AU2007203109B2 - Anomeric Derivatives of Monosaccharides - Google Patents

Description

c Z Anomeric Derivatives of Monosaccharides AUSTRALIAN Divisional application Filed: 04 July 2007 IP Australia

O

Documents received on: 4 JUL 2007 Batch No: 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 rn compounds are variously functionalized, with a view to varying lipid solubility, size, Sfunction 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 threedimensional 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.

OH OH OH

OOO

H HO OH HHO HO OH OH H HOH H OH O a,-D-Galactose a,1-D-Glucose a,l-D-Mannose S Fig. 1 C1 The first example of a combinatorial approach employing carbohydrate chemistry, 0 was a symposium report on the design and synthesis of a peptidomimetic using a glucose scaffold in the early 1990's'. 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-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.

Many of the traditional methods of carbohydrate synthesis have proved to be S 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 0 and solution phase combinatorial synthesis of carbohydrate-based libraries, and are amenable to automation. The methods of the invention yield common intermediates 0 that are suitably functionalized to provide diversity in the structure of the compounds M so generated. In this way the technology described can produce many and varied 0 N 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.

SUMMARY OF THE INVENTION In a first aspect, the invention provides a compound of formula I 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 p 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 0 0 0 0 II O O0 P W N/W oG 0 G

N

OH

0 Q 00 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: SY is selected from hydrogen, double bond oxygen to form a carbonyl, or triple bond nitrogen to form a nitrile.

O Z may be optionally absent, or is selected from hydrogen or U, Wherein U is independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, O aminoalkyl, aminoaryl, aryloxy, alkoxy, heteroaryloxy, aminoaryl, aminoheteroaryl, r 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 S 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 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 atoms, It is understood that the rules of molecular stoichiometry will be upheld by the default addition of hydrogens atoms as required.

SThe 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; SThe groups R2, R3, R4 and R5 are independently selected from hydrogen, S 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 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, 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; With the proviso that when R2 is N(Z)Y, R6 and R7 are hydrogen, and R4 and 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; S In a preferred embodiment provides for compounds of formula I in which the ring is S of the gluco, galacto or allo configuration; A further embodiment provides for compounds of formula I in which R1 is N(Z)Y and 0 R2 is N(Z)Y; 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 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, R5, R4, R3, and R2 are independently selected from OH, O-acyl, N 3 NHDde, NHDTPM, NHZ, NHBOC, phthalimide, 0protecting 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.

R

3 formula II S In a third aspect, the invention provides for a method of synthesis of compounds of C 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.

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 DOX-mpeg, polyethylene glycol etc.

R6 R7 O R1 R2 R3 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.

R6 R4 R7 0 C0 R3 R2 formula IV in which the substituent V is -OAcyl, 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, 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 DOX-mpeg, polyethylene glycol etc.

R4 R7 0 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.

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.

General Solution and Solid Phase Methods For Examples 1-21 General Method 1: Formation of a Glycosyl Bromide 0 To a solution of the anomeric-acetate compound (100 mmol) in dichloromethane 0 (250 mL) at 0°C, was added a solution of 33% HBr in acetic acid (100mL). The N 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 C 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 (50 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 re-dissolved 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 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 S 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 0 60°C on a rotary evaporator at 300 mmHg for 30 min and then over the course of 4 c h the pressure was reduced to 80 mmHg and approximately 200 mL of solvent collected. After this time a second batch of reagent (70 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 (40-600C), to provide a white solid.

General Method 5: Solution Phase Benzoylation 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 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 -200C, 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 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 S 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 0 resulting solution then washed with water, 10% citric acid, saturated sodium t' 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 00C 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 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 (40-60°C)) 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 saturated sodium chloride, dried (MgSO 4 and all solvent removed under reduced pressure to leave a solid, typically in quantitative yield.

O General Method 9: Solution Phase HBTU Coupling S 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 0 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, mC 10% citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO 4 and the CN solvent removed under reduced pressure to leave an oil. Purification of the products l"- 0 was by column chromatography (typically, silica; 50% ethyl acetate in light petroleum c 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 (90 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 (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, 0 dried (MgSO 4 and the solvent removed under reduced pressure to give an oil.

M Purification was by either column chromatography (typically: silica; 50% ethyl N acetate in light petroleum (40-60 0 or by trituation with diethyl ether. Products O were typically formed in yields of 70-80%.

(N

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-Methoxybenzyl 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 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 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 S 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, 0 dried over MgSO 4 and evaporated to dryness. Products were typically formed in N 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 (~1.4 mmol) was added. After additional 16hr, concentrated NH 4 OH 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 50 0 C 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..

General Method 19: Solution Phase Silyl 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.

S General Method 20: Coupling of Building Block to Resin The Trichloroacetimidate derivatised resin (IRORI Wang resin -1 mmol) was O weighed into the reaction vessel and washed with THF. The derivatised building r block (1.86 mmol) was dissolved in anhydrous DCM (1.2ml), added to the resin and shaken for 3 mins. BF 3 Et 2 0 (-100[l) 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 Debenzoylation 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 (5 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 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 S 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 S 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 0 DMF, THF, and MeOH before being dried under high vacuum for 12 hours.

General Method 25: Solid Phase N-Acylation Method 1 Acids were weighed into round bottom flask and DIC (diisopropylcarbodiimide) (0.25 molar) in DMF was added to make a 0.5 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 0.5 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 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 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 (15 mbar) and filled with S 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 O 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 650C 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 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.

21 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 96wells plate and evaporated in alpha RVC. The samples were re-dissolved in acetonitrile and analysed.

General Method 30: DTPM Protection of an Amine S To a stirred solution of the amino compound (20 mmol) dissolved in MeOH (150mL) at room temperature was added a solution of DTPM reagent (20 mmol) in MeOH 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, 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 30 min under nitrogen. The suspension was then cooled to 0°C, and a solution of TFA (650 mmol) in dry N,N- 22 dimethylformamide (80 mL) added in portions, and the suspension then heated at 550C 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 S 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 (MgSO 4 and the solvent removed in vacuo to leave a solid, typically in 85-95% yield.

Example 1. Synthesis of 1, 5-anhydro-4-azido-3-O-(4-chlorobenzoyl)-2, 4-dideoxy-2- 3-dimethyl-2,4,6- (1H, 3H, 5H)-trioxopyrimidin-5-ylidene) methvlaminol-6-O-(4methoxybenzyl)-D-galactitol.

AcO -a AcO 1-b Ac0Hq 0A1 AcO 0~ ACO -1 HO0 <QO c AcOi AcO AcO-H NH HN HN HN H H r H H 0 0 0 0

N-_

N

N

2 3 0 4 11- HeO MeOPh%9 q 0 MeOPh9$\- 0 JCBzOsl-7 CIBz OO~~ HN H H NH HN 1eHHN 1-fH 1-e H 0 0 Nf 710 6 0 5 0 N BnOMe N BnOMe CBzO- 1-h HO-A0 H NHN o 0 0 0 8 9 0 1-a. Synthesis of 2-deoxv-2-r(1 ,3-dimethyl-2,4,6- (1H, 3H, vlidene) methylaminol-3,4,6-0-triacety-c-D-lucoyranosyI 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, 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, 5.19 (1 H, t, J 9.8 Hz), 5.46 (1 H, t, J 9.8 Hz), 6.50 (1 H, d, J 4.0 Hz), 8.13(1 H, d, J 13.6 Hz) and 10.30(1 H, brt, J 11.6 Hz); LCMS [M+H]'=534.

1-b. Synthesis of 1,5-anhydro-2-deoxy-2-[(1,3-dimethyl-2,4,6- (1H, 3H, methylaminol-3,4,6-O-triacetyl-D-glucitol Compound 3 was synthesized according to the procedure described in General S Method 2. Compound 3, quantitative yield; Rf (product) 0.65 in ethyl acetate., 6

H

(400 MHz; CDCl 3 2.03 (3 H, 2.04 (3 H, 2.09 (3 H, 3.28 (3 H, 3.30 (3 H, 3.53(1 H, t, J 11.2 Hz), 3.68 (2 H, 4.14 (2 H, 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 (1 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); 6 c (400 MHz; CDCI 3 21.04 (CH 3 x 21.17 (CH 3 27.63 (CH 3 28.33 (CH 3 60.36 62.32 (CH 3 68.29 68.62 (CH 2 73.98 76.97 92.65 151.97 158.84 162.65 164.91 169.57 170.36 and 170.65 LCMS [M+H]'=456.

1-c. Synthesis of 1,5-anhydro-2-deoxy-2-[(1,3-dimethyl-2,4,6- (1H, 3H, methylaminol-D-glucitol Compound 3 was treated as described by General Method 3 to provide 4; Rf (product) 0.00 in 1:1 ethyl acetate/light petroleum (40-60°C), (S.M t When system changed to 9:1 acetonitrile/methanol, Rf (product) z 0.4. (S.M t 8H (400 MHz; DMSO) 3.13 (3 H, 3.14 (3 H, 3.47 (3 H, 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 (1 H, d, J 14.4 Hz) and 10.03 (1 H, br t, J 8.4 Hz); 6 c (400 MHz; DMSO) 27.63

(CH

3 28.29 (CH 3 62.00 (CH 2 62.90 67.68 (CH 2 71.37 75.42 (CH), 82.22 152.18 (C x 160.18 162.71 and 164.37 LCMS [M+H]'=330.

1-d. Synthesis of 1,5-anhydro-2-deoxy-2-[(1,3-dimethyl-2,4,6- (1H, 3H, methylaminol-4,6-O-(4-methoxybenzylidene)-D-qlucitol Compound 4 was treated as described by General Method 4, to give the desired product 5 as a solid Rf (product) z 0.1 in 1:1 ethyl acetate/light petroleum 600C), 6 H (400 MHz; CDCI 3 3.29 (3 H, 3.30 (3 H, 3.48 (5 H, 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); LCIMS [M+H]+=448.

1 Synthesis of 1 ,5-anhydro-3-O-(4-chlorobenzol)-2-deoxy-2-[( 1,3-dimethyl-2,4,6- (1 H, 3H, 5H)-trioxopyrimidin-5-ylidene) methylaminol-4,6-O-(4-methoxybenzylidene)- 0-glucitol N Compound 5 was treated according to General Method 5, to give the product 6 as a 0 off-white solid Rf (product) :-0.33 in 1:1 ethyl acetate/light petroleum (S.M :t0.17); 6 H (400 MHz; CDCI 3 3.24 (3 H, 3.25 (3 H, 3.72 (8 H, in), 4.14 (1 H, t, J 5.5 Hz), 4.35 (1 H, t, J 5.4 Hz), 5.50 (1 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 (1 H, br t, J 11 .6 Hz); LCMS [M+H]+=586.

1-f. Synthesis of 1 ,5-anhydro-3-O-(4-chlorobenzoyl)-2-deoxy-2-r( 1 3-dimethyl-2,4,6- (1 H, 3H, 5H)-trioxopyrimidin-5-ylidene) methylaminol-6-O-(4-methoxybenzyl)-Dglucitol 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) ;t0.26 in 1:1 ethyl acetate/light petroleum (40-600C). (S.M t0.33); 6 H (400 MHz; 00013) 3.23 (3 H, s), 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); LOMS +=588.

1 Synthesis of 1 ,5-anhydro-4-azido-3-O-(4-chlorobenzoyl)-2,4-dideoxy-2-[( 1,3diinethyl-2,4,6- (1 H, 3H, 5H)-trioxopyri mid in-5-yl idene) methylaininol-6-O-(4inethoxybenzyl)-D-galactitol Compound 7 was treated according to the procedure described in General Method 6 to give compound 8, Rf (product) ;t0.62 in 1:1 ethyl acetate/light petroleum.

Product recrystallised from isopropanol; LCMS =61 3.

1-h. Synthesis of 1,5-a nhyd ro-4-azido-3-O-(4-chlorobenzoyl ideoxy-2-r( 1,3dimethyl-2,4,6- (1 H, 3H, 5H)-trioxopyrimidin-5-ylidene) methylaminol-D-cialactitol Compound 8 was reacted according to General Method 3, to give the desired product 9 as a white foam, 6 H (400 MHz; ODC1 3 3.25 (3 H, 3.26 (3 H, s), 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 (11 H, d, J 13.6 Hz), and 10. 15 (1 H, br t, J 11.4 Hz); LCMVS [M+H]+=475.

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 OBnOMe

HO

2-a^ 2-a Cc, 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 [M+H] 503 589 589 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-3ylamine (13) Yellow oil, yield (100 6 H (400 MHz; CDC13) 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, 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 14.8 Hz and J 11.6 28 Hz), 6.88 (2 H, d, J 8.4 Hz) and 7.26 (2 H, d, J 8.8 Hz); LCMS =337.

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

C N OBnOMe N OBnOMe 0e 2-c

NH

2 NHR1 13. R2 CH 2

CH

3 17-51 14. R2 CH 2

C(CH

3 )2C(O)OMe R2 H 16. R2 CH 2 C(O)OtBu Analytical Data: Example of a product of General Method 9: [3-Azido-5-(3-tertbutoxycarbonylamino-propionylamino)-2-(4-methoxy-benzyloxymethyl)-tetrahydropyran-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; ethyl acetate in light petroleum 6 H (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, 3.81 (3 H, s), 4.07 (4 H, 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-(4methoxy-benzyloxymethyl)-tetrahydro-pyran-3-ylcarbamoyl]-methyl ester Sugar (15) (4.2 mmol), was coupled to acetoxyacetic acid (4.3 mmol) and after trituation with diethyl ether gave the title compound (45) as a white solid in 64%, 6

H

(400 MHz; CDCl 3 2.17 (3 H, 3.19 (1 H, t, J 10.8 Hz), 3.44 (1 H, 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 0 8.8 Hz); LCMS [M+H+Na]'=431.

Example of a product of General Method 9: N-[5-Azido-4-hydroxy-6-(4-methoxy- S 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

S (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); 8c (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 and173.35 LCMS [M+H+Na]+=423.

Example of a product of General Method 10; {3-[5-Azido-4-hydroxy-6-(4-methoxybenzyloxymethyl)-tetrahydro-pyran-3-yl]-ureido}-acetic acid ethyl ester (41) Compound 41, white solid, yield 66%; 6 H (400 MHz; DMSO) 1.17 (3 H, t, J 6.8 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); 6 c (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 (CH), 76.06 114.30 (CH x 129.03 (CH x 130.68 158.56 159.32 (C) and 171.57 LCMS =438.

Example of a product of General Method 11: [5-Acetylamino-3-azido-2-(4-methoxybenzyloxy-methyl)-tetrahydro-pyran-4-yloxy]-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%, 6 H (400 MHz; CDC13) 1.43 (9 H, s, C(CH 3 3 1.94 (3 H, 2.88 (1 H, t, J 10.0 Hz), 3.45 (4 H, 3.74 (3 H, 4.04 (4 H, m),4.40 (3 H, 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); LCMS [M+H]'=465.

Example of a product of General Method 12: 3-[3-Azido-2-(4-methoxybenzyloxymethyl)-5-(2-methoxycarbonyl-acetylamino)-tetrahydro-pyran-4-yloxy]-2,2- S dimethyl-propionic acid methyl ester (51) Derivatisation of the pivolate sugar (14) (3.6 mmol) gave the title compound as a O brown oil (51) 75 6H (400 MHz; CDCI 3 1.16 (3 H, 1.24 (3 H, 3.35 (3 H, m), 0 3.57 (6 H, 3.68 (3 H, 3.73 (3 H, 3.81 (3 H, 4.28 (3 H, 4.46 (2 H, q, J N 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); LCMS [M+H]+=523.

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

Table 1: Intermediates for synthesis of Galactitol Library.

No. RI* R2* Molecular Ion No. RI R2 Molecular Ion 17 Ria R2d [M+Hf=537 35 Rif R2a [M+H]+=508 18 Ria R2c [Mi-Naf=423 36 Rig R2d [M+H]f=465 19 Ria R2a [MjH]+=451 37 Rig R2c [Mi-H]=351 Ria R2b J[y+H]+=537 38 Rig R2a [M+H]f=379 21 Rib R2d ]'=565 39 Rig R2b [M+H]f=465 22 Rib R2c [+H+=451 40 Rih R2d [M+Hf552 23 Rib R2a =479 41 Rih R2c =438 24 Ric R2d [M+H]+=656 42 Rih R2a [M+H*466 Ric R2c [M+Hf542 43 Rih R2b [M+Hf552 26 Ric R2a [M+Hf570 44 Rli R2d [M+H]f=523 26 Rid R2d [M+H]f=656 45 Rli R2c [M+Naf=43i 28 Rid R2c [Mi-H] =542 46 Rli R2a [Mi-H] =437 29 Rid R2a [Mi-H] =570 47 Rli R2b [Mi-Hf 523 Rie R2d [Mi-H] =613 48 Rij R2d [M+H]f=523 31 Rie R2c [Mi-H=499 49 Ruj R2c [Mi-H] =409 32 Rie R2a [Mi-H=527 50 Ruj R2a [Mi-Hf =437 33 Rif R2d [Mi-Hf =594 51 Rij R2b [Mi-Hf =523 34 Rif R2c [Mi-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.

N

3 OBnOMe R2J

NHR

17-511 2-d

H

2 N OBnOMe R24~ 52-86 Table 2: Observed molecular ions of reduced azides OBnOMe 1 0

H

2 N "-NHRi 0R2 No. RI R2 Molecular Ion No. RI R2 Molecular Ion 52 Ria R2d [M+Hf5il 70 Rif R2a [M+H'482 53 Ria R2c [M+H]f=397 71 Rig R2d =439 54 Ria R2a [M+H]+=425 72 Rig R2c No Data Ria R2b No Data 73 Rig R2a [M HI=353 56 Rib R2d [M4H]=539 74 Rig R2b [M+Hf439 57 Rib R2c [M+Hf=425 75 Rih R2d [M+H]+=526 58 Rib R2a [M+H]f=453 76 Rih R2c [M-sHf=4i2 59 Ric R2d [M+Hf588 77 Rih R2a [M+Hf440 Rio R2c =474 78 Rh Rb [H]=2 (loss of acetate) 7 Rih Rb [-Hf52 61 Rio R2a [Mi-H] =502 79 Ri Rd [H]=7 (loss of acetate) 7 ii Rd 62 Rid R2d [M+Hlf=588 80 Rui R2c [M+Hlf=383 63 Rid R2c [Mi-H]+=474 81 Ri Ra [H]=1 (loss of acetate) 8 ii Ra [i ]4 64 Rid R2a [M+]=544 82 Rui R2b [M+HI*=497 Rie R2d [Mi-H] =587 83 Rij R2d [Mi-Hf+ 497 66 Rie R2c [Mi-Hf =43i 4 Rj Rc (loss of acetate) 84 Rj Rc [-Hf8 67 Rie R2a [Mi-H=50i 85 Rij R2a [M+Hf=4i1 68 Rif R2d [Mi-H]=568 86 Rlj R2b [Mi-H]=497 69 Rif R2c ,[Mi-H]=454 Sidearms for Example 2: Tables 1 and 2.

H

3

CO,'>

R2a 0 OMe 0 Rla

H

3 C CH 3 MeO R2b R2b Hy R2c

H

3 C, O,

H

3 C> II

CH

3 0 R2d 0 oR-OMe 0 R1b o RAd o 0 Rid 0

H

N 0 CH 3 0 0 CH 3 yCH 3 0 R1g

NO

O O

H

0 Rlh Rli Ro-H 3 0 R1j 2-e. Final N-Acylation 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 OBnOMe O 2-e 0 NHR1 52-86 R3HN OH R20O NHR1 87-416 Table 3: Library of 1,5-Anhydro-galactitol Compounds R3HI Retention Time HPLC Compound No. R1 R2 R3 Yield h (mins) Method 87 R1a R2a R3a 70 4.72 A 88 Rla R2a R3b 83 4.28 A 89 R1a R2a R3c 74 4.90 A Rla R2a R3d 38 4.44 A 91 Rla R2a R3e 10 4.73 A 92 Rla R2a R3f 44 4.53 A 92 R1b R2a R3b 64 4.73 A 94 R1b R2a R3g 77 4.35 A R1c R2a R3h 82 5.33 A 96 R1c R2a R3a 50 4.28 A 97 R1c R2a R3c 42 4.00 A 98 R1c R2a R3d 85 4.46 A 99 R1c R2a R3f 21 4.62; A 100 Rid R2a R3h 84 4.55 A 101 Rid R2a R3a 100 4.56 A 102 Rid R2a R3b 91 4.72 A 103 Rid R2a R3c 70 4.64 A 104 Rid R2a R3d 92 5.27 A 105 Rid R2a R3f 50 4.73 A 106 Rle R2a R3i 100 3.54 A 107 Rle R2a R3i 61 4.53 A 108 Rle R2a R3b 97 5.74 A 109 Rle R2a R3d 93 6.02 A 110 Rle R2a R3e 10 6.18 A 111 R1e R2a R3f 62 5.74 A 112 Rlf R2a R3b 80 4.55 A 113 Rlf R2a R3d 36 5.17 A 114 R1g R2a R3j 100 4.55 A 115 R1g R2a R3k 96 5.36 A 116 R1g R2a R31 100 6.66 A 117 R1g R2a R3m 100 7.01 A 118 R1g R2a R3n 100 6.39 A 119 R1g R2a R3o 97 4.44 A 120 R1 R2a R3o 95 4.37 A 121 R1g R2a R3p 90 5.40 A 122 Rlf R2a R3j 90 4.92 A 123 Rlf R2a R3k 93 5.14 A 124 Rlf R2a R3n 96 6.84 A 125 Rlf R2a R3n 95 7.19 A 126 Rif R2a R3o 72 6.48 A 127 Rif R2a R3g 63 2.60 A 128 Rib R2a R31 79 4.07 A 129 Rlh R2a R3m 77 3.52 A 130 Rih R2a R3n 100 4.09 A 131 Rih R2a R3o 54 5.36 A 132 Rih R2a R3q 74 5.50 A 133 Rih 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 Rui R2a R3n 93 5.38 A 139 Rui R2a R3v 71 3.83 A 140 Rij R2a R3m 87 4.79 A 141 Rui R2a R3n 95 5.65 A 142 Rli R2a R3r 78 5.08 A 143 Rli R2a R3s 81 5.65 A 144 Rij R2a R3t 98 5.27 A 145 Rli R2a R3n 93 5.08 A 146 Rij R2a R3v 99 4.92 A 147 Rib R2a R3m 90 4.92 A 148 Rib R2a R3n 45 5.10 A 149 Rib R2a R3r 97 5.17 A 150 Rib R2a R3s 89 5.19 A 151 Rib R2a R3t 82 5.54 A 152 Rib R2a R3n 95 5.63 A 153 Rib R2a R3v 62 6.39 A 154 Ria R2b R3b 95 6.73 A 155 Ria R2b RMd 100 7.49 A 156 Rib R2b R3b 97 6.37 A 157 Rib R2b R3d 97 5.00 A 158 Ric R2b R3w 16.5 7.47 A 159 Ric R2b R3b 98.5 5.27 A 160 Ric R2b R3d 99 5.01 A 161 Ric 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 R2b R3b 100 4.28; A 167 Rie R2b R3d 100 4.62 A 168 Rie R2b R3g 63 4.28 A 169 Rif R2b RMd 97 4.44 A 170 Rif R2b R3j 100 4.37 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 Rih R2b R3j 85 6.94 A 177 Rib R2b R3k 100 6.09 A 178 Rib R2b R31 100 4.92 A 179 Rib R2b R3m 92 4.53 A 180 Rlh R2b R3x 90 5.19 A 181 Rli R2b R3m 83 4.61 A 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 R2b R3t 96 4.18 A 186 R1i R2b R3u 100 4.46 A 187 Rli R2b R3v 100 4.94 A 188 Rlj R2b R3m 97 1.71 A 189 Rlj R2b R3p 98 1.69 A 190 Rlj R2b R3r 84 2.07 A 191 R1j R2b R3s 100 2.26 A 192 Rlj R2b R3t 100 1.69 A 193 Rlj R2b R3u 70 2.26 A 194 Rlj R2b R3v 100 1.6 A 195 Rlj R2b R3g 100 3.00 A 196 Rla R2c R3w 100 4.41 A 197 Rla R2c R3a 50 0.55 A 198 Rla R2c R3b 96 1.78 A 199 Rla R2c R3c 58 1.69 A 200 Rla R2c R3d 95 2.35 A 201 Rla R2c R3f 32 2.26 A 202 Rla R2c R3g 6 4.14 A 203 Rib R2c R3b 100 3.94 A 204 Rib R2c R3d 100 4.75 A 205 Rib R2c R3f 32 4.9 A 206 Rib R2c R3i 83 1.8 A 207 Rlc R2c R3w 77 1.69 A 208 Rlc R2c R3a 44 2.17 A 209 Rlc R2c R3b 99 4.33 A 210 Rlc R2c R3c 43 2.26 A 211 Rlc R2c R3d 93 3.34 A 212 Rid R2c R3c 94 4.18 A 213 Rid R2c R3d 90 5.36 A 214 Rid R2c R3e 15 2.17 A 215 Rid R2c R3f 91 1.89 A 216 Rle R2c R3i 100 1.78 A 217 Rle R2c R3w 97 4.55 A 218 Rle R2c R3a 80 6.20 A 219 Rle R2c R3b 94 3.25 A 220 Rle R2c R3c 62 4.09 A 221 Rle R2c R3d 91 4.35 A 222 Rle R2c R3f 37 4.48 A 223 Rlf R2c R3b 100 4.83 A 224 Rlf R2c R3d 96 5.28 A 225 R1g R2c R3j 100 1.78 A 226 R1g R2c R3k 100 4.00 A 227 R1g R2c R31 100 4.00 A 228 R1g R2c R3m 100 5.74 A 229 R1g R2c R3x 100 3.73 A 230 Rlg R2c R3o 100 5.10 A 231 R1g R2c R3q 100 4.09 A 232 R1g R2c R3p 98 5.56 A 233 R1g R2c R3r 95 6.55 A 234 Rif R2c R3j 88 6.39 A 235 Rif R2c R3k 85 5.13 A 236 Rif R2c R31 89 4.78 A 237 Rif R2c R3m 94 3.82 A 238 Rif R2c RUx 84 4.09 A 239 Rif R2c R3o 98 3.08 A 240 Rif R2c R3g 98 3.54 A 241 Rif R2c R3p 94 3.73 A 242 Rih R2c R3j 100 3.91 A 243 Rih R2c R3k 86 5.36 A 244 Rih R2c R31 98 4.83 A 245 Rih R2c R3m 96 2.35 A 246 Rih R2c RUx 100 5.28 A 247 Rif R2c R3r 88 5.13 A 248 Rlh R2c R3o 97 4.78 A 249 Rlh R2c R3g 98 4.88 A 250 Rlh R2c R3p 98 4.5 A 251 Rlh R2c R3g 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 Rlf R2c R3s 100 5.28 A 262 Rlj R2c R3t 94 5.13 A 263 Rlj R2c R3u 100 5.0;0 A 264 Rli R2c R3v 100 6.39 A 265 Rij R2c R3g 71 4.99 A 266 Rib R2c R3m 100 4.83 A 267 Rib R2c R3p 98 6.50 A 268 Rib R2c R3r 100 4.92 A 269 Rib R2c R3s 63 5.14 A 270 Rib R2c R3t 95 6.84 A 271 Rib R2c R3u 91 7.19 A 272 Rib R2c R3v 95 6.48 A 273 Rib R2d R3i 55 2.60 A 274 Rib R2d R3w 11 3.52 A 275 Rib R2d R3a 48 3.75 A 276 Rib R2d R3b 48 5.36 A 277 Rib R2d RMd 85 5.50 A 278 Rib R2d RMe 11 3.78 A 279 Rib R2d R3f 46 4.05 A 280 Rif R2d R3i 73 1.50 A 281 Rif R2d R3w 21 3.77 A 282 Rif R2d R3b 81 5.26 A 283 Rif R2d RMd 91 5.38 A 284 Rif R2d R3f 78 3.83 A 285 Rig R2d R3j 100 4.79 A 286 Rig R2d R3k 100 5.65 A 287 Rig R2d R31 100 5.08 A 288 R1g R2d R3m 100 5.65 A 289 R1g R2d R3o 100 5.27 A 290 R1g R2d R3r 100 5.08 A 291 Rlf R2d R3j 72 4.92 A 292 Rlf R2d R31 100 5.08 A 293 Rlf R2d R3x 28 5.10 A 294 Rlf R2d R3o 25 5.17 A 295 Rlf R2d R3r 100 5.19 A 296 R1h R2d R3k 72 5.54 A 297 R1j R2d R3p 56 5.63 A 298 Rlj R2d R3r 66 5.10 A 299 Rlj R2d R3t 42 6.73 A 300 R1j R2d R3u 100 7.49 A 301 Rlj R2d R3v 100 6.37 A 302 R1b R2d R3r 5 5.00 A 303 Rib R2d R3u 100 7.47 A 304 Rlc R2a R3b 100 5.27 A 305 Rle R2a R3w 88 4.72 A 306 Rla R2a R3y 64 4.61 A 307 R1b R2a R3h 95 1.69 A 308 R1b R2a R3w 13 4.09 A 309 R1b R2a R3a 76 1.69 A 310 Rib R2a R3f 59 4.18 A 311 R1c R2a R3y 90 4.46 A 312 Rle R2a R3z 84 4.94 A 313 Rlf R2a R3i 100 1.71 A 314 Rlf R2a R3w 72 1.69 A 315 Rlf R2a R3a 64 2.07 A 316 Rlf R2a R3e 82 2.26 A 317 Rlf R2a R3f 98 1.69 A 318 Rli R2a R31 42 2.26 B 319 Rli R2a R32 78 1.60 B 320 Rlj R2a R32 56 3.00 B 321 Rla R2b R33 70 4.41 A 322 Rla R2b R3f 90 0.55 A 323 R1b R2b R3w 94 1.78 B 324 R1b R2b R3c 69 1.69 B 325 R1b R2b R3e 12 2.35 B 326 R1d R2b R3i 98 2.26 B 327 Rid R2b R3z 78 4.14 A 328 R1d R2b R3w 82 2.33 B 329 R1e R2b R3z 66 4.75 A 330 Rle R2b R3c 81 4.9 B 331 Rlf R2b R3i 100 1.8 B 332 Rlf R2b R3w 91 1.69 B 333 Rlf R2b R3c 93 2.17 B 334 R1a R2c R3z 52 4.33 A 335 R1b R2c R3i 98 2.26 B 336 Rib R2c R3a 28 3.34 B 337 Rid R2c R3z 60 4.18 A 338 Rle R2c R3z 23 4.73 A 339 Rlf R2c R3i 100 2.17 B 340 Rlf R2c R3z 87 1.89 A 341 R1f R2c R3c 100 2.35 B 342 Rlf R2c R3f 48 4.55 B 343 R1b R2d R3s 50 6.20 A 344 Rla R2b R3i 22 3.25 A 345 Rla R2b R3w 100 4.09 A 346 R1a R2c R3e 34 4.35 A 347 R1b R2a R3e 53 4.48 A 348 Rlf R2a R3c 76 1.78 A 349 R1b R2b R3i 85 1.48 B 350 Rib R2b R3a 19 1.78 B 351 R1c R2a R3g 41 5.74 A 352 Rid R2a R3w 80 3.73 A 353 Rlh R2d R3x 46 5.13 A 354 R1b 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 R1b R2b R3m 52 4.88 A 359 R1b R2b R3r 84 4.49 A 360 R1b R2b R3s 64 5.57 A 361 R1b R2b R3t 63 6.87 A 362 Rib R2b R3u 100 7.13 A 363 R1b R2b R3v 51 6.44 A 364 Rli R2c R32 100 59 B 365 R1j R2c R32 42 3.36 B 366 R1b R2c R32 60 4.1 A 367 R1j R2d R32 7 4.14 A 368 R1b R2d R32 25 4.53 A 369 Rla R2e R3c 87 4.26 A 370 Rlc R2e R3a 85 4.46 A 371 R1h R2e R3o 53 4.73 A 372 Rli R2e R3v 100 5.57 A 373 Rlk R2b R3b 25 5.19 A 374 R1l R2b R3b 95 5.28 A 375 R1l R2b R3d 100 5.38 A 376 R1m 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 R1k R2c R3u 74 7.68 A 381 R1b R2f R3i 47 4.48 A 382 R1b R2f R3b 90 5.68 A 383 R1b R2f R3d 84 5.78 A 384 Rlf R2f R3i 69 4.28 A 385 Rlf R2f R3b 83 5.58 A 386 Rlf R2f R3d 89 5.68 A 387 R1g R2f R3m 45 5.68 A 388 Rlf R2f R3o 66 5.48 A 389 Rlf R2f R3p 32 5.27 A 390 R1h R2f R3k 59 6.28 A 391 R1h R2f R31 91 5.65 A 392 R1h R2f R3p 97 5.82 A 393 R1h R2f R3r 97 5.01 A 394 R1j R2f R3m 81 5.28 A 395 R1j R2f R3p 91 5.78 A 396 Rlj R2f R3t 92 6.78 A 397 Rlj R2f R3u 99 7.33 A 398 Rjji R2f R3v 100 6.63 A 399 Rib R2f R3p 89 5.91 A 400 Rib R2f R3s 82 6.18 A 401 Rib R2f R3t 100 7.03 A 402 Rib R2f R3u 88 7.83 A 403 Rll R2b R3i 54 4.4 A 404 Rio R2e R3i 70 3.82 A 405 Rll R2a R3c 39 4.46 B 406 Rll R2c R3z 69 4.18 A 407 Rif R2f R33 21 10.48 A 408 Rih R2f R3m 58 5.58 A 409 Rlh R2f RUx 92 5.60 A 410 Rli R2f R3g 73 6.2 A 411 Rib R2f R3m 46 5.68 A 412 Rik R2b R3r 50 5.14 A 413 Rik R2b R3s 54 6.05 A 414 Rik R2b R3t 88.5 7.15 A 415 Rik R2b R3u 100 7.35 A 416 Rik R2b R3v 100 6.79 A Functional Groups for Table 3 Galactitol Library 0 o Ri N'a

OH

0

OH

0 Rid 0 Vk---YOH Rib 0 0

OH

Rie 0 0 N~ OH

HI

RI c 0 N

OH

H 0 Rif 0

OAH

3 0 0 V -,OH RI h 0

NH

2 R1i 0 Rlj RI g 0

OCH

3 0 RI I 0 V N OCH 3

H

0 6 RIlm 0 A OCH 3 Rilk 0 0 0 V -,OCH 3 RI n

H

3 C CH 3 0

XOCH

3 R2e O--r0H 0 R2a 0

H

N

N

R3a R21b

'CH

3 R2c

H

3 C CH 3 0

OH

R2d R3b No y R3e 0

HOCJ'

R3j R3c 0 HNP0 0 01 R3g 0

H

2

N

R3h=Rli R3d=RIe 0

NH

2 R3i C ~HO) R3k R31 0 0 Ie HN f l

HO&

R3n=Ri a R3m 0 HO 0 R3o 0 O No- I~ R3p 0

HN

0

OH

R3q=Rl c 0 O N OH C R3r R3u R3v 0

OH

R3w=Rlj 0 HO rI 0 R3x 0 0 HR3z

CH

3 .1 R3y

HO,

OFF

R31 0 H O 0 R32=RI b 0

HN

0' NH L-R33 HPLC Methods for Comoounds in Table 3.

Method A Time H 2 0% MeCN% Flow rate ml/min 0 100 0 2 2 100 0 2 40 60 2 12 0 100 2 Agilent SB Zorbax C18 4.6 x 50mm (5qm, LC Mobile Phase: Acetonitrile Water 0.1% formic acid Method B Time H 2 0% MeCN% Flow rate ml/min 0 100 0 2 1 100 0 2 7 65 35 2 8 0 100 2 9 0 100 2 Agilent SB Zorbax Phenyl 4.6 x 150mm LC Mobile Phase: Acetonitrile Water 0.1% formic acid 'H-NMR Data for Three Compounds of Final Library.

Compound (238) IN-

H

6 H (400 MHz; CDC13) 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 0

OH

H3' /O 0 0 6 H (400 MHz; CDC13) 0.94 (3 H, t, J 7.0 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 J 4.2 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 (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; CDC13) 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 Hz), 4.77 (1 H, d, J 4.8 Hz), 6.64 (1 H, dd, J 6.4 Hz and J 2.0 Hz), 6.87 (1 H, m), 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).

Example 3: Synthesis of butvldiphen ylsilyl)-2-deoxV-D-gqlucitol.

a 1, 5-anh ydro-2-azido-3-O-benzo yI-6-O-(t- I 3-a

IHDTPM

OH

3-b H

HO

2 418 N HO Ph--Oq 0-7~h~~ HzO 3-e 0o3- 421 N 3 420 341 3 I

OTBOPS

422

N

3 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.

Example 4: Synthesis of a 1,5-anhydro-2-azido-3-O-benzovl-6-O-(tr butvldiphenylsilyl)-2-deoxy-o-qlucitol.

MeOPh O o MeOPh'0 MeOPh--'O O CIBzO--P HO-- H O 6 HOTPM 423 NH 2

N

3 (4-c) STBDPSO- HO] 0 HO O HO O° SBzO BzO-- 422 N 3 421 N 3 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-Deoxy-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 69% yield after 48 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 ml/min 0.00 90.0 10.0 2.00 1.00 90.0 10.0 2.00 S7.00 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, 532.3; 100% purity by ELSD Rt 6.84 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 ml/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 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 2.99 J 3.76Hz, 1 3.21 J 11.1, 11.5 Hz, 1 3.31 3.34 1 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 H), 5.11 J 9.2, 9.7 Hz, 1 7.28-7.43 8 7.51-7.55 1 7.58-7.56 2 8.02-8.06 2 H).

Example 5: General synthetic route for preparation of a Library of Glucitol Peptide Mimetics.

NH OTBDPS OTBDPS OTPS OTBD (RO 5I 3 HO-O (5-a O (5b BzO-- HO_ o 42 422 3 424 N 3 425 N 3

I

OR3 V R3 OH 9 OTBDPS 0 4o230 R20-0 O 5d5-O6N CR1 429 H5 428 N 3 427 3 426 3 I63 HO Final Products Final Products O HO- O Compounds 432 to 440 430 NHR1 431 NHR1 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 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 Conjugate 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 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-Acylations 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.

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.

Table 4: Library of Glucitol compounds Comp. Purity Yield R1 R2 R3 M+H Purity Rt Yield 2 No. mg 85.8 432 Rla R2a R3a 509.1 3.71 14.1 53.9

ELSD

433 Rlc R2b R3b 507.2 63.6 UV 3.38 4.9 18.7 434 Rid R2b R3c 555.2 77.9UV 4.04 14.1 435 Rid R2b R3d 541.1 3.62 8.6 30.9 73.2 436 R1a R2c R3a 369.1 0.86 9.6 50.5

ELSD

437 Rib R2c R3c 453.2 80-UV 3.18 438 R1b R2c R3d 439.1 2.52 1.6 7.1 439 Rle 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 1 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.

Side Chains for Table 4: Ny

NH

2 Ria V' aBr R2a I<-YOH 0 R3a

N.NH

2 R2b

DH

c H3A R2c 0 NH J"N'JKN H 2

H

Rib ci R3C NH 2 N' NH 2 0 RIf R3d Rif HPLC Method for Compounds in Table 4: (Agilent SIB Zorbax 0 18 4.6 x 50mm (5itm, 80A) LC Water 0.1 formic acid) Gradient as follows: Time(min) water% CH3CN% 0.00 95.0 5.0 1.00 95.0 5.0 7.00 0.0 100.0 12.00 0.0 100.0 13.00 95.0 5.0 15.00 95.0 5.0 Mobile Phase: Acetonitrile: Flow mI/mmn 2.00 2.00 2.00 2.00 2.00 2.00 Example 7: Allitol Buildinq Block Synthesis o Ph- Ph O- Ph OTfO 419 N 3 441 Bz 4 3 4 4 2 (7-c)

OTBDPS

HO

HO\

CM BzO 3 BzO 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 -250C. 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.

7d. Formation of the Differentially Protected 1,5-Anhydro Allitol Building 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 Building Block 444.

R3 2 Observed.

Comp. R1 R2 R3 R4 R5 O b se Mass H 441 N 3 H OTf Benzylidene 410.13 442 N 3 OBz H Benzv idene 382.15 443 N 3 OBz H H H 294.12 444 N 3 OBz H H TBDPS 532.15 Example 8: Prototype Library using H-Allose Buildinq Block OTBDPS OTBDPS OTBDPS HO N (8-b) Bz 44 BzO

H

O 3 ,I (8-c) c OR 1 OH OTBDPS S(8-e) O 4-CIBn 44 4-IBn CIBnO 448 447 (8-f)

OR

1

OR

1

OR

1 S a(8-)o (8-hi,j,k) HO 0 4-CBn NH 2 4 CIB NHR2 4-CIBn NHR 2 4-CIBn 4-1n 452 450 451 8-a. Coupling 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-Buildinq 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 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 Cc The resin bound compounds designated by 449 were subjected to the conditions as N described in General Method 24.

l"- 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 Intermediates 57 and Final Products R3"'- '~"/Ri1 6 R2 Compound RI R2 R3 R4 Exp. Mol M+H 453 N 3 Bz H TBDPS 532.27 454 N 3 H H TBDPS 428.20 455 N 3 p-Clbenzyl H TBDPS 552.25 456 N 3 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 Ria p-Clbenzyl H 2-Napthyl 707.40 463 Ria 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-Clbenz H p-CIBn 469.26 452b Ric p-Clbenzyl H 2-Napthyl 485.32 452c Rid p-Clbenz H p-CIBn 497.26 452d Rid p-Clbenzyl H 2-Napthyl 513.37 452f Rle p-Clbenzyl H p-CIBn 511.28 452g Rie p-Clbenzyl H 2-Napthyl 527.33 452h Rif p-Clbenzyl H p-GIBn 539.31 4521 Rlf p-Clbenzyl H 2-Napthyl 555.38 452j Rig p-Clbenzy H 4-Mebiphenyl 525.30 452k Ric p-Clbenzyl H 4-Mebiphenyl 511.20 Sidearms for Table 6 ,3 0 0 0 o o o N NmNHFmoc N NHFmoc AN NH 2 H R1a H Rib H R1c 0 o o o H.

SN

SNH

2 AN N NH N N N H H H H N Rid Rle NH 2 Rlf NH2 RN fNH 2 H Rig Example 9: Synthesis of a 1,5-anhydro-3-azido-6-O-(t-butvldimethylsilyl)-2,3dideoxy-2-[(1,3-dimethyl-2,4,6- (1H, 3H, 5H)-trioxop yrimidin-5-ylidene) methylaminol- D-allitol.

Me~OPh^~ MeOPh 0

OTBDPS

MeOPh O 0 O

OTBDPS

Y- HO 0

N

3 453 1 NHDTPM N3 454 9-a. Formation of a Aminoallitol 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 19 to provide compound 454.

Example 10: Synthesis of a 1,5-anhydro-3-azido-4-O-benzol-2,3-dideoxy-2-[(1,3dimeth yl-2, 4, 6(1 H, 3H, 5H)-trioxop vrimidin-5-ylidene) meth ylaminol-6-O-(4methoxvbenzv)--D-QU~itoI.

AcO OAc AcO AcO QAc HH r i-a) 0 0 AcO 0 456 NHDTPM 455 0 OBnOMe OH OH MeOPh--0 HO: 0 a0 457 NHDTPM

HOI;

458 NHDTPM (1 O-d)

JHDTPM

461 460 '3 459

NHDTPM

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 5; 10-g. General Method 14.

Example 11: Synthesis of a Library of Compounds by Solid Phase Techniques Usinq a Galactitol Building Block N OBnOMe N3 OH O (11-a) O (11-b) N CIBzO 4 CIBzO en 463 HDTPM 464NHDTPM CIBzO_ O 465 NHDTPM

(N

r" (11-c) N(11 (11) N (11-d) R1O R10 R1O HO 469 NHR2 468 H, 467 NHDTPM 466 NHDTPM (11-g) R3H H N 11-h) (11-i,j,k,I) R1 R1 R1 NHR2 470 HR2 471 NHR2 472 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).

Examole 12: Solid Phase Synthesis of a 2.5-Bis Amino-Allitol Library.

IDTPM

S(12-c) (12-h,i,j,k) IHR2 R3HI 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).

Example 13: Synthesis of a Library of Compound by Solid Phase Techniques Usinq a Diamino Gulitol Based Buildinq Block BzO H BzO HO R 10 o (13-a) (13-b) g o (13-c) 1 O HDTPM HDTPM N HDTPM HDTPM SN3 462N3 481 N3 482 N 3 483 O (13-d) R1 (13-h) (13-f) 0 1 3e R10 HR2 NHR2 NHR2 N N 3 R3HN 487 NH 2 486 N3 4853 484 (13-i,j,k,I)

OH

R

3 HN R2 488 13-a. General Method 20; 13-b. General Method 21; 13-c. General 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).

Example 14: Synthesis of an Exemplary Library 1 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 3§) maintain their position on the scaffold (Phe=R Lys=R 2 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

NHR

2

A

OR

3 HO4X- 0

NHR

2 NHR2

R

3 H

R

R3HIA[ NHR2

R

1 O OH

R

3

HN

D

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 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 The 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 Olinked 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 o 0 Lys (N-linked) NH 2

NH

Lys (O-linked) i NH 2

NH

2

H

2

N

Phe (N-linked) -F CH 3 Phe (0-linked) F /\CH 3 0 0 0 Trp (N-linked) I -~k N. N H~N

HH

Trp (0-linked)C cl

H

Example 15: A Gulitol N-Glycoside Buildinq Block OH OH AcO OAc AcO OAc O-0 (15-a) HO AcO OAc AcON3 489 H 490 OAc 491 Ac HO OH 0 OTBDPS HO OH (15-e) 0 0 HO-N3

N

3 HO N3 H 494 OBz 493 OBz 492 OH MeOPh MeOPh O (15-g) QI HO 4 N3 HO0 NHDTPM L~ NHDTPM 495OB 496 OB 497 HO OBnOMe

-NHDTPM

l OBz

N

3 498 Ac20, NaOAc; 15-b. General Method 34; 15-c. General Method 3; 15-d. (a) TBDPS-CI, 1,2-DCE, imidazole; 2,2-dimethoxy-propane, TsOH, MeCN; 15-e. (a) Benzoylchloride, pyridine, 1,2-DCE, DMAP; MeOH, TsOH, MeCN; 15-f. General Method 4; 15-g. General Methods 13 and 20; General Method 33.

Q) Example 16: Synthesis of Glucosyl N-Glycoside Building Block OAc AcO7O OAc OH AcO H Ac (16-a) O (16-b) H1 ACO 03 N HO -0 o HO N 3 0_ 450 NHDTPM 451 NHDTPM 0 j(16-c) c~ 499 HO 0 (16-e) (1 6-d) PhO 0 Bz BzO N3- HO 454 HDTPM NHDTPM NHDTPM I f453 452

OTBDPS

HO 0 -AO

N

3

HDTPM

455 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.

Example 17: Synthesis of Glucosylamino 2-Deoxy-2-Amino library.

MeO 00 (1 7-a) Me 456 NHDde 45 NH 2 (1 7-b) 0) S 0 N3 (1 7-c) /e-c 3 MeCHO N 3 MO R1~N3 458 NHDTPM 49NHDTPM OH HOe PB V 0MBO( PMBO 0 R10_ N3( 7 e M

N

3 (1 (1 7-d) -e R1iO3R1- 460 NH 2 461 NHDTPM 42NDP (1 7-g) 17_N__ 17i M RBO- N 3 Ri N 3 R RiO NH 2 463 NH 2 30 NH0

H

1464 1465 BocHN BocHN OMe OMe OMe PMBO 0 H HO 0 H H (17-j) R102R 0 NR107-I HO 0 RON ;AR2 NRiO N rR2NH r R (17- NH N 0o 17k 0 466 467 468 BocHN H 2 N H N H

H

2

N

17-a. Synthesis of 2-Deoxy 2-Amino Glycosyl Amine To a solution of starting material (20.51lmmol) in MeOH/DMF 150 ml) 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 p~rotected Glycosyl Amine Compound 458 was formed from reaction of 457 according to the procedure 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.

Cl 17-d. Reductive Ring Opening of a 2-Deoxy 2-NHDTPM 3-O-Alkyl Glycosyl Amine A solution of a derivative represented by 460 (4.37mmol) in dry DCM (30mL) 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, (CDC 3 6 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 5H, Ar), 6.95-6.86 2H, Ar), 5.08 1H, NapCH 2 Jgem=12.1 Hz), 4.86 1H, PMPCH 2 Jgem=10.5 Hz), 4.72 1H, PMPCH 2 4.71(d, 1H, H-lb, J1, 2 =9.2 Hz), 4.69 1H, NapCH 2 3.95 (dd, 1H, H-6a, Jgem=12.

2 Hz, J 56 a=1.7 Hz), 3.85-76 1H, H-6b), 3.81 3H, OMe), 3.74 (dd, 1H, H-4, J 3 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 General Method 7; 1H-NMR (CDCI3); 8 9.92 (dd, 1H, NH, JNH2=9.

7 Hz, JNH=CH=13.

8 Hz), 7.88 1H, 7.75-7.68 4H, Ar), 735-7.22 5H, Ar), 6.95-6.86 2H, Ar), 5.08 1H, NapCH 2 Jgem=1 2 .1 Hz), 4.86 1H, PMPCH 2 Jgem=10.5 Hz), 4.72- 4.68 3H, NapCH 2

PMPCH

2 3.80-3.74 3H, H-6a, H-6b, 3.81 (s, S 3H, OMe), 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).

¢q 17-q. 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; 1H-NMR, (CDC13) 6 7.78-7.66 4H, Ar), 7.43-7.32 5H, Ar), 6.86- 6.69 2H, Ar), 5.48 1H, CH-PMP), 5.05 1H, NapCH 2 Jgem=11.

3 Hz), 4.77 1H, NapCH 2 4.47 1H, H-lb, J1, 2 =8.9 Hz), 4.28 (dd, 1H, H-6a, Jgem=10.

3 Hz,

J

5 6 a=5.5 Hz), 3.76-3.65 2H, H-6b, 3,72 3H, OMe), 3.49 (dd, 1H, H-3, J2.3=9.

0 Hz, J 34 =9.0 Hz), 3.46 (ddd, 1H, 2.75 (dd, 1H, H-2).

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

17-i. Solution Phase Reduction of an Anomeric 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 Glucosaminyl Derivative.

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

17-k. Removal of a Boc Protectinq Group from a 2-Deoxy-2-N-Acyl-Glycosylamine Derivative.

Dissolve crude 467 (-0.21mmol) in 10mL 20% TFA in DCM and stir at room temperature for 10min. Evaporate solvents and dry the remaining syrup under high vacuum. Redissolve in DCM and wash with 1 M KOH, filter over cotton, evaporate and purify by column chromatography (eluent DCM/MeOH 10:1 1% Et 3 N) to give 71 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 Comp. R1 R2 R3 Molecular Ion 469 naphthyl phenyl H 522.33 470 naphthyl 4-Chlorophenyl H [M+H] 556.1 471 naphthyl benzyl H 536.36 472 4-chlorobenzyl a-naphthyl C(NH)NH 2 [M+H]f 598.39 Examle 18: Synthesis of a Carboxamide C-Glvcoside I OH OAcQc HO~(1 8-a) 0 (1 8-b)_ HO AcO Me AcO HOSMe Ac AcO3 -0O 473 N 3 474 N 3 475 N 3

O

OH OAcOc(18) HO O (1 8-d) NH HO Ac18e) O AcO- HOO AcO N 3 AcO 4781(N 477 N3476 N 3 ClMeOPh~\ 8f MeOPh O Me Ph O 0 479 N 3 C2e480

N

3 COHf481

N

3 CONHR1 OTBDPS HO j11 HO18~j HO 0 Bz483 N 3 CONHR1 B 482 N 3

CNR

Conditions: NaOMe/MeOH; (ii) Acetone, NBS; (iii) trichioroacetonitrie, potassium carbonate, DOM; (iv) TMS-CN, TMS-Otf, DOM; (v)NaOH/H 2 0 2 (vi) TMS-0H 2

N

2 p-methoxybenzaldehyde dimethylacetal, OSA, MeCn, DMF; (vii) LiGH, H 2 0, THF; HBTU, DIPEA, DMF, R 1

-NH

2 (viii) benzoylchloride, pyridine, 1,2-OCE, DMAP; (TsOH, MeOH, MeCN, H 2 0; TBDPS-CI, imidazole, 1,2-OCE.

Example 19: Synthesis of an Ally! C-Glycoside u- (19-a) (19-b) OH(9c OAc L*4c Y~~ON 8 N 3 486 4 3 N 48 484 (1 9-d) (1OH OAc Se SMeSe 0- -4OAc

N

3 489 N 3 OH8N 487 19-g)

OTBPS

Ph O0 Z(1 9h)HO 0 0 OSMe HO-) SMe Bz OBz Bz49 N3 490 N3491

N

3 4(1 9 2

OTBDPS

HO 0

N

3 Bz N3493 Conditions: Tf 2 O, pyridine, 0CM; NaN 3 DMF; (Hi) acetone, H 4 (iii) Ac 2

O,

pyridine; (iv) hexamethyldisilazane, 12, CH 3

-S-S-CH

3 NaOMe/MeOH; (vi) TsOH, c,c-dimethoxytoluene, MeCN; (vii) benzoylchloride, I ,2-DCE, pyridine, DMAP; (viii) TsOH, MeOH, H 2 0, MeCN; (ix) TBDPS-CI, imidazole, 1 ,2-DCE; TMS-allyI, TMS- OTf, 0CM.

Examole 20: Synthesis of a Rance of C-Glvcosides BBnOYSR Bn_ R R=H Bn~o S 494 NHAc 0495N HAc I(20-d) (20-e) OBn O~n O~n OBn C1 Bn 0 BnO BnO 0BnO 0 SAc B 496 NHAc~ 497 NHAc 498 HAc B 499g HAc

I

OH

(2 0 -h H 0 501, NHAc 500 NHAc OH OTBDPS Ph- 0 (20-k~ HO 0 BzO BzO Bzo 502 NHAc 503 NHAc 504 HAc *Ramburg..Backlund rearrangement of phthalimido thioglycosides I to give an exo methylene compound 11. The products can them be converted to a variety of Cglycosides 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, CCI 4 (iii) BH 3 HOGH, H 2 /Pd; (iv) H 2 Pd; ArX, Pd(0), H 2 /Pd; (vi) AcSH, AIBN, H2/Pd; (vii) KOH, TfN 3 RT, CH 2

CI

2 MeOH, H 2 0/cat. CUS0 4 90%; (Viii) CtXtdimethoxytoluene, TsOH, MeON/MeGH; (ix) BzCI, pyridine, MeOH/MeCN/H 2 0, TsOH: (xi) TBDPS-CI, pyridine.

Examole 21: Synthesis of an Ribofuranosvl Azide Buildina Block.

,0.OAc A 0 N 3 0 N AcO AcO 3)- (21-a) 21-b) AcO OAc AcO OAc HO OH 505 506 507 (21-c) 0 0 N3 0 kN 3 S(21-e) C2-e) _(21-d) K X X (21-f) 510 509 508

H

2

N

511 21-a. 1-Azido-2,3,5-triacetyl 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- 76 S 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 S was removed in vacuo. The residue was dissolved in DCM (500 ml), washed with 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 M gel (20-40 EtOAc/petrol) to give a yellow oil 508, 69 from tetraacetate 505. 6

H

(N (400 MHz: CDCl3) 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, 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 2.5 h, then quenched with water (20 ml) and extracted with ethyl acetate (2 x 20 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 (20-40 EtOAc/petrol) to give a white solid, 88 LCMS: >90 by ELSD, (M N 3 251. 6 H (400 MHz: CDC13) 1.31 3H, CH 3 1.49 3H, CH 3 3.09 3H, SO 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, J6.1, 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 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 0 5 in a dessicator overnight as white crystals, 51 LCMS: >95 by ELSD, (2M 711. 6 H (400 MHz: CDCI3) 1.29 3H, CH 3 77 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, 4.57 J 6.4 Hz, 2H, H3, H4), 4.78 J 5.8 Hz, 1 H, H2), 5.57 1H, H1), 7.73 J 3.2 Hz, 1 H, ArH), 7.74 J 3.2 Hz, 1 H, ArH), 7.87 J 3.2 Hz, 1 H, ArH), 7.88 S J 3.2 Hz, 1 H, ArH).

0 21-f. 1-Azido-2,3-isopropylidene-5'-amino-ribose 511 rn 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 CHCI 3 and dried (MgSO 4 The solvent was removed in vacuo to give a yellow oil, 93 LCMS: (M N 3 8 (400 MHz: CDCI3) 1.32 (bs,

CH

3

NH

2 1.50 3H, CH 3 2.84 (dd, J13.1, 6.0 Hz, 1H, H5a), 2.90 (dd, J 13.0, 8.1 Hz, 1 H, H5b), 4.24 J 7.0 Hz, 1H, H4), 4.48 J 5.8 Hz, 1 H, H3), 4.61 J 4.8 Hz, 1H, H2), 5.53 1H, H1).

References 1. K. C. Nicolaou; J. M. Salvino, K. Raynor; S. Pietranico; T. Reisine; R. M.

Freidinger, R. Hirschmann, Pept.: Chem., Struct. Biol., Proc. Am. Pept. Symp., 11 t h 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, U. Hunger, T.

Maidhof, O. Kn6ll, H. Kunz, Poster Presentation, 2 0 th International Carbohydrate Symposium, Hamburg-Germany, T. Opatz, C. Kallus, T. Wundberg, W.

Schmidt, S. Henke, H. Kunz, Poster Presentation, 20 t h International Carbohydrate Symposium, Hamburg-Germany.

3. R. Hirschmann, K.C. Nicolaou, S. Pietramico, 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. Soc., 1993, 115, 12550

Claims (11)

1. A monosaccharide compound of formula I Y a H H 00oo 0z R4 R2 R3 0formula I (N wherein, Y is selected from hydrogen, or the following, where G denotes the point of connection to the nitrogen atom in N(Z)Y; 0O O0 GsX II G X X G 0 0 0 OH Z is selected from hydrogen or alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl of 1 to 20 atoms; X is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 2 to atoms; The groups R2, R3, R4 R5 are independently selected from -OX, N(Z)Y, -OH or wherein at least two of the groups R2 to R5 are -OX or N(Z)Y, such that each instance of X is different; and where R2 is both Z and Y are not H and at least one of R4 or R5 is -OX, -N(Z)Y or and at least two of the groups R2, R3, R4 and R5 are selected from the group consisting of -OX and are not the same or and the others are 00 independently selected from hydrogen, hydroxyl; wherein only one of R4 and S R5 may represent hydroxyl; or Y and Z optionally independently combine with NN to form a ring, and wherein N(Z)Y does not represent NH 2 oO 2. The compound of claim 1, wherein the ring is selected from the a or P configuration.

3. The compound of claim 1, wherein the groups Z and Y are combined Sto form a monocyclic or bicyclic ring structure of 4 to 10 atoms.

4. The compound of claim 3, wherein the ring structure is further substituted with X groups. 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, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid.

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

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

8. The compound of claim 7 wherein at least one of R2, R3, R4, or R5 is -N(Z)Y.

9. The compound of claim 7 wherein at least two of R2, R3, R4, or are -N(Z)Y. The compound of claim 7 wherein at least two of R2, R3, R4, or are -OX.

11. A method of synthesis to form a compound of claim 7 comprising the step of reducing a compound of formula Ilia formula IIIa Wherein R 5 R 4 R 3 and R 2 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(1 H, 3H, (NHDTPM), NH-benzloxycarbonyl (NHZ), NH-tert-butoxycarbonyl (NHBOC) phthalimide,OX2, N(Z)Y and O-protecting group, X is independently selected from alkyl, alkenyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 atoms, Z is hydrogen or X, Y is selected from hydrogen, or the following, where G denotes the point of connection to the nitrogen atom in N(Z)Y; 0 G X O 0 11 0 0 G S x G O OH O G NX Q Z is selected from hydrogen or X; and Q is selected from hydrogen or X.

12. 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; H H S,0. ,N-Z General 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(1 H, 3H, 5H)-trioxopyrimidin-5-ylidene)methyl (NHDTPM), NH-benzloxycarbonyl, NH-tert-butoxycarbonyl (NHBOC), phthalimide, OX, N(Z)Y and an O-protecting group, and X ,Z and Y are as defined in claim 1.

13. The method of claim 12 wherein the support is selected from the O 0 group consisting of derivatised polystyrene, Tentagel, Wang resin, MBHA S(Methyl benzhydrylamine copoly (styrene-1 or 2%-divinylbenzene)) resin, aminomethylpolystyrene, rink amide resin, DOX-mpeg (Didioxylyl diether 00 (DOX); Polyethyleneglycol w-Monomethylether (MPEG)), and polyethylene glycol.

014. 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 12. N Alchemia Ltd 14 December 2007