different peptide residues (ie. Phe mimetic 1, 2 and 3, Lys mimetic 1, 2 and 3, and Trp mimetic 1, 2 and 35) maintain their position on the scaffold (Phe=R 1 Lys=R Trp=R3), but the different mimetics are varied in relation to one another.

PART 2: further in this example, three different mimetics of three different peptide residues (ie. Phe mimetic 1, 2 and 3, Lys mimetic 1, 2 and 3, and Trp mimetic 1, 2 and are varied in their substitution point around the scaffold, ie. Phe mimetic 1 moves from R 1 to R 2 to R 3 and so on.

R

3 HN /OH RIO A N H

NHR

2

A

OR

3

NHR

2

B

R

3 H H

H

R2

C

Table 8 R1 R2 R3 PART 1 Phe mimetic 1 Lys mimetic 1 Trp mimetic 1 Phe mimetic 2 Lys mimetic 1 Trp mimetic 1 Phe mimetic 3 Lys mimetic 1 Trp mimetic 1 Phe mimetic 1 Lys mimetic 1 Trp mimetic 2 Phe mimetic 2 Lys mimetic 1 Trp mimetic 2 Phe mimetic 3 Lys mimetic 1 Trp mimetic 2 Phe mimetic 1 Lys mimetic 1 Trp mimetic 3 Phe mimetic 2 Lys mimetic 1 Trp mimetic 3 Phe mimetic 3 Lys mimetic 1 Trp mimetic 3 Phe mimetic 1 Lys mimetic 2 Trp mimetic 1 Phe mimetic 2 Lys mimetic 2 Trp mimetic 1 Phe mimetic 3 Lys mimetic 2 Trp mimetic 1 Phe mimetic 1 Lys mimetic 2 Trp mimetic 2 Phe mimetic 2 Lys mimetic 2 Trp mimetic 2 Phe mimetic 3 Lys mimetic 2 Trp mimetic 2 Phe mimetic 1 Lys mimetic 2 Trp mimetic 3 Phe mimetic 2 Lys mimetic 2 Trp mimetic 3 Phe mimetic 3 Lys mimetic 2 Trp mimetic 3 Phe mimetic 1 Lys mimetic 3 Trp mimetic 1 Phe mimetic 2 Lys mimetic 3 Trp mimetic 1 Phe mimetic 3 Lys mimetic 3 Trp mimetic 1 WO 03/082846 PCT/AU03/00384 Phe mimetic 1 Lys mimetic 3 Trp mimetic 2 Phe mimetic 2 Lys mimetic 3 Trp mimetic 2 Phe mimetic 3 Lys mimetic 3 Trp mimetic 2 Phe mimetic 1 Lys mimetic 3 Trp mimetic 3 Phe mimetic 2 Lys mimetic 3 Trp mimetic 3 Phe mimetic 3 Lys mimetic 3 Trp mimetic 3 PART 2 Lys mimetic 1 Trp mimetic 1 Phe mimetic 1 Trp mimetic 1 Phe mimetic 1 Lys mimetic 1 Lys mimetic 2 Trp mimetic 1 Phe mimetic 1 Trp mimetic 1 Phe mimetic 1 Lys mimetic 2 Lys mimetic 3 Trp mimetic 1 Phe mimetic 1 Trp mimetic 1 Phe mimetic 1 Lys mimetic 3 Lys mimetic 1 Trp mimetic 2 Phe mimetic 2 Trp mimetic 2 Phe mimetic 2 Lys mimetic 1 Lys mimetic 2 Trp mimetic 2 Phe mimetic 2 Trp mimetic 2 Phe mimetic 2 Lys mimetic 2 Lys mimetic 3 Trp mimetic 2 Phe mimetic 2 Trp mimetic 2 Phe mimetic 2 Lys mimetic 3 Lys mimetic 1 Trp mimetic 3 Phe mimetic 3 Trp mimetic 3 Phe mimetic 3 Lys mimetic 1 Lys mimetic 2 Trp mimetic 3 Phe mimetic 3 Trp mimetic 3 Phe mimetic 2 Lys mimetic 2 Lys mimetic 3 Trp mimetic 3 Phe mimetic 3 Trp mimetic 3 Phe mimetic 3 Lys mimetic 3 various scaffold substituents Lys, Phe, and Trp mimetics 1,2 and 3, are listed in Table 3 below. It is noted that in some case amine protection is required, which is typically effected by Boc protection. It is further noted that in some cases an O-linked mimetic is required and in other cases an N-linked mimetic is required. In the cases of the O-linked Lys mimetics, the mimetic is coupled as either the para, ortho or meta nitrobenzyl derivative and subsequently reduced to the amine.

Table 9 Mimetic 1 Mimetic 2 Mimetic 3 0 0 0 Lys (N-linked) -NH2 N2 NH 2 Lys (0-linked) NH 2

NH

2

H

2

N

Phe (N-linked) F C H3 1 -14" I=

I

WO 03/082846 PCT/AIJO3/00384 cI WO 03/082846 PCT/AU03/00384 67 Example 15: A Gulitol N-Glycoside Building Block OH OH AcO QAc AGO CAc (1 5-a) (11 H O0 O AO ~ACO-- N 3 489OHOH490 OAc 491 O AG 4I HO OH oOTBOPS (1-)HO OH (1 5-e) 0N 1 3 -d 494 OBz 493Bz 42O MeO~h IMeOPh3 -O MeOPW3O MeOPh-'O 0 (15-g) 091 HO N 3 HO C-\NHDTPM

NHDTPM

496 OBz

N

3 OBz 497 4 (1 HO OBnOMe 0

NHDTPM

N3 Bz

N

3 498 15-a. AC 2 O, NaOAc; 15-b. General Method 34; 15-c. General Method 3; 16-d.

TBDPS-CI, 1,2-DCE, imidazole; 2,2-dimethoxy-propane, TsQH, MeCN; 1 5-e. Benzoylch lo ride, pyridine, 1,2-DOE, DMAP; MeOH, TsOH, MeCN, 15-f. General Method 4; 15-g. General Methods 13 and 20; General Method 33.

WO 03/082846 PCT/AU03/00384 68 Example 16: Synthesis of Glucosyl N-Glycoside Building Block QAc

OH

A H NH OAC (1 A.cO (1 6-b) H0 -0 ACON 73 H 0

N

3 0 450 NHDTPM 451 NHDTPM 499 HO 0 (16-d) Ph 0 0\ HO 0 454 'NHDTPM 43NHDTPM 452 NHDTPM I1(16-f)

OTBDPS

HO 0 BzO

N

3 16-a. General Method 34; 16-b. General Method 3; 16-c. General Method 4; 16-d. General Method 5; 16-e. General Method 18; 16-f. General Method 19.

WO 03/082846 PCT/AU03/00384 69 ExamplIe 17: Synthesis of Glucosylamino 2-Deoxy-2-Amino ibraty.

MeO-0 HO N 3 456 NHDde (1 7-a) 0 i 47NH2 (1 7-b) 00 0 (1 7-c) Me 0 MOHO N4 3 RIO 6 N 3 458 NHDTPM 49NHDTPM OH O PPMB O MBO(7f PMBO (17-d) RIO- 3 1-e RIO N- 3

N

3

O

460 NH 2 461 NHDTPM 462 NHDTPM (1 7-g) e(I-hPB (17-h- PMBRO N- RI0- N2 3 RNO H 463NH46 BocHN Oe 7-i) PMBO- 0N RIO N 2

NH

01465 BocHN OMe

HO-

(17-1) RIO ~N >-R2 0 0 HN1468 H NH

H

2

N

46G BocHN 17-a. Synthesis of 2-Deoxy 2-Amino Glycosyl Amine To a solution of starting material (20.5lmmol) in MeOH/DMF 150 mnL) was added hydrazine hydrate (92.2mmol) and the reaction mixture was stirred at room temperature for 1.5h. The solution was diluted with -400mL chloroform, washed with brine, dried over MgSO 4 filtered and the solvents evaporated. The crude product 457 was directly used for the next step.

17-b. Synthesis of 2-Deoxy 2-NHDTPM protected Glycosyl Amine Compound 458 was formed from reaction of 457 according to the procedure WO 03/082846 PCT/AU03/00384 described in General Method 17-c. Synthesis of 2-Deoxy 2-NHDTPM protected Glycosyl Amine Alkylated in the 3-Position Compounds 459 were formed according to the procedure described in General Method 7.

17-d. Reductive Ring Opening of a 2-Deoxy 2-NHDTPM 3-0-Alkyl Glycosyl Amine A solution of a derivative represented by 460 (4.37mmol) in dry DCM was cooled to 0°C and 44ml of a 1 molar solution of BH 3 in THF (44mmol) and 0.43mL of a 1 molar solution of dibutylboron triflate in DCM (0.43mmol) were added. The reaction mixture was stirred at 0°C and 0.1 eq. of Bu 2 BOTf repeatedly added at 1h intervals until t.l.c. (toluene/EtOAc 1:1) showed complete conversion (total of 0.5 eq. Bu 2 BOTf). The reaction was quenched by the addition of 8mL Et 3 N and 15mL MeOH at 0°C. After evaporation of the solvents the residue was taken up in 350mL DCM, the solution washed with half saturated brine, filtered over cotton and the solvents evaporated to yield a residue containing the product that was directly used in the next step.

17-e. Re-amino Protection of 3-O-Alkyl Glycosyl Amine Compounds 461 were formed according to the procedure described in General Method 30; 1H-NMR, (CDCI 3 8 9.92 (dd, 1H, NH, JNH, 2 9 7 Hz, JNH,=CH=13.8 Hz), 7.88 1H, 7.75-7.68 4H, Ar), 735-7.22 (m, 5H, Ar), 6.95-6.86 2H, Ar), 5.08 1H, NapCH 2 Jgem=1 2 .1 Hz), 4.86 (d, 1H, PMPCH 2 Jgem=10.

5 Hz), 4.72 1H, PMPCH 2 4.71(d, 1H, H-1b,

J

1 2 =9.2 Hz), 4.69 1H, NapCH 2 3.95 (dd, 1H, H-6a, Jgem=12.2 Hz,

J

5 6 a=1.7 Hz), 3.85-76 1H, H-6b), .3.81 3H, OMe), 3.74 (dd, 1H, H-4, J3, 4 =8.9 Hz, J 4 ,5=9.4 Hz), 3.64 (dd, 1H, H-3, J 2 ,3=9.3 Hz), 3.49 (ddd, 1H, 3.22 3H, NMe), 3.11 (dd, 1H, 3.05 3H, NMe).

17-f. Methylation of the 6-Position of a Glycosylamine Compounds 462 were formed according to the procedure described in WO 03/082846 PCT/AU03/00384 71 General Method 7; IH-NMR (CDCI3); 8 9.92 (dd, 1H, NH, JNH29.7 Hz, JNH=CHl 3 8 Hz), 7.88 I H, 7.75-7.68 (in, 4H, Ar), 735-7.22 (in, Ar), 6.95-6.86 (in, 2H, Ar), 5.08 1IH, NapCH 2 Jgeml 2 1 Hz), 4.86 1 H,

PMPCH

2 JgemlO0.5 Hz), 4.72-4.68 (in, 3H, NapCH 2

PMPCH

2 3.80- 3.74 (in, 3H, H-6a, H-6b, 3.81 3H, OMe), 3.64 (dd, 1H, H-3, J 2 3 =9.3 Hz), 3.49 (ddd, 1IH, 3.22 3H, NIVe), 3.11 (dd, 1IH, 3.05 3H, NMe).

17-gi. Removal of the DTPM Group of 2-Deoxy-2-Amino Glycosylamine compound Compounds 463 were formed according to the procedure described in General Method 8; IH-NMR, (CDCI 3 6 7.78-7.66 (in, 4H, Ar), 7.43-7.32 (in, Ar), 6.86-6.69 (in, 2H, Ar), 5.48 1H, CH-PMP), 5.05 1H, NapCH 2 Juer=ll.3 Hz), 4.77 IH, NapCH 2 4.47 1H, H-lb, J 1 2 =8.9 Hz), 4.28 (dd, 1IH, H-6a, Jge.miO 3 Hz, J5ra=5.5 Hz), 3.76-3.65 (in, 2H, H-6b, 3,72 3H,. OMe), 3.49 (dd, IH, H-3, J 2 3 =9.0 Hz, J 3 4 =9.0 Hz), 3.46 (ddd, 1H, H- 2.75 (dd, I H, H-2).

17-h. Synthesis of a 2-Deoxv-2-N-Acvl Glycosyl Amine, The compounds 464 were synthesised according to the procedure described in General Method 31.

17-i. Solution Phase Reduction of an Anoineric Azide The compounds 465 were synthesised according to the procedure described in General Method 13.

17-i. Formation of 1 -N-Acyl Derivatives of a GlucosaminVI Derivative.

The compounds 466 synthesised according to the procedure described in General Method 31.

17-k. Removal of a Boc Protectingi Group from a 2-Deoxy-2-N-AcVI- Glycosylamine Derivative.

Dissolve crude 467 (-0.21 mmiol) in IlOmL 20% TEA in DCM and stir at room WO 03/082846 PCT/AU03/00384 72 temperature for 10min. Evaporate solvents and dry the remaining syrup under high vacuum. Redissolve in DCM and wash with 1M KOH, filter over cotton, evaporate and purify by column chromatography (eluent DCM/MeOH 10:1 1% Et 3 N) to give the product (for the formation of compounds 469, 470, 471).

Yield typically 35% over two steps.

17-1. Solution Phase Guanylation (only for the formation of compound 472) To a solution of crude 467 (max. 0.22mmol) in dry DMF were added 89mg (0.44mmol) 3,5-dimethylpyrazole-l-carboxamidine nitrate and 84 pL (0.48mmol) DIPEA and the reaction mixture stirred for 3h. The solvents were evaporated and the residue dried under high vacuum to give 280mg of a mixture containing the desired product. The purification using preparative HPLC gave 8mg of the pure product 472.

OMe HO 0

H

NH

RIO NH N-R2 0 0 R3HN Comp. R1 R2 R3 Molecular Ion 469 naphthyl phenyl H [M+H] 522.33 470 naphthyl 4-Chlorophenyl H [M+H] 556.1 471 naphthyl benzyl H [M+H] 536.36 472 4-chlorobenzyl a-naphthyl C(NH)NH 2 [M+H] 598.39 WO 03/082846 PCT/AU03/00384 73 Example 18: Synthesis of a Carboxamide C-Glycoside I OH Ac

OAC

HO- S (I8a AcO-) 0 (18-b) HSMe AcO_ S Me AcO-~~ OH 473 N 3 4 N 3 475 N 3 OH OAc OAc (18-c) HO 0 (1 8-e) Ac 0 (1 8-d) N AcO- HO C02H GN AcOA C1 478 jN 3 COH477 N 3 476 N 3 (84) MeOPh~\~ MeOPh--VO0- 0 MeOPh-V O'\ HO479 N 3

O

2 M 480 N 3 048N 3

OHR

OTBDPS j18i HO 0HOA 02 BzO COH1 BzO- CONHR1 483 N 3 COH1482

N;

3 Conditions: NaOMe/MeOH; (ii) Acetone, NBS; (iii) trichioroacetonitrie, potassium carbonate, DCM; (iv) TMS-CN, TMS-Otf, DOM; (v)NaOH!H 2 02; (Vi)

TMS-CH

2

N

2 p-methoxybenzaldehyde dimethylacetal, CSA, Me~n, DMF; (vii) LiOH, H 2 0, THF; HBTU, DIPEA, DMF, R 1

-NH

2 (Viii) benzoylchloride, pyridine, 1,2-DCE, DMAP; (TsOH, MeOH, MeCN, H 2 0; (X) TBDPS-CI, imidazole, 1,2-DCE.

WO 03/082846 74 Example 19: Synthesis of an Allyl C-Glycoside PCT/AIJO3/00384 QAc AcO 0 (1 O\c Q~c

N

3 486 (1 9-e) Bz 490

OTBDPS

HO-4'

N

3 OBz 493 Conditions: Tf 2 O, pyridine, DCM; NaN 3 DMF; (ii) acetone, (iii) Ac 2

O,

pyridine; (iv) hexamethyldisilazane, 12, CH 3

-S-S-CH

3 NaOMe/MeOH; (vi) TsOH, a,a-dimethoxytoluene, MeCN; (vii) benzoylchloride, 1,2-DCE, pyridine, DMAP; (viii) TsOH, MeOH, H 2 0, MeON; (ix) TBDPS-CI, imidazole, 1,2-DOE; TMS-alyI, TMS-OTf, DOM.

WO 03/082846 PCT/AU03/00384 Example 20: Synthesis of a Range of C-Glycosides OBn OBn 0 (20-ab) C BnO SR BnO_ R=H BnO SR BnO_ 494 NHAc 495 HIc 1(20-c) (20-d) (20-e) OBn OBn OBfl OBn 0 0 _o BnO 0 BnO BnO BnO SAc BnO BnO Bno Sn 496 NHAci 497 NHAc 498 NHAc 499 HAc OH 1(209)

OH

(20-h) 0

HO

HO HO 501 i NHAc 500 HAc OH

OTBDPS

Ph V0 0j) H3! _3 0 (20-kL HO 0 B z O BzO NHcBzO c 502 NHAc 503 NHC504Hc *Ramburg..Backlund rearrangement of phthalimido thioglycosides I to give an exo methylene compound 11. The products can them be converted to a variety of C-glycosides which can be further elaborated to building blocks as exemplified by 28. The reaction pathway can furnish 0-glycosides with a large number of alkyl or aromatic side-chains at the anomeric position. Conditions: Oxone, (ii) KOH, CM 4 (iii) BH 3 HOCH, H 2 /Pd; (iv) H 2 Pd; ArX, Pd(0),

H

2 /Pd; (vi) AcSH, AIBN, H 2 /Pd; (vii) KOH, TfN 3 RT, CH 2

CI

2 MeOH,

H

2 Ofcat. CUS0 4 90%; (viii) ccya.-dimethoxytoluene, TsOH, MeCNIMeOH; (ix) BzCI, pyridine, MeOHIMeCN/H 2 0, TsOH; (xi) TBDPS-CI, pyridine.

WO 03/082846 PCT/AU03/00384 76 Example 21: Synthesis of an Ribofuranosyl Azide Building Block.

0 AcO N 3 AcO (21-a) AcO (21-b) HO NQ 3 AcO OAc AcO OAc HO OH 505 506 507 (21-c) 0 AN 14 N3 MSO 0 N 3 HO 0 NHO3 N N3 (21-e) (21-f) 510 509 508

H

2 N 3 511 21-a. 1-Azido-2,3,5-triacetvl ribose 506 To a solution of 1,2,3,5-tetraacetyl ribose 505 (0.189 mol) in dry DCM (480 ml) at room temperature was added trimethylsilyl azide (0.211 mol) followed by a solution of anhydrous SnCI 4 (9.40 mmol) in dry DCM (60 ml). The resulting colourless solution was stirred at room temperature overnight. The solution was washed with saturated sodium bicarbonate. The combined organic extracts were dried (MgSO 4 and the solvent was removed in vacuo to give a colourless oil, 100 21-b. 1-Azido ribose 507 The compound was synthesised according to the procedure described in General Method 1 (used directly in the following step).

21-c. 1-Azido-2,3-isopropylidene ribose 508 A solution of 1-azido ribose 507 (0.2 mol) in dry acetone (120 ml) and 2,2- WO 03/082846 PCT/AU03/00384 77 dimethoxypropane (488 mmol) at room temperature and under nitrogen was treated with conc. sulfuric acid (16.9 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was quenched with pyridine and the solvent was removed in vacuo. The residue was dissolved in DCM (500 ml), washed with 10 citric acid and saturated sodium bicarbonate, dried (MgSO 4 and the solvent was removed in vacuo to give a yellow oil which was purified by a squat column on silica gel (20-40 EtOAc/petrol) to give a yellow oil 508, 69 from tetraacetate 505. 5H (400 MHz: CDCI 3 1.32 3H,

CH

3 1.50 3H, CH 3 2.31 (dd, J 8.0, 5.2 Hz, 1H, OH), 3.67 (ddd, J 12.4, 7.6, 4.8 Hz, 1H, H5a), 3.77 (ddd, J 12.4, 6.2, 4.0 Hz, 1H, H5b), 4.41 (dd, J 5.2, 4.8 Hz, 1H, H4), 4.52 J 6.0 Hz, 1H, H3), 4.77 J 6.0 Hz, 1H, H2), 5.54 1H, H1).

21-d. 1-Azido-2,3-isopropylidene-5'-mesylate ribose 509 Methanesulfonyl chloride (18.1 mmol) was added over one min. to a suspension of the 2,3-isopropylidene ribose 508 (16.5 mmol) in dry pyridine (11 ml) at 0 °C and under N 2 The resulting suspension was stirred at 0 °C for h, then quenched with water (20 ml) and extracted with ethyl acetate (2 x ml). The combined organic extracts were washed with 10 citric acid and saturated NaHCO 3 dried (MgSO 4 and the solvent was removed in vacuo to give a pale yellow oil which was purified by a squat column on silica gel EtOAc/petrol) to give a white solid, 88 LCMS: >90 by ELSD, (M

N

3 251. 6 H (400 MHz: CDCI 3 1.31 3H, CH 3 1.49 3H, CH 3 3.09 (s, 3H, S0 2

CH

3 4.28 (dd, J 10.6, 6.8 Hz, 1H, H5a), 4.30 (dd, J 10.6, 6.0 Hz, 1H, H5b), 4.50 (td, J 6.1, 1.2 Hz, 2H, H3, H4), 4.72 (dd, J 6.0, 1.3 Hz, 1H, H2), 5.56 1H, H1).

21-e. 1-Azido-2,3-isopropylidene-5'-phthalimido-ribose 510 A suspension of sugar derivative 509 (14.3 mmol), potassium phthalimide (18.8 mmol) and sodium iodide (2.86 mmol) in DMF (105 ml) was heated at 100 °C for 30 min., then cooled to room temperature and diluted with water (500 ml) and cooled in an ice-water bath. The resulting product were collected by vacuum filtration, washed with water and dried over P 2 05 in a dessicator WO 03/082846 PCT/AU03/00384 78 overnight as white crystals, 51 LCMS: >95 by ELSD, (2M H) 711. 8H (400 MHz: CDCI 3 1.29 3H, CH 3 1.45 3H, CH 3 3.91 (dd, J 13.9, 8.4 Hz, 1H, H5a), 3.95 (dd, J 13.9, 6.5 Hz, 1H, H5b), 4.57 J 6.4 Hz, 2H, H3, H4), 4.78 J 5.8 Hz, 1H, H2), 5.57 1H, H1), 7.73 J 3.2 Hz, 1H, ArH), 7.74 J3.2 Hz, 1H, ArH), 7.87 J3.2 Hz, 1H, ArH), 7.88 J3.2 Hz, 1H, ArH).

21-f. 1-Azido-2,3-isopropylidene-5'-amino-ribose 511 A suspension of sugar derivative 510 (8.13 mmol) in methanol (21 ml) was treated with hydrazine hydrate (12.0 mmol) to give a pale yellow solution which was heated at reflux for 2 h. The methanol was removed in vacuo from the resulting suspension and the residue was dissolved in water (40 ml) and acidified (to pH 1) with conc. HCI. The resulting precipitate was removed by vacuum filtration and washed with water. To the filtrate was added solid sodium hydroxide (to pH 10) and the product was extracted with CHC! 3 and dried (MgSO 4 The solvent was removed in vacuo to give a yellow oil, 93 LCMS: (M N 3 8 (400 MHz: CDC13) 1.32 (bs, 5H, CH 3

NH

2 1.50 (s, 3H, CH 3 2.84 (dd, J 13.1, 6.0 Hz, 1H, H5a), 2.90 (dd, J 13.0, 8.1 Hz, 1H, 4.24 J7.0 Hz, 1H, H4), 4.48 J 5.8 Hz, 1H, H3), 4.61 J4.8 Hz, 1H, H2), 5.53 1H, H1).

WO 03/082846 PCT/AU03/00384 79 References 1. K. C. Nicolaou; J. M. Salvino, K. Raynor; S. Pietranico; T. Reisine; R.

M. Freidin ger, R. Hirschmann, Pept.: Chem., Struct. Biol, Proc. Am. Pept Symp., 11 1990 2. H. Kunz, T. Wundberg, C. Kallus, T. Opatz, S. Henke, W. Schmidt, Angew. Chem. Int. Ed., 1998, 37, No. 18, K. Kallus, T. Wundberg, W.

Schmidt, S. Henke, H. Kunz, Tet. Lett., 40, 1999, 7783-7786, (c U.

H~inger, T. Maidhof, 0. KnbII, H. Kunz, Poster Presentation, International Carbohydrate Symposium, Hamburg-Germany, T. Opatz, C. Kallus, T. Wundberg, W. Schmidt, S. Henke, H. Kunz, Poster Presentation, 20t International Carbohydrate Symposium, Hamburg- Germany.

3. R. Hirschmann, K.C. Nicolaou, S. Pietramnico, J. Salvino, E.M. Lealy, W.C. Shakepeare, P.S. Spengler, P. Hamley, A.B. Smith, T. Reisine, K.

Raynor, C. Donaldson, W. Vale, L. Maechler, R.M. Freidinger, C.D.

Strader, J. Am. Chem. So., 1993, 115, 12550

Claims (15)

1. A monosaccharide compound of formula I H H O H R4 R2 R3 formula I Wherein n is 0 or 1; at least two of the groups R2, R3, R4 and R5 are selected from the group consisting of -OX or N(T)Y and the others are independently selected from hydrogen, -OH, OX and N(T)Y; and when more than one OX group is present, the OX groups are not the same; and when n=0, at least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are N(T)Y; X is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms; T is selected from hydrogen or X; Y is selected from hydrogen, or the following, where G denotes the point of connection to the nitrogen atom in N(T)Y; 0 0 0 O O O II II II G W G W G W 0 0 O GIIO G N OH I Q Q is selected from hydrogen or W; the groups W are independently selected from the group a consisting of alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl of 2 to 20 atoms; and wherein N(T)Y ci does not represent NH 2 In n 2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1, wherein n is 1.

4. The compound of claim 1 in wherein W is substituted with a moiety selected from the group consisting of OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine,, hydrazide, hydroxamate and hydroxamic acid. The compound of claim 1 in wherein X is substituted with a moiety selected from the group consisting of OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, hydrazide, hydroxamate and hydroxamic acid.

6. The compound of claim 1, wherein Y is hydrogen.

7. The compound of claim 1 in wherein X is substituted with a moiety selected from the group consisting of OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid 7. The compound of claim 1 in wherein X is substituted with a moiety selected from the group consisting of OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine hydrazide, hydroxamate and hydroxamic acid.

8. The compound of claim 1 wherein at least three of the groups R2, R3, R4 and R5 are selected from -OX or -N(T)Y;

9. The compound of claim 1 wherein independently at least one of R2, R3, R4, or R5 is -N(T)Y. The compound of claim 1 wherein independently at least two of R2, R3, R4, or R5 are -Oalkyl.

11. N(T)Y. The compound of claim 1 wherein at least two of R2, R3, R4, or R5 is

12. The compound of claim 1 wherein R2 is -N(T)Y.

13. The compound of claim 12 wherein at least one of, R3, R4, or R5 is N(T)Y.

14. The compound of claim 12 wherein at least two of R3, R4, or R5 is N(T)Y. The compound of claim 12 wherein at least two of R2, R3, R4, or R5 are -Oalkyl.

16. A method of synthesis of compounds of claim 1, comprising the step of reducing a synthetic intermediate of formula III, H H 0 V R4 R2 R3 general formula III in which V is bromine or chlorine, R4, R3, and R2 are selected from the group consisting of OH, O-acyl, azide (N 3 NH-1-(4,4-dimethyl-2,6-dioxocyclohex-ylidene)ethyl (NHDde), NH-(1,3- dimethyl-2,4,6(1H, 3H, 5H)-trioxopyrimidin-5-ylidene)methyl (NHDTPM), NH- benzloxycarbonyl (NHZ), NH-tert-butoxycarbonyl (NHBOC), phthalimide, OX2, N(T)Y and an O-protecting group.

17. The method of claim 16, wherein the 0- protecting groups comprise acetals or ketals which protect two adjacent oxygens.

18. A method of solid phase combinatorial synthesis of compounds of claim 1, comprising the steps of: a. immobilizing a compound of formula IV onto a support through a free hydroxyl or amino function; b. selectively removing a protecting group from a protected hydroxyl functionality to provide a free hydroxyl function; and c alkylating said free hydroxyl function; formula IV wherein R4, R3, and R2 are selected from the group consisting of OH, O-acyl, azide (N 3 NH-1-(4,4-dimethyl-2,6-dioxocyclohex-ylidene)ethyl (NHDde), NH-(1,3- dimethyl-2,4,6(1H, 3H, 5H)-trioxopyrimidin-5-ylidene)methyl (NHDTPM), NH- benzloxycarbonyl (NHZ), NH-tert-butoxycarbonyl (NHBOC), phthalimide, OX, N(T)Y and an O-protecting group, and X ,T and Y are as defined in claim 1.

19. The method of claim 18 wherein the support is selected from the group consisting of derivatised polystyrene, Tentagel, Wang resin, MBHA (Methyl benzhydrylamine copoly (styrene-1 or 2%-divinylbenzene)) resin, aminomethylpolystyrene, rink amide resin, DOX-mpeg (Didioxylyl diether (DOX); Polyethyleneglycol w-Monomethylether (MPEG)), and polyethylene glycol. A method of solution phase combinatorial synthesis of compounds of claim 1, comprising the step of alkylating a free hydroxyl on a compound of formula IV according to claim 18. Alchemia Ltd