TECHNICAL FIELD

The present invention relates to methods for preparing alkenylamines from cyclic acetals or derivatives thereof, methods for preparing cyclic carbamates and cyclic dithiocarbamates from alkenylamines, and methods for preparing aminoalcohols and aminothiols from cyclic carbamates and cyclic dithiocarbamates, respectively. More particularly, the present invention relates to regio- and stereo-selective methods for preparing these compounds.

BACKGROUND ART

Owing to their properties as inhibitors of glycosidases, polyhydroxylated alkaloids have enormous therapeutic potential in diseases such as viral infection, bacterial infection, lysosomal storage disorders, cancer and diabetes. The nature of the glycosidases that will be inhibited by certain imino-sugars may, to some extent, be predicted from the number, position and configuration of the substituents. However, there can be marked differences in the inhibition of isoenzymes of a given glycosidase in different species and even within the same cell. Many tumour cells display aberrant glycosylation due to an altered expression of glycosyltransferases and levels of glycosidases are elevated in the sera of many patients with tumours. However, due largely to the limited availability of the imino-sugars, only a few (principally 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (DMJ), castanospermine and.swainsonine) have been widely studied for their therapeutic potential.

1 -Deoxynojirimycin 1 -Deoxymannojirimycin (DNJ) (DMJ)

Castanospermine Swainsonine

Five-membered imino-sugars, also known as hydroxypyrrolidines, include: the α-galactosidase inhibitor l,4-dideoxy-l,4-imino-D-lyxitol (A); the mannosidase inhibitors l,4-dideoxy-l,4- imino-D-mannitol (B) and l,4,6-trideoxy-l,4-imino-D-mannitol (C); l,4-dideoxy-l,4-imino-D- xylitol (D); l,4-dideoxy-l,4-imino-L-lyxitol (E); swainsonine, which inhibits both lysosomal α- mannosidase and monosidase II; the potent inhibitor of β-galactosidase and α-mannosidase, broussonetinine A (F); gualamycin (G); and the antibiotic anisomycin (H).

D-lyxo B R = CH ₂ OH D D-xy/o E L-lyxo C R = CH ₃

G Gualamycin H Anisomycin

Many strategies for the synthesis of hydroxypyrrolidines have been reported (see, for example, La Fera, B.; Nicotra, F. "Synthetic Methods for the Preparation of Iminosugars", Ch. 4, in Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond (1999), p. 68-92, Arnold E. Stϋtz, (Ed.), Weinheim Germany: Wiley- VC Y). Many of these strategies are lengthy, some show poor diastereoselectivity, and all employ standard protecting group manipulations. The extensive use of protecting groups has many disadvantages including the use of organic solvents for reactions, work-up, and purification, and may be environmentally deleterious. In addition, extensive protecting group manipulations lead to lengthy syntheses requiring both a protection and deprotection step per protecting group, resulting in reduced atom economy and hence, reaction efficiency.

Accordingly, it is an object of the present invention to go some way to avoiding the above disadvantages or to at least provide the public with a useful choice.

Other objects of the invention may become apparent from the following description which is given by way of example only. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a method for preparing an alkenylamine, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide the alkenylamine; optionally converting the alkenylamine into a salt, solvate or hydrate thereof; and optionally isolating the alkenylamine or salt, solvate or hydrate thereof.

In a second aspect, the present invention provides a method for preparing a cyclic carbamate or cyclic dithiocarbamate, or a salt, solvate or hydrate thereof, the method comprising: reacting an alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide the cyclic carbamate or cyclic dithiocarbamate; optionally converting the cyclic carbamate or cyclic dithiocarbamate into a salt, solvate or hydrate thereof; and optionally isolating the cyclic carbamate or cyclic dithiocarbamate or salt, solvate or hydrate thereof.

In a third aspect the present invention provides a method for preparing a cyclic carbamate or cyclic dithiocarbamate, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide an alkenylamine; reacting the alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide the cyclic carbamate or cyclic dithiocarbamate; optionally converting the cyclic carbamate or cyclic dithiocarbamate into a salt, solvate or hydrate thereof; and optionally isolating the cyclic carbamate or cyclic dithiocarbamate or salt, solvate or hydrate thereof.

In a fourth aspect, the present invention provides a method for preparing a 1,2-aminoalcohol or 1,2-aminothiol, or a salt, solvate or hydrate thereof, the method comprising: reacting an alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide a cyclic carbamate or cyclic dithiocarbamate; deprotecting the cyclic carbamate or cyclic dithiocarbamate to provide the 1,2-aminoalcohol or 1,2-aminothiol; optionally converting the 1,2-aminoalcohol or 1,2-aminothiol into a salt, solvate or hydrate thereof; and optionally isolating the 1 ,2-aminoalcohol or 1 ,2-aminothiol or salt, solvate or hydrate thereof.

In a fifth aspect, the present invention provides a method for preparing a 1,2-aminoalcohol or

1,2-aminothiol, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide an alkenylamine; reacting the alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide a cyclic carbamate or cyclic dithiocarbamate; deprotecting the cyclic carbamate or cyclic dithiocarbamate to provide the 1,2-aminoalcohol or

1,2-aminothiol; optionally converting the 1,2-aminoalcohol or 1,2-aminothiol into a salt, solvate or hydrate thereof; and optionally isolating the 1,2-aminoalcohol or 1,2-aminothiol or salt, solvate or hydrate thereof.

The invention also provides an alkenylamine, or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

The invention also provides a cyclic carbamate, or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

The invention also provides a cyclic dithiocarbamate, or a salt, solvate or hydrate thereof, when prepared by a method of the invention. The invention also provides a 1,2-aminoalcohol, or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

The invention also provides a 1,2-aminothiol, or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

The invention also provides the halogen-substituted cyclic acetal:

The invention also provides an alkenylamine selected from the group consisting of:

The invention also provides a cyclic carbamate selected from the group consisting of:

This invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.

As used herein, the term "salt" is intended to include acid addition salts of any basic moiety that may be present in a compound useful in the invention, and base addition salts of any acidic moiety that may be present in a compound useful in the invention. Such salts are generally prepared by reacting the compound with a suitable organic or inorganic acid or base. Examples of salts of basic moieties include: sulfates; methanesulfonates; acetates; hydrochlorides; hydrobromides; phosphates; toluenesulfonates; citrates; maleates; succinates; tartrates; lactates; and fumarates. Examples of salts of acidic moieties include: ammonium salts; alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts. Other salts will be apparent to those skilled in the art.

The compounds useful in the invention, and their salts or other derivatives, may form hydrates, or solvates with various solvents. The present invention contemplates such hydrates and solvates as well as the corresponding unsolvated forms.

The compounds useful in the invention may have asymmetric carbon atoms. Therefore, stereoisomers (both enantiomers and diastereomers) of such compounds can exist. The present invention contemplates the pure stereoisomers and any mixture of the isomers. For example, a pure enantiomer of a compound can be isolated from a mixture of enantiomers of the compound using conventional optical resolution techniques. Enol forms and tautomers are also contemplated, where appropriate.

The invention also contemplates "radiolabeled compounds", which are compounds that contain unnatural proportions of atomic isotopes. Such compounds may be useful as therapeutic, diagnostic or research reagents.

The general chemical terms used in the formulae herein have their usual meanings.

For example, as used herein:

the term "alkyl" is intended to include straight chain and branched chain saturated hydrocarbon groups. In one embodiment, alkyl groups comprise 1 to 30 carbon atoms. In a preferred embodiment, alkyl groups comprise the aliphatic chain of a short chain, medium chain or long chain fatty acid. In another preferred embodiment, alkyl groups comprise 1 to 6 carbon atoms. In another preferred embodiment, the alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl or t-butyl;

the term "cycloalkyr' is intended to include cyclic saturated hydrocarbon groups;

the term "alkenyl" is intended to include straight chain and branched chain unsaturated hydrocarbon groups; the term "cycloalkenyl" is intended to include cyclic unsaturated hydrocarbon groups;

the term ""alkynyl" is intended to include straight chain and branched chain hydrocarbon groups including a carbon-carbon triple bond;

the term "alkoxy" is intended to include alkyl-O- groups;

the term "cycloalkoxy" is intended to include cycloalkyl-O- groups;

the term "aryl" is intended to include aromatic radicals including, but not limited to: phenyl; naphthyl; indanyl; biphenyl; and the like. In one embodiment, preferred aryl groups comprise 4 to 10 ring carbon atoms;

the term "amino" is intended to include -NH ₂ groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group;

the term "amido" is intended to include amino-C(O)- groups;

the term "imino" is intended to include =NH groups, wherein the hydrogen atom may be replaced by an optionally substituted alkyl or aryl group;

the term "aryloxy" is intended to include aryl-O- groups;

the term "heteroaryl" is intended to include heteroaromatic radicals including, but not limited to: pyrimidinyl; pyridyl; pyrrolyl; furyl; oxazolyl; thiophenyl; and the like;

the term "heteroaryloxy" is intended to include heteroaryl-O- groups;

the term "heterocyclyl" is intended to include non-aromatic heterocyclic radicals including, but not limited to: piperidinyl; pyrrolidinyl; piperazinyl; 1,4-dioxanyl; tetrahydrofuranyl; tetrahydrothiophenyl; and the like;

the term "heterocyclyloxy" is intended to include heterocyclyl-O- groups;

the term "acyl" is intended to include -C(O)R groups, wherein R is an optionally substituted alkyl or aryl group;

the term "carboxyl" is intended to include -C(O)OH groups, wherein the hydrogen atom may be replaced by an optionally substituted alkyl or aryl group or a cation; the term "halo" is intended to mean chloro, bromo, fluoro, or iodo;

the term "metal" is intended to include, but is not limited to: lithium; sodium; potassium; magnesium; calcium; aluminium; manganese; nickel; copper; zinc; and tin;

the term "oxy" is intended to mean the -O- group;

the term "borane" is intended to include -BH ₂ groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group;

the term "boronic" is intended to include -B(OH) ₂ groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group or a metal;

the term "phosphate" is intended to include -OP(O)(OH) ₂ groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group or a metal;

the term "phosphinate" is intended to include -OP(O)H ₂ and -P(O)(OH)H groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group or a metal;

the term "phosphine" is intended to include -PH ₂ groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group;

the term "phosphite" is intended to include -OP(OH) ₂ groups wherein one or both of the - hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group or a metal;

the term "phosphonate" is intended to include -P(O)(OH) ₂ and -OP(O)(OH)H groups wherein one or both of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group or a metal;

the term "silane" is intended to include -SiH ₃ groups, wherein one, two or all three of the hydrogen atoms may be replaced, independently, by an optionally substituted alkyl or aryl group;

the term "siloxane" is intended to include -Si(O)H groups, where the hydrogen atom may be replaced by an optionally substituted alkyl or aryl group or a metal; the term "sulfate" is intended to include -OS(O) ₃ H groups, wherein the hydrogen atom may be replaced by an optionally substituted alkyl or aryl group or a metal;

the term "sulfenyl" is intended to include -SR groups, wherein R is an optionally substituted alkyl or aryl group;

the term "sulfonyl" is intended to include -S(O) ₂ R groups, wherein R is an optionally substituted alkyl or aryl group; and

the term "sulfoxide" is intended to include -S(O)R groups, wherein R is an optionally substituted alkyl or aryl group.

As used herein, the term "substituted" is intended to mean that one or more hydrogen atoms in the group indicated is replaced with one or more independently selected suitable substituents, provided that the normal valency of each atom to which the substituent/s are attached is not exceeded, and that the substitution results in a stable compound.

Unless a moiety of a compound is defined as being unsubstituted, that moiety may be substituted. In a preferred embodiment, the substituents are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkyloxy, alkenyl, cycloalkenyl, alkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy, acyl, carboxyl, amino, amido, imino, -NO ₂ , -NO, -CN, -N ₃ , -OH, sulfenyl, sulfonyl, sulfoxide, sulfate, phosphate, phosphonate, phosphinate, phosphine, phosphite and halo.

The term "substituted sulfur" is intended to include sulfate, sulfenyl, sulfonyl and sulfoxide groups.

The term "substituted silicon" is intended to include silane and siloxane groups.

The term "substituted boron" is intended to include borane and boronic groups.

The term "substituted phosphorus" is intended to include phosphate, phosphinate, phosphine, phosphite and phosphonate groups.

The term "comprising" as used in this specification means "consisting at least in part of. When interpreting each statement in this specification that includes the term ""comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner. It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

Although the present invention is broadly as defined above, those persons skilled in the art will appreciate that the invention is not limited thereto and that the invention also includes embodiments of which the following description gives examples.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a two-stage synthesis of 1,2-aminoalcohols or 1,2-aminothiols, in which a key step is the formation of a cyclic carbamate or cyclic dithiocarbamate from a precursor alkenylamine. The alkenylamines, in turn, are accessible in one step from halogenated cyclic acetals or derivatives thereof. As such, the methods of the present invention provide facile access to compounds for use in myriad applications, whether as synthetic intermediates, pharmaceutical compounds or chiral ligands for asymmetric synthesis.

One embodiment of the various aspects of the invention is illustrated in the following scheme.

II I III IV

SCHEME I

Scheme I illustrates the preparation of an alkenylamine of Formula I from a halogen-substituted cyclic acetal or a derivative thereof of Formula II. The alkenylamine may be reacted to form a cyclic carbamate (Y=O) or cyclic dithiocarbamate (Y=S) of Formula III, which may be deprotected to form a 1 ,2-aminoalcohol (Y=O) or 1 ,2-aminothiol (Y=S) of Formula IV.

Preferably, Y is O. Preferred halogen-substituted cyclic acetals include an alkoxy, substituted alkoxy, alkenyloxy or aryloxy leaving group, more preferably an alkoxy leaving group.

Preferred halogen-substituted cyclic acetals and derivatives thereof include a leaving group selected from the group consisting of halogen, -OR ¹⁰ , -NHR ¹⁰ , -N(R ¹⁰ ) ₂ , -SR ¹⁰ , -SOR ¹⁰ , -SO ₂ R ¹⁰ and -SeR ¹⁰ , wherein R ¹⁰ is independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, acyl, substituted acyl, acetimidoyl, substituted acetimidoyl, amino, substituted amino and halogen.

Accordingly, in a first aspect, the present invention provides a method for preparing an alkenylamine, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide the alkenylamine; optionally converting the alkenylamine into a salt, solvate or hydrate thereof; and optionally isolating the alkenylamine or salt, solvate or hydrate thereof.

In a preferred embodiment, the halogen-substituted cyclic acetal or derivative thereof is enantiopure and the reaction is stereo- and regioselective, such that the resulting alkenylamine is chiral.

In another preferred embodiment, the halogen-substituted cyclic acetal or derivative thereof is stereoisomerically pure and the reaction is stereo- and regioselective, such that the resulting alkenylamine is stereoisomerically pure.

One embodiment of the first aspect of the invention is a method -for preparing a compound of Formula I:

or a salt, solvate or hydrate thereof; wherein L is selected from the group consisting of:

-C(R ⁿ )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )C(R ⁴¹ )(R ⁴² )C(R ⁵¹ )(R ⁵² )-; -C(R ⁿ )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )C(R ⁴¹ )(R ⁴² )-; -C(R ¹¹ )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )-; and -C(R ¹¹ XR^)C(R ²¹ XR ²² )-; wherein R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ , R ⁴² , R ⁵¹ and R ⁵² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , and/or R ⁵¹ and R ⁵² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , R ²² and R ³² , R ³¹ and R ⁴¹ , R ³² and R ⁴² , R ⁴¹ and R ⁵¹ , and/or R ⁴² and R ⁵² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , and/or R ⁵¹ and R ⁵² together form a =C(R ⁵ ) ₂ , =CR ⁶ (XR ⁷ ), or =C(XR ⁷ ) ₂ group; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ at each occurrence are independently selected from -H, -CN, -R ⁸ , -C(X)R ⁸ , -C(X)XR ⁸ , -C(R ⁸ ) ₃ , -C(R ⁸ ) ₂ XR ⁸ , -CR ⁸ (XR ⁸ ) ₂ and -C(XR ⁸ ) ₃ ; wherein X at each occurrence is independently selected from O, NH, NR and S; and R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal; or R ³ and R ⁴ together form a =C(R ⁵ ) ₂ , =CR ⁶ (XR ⁷ ), or =C(XR ⁷ ) ₂ group; the method comprising: reacting a compound of Formula II:

wherein Z is halo, A is a leaving group, and L is as defined for Formula I; with a reaction metal, a source of ammonia and a hydride source to provide the compound of Formula I; optionally converting the compound of Formula I into a salt, solvate or hydrate thereof; and optionally isolating the compound of Formula I or salt, solvate or hydrate thereof. In a preferred embodiment, the compound of Formula II is selected from the group consisting of the compounds of Formula Ha, lib and Hc:

In a further preferred embodiment, the compound of Formula II is selected from the group consisting of the compounds of Formula Ha and lib.

In a preferred embodiment, the compound of Formula I is selected from the group consisting of the compounds of Formula Ia ₅ Ib and Ic:

_R 1i f T ² R ¹¹ J ¹² tW

Il R21 Ia I R ²¹ R ²² NH ₂ Ib _IC .

In a further preferred embodiment, the compound of Formula I is selected from the group consisting of the compounds of Formula Ia and Ib.

In another preferred embodiment, the compound of Formula I has the Formula Ia:

wherein R ¹¹ , R ¹² , R ²¹ and R ²² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I;

1 1 I O O I OO or R and R and/or R and R , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ and/or R ¹² and R ²² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In another preferred embodiment, the compound of Formula I has the Formula Ia; wherein R 11 and R" are -H, and R ¹² and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹² and R ²² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In another preferred embodiment, the compound of Formula I has the Formula Ia; wherein R ¹¹ and R ²¹ are -H, and R ¹² and R ²² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ; X at each occurrence is independently selected from O, NH, NR and S; and

R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

In another preferred embodiment, the compound of Formula I has the Formula Ia; wherein R ¹¹ and R ²¹ are -H, R ¹² is -OH; and R ²² is selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

In another preferred embodiment, the compound of Formula I has the Formula Ia; wherein R π and R ²¹ are -H, and R ¹² and R ²² are -OH.

In another preferred embodiment, the compound of Formula I has the Formula Ia; wherein R , R ²¹ and R ²² are -H, and R ¹² is -OH.

In another preferred embodiment, the compound of Formula I has the Formula Ib:

wherein

R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹¹ and R ¹² , R ²¹ and R ²² , and/or R ³¹ and R ³² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , and/or R ²² and R ³² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In another preferred embodiment, the compound of Formula I has the Formula Ib; wherein R , R and R are -H, and R , R and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R and R and/or R and R together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In another preferred embodiment, the compound of Formula I has the Formula Ib; wherein R ¹¹ , R ²¹ and R ³¹ are -H, and R ¹² , R ²² and R ³² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R , wherein R ² , R ³ and R at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ; X at each occurrence is independently selected from O, NH, NR ⁹ and S; and

R and R at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

In another preferred embodiment, the compound of Formula I has the Formula Ib; wherein R ¹¹ , R ²¹ and R ³¹ are -H; R ¹² is -OH; and

R ²² and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I. In another preferred embodiment, the compound of Formula I has the Formula Ib; wherein R ¹¹ , R ²¹ and R ³¹ are -H; R ¹² and R ²² are -OH; and

R ³² is selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

In another preferred embodiment, the compound of Formula I has the Formula Ib; wherein R ¹¹ , R ²¹ and R ³¹ are -H, and R ¹² , R ²² and R ³² are -OH.

In another preferred embodiment, the compound of Formula I has the Formula Ib; wherein R ^l , R ²¹ , R ³¹ and R ³² are -H, and R ¹² and R ²² are -OH.

In another preferred embodiment, the compound of Formula I has the Formula Ic:

wherein

R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , and/or R ⁴¹ and R ⁴² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cyeloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , R ²² and R ³² , R ³¹ and R ⁴¹ , and/or R ³² and R ⁴² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In another preferred embodiment, the compound of Formula I has the Formula Ic; wherein R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H, and R ¹² , R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹² and R ²² , R ²² and R ³² , and/or R ³² and R ⁴² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In another preferred embodiment, the compound of Formula I has the Formula Ic; wherein R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H, and R ¹² , R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ; X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

In another preferred embodiment, the compound of Formula I has the Formula Ic; wherein R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H; R ¹² is -OH; and

R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for

Formula I.

In another preferred embodiment, the compound of Formula I has the Formula Ic; wherein R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H; R ¹² and R ²² are -OH; and

R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

In another preferred embodiment, the compound of Formula I has the Formula Ic; wherein R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H; and R ¹² , R ²² , R ³² and R ⁴² are -OH.

In one embodiment, the leaving group A is selected from the group consisting of halogen, -OR ¹⁰ , -NHR ¹⁰ , -N(R ¹⁰ ) ₂ , -SR ¹⁰ , -SOR ¹⁰ , -SO ₂ R ¹⁰ and -SeR ¹⁰ , wherein R ¹⁰ is independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, acyl, substituted acyl, acetimidoyl, substituted acetimidoyl, amino, substituted amino and halogen.

Preferably, the leaving group A is -OR ¹⁰ .

In a preferred embodiment, R ¹⁰ is alkyl.

In a further preferred embodiment, R ¹⁰ is alkyl, substituted alkyl, alkenyl or aryl.

In another preferred embodiment, R ¹⁰ is selected from the group consisting of methyl, ethyl, propyl, butyl, allyl, phenyl and benzyl.

In another preferred embodiment, R ¹⁰ is methyl.

In one embodiment, Z is selected from the group consisting of -I, -Br and -Cl.

Preferably, Z is -I.

In one embodiment, the reaction metal is selected from the group consisting of lithium, sodium, potassium, zinc, barium, magnesium, titanium, zirconium, indium, and mixtures of any two or more thereof.

In a further embodiment, the reaction metal is an alloy. Preferred alloys include amalgams, such as Zn(Hg) and Na(Hg).

Preferably, the reaction metal is zinc.

In one embodiment, the source of ammonia is NH ₃ . The NH ₃ may be ammonia gas, a solution of ammonia or a mixture thereof. In those embodiments wherein the source of ammonia comprises a solution of ammonia, the solution may be aqueous ammonia or a solution of ammonia in an organic solvent, for example an alcoholic ammonia solution. Preferred alcoholic ammonia solutions comprise a solution of ammonia in methanol or ethanol.

In another embodiment, the source of ammonia is an ammonium salt.

Preferably, the ammonium salt is selected from the group consisting OfNH ₄ OH, NH ₄ Cl, NH ₄ OAc, NH ₄ HCO ₂ , NH ₄ HSO ₄ , (NH ₄ ) ₂ SO ₄ , NH ₄ HCO ₃ , (NH ₄ ) ₂ CO ₃ , and mixtures of any two or more thereof. More preferably, the ammonium salt is NH ₄ OAc. The invention also contemplates embodiments in which the source of ammonia is a mixture of NH ₃ (for example, gaseous NH ₃ and/or a solution ofNH ₃ ) and one or more ammonium salt.

Those persons skilled in the art will be able to select a suitable hydride source without undue experimentation. The hydride source must be sufficiently reactive to achieve the conversion of the halogen-substituted cyclic acetal or derivative thereof to the desired alkenylamine by reducing the intermediate iminium ion, without being so reactive that the intermediate aldehyde moiety is also reduced.

In one embodiment the hydride source is a metal hydride, such as lithium aluminium hydride or diisobutylaluminium hydride.

In another embodiment, the hydride source is a borohydride. Suitable borohydrides include, but are not limited to: NaBH ₄ , NaBH ₃ CN, LiBH ₃ CN, NaBH ₃ CN-ZnCl ₂ , NaBH ₃ CN-Ti(OzPr) ₄ , NaBH ₃ CN-Mg(C10 ₄ ) ₂ , (^-Bu) ₄ NBH ₃ CN, NaBH(OAc) ₃ , NaBH ₄ -NiCl ₂ , NaBH ₄ -ZnCl ₂ , NaBH ₄ - ZrCl ₄ , Ti(OrPr) ₄ -NaBH ₄ , and NaBH ₄ -H ₂ SO ₄ . Resins (borohydride exchange resin) and clays (NaBH ₄ on wet clay) may also be suitable.

Preferably, the borohydride is sodium cyanoborohydride (NaBH ₃ CN) or sodium triacetoxyborohydride (NaBH(O Ac) ₃ ) .

Advantageously, NaBH ₃ CN is stable in relatively strong acid solutions (pH 3), and is soluble in hydroxy lie solvents such as methanol. It also has different selectivities at different pH values. At pH 3-4 it reduces aldehydes and ketones effectively, but this reduction becomes very slow at higher pH values. At pH 6-8, the more basic imines are protonated preferentially and reduced faster than aldehydes or ketones.

Alternative hydride sources include the use of Lewis-acid catalysis, with reagents such as NaBH ₃ CN-ZnCl ₂ , NaBH ₃ CN-Ti(OzPr) ₄ , NaBH ₄ -ZnCl ₂ , NaBH ₄ -ZrCl ₄ , and Ti(OzPr) ₄ -NaBH ₄ . Some of these milder Lewis acids, for example ZnCl ₂ , may stabilise the hydride reducing agent in aqueous media.

A further alternative hydride source is sodium borohydride activated by boric acid.

Other alternative hydride sources include: nickel boride; Zn(BH ₄ ) ₂ , Zn(BH ₄ ) ₂ -ZnCl ₂ , Zn(BH ₄ ) ₂ - SiO ₂ , Zn-AcOH, polymethylhydrosiloxane (PMHS)-Ti(OzPr) ₄ , PMHS-ZnCl ₂ , PMHS- BuSn(OCOR) ₃ , Et ₃ SiH-CF ₃ CO ₂ H, (PhMe ₂ )SiH-(C ₆ Fe) ₃ , Cl ₃ SiH-DMF, PhSiH ₃ -Bu ₂ SnCl ₂ , n- Bu ₃ SnH-DMF or HMPA, H-Bu ₃ SnH-SiO ₂ and ^-Bu ₂ SnIH or W-Bu ₂ SnClH.

Borane reducing agents, including, but not limited to: pyridine-borane; picoline-borane; diborane-MeOH; and decaborane; are other alternative hydride sources.

The compounds of Formula II may be prepared by, for example: halogen substitution of an alkyl hydroxymethylfuranoside using triphenylphosphine and iodine (Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M. R.; Madsen, R. Synthesis 2002, 12, 1721-1727); halogen substitution of an alkyl (methanesulfonyloxymethyl)furanoside with tetrabutylammonium iodide in benzene (Paquette, L.A.; Pissarnitski, D; Barriault, L. J Org Chem. 1998, 21, 7389-7398); or halogen substitution of an alkyl (pαrα-toluenesulfonyloxymethyl)furanoside with sodium iodide in acetone (Liberek, B. Carbohydr Res. 2005, 340, 2039-47). However, the invention is not limited to compounds of Formula II prepared using this method and other methods of preparing these compounds will be apparent to those persons skilled in the art.

The invention also provides a compound of Formula I ₅ or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

In a preferred embodiment, the compound of Formula II is enantiopure and the resulting compound of Formula I is chiral. The compound of Formula II may be resolved into enantiomers using methods known to those persons skilled in the art.

In another preferred embodiment, the compound of Formula II is stereoisomerically pure and the resulting compound of Formula I is stereoisomerically pure.

In a second aspect, the present invention provides method for preparing a cyclic carbamate or cyclic dithiocarbamate, or a salt, solvate or hydrate thereof, the method comprising: reacting an alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide the cyclic carbamate or cyclic dithiocarbamate; optionally converting the cyclic carbamate or cyclic dithiocarbamate into a salt, solvate or hydrate thereof; and optionally isolating the cyclic carbamate or cyclic dithiocarbamate or salt, solvate or hydrate thereof. Advantageously, the method of the invention permits the efficient preparation of a cyclic carbamate or cyclic dithiocarbamate from an alkenylamine, since it provides concomitant installation of nitrogen protection. In addition, because the method does not require a 1,2-aminoalcohol or 1,2-aminothiol starting material, it provides a useful means to stereoselectively prepare these important functional motifs from an alkenylamine using simple reagents.

In a preferred embodiment, the alkenylamine is enantiopure and the reaction is stereo- and regioselective, such that the resulting cyclic carbamate or cyclic dithiocarbamate is chiral.

In another preferred embodiment, the alkenylamine is stereoisomerically pure and the reaction is stereo- and regioselective, such that the resulting cyclic carbamate or cyclic dithiocarbamate is stereoisomerically pure.

One embodiment of the second aspect of the invention is a method for preparing a compound of Formula III:

or a salt, solvate or hydrate thereof; wherein Y is O or S;

L is selected from the group consisting of:

-C(R ^π )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )C(R ⁴¹ )(R ⁴² )C(R ⁵¹ )(R ⁵² )-;

-C(R ^U )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )C(R ⁴¹ )(R ⁴² )-; -C(R ^π )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )-; and

-C(R ¹¹ XR ¹ ^C(R ²¹ XR ²² )-; wherein R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ , R ⁴² , R ⁵¹ and R ⁵² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , and/or R ⁵¹ and R ⁵² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , R ²² and R ³² , R ³¹ and R ⁴¹ , R ³² and R ⁴² , R ⁴¹ and R ⁵¹ , and/or R ⁴² and R ⁵² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , and/or R ⁵¹ and R ⁵² together form a

=C(R ⁵ ) ₂ , =CR ⁶ (XR ⁷ ), or =C(XR ⁷ ) ₂ group; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ at each occurrence are independently selected from -H, -CN, -R ⁸ , -C(X)R ⁸ , -C(X)XR ⁸ , -C(R ⁸ ) ₃ , -C(R ⁸ ) ₂ XR ⁸ , -CR ⁸ (XR ⁸ ) ₂ and -C(XR ⁸ ) ₃ ; wherein X at each occurrence is independently selected from O, NH, NR ⁹ and S; and

R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal; or R ³ and R ⁴ together form a =C(R ⁵ ) ₂ , =CR ⁶ (XR ⁷ ), or =C(XR ⁷ ) ₂ group; the method comprising: reacting a compound of Formula I, as defined above, with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide the compound of Formula III; optionally converting the compound of Formula III into a salt, solvate or hydrate thereof; and optionally isolating the compound of Formula III or salt, solvate or hydrate thereof.

Preferably, Y is O.

In a preferred embodiment, the compound of Formula III is selected from the group consisting of the compounds of Formula Ilia, IHb and HIc:

In a further preferred embodiment, the compound of Formula III is selected from the group consisting of the compounds of Formula HIa and HIb.

In a another preferred embodiment, the compound of Formula III is selected from the group consisting of the compounds of Formula Ilia', IHb' and HIc':

In another preferred embodiment, the compound of Formula III is selected from the group consisting of the compounds of Formula Ilia' and IHb'.

In another preferred embodiment, the compound of Formula III has the Formula Ilia:

wherein Y is O or S;

R , R , R and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for

Formula I; or R ¹¹ and R ¹² and/or R ²¹ and R ²² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ and/or R ¹² and R ²² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula Ilia; wherein Y is O or S;

R ¹¹ and R ²¹ are -H, and R ¹² and R ²² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹² and R ²² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl. More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula Ilia; wherein Y is O or S;

R and R are -H, and R and R are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ;

X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R and R at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula Ilia; wherein Y is O or S;

R ¹¹ and R ²¹ are -H;

R ¹² is -OH; and

R ²² is selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein

R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula Ilia; wherein Y is O or S;

R ¹¹ and R ²¹ are -H; and

R ¹² and R ²² are -OH.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula Ilia; wherein Y is O or S;

R ¹¹ , R ^2! and R ²² are -H; and

R ¹² is -OH. More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula Mb:

wherein Y is O or S; R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹¹ and R ¹² , R ²¹ and R ²² , and/or R ³¹ and R ³² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , and/or R ²² and R ³² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H, and R ¹² , R ²² and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R and R and/or R" and R together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHb; wherein Y is O or S; R ¹¹ , R ²¹ and R ³¹ are -H, and R ¹² , R ²² and R ³² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ; X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R and R at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H;

R ¹² is -OH; and

R ²² and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for

Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHb; wherein Y is O or S; R ¹¹ , R ²¹ and R ³¹ are -H; R ¹² and R ²² are -OH; and

R ³² is selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula HIb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H; and R ¹² , R ²² and R ³² are -OH.

More preferably, Y is O. In another preferred embodiment, the compound of Formula III has the Formula IHb; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ³² are -H; and

R ¹² and R ²² are -OH.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHc:

wherein Y is O or S;

R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ and R ⁴² are each independently selected from the group consisting of -H ₅ -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , and/or R ⁴¹ and R ⁴² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , R ²² and R ³² , R ³¹ and R ⁴¹ , and/or R ³² and R ⁴² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IIIc; wherein Y is O or S;

R ¹¹ , R ²ⁱ , R ³¹ and R ⁴¹ are -H, and R ¹² , R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹² and R ²² , R ²² and R ³² , and/or R ³² and R ⁴² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, siibstituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In a further preferred embodiment, the compound of Formula III has the Formula IHc; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H, and R ¹² , R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ; X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHc; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H;

R ¹² is -OH; and R ₅ R and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHc; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H;

R ¹² and R ²² are -OH; and

R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I. More preferably, Y is O.

In another preferred embodiment, the compound of Formula III has the Formula IHc; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H; and R ¹² , R ²² , R ³² and R ⁴² are -OH.

More preferably, Y is O.

In one embodiment, the compound of Formula I is obtained by reacting a compound of Formula II as in the first aspect.

In one embodiment, the halogen source is selected from the group consisting of NIS, NBS, NCS, I ₂ , Br ₂ , Cl ₂ , and mixtures of any two or more thereof. Preferably, the halogen source is I ₂ .

In one embodiment, the source of carbonate is selected from the group consisting OfLiHCO ₃ , Li ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , KHCO ₃ , K ₂ CO ₃ , and mixtures of any two or more thereof. Preferably, the source of carbonate is NaHCO ₃ .

In one embodiment, the source of carbon dioxide is selected from the group consisting of carbon dioxide gas, liquid carbon dioxide, solid carbon dioxide, and mixtures of any two or more thereof.

In one embodiment, the source of carbon disulfide is CS ₂ .

The invention also provides a compound of Formula III, or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

In a preferred embodiment, the compound of Formula I is enantiopure and the resulting compound of Formula III is chiral. If necessary, the compound of Formula I may be resolved into enantiomers using methods known to those persons skilled in the art.

In another preferred embodiment, the compound of Formula I is stereoisomerically pure and the resulting compound of Formula III is stereoisomerically pure.

In a third aspect the present invention provides a method for preparing a cyclic carbamate or cyclic dithiocarbamate, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide an alkenylamine; reacting the alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide the cyclic carbamate or cyclic dithiocarbamate; optionally converting the cyclic carbamate or cyclic dithiocarbamate into a salt, solvate or hydrate thereof; and optionally isolating the cyclic carbamate or cyclic dithiocarbamate or salt, solvate or hydrate thereof.

In a preferred embodiment, the halogen-substituted cyclic acetal or derivative thereof is enantiopure and the reactions are stereo- and regioselective, such that the resulting cyclic carbamate or cyclic dithiocarbamate is chiral.

In a preferred embodiment, the halogen-substituted cyclic acetal or derivative thereof is stereoisomerically pure and the reactions are stereo- and regioselective, such that the resulting cyclic carbamate or cyclic dithiocarbamate is stereoisomerically pure.

A preferred embodiment of the third aspect provides a method for preparing a cyclic carbamate, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide an alkenylamine; reacting the alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide to provide the cyclic carbamate; optionally converting the cyclic carbamate into a salt, solvate or hydrate thereof; and optionally isolating the cyclic carbamate or salt, solvate or hydrate thereof.

In a fourth aspect, the present invention provides a method for preparing a 1,2-aminoalcohol or

1,2-aminothiol, or a salt, solvate or hydrate thereof, the method comprising: reacting an alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide a cyclic carbamate or cyclic dithiocarbamate; deprotecting the cyclic carbamate or cyclic dithiocarbamate to provide the 1,2-aminoalcohol or

1,2-aminothiol; optionally converting the 1,2-aminoalcohol or 1,2-aminothiol into a salt, solvate or hydrate thereof; and optionally isolating the 1,2-aminoalcohol or 1,2-aminothiol or salt, solvate or hydrate thereof.

In a preferred embodiment, the alkenylamine is enantiopure and the reactions are stereo- and regioselective, such that the resulting 1,2-aminoalcohol or 1,2-aminothiol is chiral.

In another preferred embodiment, the alkenylamine is stereoisomerically pure and the reactions are stereo- and regioselective, such that the resulting 1,2-aminoalcohol or 1,2-aminothiol is stereoisomerically pure.

One embodiment of the fourth aspect of the invention is a method for preparing a compound of Formula IV:

or a salt, solvate or hydrate thereof; wherein Y is O or S;

L is selected from the group consisting of:

-C(R ⁿ )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )C(R ⁴¹ )(R ⁴² )C(R ⁵¹ )(R ⁵² )-; -C(R ¹¹ )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )C(R ⁴¹ )(R ⁴² )-;

-C(R ¹¹ )(R ¹² )C(R ²¹ )(R ²² )C(R ³¹ )(R ³² )-; and

-C(R ¹¹ XR ¹ ^C(R ²¹ XR ²² )-; wherein R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ , R ⁴² , R ⁵¹ and R ⁵² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , and/or R ⁵¹ and R ⁵² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , R ²² and R ³² , R ³¹ and R ⁴¹ , R ³² and R ⁴² , R ⁴¹ and R ⁵¹ , and/or R ⁴² and R ⁵² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl; or R ¹ ' and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , R ⁴¹ and R ⁴² , and/or R ⁵¹ and R ⁵² together form a

=C(R ⁵ ) ₂ , =CR ⁶ (XR ⁷ ), or =C(XR ⁷ ) ₂ group; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ at each occurrence are independently selected from -H, -CN, -R ⁸ , -C(X)R ⁸ , -C(X)XR ⁸ , -C(R ⁸ ) ₃ , -C(R ⁸ ) ₂ XR ⁸ , -CR ⁸ (XR ⁸ ) ₂ and -C(XR ⁸ ) ₃ ; wherein X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal; or R ³ and R ⁴ together form a =C(R ⁵ ) ₂ , =CR ⁶ (XR ⁷ ), or =C(XR ⁷ ) ₂ group; the method comprising: reacting a compound of Formula I, as defined above, with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide a compound of Formula III, as defined above; deprotecting the compound of Formula III to provide the compound of Formula IV; optionally converting the compound of Formula IV into a salt, solvate or hydrate thereof; and optionally isolating the compound of Formula IV or salt, solvate or hydrate thereof.

Preferably, Y is O.

In a preferred embodiment, the compound of Formula IV is selected from the group consisting of the compounds of Formula IVa, IVb and IVc:

In a further preferred embodiment, the compound of Formula IV is selected from the group consisting of the compounds of Formula IVa and IVb.

In another preferred embodiment, the compound of Formula IV is selected from the group consisting of the compounds of Formula IVa', IVb' and IVc':

In another preferred embodiment, the compound of Formula IV is selected from the group consisting of the compounds of Formula IVa' and IVb'. In another preferred embodiment, the compound of Formula IV has the Formula IVa:

wherein Y is O or S;

1 1 10 OI OO

R , R , R and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I;

1 1 10 OI OO or R and R and/or R and R , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ and/or R ¹² and R ²² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

In a further preferred embodiment, the compound of Formula IV has the Formula IVa; wherein

1 1 01 I O OO

R and R are -H, and R and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹² and R ²² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVa; wherein Y is O or S;

1 1 O l 10 OO

R and R are -H, and R and R are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ;

X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVa; wherein Y is O or S;

R ¹¹ and R ²¹ are -H;

R ¹² is -OH; and

R ²² is selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein

R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVa; wherein Y is O or S;

R ¹¹ and R ²¹ are -H; and

R ¹² and R ²² are -OH.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVa; wherein Y is O or S;

R ¹¹ , R ²¹ and R ²² are -H; and

R ¹² is -OH.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVb:

wherein Y is O or S;

R , R , R , R , R and R are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹¹ and R ¹² , R ²¹ and R ²² , and/or R ³¹ and R ³² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or alternatively R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , and/or R ²² and R ³² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H, and R ¹² , R ²² and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R and R and/or R and R together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVb; wherein Y is O or S; R ¹¹ , R ²¹ and R ³¹ are -H, and R ¹² , R ²² and R ³² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ;

X at each occurrence is independently selected from O, NH, NR ⁹ and S; and

R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, ^■ alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

More preferably, Y is O. In another preferred embodiment, the compound of Formula IV has the Formula IVb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H; R ¹² is -OH; and R ²² and R ³² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H;

R ¹² and R ²² are -OH; and

R ³² is selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein

R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVb; wherein Y is O or S;

R ¹¹ , R ²¹ and R ³¹ are -H; and

R ¹² , R ²² and R ³² are -OH.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVb; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ³² are -H; and

R ¹² and R ²² are -OH.

More preferably, Y is O. In another preferred embodiment, the compound of Formula IV has the Formula IVc:

wherein Y is O or S;

R ¹¹ , R ¹² , R ²¹ , R ²² , R ³¹ , R ³² , R ⁴¹ and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹¹ and R ¹² , R ²¹ and R ²² , R ³¹ and R ³² , and/or R ⁴¹ and R ⁴² , together with the carbon atom to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; or R ¹¹ and R ²¹ , R ¹² and R ²² , R ²¹ and R ³¹ , R ²² and R ³² , R ³¹ and R ⁴¹ , and/or R ³² and R ⁴² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVc; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H, and R ¹² , R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I; or R ¹² and R ²² , R ²² and R ³² , and/or R ³² and R ⁴² , together with the carbon atoms to which they are attached, form a cyclic group selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVc; wherein Y is O or S; R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H, and R ¹² , R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -N ₃ , -OR ² and -NR ³ R ⁴ , wherein R ² , R ³ and R ⁴ at each occurrence are each independently selected from -H, -R ⁸ , -C(X)R ⁸ and -C(X)XR ⁸ ; X at each occurrence is independently selected from O, NH, NR ⁹ and S; and R ⁸ and R ⁹ at each occurrence are independently selected from -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxide, substituted alkoxide, sulfur, substituted sulfur, silicon, substituted silicon, boron, substituted boron, phosphorus, substituted phosphorus and metal.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVc; wherein Y is O or S;

R ^u , R ²¹ , R ³¹ and R ⁴¹ are -H;

R ¹² is -OH; and

R ²² , R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for

Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVc; wherein Y is O or S; R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H; R ¹² and R ²² are -OH; and

R ³² and R ⁴² are each independently selected from the group consisting of -H, -R ¹ , -OR ² , -SR ² , -NR ³ R ⁴ , -NO ₂ and -N ₃ ; wherein R ¹ , R ² , R ³ and R ⁴ are as defined for Formula I.

More preferably, Y is O.

In another preferred embodiment, the compound of Formula IV has the Formula IVc; wherein Y is O or S;

R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ are -H; and

R ¹² , R ²² , R ³² and R ⁴² are -OH.

More preferably, Y is O. It will be appreciated that the compounds of Formula I, II, III and IV are contemplated as chemically feasible compounds.

In one embodiment of the invention, the group L includes five or fewer spiro rings and/or fused rings. In another embodiment of the invention, the group L includes four or fewer spiro rings and/or fused rings. In another embodiment of the invention, the group L includes three or fewer spiro rings and/or fused rings. In another embodiment of the invention, the group L includes two or fewer spiro rings and/or fused rings. In another embodiment of the invention, the group L includes one or no spiro rings and/or fused rings. In another embodiment of the invention, the group L includes no spiro rings and/or fused rings.

The compound of Formula III may be deprotected to provide the compound of Formula IV using known methods. Such methods include, but are not limited to: reactions under alkaline conditions, for example with sodium hydroxide in ethanol at reflux temperature; reactions under acidic conditions, for example with 6N aqueous HCl at reflux temperature; and reaction with peroxides, for example LiOOH or H ₂ O ₂ ZLiOH.

In one embodiment, the method further comprises reacting a compound of Formula II, as defined above, with a reaction metal, a source of ammonia and a hydride source to provide the compound of Formula I.

The invention also provides a compound of Formula IV, or a salt, solvate or hydrate thereof, when prepared by a method of the invention.

In a preferred embodiment, the compound of Formula I is enantiopure and the resulting compound of Formula IV is chiral. If necessary, the compound of Formula I may be resolved into enantiomers using methods known to those persons skilled in the art.

In another preferred embodiment, the compound of Formula I is stereoisomerically pure and the resulting compound of Formula IV is stereoisomerically pure.

In a fifth aspect, the present invention provides a method for preparing a 1,2-aminoalcohol or 1 ,2-aminothiol, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide an alkenylamine; reacting the alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide or a source of carbon disulfide to provide a cyclic carbamate or cyclic dithiocarbamate; deprotecting the cyclic carbamate or cyclic dithiocarbamate to provide the 1,2-aminoalcohol or 1,2-aminothiol; optionally converting the 1,2-aminoalcohol or 1,2-aminothiol into a salt, solvate or hydrate thereof; and optionally isolating the 1,2-aminoalcohol or 1,2-aminothiol or salt, solvate or hydrate thereof.

In a preferred embodiment, the halogen-substituted cyclic acetal or derivative thereof is enantiopure and the reactions are stereo- and regioselective, such that the resulting 1,2-aminoalcohol or 1,2-aminothiol is chiral.

In another preferred embodiment, the halogen-substituted cyclic acetal or derivative thereof is stereoisomerically pure and the reactions are stereo- and regioselective, such that the resulting 1,2-aminoalcohol or 1,2-aminothiol is stereoisomerically pure.

In one embodiment of the second, third, fourth and/or fifth aspects, the alkenylamine is reacted with a halogen source, a base and a source of carbonate or a source of carbon disulfide to provide a cyclic carbamate or cyclic dithiocarbamate.

In one embodiment of the second, third, fourth and/or fifth aspects, a compound of Formula I is reacted with a source of carbonate or a source of carbon disulfide to provide a compound of Formula III.

In another embodiment of the second, third, fourth and/or fifth aspects, the alkenylamine is reacted with a halogen source, a base and a source of carbonate to provide a cyclic carbamate.

In another embodiment of the second, third, fourth and/or fifth aspects, the alkenylamine is reacted with a halogen source, a base and a source of carbon dioxide to provide a cyclic carbamate.

In another embodiment of the second, third, fourth and/or fifth aspects, the alkenylamine is reacted with a halogen source, a base and a source of carbon disulfide to provide a cyclic dithiocarbamate.

A preferred embodiment of the fifth aspect provides a method for preparing a 1,2-aminoalcohol, or a salt, solvate or hydrate thereof, the method comprising: reacting a halogen-substituted cyclic acetal or a derivative thereof with a reaction metal, a source of ammonia and a hydride source to provide an alkenylamine; reacting the alkenylamine with a halogen source, a base and a source of carbonate or a source of carbon dioxide to provide a cyclic carbamate; deprotecting the cyclic carbamate to provide the 1 ,2-aminoalcohol; optionally converting the 1,2-aminoalcohol into a salt, solvate or hydrate thereof; and optionally isolating the 1,2-aminoalcohol or salt, solvate or hydrate thereof.

In another aspect, the present invention provides the halogen-substituted cyclic acetal:

In a preferred embodiment, the halogen-substituted cyclic acetal has the following stereochemistry :

In another aspect, the present invention provides an alkenylamine selected from the group consisting of:

In a preferred embodiment, the alkenylamine is selected from the group consisting of:

In another aspect, the present invention provides a cyclic carbamate selected from the group consisting of:

In a preferred embodiment, the cyclic carbamate is selected from the group consisting of:

In another preferred embodiment, the cyclic carbamate is selected from the group consisting of:

In another preferred embodiment, the cyclic carbamate is selected from the group consisting of:

Those persons skilled in the art will appreciate that, in the course of preparing the compounds useful in the invention, the functional groups of intermediate compounds may need to be protected by protecting groups. Functional groups which it may be desirable to protect include, but are not limited to: hydroxyl; amino; and carboxylic acid groups. Protecting groups may be added and removed in accordance with techniques that are well known to those persons skilled in the art. The use of protecting groups is described in, for example, J. W. F. McOmie (ed.),

Protective Groups in Organic Chemistry, Plenum Press, London, 1973 and T. W. Greene and P. G. M. Wutz, Protective Groups in Organic Synthesis, 3 ^rd edition, Wiley, New York, 1999. Those persons skilled in the art will be able to select suitable solvents and conditions for the reactions within the scope of the invention without undue experimentation. The selection of solvents will be influenced by, for example, reagent and product solubility considerations. In some embodiments, the use of solvent mixtures will be advantageous.

In one embodiment, the solvent is an aqueous solvent system, which typically comprises either water or a mixture of water and one or more suitable organic solvent. The organic solvent may be miscible or immiscible with water. In some embodiments, the aqueous solvent system comprises a two phase solvent mixture and includes a phase transfer catalyst. Suitable organic solvents include, but are not limited to: alcohols, for example methanol and ethanol; acetonitrile; dioxane; tetrahydrofuran; dimethyl formamide; and dimethyl sulfoxide.

The reaction may be carried out at ambient temperature. In alternatives embodiments, the reaction mixture may be heated or cooled, using standard techniques.

The product compound may be isolated from the reaction mixture using standard techniques known in the art. Such techniques include, but are not limited to: filtration; solvent extraction; and evaporation.

The product compound may optionally be purified, using standard techniques known in the art, either as part of, or following isolation from the reaction mixture.

The following non-limiting examples are provided to illustrate the present invention and in no way limit the scope thereof.

EXAMPLES

The precursor cyclic acetal compounds 1, 5, 9, 13, 17, and 21 were prepared using a literature procedure (Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M. R.; Madsen, R. Synthesis 2002, 12, 1721-1727). Cyclic acetal 25 was prepared by an analogous procedure.

Example 1

(2S,3S)-l-Amino-pent-4-ene-2,3-diol (2). To a solution of halogenated cyclic acetal 1 (60 mg, 0.22 mmol) in a saturated solution OfNH ₄ OAc in EtOH (4 mL) was added Zn (72 mg, 1.1 nimol), NaCNBH ₃ (47 mg, 0.4 mmol) and 30% aqueous NH ₃ (1.6 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in /PrOH and a solution of 20% HCl in /PrOH was added (4.6 g, 28 mmol). The solution was filtered through celite and concentrated under reduced pressure. The filtrate was dissolved in /PrOH (4 mL) and filtered through cotton wool. The solution was dry loaded on to silica gel and purified by gradient flash chromatography (DCM/EtOH/MeOH/30% aqueous NH ₃ , from 25/2/2/1 to 5/2/2/1, v/v/v/v) to give the alkenylaniine 2 as the HCl salt (32 mg, 0.21 mmol, 95%). R/= 0.37 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ²⁰ - -40.0 (c = 0.07, EtOH); ¹ H NMR (300 MHz, D ₂ O) δ 5.71 (ddd, J _3,4 = 6.4 Hz, J ₄ , _5-c * = 10.5 Hz, = 17.1 Hz, IH, H-4), 5.34 (d, J ₄ , ₅ . _trans - 17.1 Hz, IH, E-5-trans), 5.28 (d, J ₄ , ₅ -cis = 10.5 Hz, IH, H-5-cis), 4.10 (dd, J _2,3 = 5.0 Hz, J _3^4 = 6.4 Hz, IH, H-3), 4.05 (s, IH, NH), 3.81 (ddd, J _la,2 = 3.3 Hz, J _2;3 = 5.0 Hz, J _lb;2 = 9.7 Hz, IH, H-2), 3.15 (dd, J _la>2 = 3.3 Hz, J _1Mb = 13.2 Hz ₅ IH ₅ H-Ia), 2.98 (dd ₅ J _lb , ₂ = 9.7 Hz ₅ J _la , _lb = 13.2 Hz, IH, H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 135.8 (C4), 117.9 (C5), 73.9 (C3), 72.0 (CZ), 42.0 (Cl); IR (film) 3405, 3212, 2888, 1555, 1434, 1183, 1127, 1016, 838 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ H ₁₂ O ₂ N] ⁺ : 118.0863, obsd.: 118.0871.

(2S,3S)-l-Amino-pent-4-ene-2,3-diol (2) was also prepared using the following procedure. To a solution of halogenated cyclic acetal 1 (60.1 mg, 0.22 mmol) in a saturated solution OfNH ₄ OAc in EtOH (5 mL) was added activated Zn (72.0 mg, 1.1 mmol), NaCNBH ₃ (42 mg, 0.66 mmol) and 30% aqueous NH ₃ (2 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in water and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5- 15% aqueous NH ₃ . Alkenylamine 2 was obtained as the HCl salt (32 mg, 0.21 mmol, 95%).

(6S,7S,7aR) ₇ 6,7-Dihydroxy-tetrahydro-pyrroIo[l,2-c]oxazol-3-one (3). To a solution of alkenylamine 2 hydrochloride (8 mg, 0.05 mmol) in water (0.25 mL) was added NaHCO ₃ (6.4 mg, 0.075 mmol) and I ₂ (14 mg, 0.055 mmol). The solution was stirred 18 h at room temperature then filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (hexanes/EtOAc, 1/3, v/v) gave carbamate 3 as a white powder (8 mg, 0.05 mmol, 99%). [α] _D ¹⁹ = -26.1 (c = 0.4, EtOH); ¹ H NMR (500 MHz, D ₂ O) δ 4.61 (t, J ₄ , _5a = J _5aj5b = 9.1 Hz, IH, H-5a), 4.49 (dd, J ₄ , _5b = 3.3 Hz, J _5a , ₅ b = 9.1 Hz, IH, H-5b), 4.36 (d, J _la>2 = 5.2 Hz, IH, H-2), 4.27 (dt, J ₄ , _5a = 8.5 Hz, J _4;5b = J3,4 = 3.3 Hz, IH, H-4), 4.01 (d, J ₃ , ₄ = 3.3 Hz, IH, H-3), 3.77 (dd, J _la , ₂ = 5.2 Hz ₅ J _la , _lb = 12.7 Hz, IH, H-Ia), 3.10 (d, J _la , _lb = 12.7 Hz, IH ₃ H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 164.4 (C6), 76.4 (C2), 74.2 (C3), 63.9 (C5), 62.0 (C4), 52.2 (Cl); IR (film) 3363, 2947, 2835, 1652, 1449, 1412, 1205, 1113, 1018 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₆ H ₁₀ O ₄ N] ⁺ : 160.0604, obsd.: 160.0605.

The procedure above was repeated using alkenylamine 2 hydrochloride (7.5 mg, 0.050 mmol) in water (1 mL), NaHCO ₃ (6.3 mg, 0.075 mmol), and I ₂ (14 mg, 0.055 mmol) to give carbamate 3 as an amorphous white powder (8 mg, 0.050 mmol, 99%).

(2R,3S,4S)-2-Hydroxymethyl-pyrrolidine-3,4-diol (4). To a solution of carbamate 3 (6.6 mg, 0.042 mmol) in EtOH (0.21 mL) was added NaOH (17 mg, 0.42 mmol). The solution was stirred at reflux for 2 h, cooled and purified by ion-exchange chromatography (Dowex H ⁺ ) eluting with 5-15% aqueous NH ₃ . HCl in isopropanol was added and concentration in vacuo gave 4 as the HCl salt (7 mg, 0.04 mmol, 99%). R ₇ = 0.90 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ²⁰ = -6.4 (c = 0.5, H ₂ O); ¹ H NMR (300 MHz, D ₂ O) δ 4.37 (d, J _la>2 = 4.4 Hz, IH, H-2), 4.30 (s, IH, H-3), 4.01 (m, IH, H-5a), 3.88 (m, 2H, H-4 and H-5b), 3.64 (dd, J _la>2 = 4.4 Hz, J _1Mb = 13.0 Hz, IH, H-Ia), 3.28 (d, J _la , _lb = 13.0 Hz, IH, H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 74.3 (C2 or 3), 74.2 (C3 or 2), 62.9 (C4), 57.2 (C5), 50.4 (Cl). IR (film) 3334, 3172, 2974, 2886, 1380, 1328, 1088, 1045 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ H ₁₂ O ₃ N] ⁺ : 134.0812, obsd.: 134.0818.

The procedure above was repeated using carbamate 3 (6.5 mg, 0.041 mmol) in EtOH (1 mL) and NaOH (16 mg, 0.4 mmol) to give 4 as the HCl salt (7.0 mg, 41 μmol, 99%).

Example 2

5 6 7 8

(2S,3R)-l-Amino-pent-4-ene-2,3-diol (g^ -p _{0 a} solution of halogenated cyclic acetal 5 (51 mg, 0.19 mmol) in a saturated solution OfNH ₄ OAc inEtOH (4 mL) was added Zn (61 mg, 0.95 mmol), NaCNBH ₃ (40 mg, 0.4 mmol) and 30% aqueous NH ₃ (1.6 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in /PrOH and a solution of 20% HCl in /PrOH was added (3.9 g, 23 mmol). The solution was filtered through celite and concentrated under reduced pressure. The filtrate was dissolved in /PrOH (4 niL) and filtered through cotton wool. The solution was dry loaded on to silica gel and purified by gradient flash chromatography (DCM/EtOH/MeOH/30% aqueous NH ₃ , from 25/2/2/1 to 5/2/2/1, v/v/v/v) to give the alkenylamine 6 as the HCl salt (26 mg, 0.17 mmol, 91%). R/= 0.41 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ¹⁸ = +8.2 (c = 0.28, EtOH); ¹ H NMR (300 MHz, D ₂ O) δ 5.88 (ddd, J ₃ , ₄ = 6.6 Hz, J _4;5-c/ , = 10.5 Hz, = 17.1 Hz, IH, H-4), 5.35 (d, J _A>tram = 17.1 Hz, IH, U-5-tmns), 5.31 (d, J ₄ , _5-c/ , = 10.5 Hz, IH, n-5-cis), 4.12 (dd, J ₂ , ₃ = 5.6 Hz, J _3,4 - 6.6 Hz, IH, H-3), 3.81 (ddd, J _la>2 = 3.0 Hz, J _2,3 - 5.6 Hz, J _lb;2 = 9.7 Hz, IH, H-2), 3.23 (dd, Ji _a,2 = 3.0 Hz, Ji _Mb = 13.2 Hz, IH, H-Ia), 2.95 (dd, Ji _b,2 = 9.7 Hz, Ji _a j _b = 13.2 Hz, IH, H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 135.4 (C4), 118.3 (C5), 74.0 (C3), 69.8 (C2), 41.1 (Cl); IR (film) 3345, 2946, 2835, 1651, 1450, 1018 cm- ¹ . HRMS(ESI) m/z calcd. for [C ₅ H ₁₂ O ₂ N] ⁺ : 118.0863, obsd.: 118.0873.

(2S,3R)-l-Amino-pent-4-ene-2,3-diol (6) was also prepared using the following procedure. To a solution of halogenated cyclic acetal 5 (51.2 mg, 0.19 mmol) in a saturated solution OfNH ₄ OAc inEtOH (4 mL) was added activated Zn (62 mg, 0.95 mmol), NaCNBH ₃ (36.4 mg, 0.57 mmol) and 30% aqueous NH ₃ (1.5 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in H ₂ O and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5- 15% aqueous NH ₃ . Alkenylamine 6 was obtained as the HCl salt (26 mg, 0.17 mmol, 91%).

(6S,7R,7aS)-6,7-Dihydroxy-tetrahydro-pyrrolo[l,2-c]oxazol -3-one (7). To a solution of alkenylamine 6 hydrochloride (30 mg, 0.20 mmol) in water (1 mL) was added NaHCO ₃ (25 mg, 0.30 mmol) and I ₂ (55 mg, 0.22 mmol). The solution was stirred 18 h at room temperature then filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (hexanes/EtOAc, 1/3, v/v) gave carbamate 7 as a white powder (29 mg, 0.19 mmol, 93%). [α] _D ¹⁹ = +32.2 (c = 0.3, EtOH); ¹ H NMR (500 MHz, D ₂ O) δ 4.52 (m, 3H, H-2, H- 5a and H-5b), 4.14 (ddd, J ₃ , ₄ = 3.1 Hz, J _4> = 5.0 Hz, J _4;5b = 7.9 Hz, IH, H-4), 4.01 (dd, J _3j4 = 3.1 Hz, J _2,3 = 3.3 Hz, IH, H-3), 3.51 (dd, J _la,2 = 8.1 Hz, J _Ia , _lb = 10.8 Hz, IH, H-Ia), 3.15 (dd, J _lb , ₂ = 7.9 Hz, Ji _a ,i _b = 10.8 Hz, IH, H-Ib); ¹³ C NMR (75 MHz ₅ D ₂ O) δ 164.1 (C6), 73.2 (C2), 70.6 (C3), 64.3 (C5), 61.5 (C4), 48.6 (Cl); IR (film) 3332, 2977, 1717, 1474, 1411, 1250, 1130, 1068 cm- ¹ . HRMS(ESI) m/z calcd. for [C ₆ H ₉ O ₄ NNa] ⁺ : 182.0424, obsd.: 182.0429. The procedure above was repeated using alkenylamine 6 hydrochloride (30 mg, 0.20 mmol) in water (1 niL), NaHCO ₃ (25 mg, 0.3 mmol), and I ₂ (55.8 mg, 0.22 mmol) to give carbamate 7 as an amorphous white powder (29 mg, 0.18 mmol, 93%).

(2S,3Rj4S)-2-Hydroxymethyl-pyrrolidine-3,4-diol (8). To a solution of carbamate 7 (6.4 mg, 0.040 mmol) in EtOH (0.20 mL) was added NaOH (16 mg, 0.40 mmol). The solution was stirred at reflux for 2 h, cooled and purified by ion-exchange chromatography (Dowex H ⁺ ) eluting with 5-15% aqueous NH ₃ . HCl in isopropanol was added and concentration in vacuo gave 8 as the HCl salt (6.6 mg, 97%). R/= 0.11 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ¹⁹ = -22.4 (c = 0.3, H ₂ O); ¹ H NMR (500 MHz, D ₂ O) δ 4.47 (dt, J _2>3 = 4.1 Hz, J _la , ₂ = J _lb , ₂ = 7.4 Hz, IH, H-2), 4.32 (t, J _2;3 = J _3;4 = 4.2 Hz, IH, H-3), 3.96 (dd, J ₄ , _5a = 5.0 Hz, J _5a , _5b = 12.1 Hz, IH, H-5a), 3.86 (dd, J _4j5b = 8.4 Hz, J _5aJSb = 12.1 Hz, IH, H-5b), 3.71 (ddd, J _3j4 = 4.2 Hz, J ₄ ,5 _a = 5.0 Hz, J ₄ ,5b = 8.4 Hz, IH, H-4), 3.50 (dd, J _la , ₂ = 7.4 Hz, J _la , _lb = 12.2 Hz, IH ₅ H-Ia), 3.18 (dd, J _lb , ₂ = 7.4 Hz, J _laαb = 12.2 Hz, IH, H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 69.9 (CZ), 69.7 (C3), 62.4 (C4), 57.6 (C5), 46.9 (Cl); IR (film) 3369, 3198, 2956, 2857, 1456, 1266, 1127, 1056 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ Hi ₂ O ₃ N] ⁺ : 134.0812, obsd.: 134.0813.

The procedure above was repeated using carbamate 7 (6.4 mg, 40 μmol) in EtOH (1 mL) and NaOH (16 mg, 0.4 mmol) to give 8 as the HCl salt (6.6 mg, 39 μmol, 97%).

Example 3

9 10 11 12

(2R,3R)-l-Amino-pent-4-ene-2,3-diol (10). To a solution of halogenated cyclic acetal 9 (274 mg, 1 mmol) in a saturated solution OfNH ₄ OAc in EtOH (20 mL) was added activated Zn (327 mg, 5 mmol), NaCNBH ₃ (188 mg, 3 mmol) and 30% aqueous NH ₃ (8 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in water and purified directly by ion-exchange chromatography (DoWeX H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ . Alkenylamine 10 was obtained as the HCl salt (143 mg, 93 mmol, 93%). R/= 0.61 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ²⁰ = +50.6 (c = 1.0, EtOH); ¹ H NMR (500 MHz, D ₂ O) δ 5.74 (ddd, J _3;4 = 5.3 Hz, J _4,5-c/ , = 10.5 Hz, As-t _ran s = 17.3 Hz, IH, H-4), 5.23 (d, J ₄ , _5- , _rarø = 17.3 Hz, IH, H-5- trans\ 5.17 (d, J ₄ , ₅ . _c ,-, - 10.5 Hz, IH, U-5-cis), 3.99 (t, J _3j4 = J ₂ , ₃ = 5.3 Hz, IH, H-3), 3.70 (ddd, J _la,2 = 2.8 Hz, J ₂ , ₃ = 5.3 Hz, J _lb , ₂ = 9.9 Hz, IH, H-2), 3.03 (dd, J _la , ₂ = 9.9 Hz, J _la , _lb = 13.1 Hz ₅ IH, H-Ia), 2.87 (dd, J _la , ₂ = 2.8 Hz, J _la>lb = 13.1 Hz, IH, H-Ib); ¹³ C NMR (125 MHz, D ₂ O) δ 135.4 (CA), 118.2 (C5), 73.7 (C3), 69.7 (C2), 41.5 (Cl); IR (film) 3412, 3252, 3045, 1632, 1432, 1013 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ H ₁₂ O ₂ N] ⁺ : 118.0868, obsd: 118.0869.

(6R,7R,7aR)-6,7-Dihydroxy-tetrahydro-pyrroIo[l,2-c]oxazoI -3-one (11). To a solution of the alkenylamine 10 hydrochloride (40 mg, 0.26 mmol) in water (1 mL) was added NaHCO ₃ (25 mg, 0.39 mmol) and I ₂ (73 mg, 0.29 mmol). The solution was stirred 18 h at room temperature then filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography (hexanes/EtOAc, 1/3, v/v). Carbamate 11 was isolated as an amorphous white powder (30 mg, 0.19 mmol, 73%). [α] _D ¹⁸ = +20.1 (c - 0.6, EtOH); ¹ H NMR (500MHz, D ₂ O) δ 4.51 (t, J4, _5a = J5a, _5b = 9.2 Hz, IH, H-5a) 4.38 (dd, J _5a , _5b = 9.2 Hz, J _4;5b ="2.9 Hz, IH, H-5b), 4.27 (d, J _la,2 = 5.1 Hz, IH, H-2), 4.17 (dt, J _4,5a = 9.2 Hz, J ₄ , _5b = J ₃ , ₄ = 2.9 Hz, IH, H4), 3.90 (d, J ₃ , ₄ - 2.9 Hz, IH, H-3), 3.67 (dd, J _la,2 = 5.1 Hz, Ji _Mb = 12.5 Hz, IH, H-Ia), 3.01 (d, Ji _Mb = 12.5 Hz, IH, H-Ib); ¹³ C NMR (125 MHz, D ₂ O) δ 164.4 (C6), 76.5 (C2), 74.3 (C3), 64.0 (C5), 62.0 (C4), 52.2 (Cl); IR (film) 3372, 2954, 2845, 1715, 1635, 1416, 1253, 1079, 955 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₆ H ₉ O ₄ NNa] ⁺ : 182.0424, obsd.: 182.0429.

(2S,3R,4R)-2-HydroxymethyI-pyrrolidine-3,4-dioI (12). To a solution of carbamate 11 (13 mg, 0.08 mmol) in EtOH (1 mL) was added NaOH (19 mg, 0.8 mmol). The solution was stirred at reflux for 2 h then cooled and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ . 12 was isolated as the HCl salt (9.9 mg, 0.07 mmol, 90%). R ₇ = 0.21 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ²⁰ = +8.2 (c=0.5, H ₂ O); ¹ H NMR (500MHz, D ₂ O) δ 4.26 (d, J _la>2 = 4.5 Hz, IH, H-2), 4.19 (d, J _3j4 = 3.8 Hz, IH, H-3), 3.89 (dd, J ₄ , _5a = 5.5 Hz, J _5a>5b = 11.5 Hz, IH, H-5a), 3.77 (dd, J _4,5b = 7.7 Hz, J _5a , _5b = 11.5 Hz, IH, H-5b), 3.62 (ddd, J _3>4 = 3.8 Hz, J _4,5a = 5.5 Hz, J _4>5b = 7.7 Hz, IH, H-4), 3.46 (dd, J _la , ₂ = 4.5 Hz, Ji _Mb = 12.8 Hz, IH, H-Ia), 3.04 (d, J _la , _lb = 12.8 Hz, IH, H-Ib); ¹³ C NMR (125 MHz, D ₂ O) δ 74.6 (C2), 74.5 (C3), 62.5 (C4), 57.6 (C5), 50.4 (Cl); IR(film) 3317, 2944, 2832, 1654, 1449, 1415, 1113, 1021 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ H ₁₂ O ₃ N] ⁺ : 134.0817, obsd.: 134.0817. Example 4

13 14 15 16

(R)-5-Amino-pent-l-en-3-ol (14). To a solution of halogenated cyclic acetal 13 (100 mg, 0.38 mmol) in a saturated solution OfNH ₄ OAc in EtOH (7.5 niL) was added activated Zn (124 mg, 1.9 mmol), NaCNBH ₃ (73 mg, 1.14 mmol) and 30% aqueous NH ₃ (3 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in water and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ . Alkenylamine 14 was obtained as the HCl salt (42 mg, 0.31 mmol, 81%). R/= 0.4 (DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [αJ _D ¹⁷ = -3.2 (c=0.1, EtOH); ¹ H NMR (300MHz, D ₂ O) δ 5.35 (ddd, J _2a,3 = 6.06 Hz, J4, _5b =10.5 Hz, J ₄ , _5a = 17.3 Hz, IH, H4), 5.06 (dd, J _5a , _5b = 1.3 Hz, J ₄ , _5a = 17.3 Hz, IH, H-5a), 5.04 (dd, J _5a , _5b = 1.3 Hz, J ₄ , _5b = 10.5 Hz, IH, H-5b), 4.04 (dd, J _3;4 = 6.06 Hz _. , J _2,3 = 12.5 Hz, IH ₅ H-3), 2.96 (m, 2H, H-I), 1.38 (m, 2H, H-2); ¹³ C NMR (125 MHz, D ₂ O) δ 138.8 (C4), 115.8 (C5), 70.1 (C3), 36.3 (Cl), 32.9 (C2); IR (film), 3359, 3047, 2955, 2927, 2854, 1635, 1428, 1134, 1056 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ H ₁₂ NO] ⁺ : 102.0919, obsd.: 102.0921.

(7S,7aS)-7-Hydroxy-tetrahydro-pyrrolo[l,2-c]oxazol-3-one (15). To a solution of the alkenylamine 14 hydrochloride (30 mg, 0.21 mmol) in water (1 mL) was added NaHCO ₃ (20 mg, 0.32 mmol) and I ₂ (59 mg, 0.23 mmol). The solution was stirred 18 h at room temperature then filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography (hexanes/EtOAc, 1/3, v/v). Carbamate 15 was isolated as an amorphous white powder (33 mg, 0.20 mmol, 99%). [α] _D ¹⁷ = +7.0 (c = 0.1, EtOH); ¹ H NMR (500MHz, D ₂ O) δ 4.42 (t, J _5a , _5b = J4,sb = 9.2 Hz, IH, H5a), 4.34 (dd, J ₄ , _5b = 3.6 Hz, J _5a , _5b = 9.2 Hz, IH, H-5b), 4.08 (t, J _3,4 = J ₂ a,3 = 3.6 Hz, IH, H-3), 3.90 (td, J _3;4 = J _4;5b = 3.6 Hz, J4, _5b = 9.2 Hz, IH, H-4), 3.37 (ddd, Jia,2 _b = 8.1 Hz, J _la , _2a = 9.5 Hz, J _la ,ib = 10.9 Hz, IH, H-Ia), 3.15 (ddd, Ji _b , _2b = 2.2 Hz, J _lb;2a = 10.0 Hz, J _la,lb = 10.9 Hz, IH, H-Ib), 2.06 (ddd, J _la,2a = 9.5 Hz, Ji _bi2a = 10.0 Hz, J _2a , _2b - 14.2 Hz, IH, H-2a), 1.93 (ddd, Ji _b , _2b = 2.2 Hz, Ji _a , _2b - 8.1 Hz, J _2a , _2b = 14.2 Hz, IH, H-2b); ¹³ C NMR (125 MHz, D ₂ O) δ 69.6 (C3), 64.4 (C4), 64.3 (C5), 43.0 (Cl), 33.7 (C2); IR (film), 3419, 3385, 3047, 2986, 2931, 1730, 1448, 1087 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₆ H ₉ NO ₃ Na] ⁺ : 166.0486 obsd.:166.0480.

(2R,3R)-2-(Hydroxymethyl)-3-hydroxypyrrolidine (16). To a solution of carbamate 15 (10 mg, 70 μmol) in EtOH (1 niL) was added NaOH (17 mg, 0.7 mmol). The solution was stirred at reflux for 2 h then cooled and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ . 16 was isolated as the HCl salt (8.2 mg, 70 μmol, 99%). R/= 0.1 ((DCM/EtOH/MeOH/30% aqueous NH ₃ , 5/2/2/1, v/v/v/v); [α] _D ¹⁷ - +10.0 (c=0.09, EtOH); ¹ H NMR (500MHz, D ₂ O) δ 4.27 (dt, J _2b,3 = 1.5 Hz, J _2a,3 = J ₃ , ₄ = 4.9 Hz, IH, H3), 3.98 (dd, J _4;5a = 4.9 Hz, J _5%5b = 12.1 Hz, IH, H-5a), 3.83 (dd, J _4,5b = 8.5 Hz, J _5a,5b = 12.1 Hz, IH, H-5b), 3.31 (td, J ₃ , ₄ = J4, _5a = 4.9 Hz, J ₄ , _5b = 8.5, IH, H-4), 3.25 (ddd, J _la , _2b = 7.6 Hz, J _la , _2a = 9.6 Hz, Ji _a , _lb = 11.6 Hz, IH, H-Ia), 3.21 (ddd, Ji _b,2b = 3.4 Hz, J _lb;2a = 9.9 Hz, J _la,lb = 11.6 Hz, IH, H-Ib), 2.13 (dddd, J _2a,3 = 4.9 Hz, J _2a,la = 9.6 Hz, J _2a,lb = 9.9 Hz, J _2a;2b = 14.1 Hz, IH, H-2a), 2.05 (dddd, J _2b;3 = 1.5 Hz, J _2b,lb = 3.4 Hz, J _2b, i _a = 7.6 Hz, J _2a,2b = 14.1 Hz, IH, H-2b); ¹³ C NMR (125 MHz, D ₂ O) δ 70.8 (C3), 64.1 (C4), 59.0 (C5), 42.9 (C2), 33.3 (Cl); IR (film), 3397, 3364, 2960, 2932, 2874, 1720, 1601, 1168, 1064 cm ^"1 . HRMS(ESI) m/z calcd. for [C ₅ Hi ₂ NO ₂ J ⁺ : 118.0868 obsd. : 118.0870.

Example 5

17 18

(2S,3S,4R)-l-Amino-hex-5-ene-2,3,4-triol (18). To a solution of halogenated cyclic acetal 17 (890 mg, 2.93 mmol) in a saturated solution OfNH ₄ OAc in EtOH (60 mL) was added activated Zn (958 mg, 14.7 mmol), NaCNBH ₃ (561 mg, 8.79 mmol) and 30% aqueous NH ₃ (23 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in water and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ . Alkenylamine 18 was obtained as the HCl salt (501 mg, 2.74 mmol, 93%). ¹ H NMR (300 MHz, D ₂ O) δ 5.71 (ddd, J4, ₅ J _5fi . _lrms = 17.2 Hz, IH, U-6-trans), 5.14 (d, J _5;6-c/ , = 10.6 Hz, IH, H-6-cw), 4.05 (dd, J _3,4 = 6.7, J ₄ , ₅ *= 6.9 Hz, IH, H-4), 3.80 (ddd, J ₂₃ = 2.9, Ji _a , ₂ = 4.8, J _lba = 7.6 Hz, IH, H-2), 3.36 (dd, J _2>3 = 2.9, J ₃ , ₄ = 6.7 Hz, IH, H-3), 2.98 (m, 2H ₃ H-Ia and H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 135.8 (C5), 118.4 (C6), 74.2 (C3), 73.2 (C4), 67.0 (C2), 42.3 (Cl). HRMS(ESI) m/z calcd. for [C ₆ H _M NO ₃ ] ⁺ : 148.0974, obsd.: 148.0977.

Example 6

(2S,3S,4S)-l-Amino-hex-5-ene-2,3,4-triol (22). To a solution of halogenated cyclic acetal 21 (520 mg, 1.71 mmol) in a saturated solution OfNH ₄ OAc in EtOH (34 mL) was added activated Zn (559 mg, 8.6 mmol), NaCNBH ₃ (327 mg, 5.13 mmol) and 30% aqueous NH ₃ (14 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in water and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ . Alkenylamine 22 was obtained as the HCl salt (215 mg, 1.46 mmol, 86%). ¹ H NMR (500 MHz, D ₂ O) δ 5.93 (ddd, J ₄ , ₅ = 7.0, J _5,6-c/ , = 10.5, J _5fi . _trms = 17.4 Hz, IH, H-5), 5.35 (dt, J _5,6-/ra , _ω = 17.4, - Jβ-cisfi-trans = 1.2 Hz IH, H-6-c/tf), 4.12 (dd, J ₃₌₄ = 8.0, J _4;5 = 7.1 Hz, IH, H-4), 4.10 (ddd, J _2,3 = 2.4, J _la,2 = 7.5, J _lb>2 = 7.5 Hz, IH, H-2), 3.44 (dd, J _2>3 = 2.4, J _3;4 = 8.0 Hz, IH, H-3), 3.13 (m, 2H, H-Ia and H-Ib); ¹³ C NMR (75 MHz, D ₂ O) δ 136.8 (C5), 118.3 (C6), 73.7 (C3), 72.0 (C4), 66.3 (CZ), 42.4 (Cl). HRMS(ESI) m/z calcd. for [C ₆ H _i4 NO ₃ ] ⁺ : 148.0974, obsd.: 148.0973.

(6S,7R,8S,8aR)-6,7,8-Trihydroxy-hexahydro-oxazolo[3,4-α] pyridin-3-one (23). Alkenylamine 22 hydrochloride (7.9 mg, 0.050 mmol) was subjected to the general iodocyclisation/carbamate formation procedure, as described above for Examples 1 to 4. Carbamate 23 was isolated as an amorphous white powder (8 mg, 0.050 mmol, 99%). ¹ H NMR (500MHz, D ₂ O) δ 4.47 (t, J ₅ , _6a = J _6a , _6b = 9.0 Hz, IH, H-6a), 4.35 (dd, J _5,6b = 5.0, J _6a,6b = 9.0 Hz, IH, H-6b), 4.05 (ddd, J ₄ , ₅ = 1.9, J ₅ , _6b = 5.0, J ₅ , _6a = 9.0 Hz, IH, H-5), 3.96 (dd, J ₄ , ₅ = 1.9, J ₃ , ₄ = 2.3 Hz, IH, H-4), 3.90 (dd, J ₁ ^ = 6.1, j _la>lb = 13.1 Hz, IH, H-Ia), 3.79 (ddd, Ji _a,2 = 6.1, J _2,3 = 9.7, Ji _b)2 = 10.5 Hz, IH, H-2), 3.57 (dd, J ₃ , ₄ = 2.3, J ₂ , ₃ = 9.7 Hz, IH, H-3), 2.82 (dd, J _lb;2 = 10.5, J _{1 Mb} = 13.1 Hz, IH, H-Ib); ¹³ C NMR (100MHz, D ₂ O) δ 159.7 (C7), 73.6 (C3), 69.0 (C4), 65.0 (C2), 63.9 (C6), 56.6 (C5), 44.0 (Cl). HRMS(ESI) m/z calcd. for [C ₇ H ₁₁ O ₅ NNa] ⁺ : 212.0535, obsd. 212.0532.

Example 7

25 26

(3S,4R)-6-Amino-hex-l-ene-3,4-diol (26). To a solution of halogenated cyclic acetal 25 (58 mg, 0.214 mmol) in a saturated solution OfNH ₄ OAc in EtOH (4.5 mL) was added activated Zn (70.0 mg, 1.1 mmol), NaCNBH ₃ (41 mg, 0.64 mmol) and 30% aqueous NH ₃ (1.7 mL). The mixture was stirred at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in H ₂ O and purified directly by ion-exchange chromatography (Dowex H ⁺ ). The product was eluted using 5-15% aqueous NH ₃ .

Alkenylamine 26 was obtained as the HCl salt (35 mg, 0.21 mmol, 99%). ¹ H NMR (500 MHz, D ₂ O) δ 5.88 (ddd, J _4>5 = 6.7, J ₅ , _6-c/ , = 10.5, \ _Uram = 17.9 Hz, IH, H-5), 5.32 (d, J _5fi . _tmιis = 17.9 Hz, IH, n-6'trans), 5.30 (d, J _5;6-c« = 10.5 Hz IH, H-6-cis), 4.06 (dd, J ₃ , ₄ = 4.6, J ₄ , ₅ - 6.7 Hz, IH, H-4), 3.73 (ddd, J _2a>3 = 3.0, J _3>4 = 4.6, J _2b,3 = 9.6 Hz, IH, H-3), 3.13 (m, 2H, H-Ia and H-Ib), 1.93 (m, IH, H-2a), 1.87 (m, IH, H-2b); ¹³ C NMR (125 MHz, D ₂ O) δ 135.5 (C5), 118.0, (C6), 75.4 (C4), 71.6 (C3), 37.1 (Cl), 28.9 (C2). HRMS(ESI) m/z calcd. for [C ₆ H ₁₄ NO ₂ ] ⁺ :132.1025, obsd.:132.1022.

Analysis of the NMR spectra indicated that each of the iodocyclisation/carbamate formation reactions proceeded with diastereoselectivity.

It is not the intention to limit the scope of the invention to the abovementioned examples only. As would be appreciated by a skilled person in the art, many variations are possible without departing from the scope of the invention as set out in the appended claims.