FIELD The present invention relates to synthetic processes for the preparation of compounds bearing a dioxanyl moiety, in particular to compounds bearing a dioxanyl side chain attached to a mono- or polycyclic core moiety, more particularly a cyclopentabenzofuran core moiety. The invention also relates to intermediate compounds used in these processes. Compounds which can be prepared by the process of the invention can be used as candidates for screening for potential therapeutic activity, thus the invention also relates to compounds obtainable or prepared by the methods described herein, in particular to those having cytotoxic or cytostatic activity.

BACKGROUND The genus Aglala {Meliaceae) comprises over 100 (mostly woody) species occurring in Indo-Malaysia and the Western Pacific region. Isolable from extracts of many Aglaia species are a family of cyclopentabenzofuran lignan compounds known as rocaglamide derivatives, the first such described compound rocaglamide (1) itself which was shown to have significant antileukemic activity against P388 lymphocytic leukemia in CDF mice (US Patent No. 4,539,414) .

Subsequent studies identified numerous other cyclopentabenzofuran lignans from Aglaia species (see for example Cui et al, Tetrahedron, 1997, 53, 17625-17632; Ko et al, European J. Pharmacol., 1992, 218, 129-135; Lee et al, Chem. Biol. Interact., 1998, 115(3) : 215-218/ Ohse et al, J. Nat. Prod., 1996, 59(7) : 650 652; Bohnenstengel et al, Z. Naturforsch, 1999, 54C(12) : 55-60; Bohnenstengel et al, Z. Naturforsch, 1999, 54C(12) : 1075-1083; Wu et al, J. Nat. Prod., 1997, 60, 606-608; Dreyer et al, J. Nat. Prod., 2001, 64, 415-420; Gϋssregan et al, Z. Naturforsch, 1991, 52(5/6), 339-344; Brader et al, J. Nat. Prod., 1998, 61, 1482-1490; Wang et al, Planta Med., 2001, 67, 555-557; Proksch et al, Curr. Org. Chem., 2001, 5, 923-938; WO 97/08161 and JP 97171356. A number of rocaglamide derivatives have also been shown to exhibit insecticidal activity (see for example Hiort et al, J. Nat. Prod., 1999, 62, 1632-1635; Chaidir et al, Phytochemistry, 1999, 52, 837-942; Nugroho et al, Phytochemistry, 1999, 51, 367- 376; Ishibashi et al, Phytochemistry, 1993, 32, 307-310; Schneider et al, Phytochemistry, 2000, 54, 731-736; Satasook et al, Pestic. Sci. , 1992, 36, 53-58; Molleyres et al, Pestic. Sci., 1999, 55, 486-503; Nugroho et al, Phytochemistry, 1997, 44, 1455-1461; Nugroho et al, Phytochemistry, 1997, 45, 1579-1585; and Janpasert et al, Phytochemistry, 1999, 32, 67-69) . Insecticidal compounds with a closely related core structure were isolated from Aglaia roxburghiana and are described in WO 96/04284 for use as active ingredients in agrochemical formulations. More recently, two new isomers (2A) and (2B) of the cyclopentabenzofuran compound (2) have been isolated from Aglaia leptantha Miq. In contrast to many of the previously reported rocaglamide derivatives, these compounds were found to possess hitherto unknown dioxanyloxy substitution at the 6-position of the cyclopentabenzofuran core.

(2A) {28}

Not only did the two isomers possess cytostatic activity as observed for a number of previously reported rocaglamide derivatives, they also surprisingly exhibited significant cytotoxic activity, a property not shared by these rocaglamide derivatives having a methoxy substituent at the 6-position of the cyclopentabenzofuran core. Although synthetic routes to rocaglamide and its derivatives have been devised (see for example Trost et al, J. Am. Chem. Soc.r 1990, 112, 9022-9024; Davey et alr J. Chem. Soc. , Perkin Trans. 1, 1992, 2657-2666 and US Patent No. 6,420,393) there is no known synthetic access to the dioxanyl moiety of (2) . In view of their dual cytostatic and cytotoxic properties, there exists a need, therefore, for synthetic access to compounds of formula (2) and derivatives and analogues thereof as well as other compounds bearing the unique dioxanyl moiety.

SUMMARY According to the present invention there is provided - A -

a process for the preparation of a compound of formula (I)

or a salt or prodrug thereof in which A is an optionally substituted and/or optionally protected mono- or polycyclic aromatic core moiety; 51 is OR2 and is H, or Z1 is H and Z2 is OR2 Z3 is OR3 and Z4 is H, or Z3 is H and Z4 is OR3; and R1 to R3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic group, a C-I linked saccharide and a protecting group; or R1 and R2 together with the oxygen atoms to which they are attached form an optionally substituted 5 to 6 membered ring comprising the step of: (i) coupling the compound of formula (II)

in which R1, Z1, Z2, Z3 and Z4 are as defined in formula (I) above; and Y is hydrogen or a protecting group with an optionally substituted and/or optionally protected mono- or polycyclic aromatic group. The coupling step (i) preferably involves the use of Mitsunobu reaction conditions . The invention also provides a compound of formula (I) obtainable or prepared by the process defined above. The invention further provides a compound of formula (I1) which is a compound of formula (I) other than when A is

in which X is OR8 or NR9R10; and R4 to R10 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic group and a C-I linked saccharide; and R and R are each independently hydrogen or, alternatively, OR4 and R11, and/or OR5 and R12 together form a methylenedioxy group. A preferred compound of formula (I) has the formula (IA1)

in which Z1 to Z4 are as defined in formula (I) above; Z5 = C(O)X and Z6 = H, or Z5 H and Z& = C(O)X; Z7 = Ph and Z8 = H, or Z' = H and Z8 = Ph; in which X is OR8 or NR9R10, and each R1 to R10 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic group, a C-I linked saccharide and a protecting group; R11 is hydrogen, or alternatively, OR4 and R11 together form a methylenedioxy group; Ph is optionally substituted phenyl; and Z9 is an optional substituent. A preferred compound of formula (IA') has the formula (IA")

in which Z1 to Z8, R1, R4, R6 and R7 are as defined in formula (IA') above; and R12 is hydrogen or alternatively OR5 and R12 together form a methylenedioxy group. In another preferred embodiment, the compound of formula (IA") is one of 2C, 2D, 3A-D, 4A-D or 5A-D.

2C Z1= OH, Z2 = H, Z3 = H, Z4 - OMe, Z5 = H, Z6 = CO2Me, Z7 = Ph, Z8 = H 2D Z1= H, Z2 = OH, Z3 = H, Z4 = OMe, Z5 = H, Z6 = CO2Me, Z7 = Ph, Z8 = H 3A Z1= OH, Z2 = H, Z3 = OMe, Z4 = H, Z5 = CO2Me, Z6 = H, Z7 = H, Z8 = Ph 3B Z1= H, Z2 = OH, Z3 = OMe, Z4 = H, Z5 = CO2Me, Z6 = H, Z7 = H, Z8 = Ph 3C Z1= OH, Z2 = H. Z3 = H, Z4 = OMe, Z5 = CO2Me, Z6 = H, Z7 = H, Z8 = Ph 3D Z1= H, Z2 = OH, Z3 = H, Z4 = OMe, Z5 = CO2Me, Z6 - H, Z7 = H, Z8 = Ph 4A Z1= OH, Z2 = H, Z3 = OMe, Z4 = H, Z5 = H, Z6 = CONMe2, Z7 = Ph, Z8 = H 4B Z1= H, Z2 = OH, Z3 = OMe, Z4 = H, Z5 = H, Z6 = CONMe2, Z7 = Ph, Z8 = H 4C Z1= OH, Z2 = H, Z3 = H, Z4 = OMe, Z5 = H, Z6 = CONMe2, Z7 = Ph, Z8 = H 4D - = CONMe2, Z /7' =_ - Ph, Z8 = H 5A Z1= OH, Z2 = H, Z3 = OMe, Z4 = H, Z5 = CONMe2, Z6 = H, Z7 = H, Z8 - Ph 5B Z1= H, Z2 = OH, Z3 = OMe, Z4 = H, Z5 = CONMe2, Z6 = H, Z7 - H, Z8 = Ph 5C Z1= OH, Z2 = H, Z3 = H, Z4 = OMe, Z5 = CONMe2, Z6 = H, Z7 = H, Z8 = Ph 5D Z1= H, Z2 - OH, Z3 = H, Z4 = OMe, Z5 = CONMe2, Z6 = H, Z7 - H, Z8 = Ph The intermediate compound of formula ( II ) is also novel and forms an aspect of the invention . In one embodiment of the invention, the compound of formula ( II ) is a compound of formula ( II-aa) , ( II-ab) , ( II-ba ) or ( II-bb) , or a salt or prodrug thereof :

(H-aa) (π-ba)

(II-ab) (II-bb)

in which R1, R2, R3 and Y are as defined above. The invention also provides a process for the preparation of a compound of formula (II), particularly compounds of the formula (II-aa) , (II-ba) , (II-ab) and (II-ba) defined above which comprises the steps of: (i) acetal cleavage of compound (Hi)

in which R3 and Y are as defined in formula (II) above to form compound (Ilii) in which R3 and Y are as defined in formula (II) above; (ii) periodate cleavage of compound (Ilii) to form compound (Iliii)

(Iliii)

in which R3 and Y are as defined in formula (II) above; (iϋ) reduction of compound (Iliii) to form compound (Iliv)

(Iliv) in which Y is as defined in formula (II) above; and (iv) optionally protecting compound (Iliv) with R1 and/or R2. The intermediates used in the preparation of the compound of formula (II), namely compounds (Ilii) - (Iliv) , are also novel and form part of the invention. In one embodiment, the optionally substituted and/or optionally protected mono- or polycyclic aromatic core moiety A is an optionally substituted and/or optionally protected fused polycyclic heterocyclic group having at least one aromatic ring such as an optionally substituted and/or optionally protected cyclopentabenzofuran for example having the formula (A!)

in which Z5 to Z9, R4, R . R7 and R11 are as defined in formula (IA') above. Preferred Z7-Z9 independently include optionally substituted phenyl, optionally substituted C5-C6 cycloalkyl, an optionally substituted 5- or 6-membered heterocyclic group (such as optionally substituted pyridyl) , and optionally substituted alkyl (such as i- propyl, sec- and t-butyl) . In a particularly preferred embodiment the compound of formula (A1) has the formula (A")

in which R4 to R7, Rαxi±, R and Z to Z are as defined in formula (IA") above. In another embodiment, the optionally substituted and/or optionally protected mono- or polycyclic aromatic core moiety A is an optionally substituted and/or optionally protected phenyl such as

wherein R' and R" are as defined in formula ( above for R1 to R3. Thus, the present invention also provides a process for the preparation of a compound of formula (A") which comprises the steps of: (i) coupling compound (A"i)

(A"i)

in which R5 is as defined in formula (A") above, R13 is hydrogen or a protecting group and L is a leaving group with compound (A"ii)

(A"ii) in which R is a protecting group, R4 is as defined in formula (A") above and R14 is hydrogen or a protecting group to form compound (A"iii)

(A"iii) in which R, R4, R5 and are as defined in formula (A") above; (ii) cyclisation of compound (A"iii) to form compound (A"iv)

(A11Iv) in which R, R4 and R5 are as defined in formula (A") above; (iii) conjugate addition of compound (A"iv) with cinnamaldehyde to form compound (A1V)

in which R, in formula (A") above; cyclisation of compound (A1V) to form compound (A1Vi;

in which R, R4 and R5 are as defined in formula (A") above; and (v) optionally removing protecting groups from compound (A1Vi) when present. The present invention also provides an alternative process for the preparation of the compound of formula (A") as defined above which comprises the steps of: (i) 3+2 cyclisation of compound (A'Vii)

in which R is as defined above and R4 to R6 and R8 are as defined above to form compound (A'Viii) (A viii)

in which R is as defined above and R4 to R6 and R8 are as defined above; (ii) α - ketol shift of compound (A'Viii) to form compound (A"ix)

(A"ix) in which R is as defined above and R4 to R6 and R8 are as defined above; (iii) reduction of compound (A"ix) ; and (iv) optionally removing protecting groups from compound (A"ix) when present. Further according to the present invention there is provided a process for the preparation of compound (A'Vii) which comprises the steps of: (i) oxidation of compound (A"x)

(A x) in which R is as defined above to form compound (A"xi)

(A"xi)

(ii) installation of R4 and R5 on compound (A"xi) to form compound (A"xii)

(A xxi) in which R is as defined above and R4 and R5 are as defined in formula (A") above; and (iii) oxidation of compound (A"xii) . It will be appreciated that when R6 and/or R7 are other than hydrogen that one or both of these groups can be installed during any suitable step of the process for preparing formula (A") . The intermediates used in the preparation of compound (A") , namely compounds (A11Ui) to (A1Vi) , (A'Viii) and (A"ix) when R is not methyl, are also novel and form part of the invention.

DESCRIPTION In the claims of this application and in the description of the invention, except where the context requires otherwise due to express language or necessary implication, the words "comprise" or variations such as "comprises" or "comprising" are used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. It must be noted that, as used in the subject specification, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound, as well as two or more compounds; and so forth. The term "alkyl" refers to a straight chain, branched or cyclic hydrocarbon group, preferably Ci_2o alkyl, more preferably Ci-I0 alkyl, most preferably Cχ-6 alkyl. The term "Ci-Cβ alkyl" refers to a straight chain, branched or cyclic alkyl group of 1 to 6 carbon atoms. Examples of "Ci- 6 alkyl" include methyl, ethyl, iso-propyl, n-propyl, n- butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2,2- dimethylpropyl, π-hexyl, 2-methylpentyl, 2,2- dimethylbutyl, 3-methylpentyl and 2, 3-dimethylbutyl. Examples of cyclic C3_6 alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other examples of alkyl include heptyl, 5-methylhexyl, 1-methylhexyl, 2,2- dimethylpentyl, 3, 3-dimethylpentyl, 4, 4-dimethylpentyl, 1, 2-dimethylpentyl, 1, 3-dimethylpentyl, 1, 4-dimethyl¬ pentyl, 1, 2, 3-trimethylbutyl, 1, 1, 2-trimethylbutyl, 1,1,3- trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1, 1, 3, 3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8- methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3- butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6- , 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. The term "alkenyl" refers to a straight chain, branched or cyclic hydrocarbon group having at least one carbon-carbon double bond, preferably C2-20 alkenyl, more preferably C2-β alkenyl. Examples include ethenyl, propenyl, allyl, butenyl and 4-methyl butenyl. The term "alkynyl" refers to straight chain or branched hydrocarbon groups having at least one carbon- carbon triple bond, preferably C2-20 alkynyl, more preferably C2-6 alkynyl. Examples include propargyl and butynyl. The term "aryl", denotes single, polynuclear, conjugated or fused residues of aromatic hydrocarbons. Examples include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl and phenanthrenyl. Preferred aryl groups include phenyl and naphthyl. The term "heterocyclic group" refers to saturated or unsaturated, monocyclic or polycyclic hydrocarbon groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclic groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl. Preferred heterocyclic aryl groups include pyridyl, thienyl, furyl, pyrrolyl. The term "acyl", refers to a group -C(O)-R wherein R is any carbon containing moiety such as an optionally substituted alkyl or aryl group. Examples of acyl include straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl] . Optional substituents for "alkyl", "alkenyl", "alkynyl", "aryl", "heterocyclic group" and "acyl" include halo (bromo, fluoro, chloro, iodo) , hydroxy, thio, Ci-6 alkyl (e.g. methyl, ethyl, propyl (n and i- isomers), cyclopentyl and cyclohexyl) , Ci_6 alkoxy (e.g. methoxy, ethoxy, propoxy (n- and i- isomers) , butoxy {n-r sec- and t-isomers)), Ci_6 alkylthio, nitro, amino, Cχ-6 alkylamino (e.g. methylamino, ethylamino, propyl (Ώ- and i- isomers) amino) , Cχ-6 dialkylamino (e.g. dimethylamino, diethylamino, diisopropylamino) , 3-6-membered N-containing cyclic group (such as piperidyl, pyrrolidinyl, piperazinyl, imidazolidinyl and pyrazolidinyl) , phenyl, hydroxyphenyl, Ci-6 alkyloxyphenyl, halomethyl (e.g. trifluoromethyl, tribromomethyl, trichloromethyl) , halomethoxy (e.g. trifluoromethoxy, tribromomethoxy, trichloromethoxy) , CO2H, CO2Ci-6alkyl, CONRxR7 (wherein Rx and Ry are independently H or Ci_6 alkyl) , acetyl and a methylene dioxy group. An optional substituent for alkyl also includes replacement of CH2 by C(O) . Preferred C-I linked saccharides are a furanose or pyranose saccharide (sugar) substituent which can be linked through the saccharides' 1-carbon (conventional chemical numbering) to form an acetal at an oxy group, such as any one of positions Ri, R2, R3, R4, R5, Rε or R7 or an ester linkage at the R8 or an amide at R9 or Ri0 position of formula (I1) - Exemplary saccharide groups include reducing sugars such as glucose, ribose, arabinose, xylose, mannose and galactoses, each being linked to an oxygen atom through the C-I carbon of the saccharide group. Glycosidic formation may be effected chemically, e.g. by reacting the starting compound with a protected sugar compound in which C-I has been activated by halogenation for coupling with the hydroxyl or carboxyl groups and the sugar hydroxyls have been blocked by protecting groups or glycosidic formation can be carried out under Lewis acid catalysis. Alternatively, glycoside formation may be effected enzymatically using an appropriate glycosyltransferase such as UDP-galactose dependent galactosyltransferase and UDP-glucose dependent glycosyltransferase (SIGMA) . As used herein a "protecting group" refers to an introduced functionality which renders a particular functional group, such as a hydroxy, amino, carbonyl or carboxy group, unreactive under selected conditions and which may later be optionally removed to unmask the functional group. A hydroxy protecting group is one which can temporarily render a hydroxy group unreactive. A protected hydroxy group refers to a hydroxy group which has temporarily been rendered unreactive by a hydroxy protecting group. A protected phenyl group is taken to be one in which attached reactive substituents, such as OH, NH2, are protected by a protecting group. Suitable protecting groups are known in the art and are described in Protective Groups in Organic Synthesis, Third Edition, T.W. Greene and P.G. White, John Wiley & Sons, Inc., 1999, (the contents of which are incorporated herein by reference) as are methods for their installation and removal. Examples of protecting groups which may be used to protect a hydroxy group include, but are not limited to, silyl groups (e.g. trimethylsilyl, fc- butyldimethylsilyl, t-butyldiphenylsilyl) , benzyl groups (e.g. benzyl, methoxybenzyl, nitrobenzyl) , alkyl groups (e.g. methyl, ethyl, n- and i-propyl, and n-, sec- and t- butyl), acyl groups (e.g. acetyl and benzoyl) . It will be recognised that some R groups as described herein may also act as a protecting group and vice versa. As used herein, a "mono- or polycyclic aromatic core moiety" refers to a mono- or polycyclic, aromatic, saturated or non-saturated hydrocarbon residue or a mono- or polycyclic, aromatic heterocyclic residue. A polycyclic core moiety may be fused or non-fused, and each ring may independently be aromatic or non-aromatic, saturated or non-saturated provided that at least one of the rings is aromatic. A polycyclic core moiety also includes spirocyclic groups which may be saturated or unsaturated. A polycyclic core moiety may contain 2, 3, 4 or more rings. Where the mono- or polycyclic core moiety is a heterocyclic residue, the residue may contain one or more heteroatoms in one or more rings of the cyclic core moiety. A ring may contain more than one heteroatom. Where the heterocyclic residue is polycyclic, one or more rings may contain one or more heteroatoms while other rings may contain no heteroatoms. Heteroatoms may be wholly contained within one ring or at a ring junction between two or more fused rings. The mono- or polycyclic core moiety may be unsubstituted or substituted with one or more substituents at one or more carbon atoms of the cyclic core moiety. Where allowed by valency constraints, one or more heteroatoms (e.g. N) may also be substituted by one or two optional substituents such as an alkyl, aryl or acyl group. The term heteroatom is intended to refer to any atom which can replace a carbon atom in a cyclic hydrocarbon group. Examples of particular heteroatoms contemplated by the present invention include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, selenium and tellurium. Particularly preferred heteroatoms include nitrogen, oxygen and sulfur. Examples of mono- or polycyclic core moieties include: monocyclic hydrocarbon groups such as phenyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl; fused polycyclic hydrocarbon groups such as naphthyl, pentalenyl, idenyl, isoidenyl, tetralinyl, azulenyl, heptalenyl, biphenylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, asymm-indacenyl, symm- indacenyl, fluoranthrenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyl, naphthacenyl, plejadenyl, picenyl, perylenyl, pentaphenyl, pentacenyl, indanyl, acenaphthenyl, cholanthrenyl, aceanthrenyl, acephenanthrenyl and the following group:

in which m and n are independently 0 or 1 and X = CH2; monocyclic heterocyclic groups such as thienyl, furanyl, pyrrolyl, isopyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, pyrazolyl, imidazolyl, isoirαidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazoϊyl, oxadiazolyl, dioxinyl, dioxanyl, pyridinyl, pyridazinyl, trianzinyl, oxazinyl and isoxazinyl; fused polycyclic heterocyclic groups such as benzo [b] thienyl, indolyl, iso-indolyl, indolinyl, isoindolinyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, quioxalinyl, quinazolinyl, quinolinyl, carbazolyl, carbolinyl, phenanthidinyl, pteridinyl, napthyridinyl, phthalazinyl, acridinyl, phenanthralinyl, phenazinyl, benzofuranyl, isobenzofuranyl, cyclopentabenzofuranyl, benzimidazolyl, chromenyl, xanthenyl, chromanyl, isochromanyl, phenoxazinyl, phenothiazinyl, thiathrenyl, phenoxathiinyl, thiathrenyl, 2, 3-dihydrobenzofuranyl, 2,3- dihydrobenzo [b] thienyl, azatetralinyl, thiatetralinyl, and the following group:

in which m and n are independently 0 or 1, and X' is selected from 0, NH, N-alkyl, N-acyl and S. Preferably, X' is O. One contemplated sub-group of mono- or polycyclic core moieties includes: naphthyl, indanyl, chromanyl, tetralinyl, 2, 3-dihydrobenzofuranyl, 2,3- dihydrobenzo [b] thienyl, azatetralinyl, thiatetralinyl, indolinyl, biphenylenyl, phenanthrenyl, anthracenyl, triphenylenyl, naphthacenyl, indolyl, iso-indolyl, indazolyl, benzofuranyl, isobenzofuranyl cyclopentabenzofuranyl, and benzimidazolyl. Each core moiety may be substituted one or more times by one or more (same or different) optional substituents. The substituents for the mono- or polycyclic core moieties include alkyl (such as methyl, ethyl, (n- and i-) propyl and {n-r sec- and t-)butyl, and C5-C6 cycloalkyl) , alkyloxy (such as methoxy, ethoxy, {n- and i-)propoxy and {n-r sec- and t-)butoxy), acyl (such as acetyl and benzoyl), acyloxy (such as acetoxy and benzoyloxy) , aryl (such as phenyl and pyridyl) , aryloxy (such as phenoxy) , arylalkyl (such as benzyl), arylalkyloxy (such as benzyloxy) , cycloalkylalkyl, cycloalkylalkyloxy, arylacyl, arylacyloxy, cycloalkylacyl, cycloalkylacyloxy, C-I linked saccharide, C-I linked glucoside, alkylamino (such as methylamino, ethylamino and propylamino) , dialkylamino (such as dimethylamino, diethylamino, dipropylamino) and alkylthio; wherein "alkyl", "aryl" and "acyl" (as used alone or in a group defined by a compound word) may be further optionally substituted as described respectively for "alkyl", "aryl" and "acyl" above. Other substituents for the mono- or polycyclic core moieties include hydroxy, thio, nitro, heterocyclyl, C(O)X, wherein X is OR8 or NR9R10 (R8-R10 are selected from the group as defined for R1- R3 above) or replacement of a CH2 group by C(O) . "Heterocyclyl", when used in the context of a substituent for a mono- or polycyclic core moiety, refers to a cyclic hydrocarbon residue wherein one or more carbon atoms is replaced by one or more heteroatoms which may be the same or different. Examples thereof include piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, and thiomorpholinyl. A heterocyclyl group may be further optionally substituted by a substituent as defined for the optional substituents for "alkyl", "aryl" and "acyl". Some particular core moieties contemplated by the present invention include:

in which p is 0 or 1 and X" is selected from O, CH2, NH, N-alkyl, N-aryl, N-acyl and S. In particularly preferred forms of the invention, the above illustrated core moieties are attached to the dioxanyloxy group at the left hand side benzene ring, meta- to the OMe group. It will, however, also be recognised that attachment at the ortho- or para- positions is also possible. The invention includes within its scope pharmaceutically acceptable salts, or prodrugs of compounds of formula (I), particularly of formulae (IA1) and (IA") . The term "salt, or prodrug" includes any pharmaceutically acceptable salt, ester, glycoside, solvate, hydrate or any other compound which is not biologically or otherwise undesirable and induces the desired pharmacological and/or physiological effect. Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. The preparation of salts can be carried out by methods known in the art. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention, since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts. The compounds of the invention may be in crystalline form or as a solvate (e.g., hydrates) . Methods of solvation will be known to those skilled in the art. Prodrugs of compounds of formula (I) are also within the scope of the invention. The term "prodrug" includes derivatives that are converted in vivo to the compounds of the invention and include for example, ester (e.g. acetate) and glycoside derivatives of free hydroxy groups, which may undergo in vivo degradation to release a compound of the invention. Other suitable prodrugs may include esters of free carboxylic acid groups. The preparation of suitable prodrugs is further described in Design of Prodrugs, H. Bundgaard, Elseveir, 1985, the contents of which is incorporated by reference. It will also be recognised that compound of formula (I) may possess asymmetric centres (both within the dioxanyl side chain and core moiety A) and therefore, unless specified, are capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres, e.g. greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example chiral intermediates, or mixtures may be resolved by conventional methods, e.g. chromatography, or use of a resolving agent. In one embodiment, compounds of the invention have a polycyclic core moiety of formula (A1) (to afford compounds of formula (IA1) ) and a particularly preferred polycyclic core moiety has the formula (A") (to afford compounds of formula (IA") ) . Some preferred examples of substituents for a Z7-Z9 group which is a phenyl group in formula (A1) , particularly a Z9 phenyl group include: methylene dioxy, hydroxy, Ci_4 alkoxy (e.g. methoxy, ethoxy) and a C-I linked glucoside group. Particularly preferred embodiments thereof include:

wherein Group 1: RA is H; RB is selected from H, OH, OMe, sugar1 and sugar2; and Rc is OMe Group 2: RA is selected from H and OMe; RB is selected from H and OMe; and Rc is OMe Group 3: RA is H and RB and Rc together form a methylene dioxy group Group 4: RA is H, RB is selected from H, OH and OMe; and Rc is OMe. In another embodiment of (A1) , R6 is selected from H, Me or Et. In yet another embodiment of (A1) , Z5 or Z5, is selected from CO2Me, CONMe2, CONHMe, CONH (CH2) 40H and CO2H. In still another embodiment of (A1), R7 is H or Ac. In a particularly preferred form of this embodiment, (A') is (A") as defined above. Thus, particularly preferred compounds of the invention have the formula (IA") as defined above in which Z1 = OR2 and Z2 = H, or Z1 = H and Z2 = OR2; Z3 = OR3 and Z4 = H, or Z3 = H and Z4 = OR3; Z5 = C(O)X and Z6 = H, or Z5 = H and Z6 = C(O)X; Z7 = Ph and Z8 = H, or Z7 = H and Z8 = Ph wherein X is OR8 or NR9R10; and each Rx-R10 independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic group, a C-I linked saccharide and a protecting group R11 and R12 are each independently hydrogen, or alternatively, OR4 and R11, and/or OR5 and R12 together form a methylenedioxy group; and Ph is unsubstituted phenyl. In one embodiment of compounds of formula (IA"), when R1 is H, Z1 or Z2 is OH, Z3 is OMe, R4 and R5 are both Me, R6, R7, R11 and R12 are all H and Z6 is CO2Me, then Z7 is not Ph. In another embodiment, when R1 is Ac, Z1 or Z2 is Ac, Z3 is OMe, R4 and R5 are both Me, R6, R7, R11 and R12 are all H and Z6 is CO2Me, then Z7 is not Ph. In another embodiment of compounds of formula (IA"), when Z3 is OR3, Z6 is C(O)X, and R11 and R12 are both H, then Z7 is not Ph. Access to the dioxanyl compounds of formula (I) can be achieved starting with reaction of the commercially available (Fluka) D-glucose derivative with the appropriate HO-X group followed by deacetylation (Scheme 1) •

NaOMe

Scheme 1 It will be appreciated that the galactose derivative may be used instead of the glucose derivative as the starting material so as to provide the alternative stereochemistry at the non-ring centre of the dioxanyl group for compound (2A) . With the coupled glucose compound in hand, the next step involves selective protection of the C4 hydroxy group with a protecting group in anticipation of an oxidative cleavage step which forms the dioxanyl ring. Any protecting group able to withstand the oxidative cleavage may be suitable. A preferred protecting group is benzyl or substituted benzyl. The methods for installing the C4 hydroxy protecting group depend on the protecting group chosen and are known in the art and described in Green & Wutz (supra) . Formation of a 1,3 benzylidene acetal and subsequent cleavage affords the benzyl protected C4 hydroxy group. Methods for the formation of benzylidene acetals and their subsequent partial cleavage to afford a protected hydroxy group are described in Green & Wutz (supra) pages 217-228. Suitable reagents for the formation of the benzylidene acetal include PhCH(OMe)2, p- MeOC6H4CH(OMe2), PhCHO and 2,4-(MeO)2C6H3CHO. Thus, formation of the appropriate benzylidene acetal followed by partial cleavage affords the C4 protected glucose compound in anticipation of the dioxanyl formation. (Scheme 2) . Scheme2

Subsequent oxidative cleavage (such as described by Heidelberg et al, J. Prakt. Chem. , 1998, 340, 223-232) of the C4 protected compound followed by reduction affords the trioxy dioxanyl compound, as a mixture of C2 epimers which may optionally be separated using standard separating procedures known in the art (e.g. chromatography) . The oxidative cleavage step may be carried out using any suitable oxidising agent, e.g. NaIO4 or Pd (OAc) 4. Selective reduction of the resulting aldehyde to the corresponding alcohol may be achieved by protection of any free hydroxy groups followed by treatment with a suitable reducing agent (Scheme 3) . Suitable reducing agents are known in the art and include hydrides such as NaBH4, DiBAL and LiAIH4.

Scheme3

The resulting compound affords the correct stereochemistry at the non-ring chiral centre of the dioxanyl group for compound (2B) . The alternative stereochemistry required for compound (2A) can be obtained using suitable inversion conditions known in the art (e.g. Mitsunobu conditions such as described in Martin and Dodge, Tetrahedron Lett., 1991, 32, 3017) . Thus, the suitably protected (and debenzylated) compound can be subjected to inversion conditions to invert the configuration of the non-ring chiral hydroxy group as per Scheme 4 below. One possible synthetic route to the compound of formula (II) is shown in Scheme 5.

P is a protecting group R3 is as defined above Scheme 4

1 ) 4A sieves, Ag2Cθ3, PMB-OH

AcO

DiBALH OPMB TBSCI, imidazole, OPMB THF DMF HO TBSO 0°C, 16 h OBn OH 0°C, 2 h OBn "OH 10 11

12 13

Scheme 5 Two possible synthetic routes to appropriate dioxanyl substituted phenyl compounds having alternative stereochemistry at the non-ring chiral centre of the dioxanyl group are shown in Schemes 6 and 7.

Scheme 6

Ph3P, p-nitrobenzoic acid TBAF, THF OPMB Pd(OH)21 H2, OPMB DlAD, Toluene MeOH 0°C, 1.5 h rt, 1.5 h rt, 3 d HO J ViO OBn OMe OH OMe 18 19

Scheme 7 Another possible synthetic route to the compound of formula (II) is shown in Scheme 8.

a. H2ZPd(OH)2C, CH3OH. b. PPh3, p-nitrobenzoic acid, DIAD, toluene, 1 h, rt. c. K2CO3, CH3OH, 40 mins, rt. d. TBDMS-OTf,2,6-lutidine,2hrs rt. e. 10%Pd/C, CH3OH

Scheme 8

One possible synthetic route to form the cyclopentabenzofuran core is shown in Scheme 9

commercially available 26 27

cyclisation

conjugate addition

cyclisation

Scheme9

Another possible synthetic route to form the cyclopentabenzofuran core is shown in Scheme 10.

The cyclopentabenzofuran core and indeed any other mono- or polycyclic aromatic group can be coupled to the compound of formula (I) in a manner analogous to the coupling step described for the appropriately substituted phenyl above. The compound of formula (II) and the optionally substituted and/or optionally protected mono- or polycyclic aromatic group may be coupled to form the compound of formula (I) using Mitsunobu reaction conditions . When the monocyclic aromatic group is an appropriately substituted phenyl group, the compound of formula (II) is suitably coupled using the Mitsunobu reaction. Two possible synthetic routes to couple the cyclopentabenzofuran core to the compound of formula (II) are shown in Schemes 11 and 12 for compound (2B) and Schemes 13 and 14 for compound (2A) .

Scheme 11

2B

Scheme 12

Scheme 13

2A

Scheme 14 Other possible synthetic routes to couple the cyclopentabenzofuran core to the compound of formula ( II ) are shown in Scheme 15 for compound ( 2B ) and Scheme 16 for compound ( 2A) .

ISJ

58 c. i. TBAF, THF, 2h. ii. H2, Pd/C, EtOH iii. Separation. Scheme 15 In a preferred embodiment of the invention, the synthetic processes described herein can be used to gain access to compounds (2A) and (2B) . Thus, compounds of formula (II) act as useful intermediates in the synthesis of compounds of formula (I), such as (IA1) and (IA") . The invention therefore also provides an intermediate compound formula (II) as defined above. Formation of (2A) requires the formation of the alternative epimer at the non-ring chiral centre of the dioxanyl group. This can be achieved by subjecting a suitably protected form of the dioxy dioxanyl compound to appropriate inversion conditions (e.g. Mitsunobu conditions) . Examples of the inversion processes are shown in Schemes 17 and 18.

2B

Ph3P, p-nitrobenzoic acid DIAD.Toluene 13 h, rt 79%

NaOMe, MeOH 15 mins, rt 100%

2A

Scheme 17

2A

PhsP, p-nitrobenzoic acid DIADJoluene 6d, rt 80%

NaOMe, MeOH 1 h, rt 73%

Scheme 18 The inversion process thus provides access to the alternative stereoisomer. Accordingly, one embodiment of the invention provides a compound of formula [ II-i-a ) where R to R3 and Y are as defined above.

(II-i-a)

Another embodiment of the invention provides a compound of formula (II-i-b) where R3--R3 and X are as described above.

(II-i-b)

It will be recognised that the cleavage step (ii) to form the dioxanyl ring of compounds of formula (II) will afford a mixture of axial and equatorial acetals. These can be separated using standard separation procedures known to the skilled person, e.g. chromatography. Thus, in a further embodiment of the invention, there is provided a compound of formula (II-ii-a) .

In still another embodiment of the invention, there is provided a compound of formula (II-ii-b) .

It is therefore possible to form four separate stereoisomers of formula (I) illustrated as (I-aa) , (I-ab), (I-bb) and (I-ba) below.

(I-aa) (f-ba)

(I~ab) (I-bb) In particularly preferred forms of (I-aa) , (I-ba), Cr¬ ab) and (I-bb) , A is an optionally substituted phenyl group, or a group of formula (A1) , more preferably formula (A") as described above for (IA1) and (IA") , respectively. In addition to compounds (2A) and (2B) the present invention also provides access to compounds of formulae (2C) and (2D) .

(2C) (2D)

(3A) - (3D) could be synthesised from 32 via Schemes 8 to 12 above.

(3D) <3C) It will also be recognised that replacement of the CO2Me group with the dimethylamino group of rocaglamide at the appropriate stage (see Trost et al supra) will provide the dimethylamino analogues of (2A) -(2D) and (3A) - (3D) ,Compounds (4A) -(4D) and (5A) -(5D) respectively (as hereinbefore illustrated) . It will be recognised that inversion of the stereochemistries of the two vicinal hydroxy groups attached to the cyclopentabenzofuran core will provide a further 16 analogues of (2A) -(2D), (3A) -(3D), (4A) -(4D) and (5A) -(5D) . Methods for the conversion of a carboxylic acid or ester group; i.e. where X is OR8 to an amide (X is NR9R10) are known to the skilled person and may include treatment of a carboxylic acid with an appropriate amine in the presence of a coupling reagent such as DCC or treatment of an acid halide with the appropriate amine. Other methods which may be suitable are described in Larock, R.E, Comprehensive Organic Transformations pp 963-995, VCH Publishers (1989) . One possible synthetic route to form the primary, secondary and tertiary amides derivatives of compounds of formula (IA") is shown in Scheme 19.

Scheme 19

It will be appreciated that the amide derivatives of formula (IA") can be prepared using either the natural or synthetically prepared compounds of formula (2) as starting materials. The compounds of the invention, in particular compounds having a formula (IA1), more particularly (IA"), may be found to possess biological activity, in particular cytostatic and/or cytotoxic activity. Assay methods for determining suitable biological activity are known in the art. Therefore certain compounds described herein may be useful in the treatment of diseases and conditions involving cellular hyperproliferation, or cancer or a cancerous condition. Therefore, the present invention may also provide a method for the treatment of cancer or a cancerous condition or a disease state or condition associated with cellular hyperproliferation comprising the administration of a treatment effective amount of a compound of formula (I) , such as formula (IA1) or (IA") , or a salt or prodrug thereof, to a subject in need thereof, as well as to the use of compounds of the invention in the manufacture of a medicament therefor. Cancerous conditions which may be treated by biologically active compounds of the present invention include conditions wherein the cancers or tumours may be simple (monoclonal, i.e. composed of a single neoplastic cell type), mixed (polyclonal, i.e. composed of more than one neoplastic cell type) or compound (i.e. composed of more than one neoplastic cell type and derived from more than one germ layer) and may include benign and malignant neoplasia/hyperplasia. Some examples of cancerous conditions which may be treated by the present invention include leukemia and breast, colon, bladder, pancreatic, endometrial, head and neck, mesothelioma, myeloma, oesophagal/oral, testicular, thyroid, uterine, prostate, renal, lung, ovarian, cervical brain, skin, liver, bone, bowel and stomach cancers, sarcomas, tumours and melanomas. Examples of benign hyperplasias include those of vascular (e.g. hemangioma), prostate, renal, adrenal, hepatic, colon (e.g. colonic crypt), parathyroid gland and other tissues. As some compounds of the invention may have cytostatic as well as cytotoxic properties, they may also have potential use as therapeutic agents in the suppression of the growth of target populations of cells other than cancer or tumour cells, for example disease states or conditions associated with cellular hyperproliferation. Such conditions may include atherosclerosis and restenosis (neointimal hyperplasia) and hyperproliferation due to or accompanying an inflammatory response, e.g. arthritis, (including rheumatoid arthritis, osteoarthritis and inflammatory arthritis) , psoriasis and periodontal disease, or cellular hyperproliferation due to the viral infection of cells such as human papilloma virus. The compounds of the invention having cytostatic and/or cytotoxic activity, may be used in therapy in conjunction with other therapeutic compounds, such as anti-cancer compounds, including paclitaxel, camptothecin, vinblastin and doxorubicin.

EXAMPLES The invention will now be described with reference to the following Examples which are included for the purpose of illustrating certain embodiments and are not be construed as limiting the generality hereinbefore described.

General Methods Analytical thin layer chromatography (TLC) was conducted on aluminium backed 2 mm thick silica gel 60 GF254. Compounds were visualised with solutions of 20% w/w phosphomolybdic acid in ethanol. Melting points were determined on a Kofler hot stage apparatus and are uncorrected. Optical rotations were recorded in a 10 cm microcell on a Perkin-Elmer 241 MC polarimeter or on a JASCO DIP-1000 digital polarimeter for a 1 mL solution and units for [α] are deg.cm2g~1. Infrared spectra were run as thin films on NaCl plates and recorded using a Perkin Elmer 1600 series FTIR or a Bio-rad FTS 165 FTIR spectrometer. Proton nuclear magnetic resonance (1H NMR, 300 MHz) and proton decoupled carbon nuclear magnetic resonance spectra (13C NMR, 75.5 MHz) were recorded for deuterochloroform solutions on a Varian Unity 300, Varian Inova 500MHz or a Unity Plus 400 instrument with residual chloroform as internal standard, unless otherwise stated. Chemical shifts (α) are reported in parts per million (ppm) and are followed by multiplicity, coupling constants (J) given in Hertz (Hz), integration and assignments. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad or obscured. Flash chromatography was carried out using Merck silica gel 60 according procedure described by Still et al, J. Org. Chem. , 1978, 43, 2923. Anhydrous tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl or sodium metal under a nitrogen atmosphere. Anhydrous diethyl ether (Et2θ) was distilled from sodium benzophenone ketyl and sodium metal under a nitrogen atmosphere. Dry methanol (MeOH) was distilled from magnesium methoxide and stored over 4A molecular sieves. Acetonitrile, benzene, dichloromethane (CH2Cl2) and triethylamine (NEt3) were freshly distilled from calcium hydride under a nitrogen atmosphere. 2λ/VIλ/-dimethylformamide (DMF) was dried by storing over activated 4A molecular sieves (pellets) . Deuterochloroform was dried by passage through a column (6mm x 6cm) of basic AI2O3 (Brockman Activity 1) . All other commercial reagents were used as received. Petrol refers to the fraction boiling between 40 and 6O0C. EtOAc refers to AR ethyl acetate. The following Examples illustrate the formation of two isomers of formula (I) . Some alternative reagents and reaction conditions are indicated for each step and it will be recognised that these will also be applicable in the analogous preparation of other compounds of formula (I), particularly compounds of formula (IA1) and (IA") . Example 1 (a) Starting material preparation - 2f3,4r 6-Tetra-O-a.cetyl- α-D-glucopyranosyl bromide (6) 1>2

C-]4H-IgBrOg MoI.Wt.: 411.2 CAS no.:572-09-8

β-D-glucose pentaacetate (33.0 g, 84.5 mmol, ALDRICH) was reacted under nitrogen with a 30% solution of HBr in acetic acid (70 mL, 351 mmol ) at 00C. After completion of addition, the reaction mixture was warmed to room temperature and stirred for 18 h. TLC (40% EtOAc/Petrol) indicated the disappearance of starting material. The reaction mixture was then poured into ice and extracted three times with CH2CI2. The combined organic extracts were carefully washed with saturated aqueous NaHC03 (3x) , brine (2x) , dried (MgSO4) , filtered and concentrated to give the α- bromide 6 as a white solid (34.7 g, 96%) .

1H NMR (300 MHz) δ 2.04 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.10 (s, 3H, OAc) , 2.10 (s, 3H, OAc), 4.09-4.36 (m, 3H, H5-H6) , 4.84 (dd, J = 3.9 Hz, IH, H2) , 5.16 (t, J = 9.6 Hz, IH, H3), 5.56 (t, J = 9.9 Hz, IH, H4), 6.61 (d, J = 4.2 Hz, IH, Hl) ;

This compound is commercially available from FLUKA (10 g- 70.30, 50 g-224.90) . (b) Benzylidene formation - 4-Methoxybenzyl 4,6-O- benzylidene-β-D-glucopyranose (7) 1/3'4

To a solution of freshly distilled 4-methoxybenzyl alcohol (7.3 inL, 8.1 g, 58.5 mmol) in distilled CH2Cl2, under an argon atmosphere, covered in aluminium foil, was added oven-dried 4A molecular sieves (3.2 g) and silver carbonate (9.1 g, 33.2 mmol) and the resulting solution stirred for 15 mins . A solution of the α-bromide (6) (8 g, 19.5 mmol) in distilled CH2Cl2 was then added at O0C. The mixture was stirred at room temperature for 16 h after which the solution was diluted with CH2Cl2 and filtered through a pad of Celite and concentrated. The crude mixture was purified using silica gel column chromatography eluting with 30-50% EtOAc/Petrol to give the 4-methoxybenzyl 2, 3, 4, 6-Tetra-O- acetyl-β-D-glucopyranoside (8.5 g) which was contaminated with 4-methoxybenzyl alcohol (70:30 mixture favouring the glucopyranoside) . The crude mixture was then dissolved in AR methanol (80 inL) and a solution of sodium methoxide in methanol (25% wt, 1 mL, 4.62 mmol) was then added under an argon atmosphere. The solution was stirred for 2 h at room temperature and then neutralised by the addition of Amberlite resin IR 120 (H+) . The solution was filtered through a pad of Celite "washing the cake well with EtOAc and then concentrated under reduced pressure to afford the 4- Methoxybenzyl-β-D-glucopyranose (5.3 g) . To a solution of 4- methoxybenzyl-β-D-glucopyranose (5.34 g, 17.8 mmol) in distilled acetonitrile (59 mL) was added benzaldehyde dimethylacetal (5.35 mL, 35.6 mmol) then camphorsulfonic acid (207 mg, 0.89 mmol) and the mixture stirred at room temperature for 2O h under an argon atmosphere. Triethylamine (20 mL) was added and the solution stirred for 15 mins. The solvents were removed under reduced pressure and the resulting crude solid was purified using silica gel column chromatography eluting with 50%—»70% EtOAc/petrol to give 4.89 g (65%, over three steps) of 4-Methoxybenzyl 4,6- O-benzylidene-β-D-glucopyranose (7) as a white solid:

1H NMR (300 MHz) δ 2.64 (bs, IH, C2-OH) , 2.83 (bs, IH, C3- OH), 3.42-3.85 (m, 4H, H2, H3, H6) , 3.81 (s, 3H, OMe), 4.37 (dd, J = 4.8 Hz, IH, H4), 4.48 (d, J = 7.8 Hz, IH, H5) , 4.72 (ABq, J = 11.1 Hz, 2H, CH2Ph), 5.54 (s, IH, CH-Ph), 6.89-7.48 (m, 1OH, ArH) .

Alternative solvents : DMF Alternative acetals : p-MeOC6H4CH ( OMe ) 2 , PhCHO, 2 , 4 - (MeO ) 2C6H3CHO Alternative acids : TsOH, CSA, PPTS , ZnCl2

( c ) Partial benzylidene cleavage - 4 -Methoxybenzyl 4-O- benzyl-β-D-glucopyranoside ( 8 ) 5

C2iH26θ7 MoI.Wt:390.4

To 4-Methoxybenzyl 4, 6-0-benzylidene-β-D-glucopyranose (7) (4.05 g, 10.4 mmol) was added a solution of BH3 in THF (1.0 M, 78 mL, 78 mmol) at O0C under an argon atmosphere and the mixture was stirred for 10 min. A solution of Bu2BOTf in CH2Cl2 (1.0 M, 10.4 mL, 10.4 mmol) was then added dropwise and the resulting mixture was stirred at O0C for 20 h. NEt3 (15 mL, 10.9 g, 108 mmol) was added at 00C over 45 min followed by the addition of methanol (300 mL) over 1 h. The solvents were removed under reduced pressure and the mixture co-distilled with MeOH three times (100 rαL) . The crude mixture was purified using silica gel column chromatography eluting with 70% EtOAc/petrol to give the 4-O-benzyl ether (8) (2.65 g, 65%) as a white solid:

mp = 104-1060C [(X]25D -29.3° (c 1.01, CH2Cl2); IR (KBr) 3403, 2985, 2956, 1643, 1612 1461 cm"1; 1H NMR (300 MHz) δ 1.60 (bs, IH, C6-OH) , 2.03 (t, J = 6.8 Hz, 2H, CH2OH), 2.83 (bs, IH, C3-OH) , 2.89 (bs, IH, C2-OH) , 3.31- 3.88 (m, 4H, H2-H5) , 3.77 (s, 3H, OMe), 4.34 (d, J = 8 Hz, IH, Hl) , 4.66 (ABq, J = 11.2 Hz, 2H, CH2Ph), 4.75 (ABq, J = 11.2 Hz, 2H, CH2Ph), 6.87 (d, J = 8.4 Hz, 2H, ArH), 7.24-7.33 (m, 7H, ArH) ; 13C NMR (75.5 MHz) δ 26.4, 55.2, 62.0, 70.6, 71.2, 73.9, 74.6, 75.2, 76.5, 101.4, 113.9, 128.0, 128.1, 128.5, 128.9, 129.8, 138.1, 159.5; HRMS (ESI) : Calcd for C2IH26NaO7+ [M+Na]+ : 413.1576, found 413.1572.

Alternative methods of cleaving the benzylidene moiety : LiAlH4-AlCl3 in THF, Me2NHBH3-BF3 - OEt2 in CH2Cl2 , Me3NBH3-AlCl3 in toluene

(d) Oxidative cleavage - Aldehyde (9)

9 C 21H24°7 MoI. Wt.: 388. A

To a solution of the benzyl ether (8) (1.7 g, 4.35 mmol) in THF (15 mL) was added a solution of sodium periodate (2.98 g, 13.9 mmol) in water (15 mL) dropwise at room temperature. After 10 mins of stirring, the solution changed colour from white to pink and a precipitate had formed. The mixture was stirred for 5 h and was then diluted with CH2CI2. Water was added and the aqueous layer extracted three times with CH2Cl2. The combined organic extracts were washed with water, brine, dried (Na2SO4) , filtered and concentrated to give the aldehyde (9) as a white solid (1.69 g) :

IR (KBr) 3436, 2936, 2874, 1734, 1642, 1614, 1515, 1249cm"1; 1H NMR (400 MHz) δ 3.33-4.10 (m, 14H, H1-H5, C-OH, major and minor), 3.80 (s, 3H, OMe, major), 3.80 (s, 3H, OMe, minor) , 4.42-4.82 (m, 8H, CH2Ph major and minor) , 6.83-7.36 (m, 18H, ArH, major and minor), 9.57 (d, J = 2Hz, IH, CHO, major), 9.64 (d, J = 1.6Hz, IH, CHO, minor) ; 13C NMR (100 MHz) δ 26.4, 55.2, 61.9, 70.5, 71.1, 73.9, 74.6, 75.1, 76.5, 77.0, 101.3, 113.8, 113.8, 127.9, 128.0, 128.0, 128.1, 128.4, 128.5, 128.8, 129.8, 137.4, 138.0, 159.3, 159.4, 200.7, 200.8; HRMS (ESI) : Calcd for C2IH24NaO7+ [M-HSIa]+ : 411.1420, found 411.11422.

Alternative oxidants: Pd(OAc)4

(e) Reduction - Diol (10)

C2-|H26θ7 MoI. Wt.: 390.4

To a solution of the aldehyde (9) (1.57 g, 4.05 mmol) in anhydrous THF (28 mL) was added at 00C under an argon atmosphere, a solution of DIBALH in THF (1.0 M, 7.7 mL, 7.7 mmol) . The resulting solution was stirred at O0C for 16 h, after which an aqueous solution of (+) -sodium tartrate (0.5 M, 150 iriL) and EtOAc (100 raL) were added and further stirred for 4 h until 2 clear layers evolved. Most of the THF was removed under reduced pressure and the mixture diluted with EtOAc and water. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were washed with water, brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 40% EtOAc/petrol which gave the diol (10) as a colourless oil (1.13 g, 76% over two steps) :

IR (thin film) 3430, 2937, 2879, 2874, 1642, 1614, 1515cm"1; 1H NMR (400 MHz) δ 1.72 (bs, IH, C6-OH, minor), 2.04 (bs, IH, C6-OH, major), 2.63 (bs, IH, C2-OH, minor), 3.15 (bs, IH, C2-OH, major), 3.35-3.68 (m, 6H, H5, H6, major and minor), 3.76 (s, 3H, OMe, major), 3.76 (s, 3H, OMe, minor), 3.95 (t, J = 11.2 Hz, 2H, H3ax, major and minor) , 4.02 (d, J = 2.8 Hz, IH, H3eq, major), 4.05 (d, J = 2.8 Hz, IH, H3eq, minor), 4.10 (ddd, J = 10, 7.2, 2.8 Hz IH, H4, minor), 4.27 (ddd, J = 10.8, 7.6, 2.8 Hz IH, H4, major), 4.48 (s, IH, H2, minor), 4.54 (s, IH, H2, major), 4.55 (ABq, J = 11.6 Hz, 4H, CH2Ph, major and minor), 4.61 (ABq, J = 11.6 Hz, 4H, CH2Ph, major and minor) , 4.73 (s, IH, Hl, minor) , 4.79 (s, IH, Hl, major), 6.85-6.82 (m, 4H, ArH, major and minor), 7.23-7.30 (m, 14H, ArH, major and minor); 13C NMR (100 MHz) δ 55.3, 60.2, 60.5, 60.8, 65.8, 65.8, 67.6, 68.5, 69.3, 70.6, 70.8, 72.4, 72.5, 76.7, 77.0, 77.3, 78.5, 78.9, 89.3, 91.2, 93.9, 94.3, 113.8, 113.9, 127.9, 128.1, 128.6, 128.9, 130.0, 130.0, 137.5, 137.6, 159.4; HRMS (ESI) : Calcd for C2IH26NaO7+ [M+Na]+ : 413.1576, found 413.1577.

Alternative acylating agents: acetic anhydride Alternative base: pyridine Alternative method for reduction of aldehyde (9) to alcohol (10) DiBALH or NaBH4 (at low temp. -780C) ( f ) Protection - Silyl ether (11)

C27H40O7Si MoI. WL: 504.7

To a solution of the diol (10) (1.13 g, 2.89 mmol) in DMF (41 mL) , cooled to O0C under an argon atmosphere, was added imidazole (310 mg, 4.55 mmol) and TBSCl (558 mg, 3.90 mmol) and the mixture stirred for 2 h at 00C. Water and Et2O were added and the mixture stirred at 00C for 2 h and at room temperature for 2 h until 2 clear layers evolved. The aqueous layer was extracted three times with ether and the combined organic extracts were washed with water, brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 20% EtOAc/petrol which gave the silyl ether (11) (1.15 g, 79%) as a colourless oil: IR (thin film) 3434 2957, 2934, 1642, 1615, 1515 cm"1; 1H NMR (400 MHz) δ 0.007 (s, 6H, Si (CH3)2C (CH3) 3, major), 0.014 (s, 6H, Si (CE3) 2C(CH3) 3, minor), 0.841 (s, 18H, Si (CH3) 2C(CH3) 3, major and minor) , 2.61 (d, J = 5.6 Hz, 2H, OH, major and minor), 3.25-3.82 (m, 6H, H5, H6, major and minor), 3.73 (s, 6H, OMe, major and minor), 3.96 (t, J = 11.2 Hz, 2H, H3ax, major and minor), 3.98 (d, J = 2.8 Hz, IH, H3eq, major) , 4.01 (d, J = 2.8 Hz,- IH, H3eq, minor), 4.08 (ddd, J = 9.2, 6, 2.4 Hz, IH, H4, minor), 4.23 (ddd, J = 10.8, 6.8, 3.2 Hz, IH, H4, major), 4.49 (s, IH, H2, minor), 4.54 (s, IH, H2, major), 4.53 (ABq, J = 12 Hz, 4H, CH2Ph, major and minor), 4.56 (ABq, J = 11.6 Hz, 4H, CH2Ph, major and minor), 4.73 (s, IH, Hl, minor), 4.75 (s, IH, Hl, major), 6.82-6.79 (m, 4H, ArH, major and minor) , 7.19-7.27 (m, 14H, ArH, major and minor); 13C NMR (100 MHz) δ.-5.5, -5.4, -5.4, 18.2, 18.2, 25.9, 25.9, 55.2, 59.8, 60.4, 62.1, 62.3, 65.6, 65.8, 67.2, 68.2, 68.9, 70.5, 72.7, 72.8, 79.3, 79.7, 89.2, 91.2, 93.8, 94.2, 1137.8, 113.8, 127.6, 127.6, 127.7, 127.8, 128.3, 129.8, 138.2, 138.2, 159.3, 159.4; HRMS (ESI) : Calcd for C27H40NaO7Si+ [M+Na]+ : 527.2441, found 527.2442.

Alternative bases: imidazole, 2, 6-lutidine, pyridine, NEt3, NaH, DBU ( 1, 8-diazobicyclo [5.4.0] undec-7-ene) Alternative solvents: DMF, THF, acetonitrile, dichloromethane Alternative silylchlorides: TESCl (triethylsilylchloride) , TBDPS (tertbutyldiphenylsilylchloride, TMSCl (trimethylsilylchloride) , TBDMSCl ( fcert- butyldimethylsilylchloride, TIPSCl (triisopropylsilylchloride) Alternative protecting groups: benzyl, pivaloyl, as covered by Greene and Wutz {supra) (g) Methylation and Separation - Methyl ketals (12) and (13) :

To a solution of the lactols (11) (282 mg, 0.559 rranol) in distilled THF (6.2 mL) , under an argon atmosphere, at - 780C, was added a solution of n-BuLi in hexanes (2.1 M, 0.480 mL, 1.01 mmol) dropwise followed by the addition of methyl triflate (169 mg, 0.117 mL, 1.03 mmol) . The solution was then stirred at 00C for 17 h and the mixture was diluted with saturated aqueous NaHC03 and ether. The aqueous layer was extracted three times with ether and the combined organic extracts were washed with saturated aqueous NaHCO3, water, brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 5%—>15% EtOAc/petrol to give the methyl ketal (12) (130 mg, 76%, based on recovered starting material) as a colourless oil:

[α]24D-94.7° (c 1.07, CH2Cl2); IR (thin film) 2937, 2858, 1739, 1614, 1587, 1515, 1469, 1245 cm"1; 1H NMR (400 MHz) δ 0.064 (s, 3H, Si (CH3) 2C (CH3) 3) , 0.072 (s, 3H, Si ( CIi3) 2C(CH3) 3) , 0.90 (s, 9H, Si (CH3) 2C ( CH3) 3) , 3.38 (s, 3H, OMe) , 3.40-3.49 (m, 2H, H6) , 3.80 (s, 3H, OMe) , 3.68- 3.91 (m, 3H, H3ax, H3eq, H5) , 4.29 (ddd, J = 10.5, 7.2, 3.3 Hz, IH, H4) , 4.35 (s, IH, H2) , 4.53 (s, IH, Hl) , 4.59 (ABq, J = 11.7 Hz, 2H, CH2Ph) , 4.66 (ABq, J = 11.7 Hz, 2H, CH2Ph) , 6.84-6.86 (m, 2H, ArH) , 7.24-7.32 (m, 7H, ArH) ; 13C NMR (100 MHz) δ.-5.4, -5.4, 18.3, 25.9, 54.8, 55.2, 60.2, 62.1, 65.5, 68.0, 72.7, 79.8, 93.7, 95.7, 113.8, 127.6, 127.9, 128.3, 129.1, 129.9, 138.3, 159.3; HRMS (ESI) : Calcd for C28H42NaO7Si+ [M+Na]+ : 541.2597, found 541.2602.

Further elution gave the equatorial methyl ketal (13) (17 mg, 10%) as a colourless oil:

[α]18D-27.5° (c 2.00, CH2Cl2) ; IR (thin film) 2930, 2856, 1728, 1612, 1514, 1463, 1250cm"1; 1H NMR (400 MHz) δ 0.064 (s, 3H, Si (CE3) 2C (CH3) 3) , 0.071 (s, 3H, Si (CH3) 2C (CH3) 3) , 0.90 (s, 9H, Si (CH3) 2C (CH3) 3) , 3.31 (s, 3H, OMe) , 3.33-3.50 (m, 2H, H6) , 3.80 (s, 3H, OMe) , 3.65- 3.89 (m, 3H, H3ax, H3eq, H5) , 4.27 (ddd, J = 10.5, 6.9, 3.0 Hz, IH, H4) , 4.44 (s, IH, H2) , 4.53 (s, IH, Hl) , 4.58 (ABq, J = 11.7 Hz, 2H, CH2Ph) , 4.67 (ABq, J = 11.4 Hz, 2H, CH2Ph) , 6.85-6.88 (m, 2H, ArH) , 7.25-7.34 (m, 7H, ArH) ; 13C NMR (100 MHz) δ.-5.4, -5.4, 18.3, 25.9, 55.3r 58.5, 60.2, 62.3, 65.7, 67.1, 68.0, 72.4, 72.8, 80.0, 94.0, 94.6, 113.8, 127.6, 127.9, 128.3, 129.2, 129.9, 138.4, 159.3; HRMS (ESI) : Calcd for C28H42NaO7Si+ [M+Na]+ : 541.2597, found 541.2591.

Alternative bases: n-BuLi, KH, potassium tert-butoxide Alternative methylating agents: MeOTf (methyl triflate) , dimethylsulfate Alternative solvents: THF, acetonitrile, toluene, benzene, dioxane (h) Deprotection of PMB ether - Lactols (14)

14 C2θH34θ6Si MoI.Wt: 398.8

To a solution of the PMB ether (12) (175 mg, 0.337 mmol) in CH2Cl2 (4.2 mL) and water (0.240 inL) was added 2,3- Dichloro-5, 6-dicyano-l, 4-benzoquinone (153 mg, 0.674 mmol) at O0C and the reaction mixture was then warmed to room temperature and stirred for 17 h. CH2Cl2 was added to the reaction mixture and filtered through a pad of Celite. The solution was then concentrated and the crude residue was purified using silica gel column chromatography eluting with 15% EtOAc/petrol to give (14) (77 mg, 57%) as a colourless oil. IR (thin film) 3423, 2929, 2856, 1641, 1462, 1257cm"1; 1H NMR (400 MHz) δ -0.004 (s, 12H, Si (CH3) 2C (CH3) 3, major and minor) 0.84 (s, 18H, Si (CH3) 2C (CH3) 3, major and minor) , 3.14 (d, J = 6 Hz, 2H, OH, major and minor), 3.35 (s, 3H, OMe, major), 3.40 (s, 3H, OMe, minor), 3.39-3.48 (m, 4H, H6, major and minor), 3.56-3.83 (m, 6H, H3ax, H3eq, H5, major and minor) , 3.89 (ddd, J = 10, 6.8, 3.6 Hz, IH, H4, minor) , 4.26 (ddd, J = 9.6, 6.4, 3.2 Hz, IH, H4, major), 4.31 (s, IH, H2, major), 4.33 (d, J = 2 Hz, IH, H2, minor), 4.68 (d, J = 2 Hz, IH, Hl, minor), 4.61 (ABq, J = 11.6 Hz, 4H, CH2Ph, major and minor), 4.82 (d, J = 5.2 Hz, IH, Hl, major), 7.20- 7.27 (m, 1OH, ArH, major and minor); 13C NMR (100 MHz) 5.-5.5, -5.5, -5.4, 18.2, 25.9, 54.8, 55.3, 59.6, 59.9, 62.2, 62.6, 65.7, 72.8, 72.9, 73.7, 79.4, 79.7, 90.1, 91.6, 95.6, 96.0, 127.6, 127.9, 127.9, 128.3, 138.3; (i) Coupling to phenol and separation of isomers - Coupled products (16) and (17)

16 C34H46 O8Si 17 MoI. Wt.: 610.8

To a mixture of the lactols (14) (24.5 mg, 0.0615 mmol) in toluene (0.6 mL) under an argon atmosphere, was added the phenol (15) (17 mg, 0.0738 mmol), triphenylphosphine (22.6 mg, 0.0861 mmol) and oven-dried 4A molecular sieves (20 mg) and the resulting solution was stirred for 20 mins at room temperature. The mixture was cooled to 00C and diisopropylazodicarboxylate (19 μL, 0.0984 mmol) was added. The solution was stirred at 00C under an argon atmosphere for 2 h. The solvent was removed under reduced pressure and the crude residue was purified by silica gel column chromatography eluting with 5% EtOAc/Petrol gave (16) (16.5 mg, 43%) :

[Ct]24D -84.2° (c 1.57, CH2Cl2) ; IR (thin film) 2927, 2854, 1736, 1601, 1454, 1136 cm"1; 1H NMR (400 MHz) δ -0.107 (s, 3H, Si (CH3) 2C (CH3) 3) , -0.065 (s, 3H, Si (CH3) 2C(CH3) 3) , 0.77 (s, 9H, Si (CH3) 2C (CH3) 3) , 3.41 (s, 3H, OMe) , 3.51-3.80 (m, 4H, H3eq, H5, H6) , 3.74 (s, 3H, OMe) , 3.89 (t, J = 11.2 Hz, IH, H3ax) , 4.24 (ddd, J = 10.4, 6.8, 2.8 Hz, IH, H4) , 4.56 (s, IH, H2) , 4.66 (ABq, J = 11.6 Hz, 2H, CH2Ph) , 4.93 (s, 2H, CH2Ph, C5' ) , 5.23 (s, IH, Hl) , 6.18-6.25 (m, 3H, H2' , H4; H6' 7.20-7.36 (m, 1OH, ArH) ; 13 C NMR (100 MHz) δ.-5.6, 18.1, 25.8, 54.9, 55.3, 60.0, 62.8, 66.6, 70.0, 72.8, 79.7, 93.6, 95.3, 95.3, 95.5, 95.7, 127.5, 127.8, 128.0, 128.3, 128.5, 136.7, 138.4, 158.0, 160.5, 161.3; Further elution gave the equatorial coupling product (17) (3.2 mg, 8.5%) as a colourless oil:

[Ci]24D +6.3° (c 0.79, CH2Cl2) ; IR (thin film) 3422, 2928, 2854, 1726, 1601, 1466, 1263, 1140 cm"1; 1H NMR (400 MHz) δ -0.056 (s, 6H, Si [CH3) 2C (CH3) 3) , 0.81 (s, 9H, Si (CH3) 2C(CHs)3) , 3.47 (s, 3H, OMe), 3.54-3.83 (m, 5H, H3, H5, H6), 3.67 (s, 3H, OMe), 3.96 (ddd, J = 10.4, 7.6, 3.2 Hz, IH, H4), 4.54 (s, IH, H2) , 4.61 (ABq, J = 11.2 Hz, 2H, CH2Ph) , 4.93 (s, 2H, CH2Ph, C5' ) , 5.08 (d, J = 2 Hz , IH, Hl) , 6.18-6.25 (m, 3H, H2' , H4' , H6' ) , 7.20-7.36 (m, 1OH, ArH) ; 13C NMR (100 MHz) δ.-5.6, -5.5, 18.2, 25.9, 29.7, 55.3, 55.4, 60.0, 62.4, 70.1, 72.8, 73.6, 79.1, 95.1, 95.6, 96.0, 96.1, 96.4, 127.6, 127.6, 128.0, 128.0, 128.3, 128.5, 136.7, 138.3, 158.6, 160.4, 161.3; Alternative reagents: General Mitsunobu conditions are applicable

Example 2 (a) Starting material preparation - Alcohol (18)

C22H23O7 MoI.Wt.:404.5

To a solution of the silyl ether (12) (270 mg, 0.521 mmol) in THF (3 mL) was added TBAF (408 mg, 1.56 mmol) at 00C under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred for 1.5 h. Et2O and water were added to the mixture and the organic extract was washed with water, brine, dried (Na2SO^ , filtered and concentrated. Purification of the crude residue using silica gel column chromatography eluting with 40% EtOAc/petrol gave (18) (190 mg, 90%) as a colourless oil:

[α]17D-H3.4° (c 1.09, CH2Cl2); IR (thin film) 3476, 2931, 2875, 1735, 1613, 1587, 1515, 1455, 1249 cm"1; 1H NMR (400 MHz) δ 2.06 (bs, IH, OH), 3.37 (s, 3H, OMe) , 3.40-3.46 (m, 2H, H6) , 3.67-3.84 (m, 3H, H3ax, H3eq, H5) , 3.77 (s, 3H, OMe), 4.30 (ddd, J = 10.4, 7.6, 2.8 Hz, IH, H4), 4.36 (s, IH, H2) , 4.55 (s, IH, Hl), 4.56 (ABq, J = 11.6 Hz, 2H, CH2Ph), 4.63 (ABq, J = 11.2 Hz, 2H, CH2Ph), 6.84-6.86 (m, 2H, ArH), 7.24-7.36 (m, 7H, ArH); 13C NMR (100 MHz) δ.54.8, 55.2, 60.4, 60.4, 65.6, 68.3, 72.3, 78.9, 93.9, 95.7, 113.8, 127.9, 128.0, 128.5, 129.0, 130.0, 137.6, 159.3; HRMS (ESI) : Calcd for C22H28NaO7 [M+Na]+ : 427.1733, found 427.1733. Alternative reagents: Dilute HCl, THF/H2O

(b) Hydrogenolysis - Diol (19)

C15H22O7 MoI.Wt.:314.3

To a solution of the benzyl ether (18) (19.3 mg, 0.0477 mmol) in MeOH (2 mL) was added Pd(OH)2 (7 mg) and the resulting mixture was stirred under a hydrogen atmosphere for 1.5 h. The mixture was filtered through a pad of Celite and the pad washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50%-»70% EtOAc/petrol to give the diol (19) (13.5 mg, 90%) as a colourless oil:

[(X]20D -159.3° (c 0.68, CH2Cl2); W

- 69 -

IR (thin film) 3419, 2928, 2838, 1615, 1516, 1450 cm"1; 1H NMR (400 MHz) δ 2.04 (brs, IH, C6-OH) , 2.57 (brs, IH, C5- OH), 3.39 (s, 3H, OMe), 3.64-3.77 (m, 3H, H5, H6) , 3.80 (s, 3H, OMe), 3.90 (t, J = 11.2 Hz, IH, H3ax) , 4.11 (ddd, J = 10.4, 6, 2.8 Hz, IH, H4), 4.36 (s, IH, H2), 4.57 (ABq, J = 11.6 Hz, 2H, CH2Ph), 4.56 (s, IH, Hl), 6.86-7.29 (m, 5H, ArH) ; 13C NMR (100 MHz) δ -54.9, 55.3, 59.6, 63.0, 67.1, 68.7, 71.7, 94.2, 95.7, 113.9, 129.0, 129.9, 159.4; HRMS (ESI) : Calcd for Ci5H22NaO7 [M+Na]+ : 337.1263, found 337.1261. Alternative reagents: Palladium-based hydrogenation catalysts e.g. Pd(OH)4

(c) Mitsunobu inversion - Diol (21)

G15H22O7 MoI.Wt.: 314.3

To a solution of the diol (19) (13.5 mg, 0.0429 mmol) in distilled toluene (1.7 mL) was added at 00C, triphenylphosphine (113 mg, 0.429 mmol), 4-nitrobenzoic acid (63.2 mg, 0.378 mmol), diisopropylazodicarboxylate (84 μL, 0.429 mmol) and the mixture stirred at room temperature for 3 d. The volatiles were concentrated and the crude residue was purified using silica gel column chromatography eluting with 20% EtOAc/petrol to give the bis p-nitrobenzoate esters (20) which was dissolved in MeOH (1 mL) and at room temperature under an argon atmosphere, was added potassium carbonate (5.4 mg, 0.0392 mmol) . The resulting mixture was stirred for 30 mins . The solution was then concentrated and CH2Cl2 and brine were added to the residue. The organic extract was washed with brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 60% EtOAc/petrol to give the diol (21) (9.5 mg, 70% over two steps) as a colourless oil:

[Ot]19D -111.6° (c 0.48, CH2Cl2); IR (thin film) 3445, 3056, 2987, 2931, 2856, 2928, 2838, 1614, 1515, 1266 cm"1; 1H NMR (400 MHz) δ 2.11 (brs, IH, C6-OH) , 2.60 (brs, IH, C5- ' OH) , 3.40 (s, 3H, OMe) , 3.47 (dd, J = 11.2, 2.8 Hz, IH, H3eq) , 3.60-3.66 (m, 3H, H5, H6) , 3.81 (s, 3H, OMe) , 4.02 (t, J = 11.2 Hz, IH, H3ax) , 4.19 (dt, J = 11.2, 3.6 Hz, IH, H4) , 4.38 (s, IH, H2) , 4.57 (ABq, J = 11.6 Hz, 2H, CH2Ph) , 4.62 (s, IH, Hl) , 6.87-7.29 (m, 5H, ArH) ; 13C NMR (100 MHz) δ 54.9, 55.3, 59.0, 63.7, 67.7, 68.9, 70.7, 94.4, 95.6, 113.9, 128.9, 129.8, 159.5; HRMS (ESI) : Calcd for Ci5H22NaO7 [M+Na]+ : 337.1263, found 337.1260. Alternative reagents: General Mitsunobu conditions are applicable

(d) Protection Step - Bis TBS ether (22)

22 C27H50O7Si2 MoI. Wt: 542.9

To a solution of the diol (21) (39.4 mg, 0.0919 mmol) in CH2Cl2 (4 mL) , cooled to 0°C under an argon atmosphere, was added 2, 6-lutidine (64.2 μL, 0.552 mmol) and TBSOTf (84.4 μL, 0.368 mmol) and the mixture stirred for 22 h at room temperature. Saturated aqueous NaHCO3 and Et2O were added and the mixture stirred at room temperature for 30 mins until 2 clear layers evolved. The aqueous layer was extracted three times with ether and the combined organic extracts were washed with saturated aqueous NaHCO3, water, saturated aqueous CuSO4, water, brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 5-10% EtOAc/petrol which gave the silyl ether (22) (43.1 mg, 86%) as a colourless oil:

[α]21D-86.2° (c 0.5, CH2Cl2); IR (thin film) 3421, 3055, 2932, 2856, 1639, 1514, 1265 cm"1; 1H NMR (400 MHz) δ 0.05 (s, 6H, Si [CH3) 2C (CH3) 3) , 0.079 (s, 3H, Si (CH3) 2C(CH3) 3) , 0.099 (s, 3H, Si (CH3) 2C (CH3) 3) , 0.88 (s, 9H, Si (CH3) 2C(CH3) 3) , 0.90 (s, 9H, Si (CH3) 2C (CH3) 3) , 3.37 (s, 3H, OMe) , 3.50-3.76 (m, 4H, H3eq, H5, H6) , 3.79 (s, 3H, OMe), 3.92 (t, J = 11.2 Hz, IH, H3ax) , 4.29 (ddd, J = 7.6, 4.8, 2.8 Hz, IH, H4), 4.34 (s, IH, H2), 4.59 (s, IH, Hl) , 4.59 (ABq, J = 11.6 Hz, 2H, CH2Ph), 6.84-7.28 (m, 4H, ArH) ; 13C NMR (100 MHz) δ -5.4, -5.4, -4.8, -4.4, 18.1, 18.3, 25.8, 25.9, 54.6, 55.2 59.4, 63.9, 67.9, 68.2, 73.2, 94.0, 95.8, 113.8, 129.4, 129.9, 159.3; HRMS (ESI) : Calcd for C27H50NaO7Si2+ [M+Na]+ : 565.2993, found 565.2984. Alternative protecting groups: acetates, benzyl groups, benzoates (e) Deprotection - Lactols (23)

C10H42O6Si2 MoI. Wt.: 422.7

To a solution of the PMB ether (22) (43.1 mg, 0.0794 mmol) in CH2Cl2 (2.2 mL) and water (0.129 inL) was added 2,3- Dichloro-5, 6-dicyano-l, 4-benzoquinone (27 mg, 0.119 mmol) at 00C and the reaction mixture was then warmed to room temperature and stirred for 18 h. CH2Cl2 was added to the reaction mixture and filtered through a pad of Celite. The solution was then concentrated and the crude residue was purified using silica gel column chromatography eluting with 5-10% EtOAc/petrol to give (23) (8.6 mg, 26%) as a colourless oil:

1H NMR (400 MHz) δ 0.050 (s, 6H, Si (CiT3) 2C (CH3) 3, major and minor) , 0.054 (s, 6H, Si [CH3) 2C (CH3) 3, major and minor) , 0.073 (s, 6H, Si (CH3) 2C (CH3)3, major and minor) , 0.079 (s, 6H, Si [CH3) 2C (CH3) 3, major and minor) , 0.89 (s, 36H, Si (CH3) 2C(Ciϊ3)3, major and minor) , 2.73 (d, J = 5.6 Hz, 2H, OH, major and minor) , 3.41 (s, 3H, OMe, major) , 3.46 (s, 3H, OMe, minor) , 3.44-3.98 (m, 1OH, H3, H5, H6, major and minor) , 4.26 (ddd, J = 11.2, 7.2, 3.2 Hz, 2H, H4, major and minor) , 4.37 (s, IH, H2, major) , 4.38 (d, J = 2 Hz, IH, H2, minor) , 4.72 (dd, J = 12.8, 2 Hz, IH, Hl, minor) , 4.92 (d, J = 5.2 Hz, IH, Hl, major) ; 13C NMR (100 MHz) δ.-5.4, -4.8, -4.3, 18.3, 25.8, 25.9, 29.7, 54.7, 55.2,- 59.2, 63.7, 67.7, 73.0, 73.1, 90.4, 95.8, 96.1. (f) Coupling to phenol and separation of isomers - Coupling products (24) and (25)

To a mixture of the lactols (8.6 mg, 0.0203 mrαol) in toluene under an argon atmosphere, was added the phenol (15) (28.1 mg, 0.122 mmol) , triphenylphosphine (37.2 mg, 0.142 itunol) and oven-dried 4A molecular sieves (50 mg) and the resulting solution was stirred for 20 mins at room temperature. The mixture was cooled to 0°C and diisopropylazodicarboxylate (32 μL, 0.162 mmol) was added. The solution was stirred at O0C under an argon atmosphere for 2 h. The solvent was removed under reduced pressure and the crude residue was purified by silica gel column chromatography eluting with 5% EtOAc/Petrol gave (24) (4.7 mg, 41%) :

1H NMR (400 MHz) δ -0.064 (s, 3H, Si (CH3) 2C (CH3) 3) , -0.024 (s, 3H, Si (CH3)2C (CH3) 3) , 0.021 (s, 3H, Si (CH3) 2C (CH3) 3) , 0.042 (s, 3H, Si (CH3J2C (CH3) 3) , 0.80 (s, 9H, Si (CH3) 2C (CH3) 3) , 0.86 (s, 9H, Si (CH3) 2C (CH3) 3) , 3.45 (s, 3H, OMe), 3.48-3.76 (m, 4H, H3eq, H5, H6) , 3.73 (s, 3H, OMe), 4.06 (t, J = 11.2, IH, H3ax) , 4.11-4.31 (m, IH, H4), 4.54 (s, IH, H2) , 4.98 (s, 2H, CH2Ph), 5.28 (s, IH, Hl), 6.18-6.35 (m, 3H, ArH), 7.31-7.43 (m, 5H, ArH) ;

Further elution gave the equatorial isomer (25) (2.9 mg, 21%) :

1H NMR (400 MHz) δ -0.007 (s, 3H, Si (CH3) 2C (CH3) 3) , 0.027 (s, 6H, Si (CH3)2C(CH3) 3), 0.032 (s, 3H, Si (CH3) 2C (CH3) 3) , 0.85 (s, 9H, Si (CH3) 2C(CH3) 3) , 0.87 (s, 9H, Si (CH3) 2C (Cu3) 3) , 3.41-4.O0' (m, 6H, H3-H6) , 3.52 (s, 3H, OMe) , 3.73 (s, 3H, OMe) , 4.57 (d, J = 2 Hz, IH, H2) , 4.99 (s, 2H, CH2Ph) , 5.17 (d, J = 2 Hz, IH, Hl) , 6.22-6.32 (m, 3H, ArH) , 7.31-7.43 (m, 5H, ArH) ;

Further elution gave the starting lactols (23) (2.0 mg, 38%) Alternative reagents: General Mitsunobu conditions are applicable

References for Examples 1 and 2 :

1. Bazin, H. G.; Wolff, M. W.; Linhardt, R. J. J. Org. Chem. 1999, 64, '144.

2. Mitchell, S. A.; Pratt, M. R.; Hruby, V. J.; PoIt, R. J. Org. Chem. 2001, 66, 2327.

3. Kaji, E.; Lichtenthaler, F., W; Osa, Y.; Takahashi, K.; Matsui, E.; Zen, S. Chem. Lett. 1992, 707.

4. Kaji, E.; Lichtenthaler, F., W; Osa, Y.; Takahashi, K.; Zen, S. Bull. Chem. Soc. Jpn. 1995, 68, 2401.

5. Jiang, L.; Chan, T. -H. Tetrahedron Lett. 1998, 39, 355. Example 3 (a) Preparation of starting material - Methyl (4- methoxyphenyl) acetate (26)x

26 Ci0H-I2O3 MoI. Wt: 180.20

A solution of (4-methoxyphenyl) acetic acid (10 g, 0.06 mol) in 5% methanolic HCl2 was heated at reflux for 2hrs. After cooling to room temperature water was added and extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaHCO3 solution, dried (MgSO4) , filtered, and concentrated in vacuo to afford (26) as pale yellow oil (10.34 g, 95%) .

1H NMR (400 MHz) δ 3.57 (s, 2H), 3.68 (s, 3H), 3.79 (s, 3H) , 6.86 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H) . 13C NMR (100MHz) δ 40.19, 51.92, 55.16, 113.92, 125.97, 130.21, 158.62, 172.30.

IR (thin film) cm-"11 821, 1249, 1439, 1514, 1612, 1737, 2955 (b) Bromination - Methyl α-bromo (4-methoxyphenyl) acetate (27)3

27 C"ioHi iBrC>3 MoI. Wt: 259.10

To a solution of methyl (4-methoxyphenyl) acetate (26) (10.34 g, 0.057 mol) in CCl4 (190 inL) under a nitrogen atmosphere was added NBS (14.35 g, 0.08 mol) and was heated at reflux under UV light for 30 min. After cooling to room temperature petroleum spirits was added and stirred for 30 min before being filtered and concentrated in vacuo to afford the crude product. Flash chromatography over silica gel and elution with 10% EtOAc-petroleum spirits gave (27) as pale yellow oil (12.44 g, 83%) .

1H NMR (400 MHz) δ 3.78 (s, 3H), 3.81 (s, 3H) , 5.35 (s, IH) , 6.88 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H) . 13C NMR (100MHz) δ 46.43. 53.29. 55.34. 114.23. 127.65 130.07. 16.29. 168.91.

IR (thin film) cm"1 743, 832, 1255, 1437, 1513, 1608, .1749, 2955. (c) Phenol alkylation - (3-Benzyloxy-5-methoxy-phenoxy) - (4- methoxy-phenyl) -acetic acid methyl ester (28)4

C24H24O6 MoI. Wt.:408.44

To a solution of methyl α-bromo (4-methoxyphenyl) acetate (27) (5.35 g, 0.02 mol) in 2-butanone (40 mL) under an argon atmosphere was added K2CO3 (5.70 g, 0.04 mol) followed by 3-benzyloxy-5-methoxy phenol (5.67 g, 0.024 mol) in 2-butanone (63 mL) and heated at reflux for 2 hours. After cooling to room temperature water was added and stirred until two clear layers formed before being extracted with Et2O. The combined organic extracts were washed with water, dried (MgSO4) , filtered, and concentrated in vacuo to afford the crude product. Then Et2O was added and the organic layer was washed with IM NaOH followed by water, dried (MgSO4) , filtered, and concentrated in vacuo to afford (28) as thick yellow oil (6.7 g, 79%) .

1H NMR (400 MHz) 6 3.73 (s, 3H), 3.74 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 5.54 (s, IH), 6.14 (t, J = 2 Hz, IH), 6.18 (t, J = 2 Hz, IH), 6.20 (t, J = 2 Hz, IH), 6.91 (d, J = 8.8 Hz, 2H), 7.32-7.42 (m, 5H), 7.46 (d, J = 8.8 Hz, 2H) . 13C NMR (100MHz) δ 52.57, 55.93, 55.33, 70.09, 78.08, 94.60, 94.87, 94.91, 114.22, 127.30, 127.57, 128.00, 128.50, 128.56, 136.69, 159.08, 160.14, 160.63, 161.42, 170.45. IR (thin film) cm"1 820, 1250, 1471, 1513, 1615, 1755, 2955. HRMS (ESI) : Calcd for C24H24NaO6+ [M+Na]+ : 431.1471, found 431.1465. (d) Hydrolysis - (3-Benzyloxy-5-methoxy-phenoxy) - (4- raethoxy-phenyl) -acetic acid (29) 4

C23H22O6 MoI. Wt.: 394.42

To a solution of (28) (6.69 g, 0.016 mol) in MeOH (167 mL) and water (15 mL) was added K2CO3 (2.71 g, 0.019 mol) and heated at reflux for 1 hour. The MeOH was removed in vacuo before water was added and washed with Et2O. Then EtOAc was added to the aqueous layer before it was acidified with concentrated HCl until the pH = 1. Then the product was extracted into EtOAc washed with water, dried (MgSθ4) , filtered, and concentrated in vacuo to afford (29) as a tan gum (5.66 g, 89%) .

1H NMR (400 MHz) δ 3.72 (3H, s), 3.80 (3H, s), 4.97 (2H, s), 5.54 (IH, s), 6.14 (IH, t J = 2 Hz), 6.18 (IH, t J = 2 Hz) , 6.19 (IH, t J = 2 Hz), 6.91 (2H, d J = 8.7 Hz), 7.32-7.42 (5H, m) , 7.46 (2H, d J = 8.7 Hz) . 13C NMR (100MHz) δ 55.30, 55.34, 70.10, 77.64, 94.66, 94.99, 95.07, 114.31, 126.68, 127.55, 128.03, 128.49, 128.57, 136.59, 159.66, 160.26, 160.62, 161.43, 173.92.

IR (thin film) cm"1 824, 1154, 1251, 1472, 1513, 1600, 1728, 2840, 2937. HRMS (ESI) : Calcd for C23H22NaO6+ [M+Na]+ : 417.1314, found 417.1308.

(e) Cyclisation - Trifluoro-acetic acid 6~benzyloxy-4- methoxy-2- (4-methoxy-phenyl) -benzofuran-3-yl ester (3O)5

30 C25H19F3O6 MoI. Wt: 472.41

(f) Hydrolysis - Trifluoro-acetic acid 4-benzyloxy-6- methoxy-2- (4-methoxy-phenyl) -benzofuran-3-yl ester (31)

31 C25Hi9F3θ6 MoI.Wt:472.41

To a flask charged with (29) (630 mg, 1.6 mmol) under an argon atmosphere was added trifluoroacetic anhydride (2 mL) and heated at reflux for 30 min. Once cooled (00C) Et2O was added followed by the careful addition of saturated aqueous NaHCθ3 until basic and the product was then extracted into Et2O. The combined organic extracts were washed with saturated aqueous NaHCθ3, dried (MgSO4) , filtered and concentrated in vacuo to give a mixture of (30) and (31) as a yellow foam (659 mg, 87%) .

1H NMR (400 MHz) δ 3.82 (3H, s) , 3.83 (3H, s) , 3.84 (3H, s) , 3.85 (3H, s), 5.06 (2H, s) , 5.09 (2H, s) , 6.38 (IH, ά J = 2 Hz), 6.41 IH, d J = 2 Hz), 6.64 (IH, d J = 2 Hz), 6.70 (IH, d J = 2 Hz, ,, V(-2CIHl/, <dΛ LJJ —= -9J UHώzI) f, 6.98 (2H, d J = 9 Hz), 7.34-7.48 (1OH, m) , 7.68 (4H, d J = 9 Hz 13C NMR (100MHz) δ 55.34, 55.65, 55.82, 70.64, 70.67, 88.76, 89.78, 95.82, 96.20, 106.72, 106.78, 114.40, 121.12, 126.28, 127.56, 127.98, 128.17, 128.24, 128.56, 128.67, 132.57, 135.74, 136.47, 141.69, 141.80, 151.86, 152.78, 153.45, 153.72, 158.90, 159.66, 159.68, 159.73. 19F NMR (376 MHz) δ -75.91, -75.92. (solvent = d6-benzene, referenced to CFCl3 = O.OOppm.) IR (thin film) cm'1 737, 823, 1256, 1424, 1512, 1607, 1677, 1738, 2941.

(g) Hydrolysis - 6-Benzyloxy-4-methoxy-2- (4-methoxy- phenyl) -benzofuran-3-one (32) 4-Benzyloxy-6-methoxy-2- (4-methoxy-phenyl) -benzofuran-3-one (33) To a chilled (00C) 1:1 solution of (30) and (31) (56 mg, 0.12 mmol) in MeOH (1 mL) under an argon atmosphere was added K2CO3 (20 mg) and stirred for 20 min. Then Et2O and water were added and stirred until two clear layers formed followed by extraction with Et2O. MeOH was removed in vacuo before water was added and washed with EtaO. The combined organic extracts were washed with water, dried (MgSO4) , filtered and concentrated in vacuo to afford the crude product. Flash chromatography over silica gel and elution with 10%-20% EtOAc-petroleum spirits gave (32) and (33) as pale yellow solids (15.5 mg, 34%) and (9 mg, 20%) , respectively.

C23H20O5 MoI. Wt.: 376.40

(32)

1H NMR (400 MHz) δ 3.79 (3H, s) , 3.89 (3H, s) , 5.12 (2H, s) , 5.43 (IH, s) , 6.12 (IH, d J = 2 Hz) , 6.29 (IH, d J = 2 Hz) , 6.88 (2H, d J - 8.6 Hz) , 7.29 (2H, d J = 8.6 Hz) , 7.37-7.44 (5H, m) . 13C NMR (100MHz) δ 55.23, 55.99, 70.74, 86.62, 89.64, 93.68, 104.00, 114.10, 126.57, 127.61, 128.01, 128.45, 128.72, 135.41, 159.31, 159.93, 160.99, 175.79, 194.84. IR (KBr) cm"1 818, 1156, 1251, 1465, 1513, 1618, 1702, 2933. HRMS (ESI) : Calcd for C23H20NaO5+ [M+Na]+ : 399.1208, found 399.1208.

C23H20O5 MoI. Wt.: 376.40

(33)

1H NMR (400 MHz) δ 3.80 (3H, s) , 3.85 (3H, s), 5.21 (2H, s), 5.44 (IH, s) , 6.07 (IH, d J = 2 Hz), 6.23 (IH, d J = 2 Hz) , 6.89 (2H, d J = 8.8 Hz), 7.32 (2H, d J = 8.8 Hz), 7.34-7.40 (5H, m) .

13C NMR (100MHz) δ 55.25, 55.93, 70.30, 86.58, 89.04, 94.73, 104.09, 114.11, 126.62, 126.67, 127.70, 127.84, 128.54, 135.88, 158.22, 159. 169.74, 175.80, 194.48 IR (KBr) cm-"11 821, 1161, 1255, 1446, 1515, 1617, 1702, 2995 MPt 129- 131 0C HRMS (ESI ) : Calcd for C23H20NaO5+ [M+Na ] + : 399 . 1208 , found 399 . 1207 .

References for Example 3: [1] Mohan, R.; Katzenellenbogen, J. A. J. Org. Chem. 1984, 49, 1238.

[2] Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis. ; Wiley: New York, 1967; Vol. 1, p688.

[3] Sweeney, J. B.; Tavassoli, A.; Carter, N. B.; Hayes, J. F. Tetrahedron 2002, 58, 10113.

[4] Hall, R. G.; Szczepanski, H.; Bruce, I.; Cooke, N. G. ; Diorazio, L. J.; Dobler, M.; Cederbaum, F. Patent number: DE 99-19934952 Germany, 2000.

[5] Ferrier, R. J.; Tedder, J. M. J. Chem. Soc. 1957, 1435.

Example 4 Hydrolysis of C-5 alcohol: Synthesis of 2A from 2B (a) bis-p-nitrobenzoate ester (38) x

38

To a solution of the 2B (14.7 mg, 0.0225 mmol) in toluene (1 mL) was added at O0C under an argon atmosphere, triphenylphosphine (88.4 mg, 0.337 mmol), 4-nitrobenzoic acid (49.5 mg, 0.296 irimol) , diethylazodicarboxylate (66 μL, 68.1 mg, 0.337 mmol) and the mixture stirred at rt for 13 h. The volatiles were concentrated and the crude residue was purified using silica gel column chromatography eluting with 40% → 60% EtOAc/petrol to give (38) (16.8 mg, 79%) as a gummy white solid.

[(X]20D -41.4° (c 1.34, CH2Cl2) IR (thin film) 1131, 1262, 1529, 1633, 1654, 2096 cm"1 1H NMR (400 MHz) δ 3.47 (3H, s) , 3.65 (3H, s), 3.71 (3H, s), 3.85 (3H, s), 4.01-4.15 (3H, m) , 4.52-4.68 (4H, m) , 5.02 (IH, dd, J = 2.0, 9.2 Hz), 5.38 (IH, s) , 5.61 (IH, dt J = 3.8, 8.5 Hz), 6.25 (IH, d J = 2.4 Hz), 6.46 (2H, d J = 2.4 Hz), 6.66 (2H, d J = 12 Hz), 6.77 (2H, d J = 4.8 Hz), 6.79 (2H, d J = 3.2 Hz) , 7.02-7.06 (5H, m) , 7.94 (2H, d J = 12.2 Hz), 8.11 (2H, d J = 12.2 Hz), 8.28 (4H, ABq J = 2.3, 11.8 Hz) . 13C NMR (100 MHz) δ.29.68, 50.11, 51.96, 54.83, 55.08, 55.28, 55.84, 58.60, 60.39, 62.37, 66.34, 70.56, 77.20, 79.63, 92.70, 93.36, 93.42, 95.41, 101.86, 110.01, 112.69, 123.60, 123.78, 125.95, 126.61, 127.66, 127.74, 128.92, 130.61, 131.05, 134.08, 134.24, 136.57, 150.52, 150.92, 156.91, 158.77, 159.94, 160.52, 163.98, 164.05, 170.23. HRMS (ESI) : Calcd for C48H44N2NaOi9+ [M + Na]+ 975.2436, found 975.2429. (b) 2A

2A

To a solution of the bis-ester (38) (12.9 mg, 0.0135 mmol) in dry MeOH (1 mL) was added at rt under an argon atmosphere 3 drops of a 25wt% solution of NaOMe in MeOH, and the mixture was stirred for 15 min. The mixture was neutralised by the addition of Amberlite until the pH was 7. After filtering the volatiles were concentrated and the crude residue was purified using silica gel column chromatography eluting with CHCl3/Me0H (6:1) to give the 2A (8.9 mg, 100%) as a gummy white solid.

Physical data was characteristic of authentic 2A.

Example 5 Inversion of the C-5 alcohol : Synthesis of 2B from 2A (a) bis p-nitrobenzoate ester (39) 1

39 To a solution of the 2A (19.5 mg, 0.0298 mmol) in toluene (1.3 mL) was added at 00C under an argon atmosphere, triphenylphosphine (117 mg, 0.447 mmol), 4-nitrobenzoic acid (65.7 mg, 0.393 mmol), diethylazodicarboxylate (88 μL, 90.4 mg, 0.447 mmol) and the mixture stirred at rt for 6 days. The volatiles were concentrated and the crude residue was purified using silica gel column chromatography eluting with 30%->60% EtOAc/petrol to give (39) (22.6 mg, 80%) as a gummy white solid.

1H NMR (400 MHz) δ 3.51 (3H, s), 3.63 (3H, s), 3.73 (3H, s), 3.88 (3H, s), 4.63-4.76 (4H, m) , 4.99 (IH, d, J = 9.2 Hz) , 5.30 (IH, d, J = 8.8 Hz), 5.44 (IH, m) , 6.24 (IH, d J = 2.0 Hz), 6.42 (2H, d J = 2.0 Hz), 6.66 (2H, d J = 11.2 Hz), 6.74 (2H, d J = 4.4 Hz), 6.77 (2H, d J = 2.8 Hz), 7.01-7.05 (5H, m) , 7.89 (2H, d J = 11.4 Hz), 8.06 (2H, d J = 11.4 Hz), 8.15 (2H, d J = 11.6 Hz), 8.27 (2H, d J = 11.6 Hz) .

(b) 2B

2B

To a solution of the bis-ester (39) (22.6 mg, 0.024 mmol) in dry MeOH (1 mL) was added at rt under an argon atmosphere 5 drops of a 25wt% solution of NaOMe in MeOH, and the mixture was stirred for 1 h. The mixture was neutralised by the addition of Amberlite until the pH was 7. After filtering the volatiles were concentrated and the crude residue was purified using silica gel column chromatography eluting with CHCl3/MeOH (6:1) to give the 2B (11.2 mg, 73%) as a gummy white solid.

Physical data was characteristic of authentic 2B.

Reference for Example 5:

1. Martin S F and Dodge J A (1991) Tetrahedron Lett. 32, 3017.

Example 6 ( a ) Hydrolysis of ester (2A) to acid (40)

Ester (2A) (38.5 mg, 0.0588 mmol) was dissolved in 0.4% KOH/aqueous MeOH [MeOH-H2O (5:10)] and heated to 5O0C for 2h. The reaction mixture was cooled to O0C and mixture diluted with ether and saturated aqueous NaCl. The aqueous layer was acidified to pH 2 and the mixture warmed to room temperature until 2 clear layers evolved. The aqueous layer was extracted with ether four times and the organic layers combined, dried (Na2SO^ and evaporated to afford the acid (40) (35 mg, 93%) which was used immediately in the next reaction: 1H NMR (300 MHz) δ 3.44 (s, 3H, OCH3, 2'"), 3.48 (s, 2H, Cl- OH, C8b-OH) , 3.49-3.63 (m, 4Hz, IH, H3'"eq, H5m, H61") , 3.70 (s, 3H, OCH3, 8), 3.73 (s, 3H, OCH3, 41) , 3.85 (dd, J = 13.5, 6.3 Hz, IH, H2), 4.02 (t, J = 11.1 Hz, IH, H3"'ax) , 4.10 (br t, J = 11.2 Hz, IH, H4"1) , 4.25 (d, J = 14 Hz, IH, H3) , 4.52 (s, IH, H21") , 4.97 (d, J = 6.3 Hz, IH, Hl), 5.24 (s, IH, Hl'"), 6.22 (s, IH, H7), 6.38 (s, IH, H5), 6.62 (s, 2H, H31, H51) , 6.87 (s, H2", H6") , 7.02 (s, 2H, H3", H5") , 7.03 (s, IH, H4"), 7.04 (br d, J = 7.2 Hz, 2H, H21, H6') . Alternative reagents: LiOH, NaOH

(bi) Amidation of acid (40) to primary amide (41)

To a solution of the acid (40) (6.6 mg, 0.0103 mmol) in dry DMF (0.3 mL) was added at O0C, PyBOP (14.6 mg, 0.0237 mmol), HOBt (3.8 mg, 0.0237 mmol), diisopropylethylamine (11.3 μL, 0.0649 mmol) and ammonium chloride (1.8 mg, 0.0330 mmol) . The solution was warmed to room temperature and stirred for 14 h after which water and EtOAc were added and stirred until 2 clear layers evolved. The solution was cooled to 00C and 1% HCl was added slowly until the pH of the aqueous layer was 2. The solution was warmed to room temperature, stirred for 10 mins and extracted twice with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCU3, water, brine, dried (Na2S0,j) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 5%-10% methanol in chloroform to provide the primary- amide (41) (5 mg, 76%) as an amorphous solid:

■ [CX]23D -105.2° (c 0.33, CH2Cl2); IR (thin film) 3414, 3055, 2988, 2956, 2093, 1656, 1630, 1265 cm"1; 1H NMR (300 MHz) δ 1.66 (bs, IH, C6"'-OH), 2.67 (bs, IH, C5"'-OH) , 3.48 (s, 3H, OCH3, 2"') , 3.53 (s, IH, Cl-OH, C8b- OH), 3.55 (s, IH, C8b-OH) , 3.55-3.78 (m, 4H, H3'"eq, H5" ' , H6" ' ) , 3.68 (s, 3H, OCH3, 4'), 3.81(s, 3H, OCH3, 8), 3.99 (m, IH, H2), 4.11(t, J = 11.4 Hz, IH, H3'"ax), 4.22 (m, IH, H4"r) , 4.30 (d, J = 13.5 Hz, IH, H3), 4.58 (s, IH, H2 '") , 4.95 (d, J = 5.4 Hz, IH, Hl) , 5.32 (s, IH, Hl'"), 5.58 (bs, IH, NH), 6.06 (bs, IH, NH), 6.24 (s, IH, H7), 6.43 (s, IH, H5), 6.63 (br d, J = 8.7 Hz, 2H, H3 ' , H5 ' ) , 6.92-7.06 (m, 4H, H2", H6", H2', H6') , 7.06 (m, 2H, H3", H5"),7.10 (m, IH, H4") ; 13C NMR (500 MHz) δ 47.0, 47.2, 51.3, 53.4, 55.1, 55.1, 55.9, 59.0, 63.1, 68.2, 70.7, 79.2, 92.3, 93.1, 93.8, 94.2, 95.0, 95.2, 101.9, 108.7, 112.7, 112.9, 126.4, 126.9, 128.0, 128.2, 128.9, 136.5, 157.4, 158.8, 159.9, 160.9, 172.8 HRMS (ESI) : Calcd for C33H37NNaOi2+ [M+Na]+ : 662.2213, found. Alternative reagents: ammonium chloride, DCC, EDC (bii) Amidation of acid (40) to secondary amide (42)

To a solution of the acid (40) (7 rag, 0.0109 mmol) in dry CH2Cl2 (2 mL) was added at 00C, MeNH2-HCl (4.6 mg, 0.0676 mmol) , DCC (13 mg, 0.0632 mmol) and DMAP (19.4 mg, 0.159 mmol) . The solution was warmed to room temperature and stirred for 2 d after which water and CH2Cl2 were added. The solution was cooled to 00C and 1% HCl was added slowly until the pH of the aqueous layer was 2. The solution was warmed to room temperature, stirred for 10 mins and extracted twice with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaHCU3, water, brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 5%-10% methanol in chloroform to provide the secondary amide (42) (5.5 mg, 77%) as an amorphous solid :

[α]23D -95.5° (c 0.32, CH2Cl2); IR (thin film) 3411, 3055, 2988, 2956, 2098, 1658, 1264 cm"1; 1H NMR (300 MHz) δ.1.67 (bs, IH, C6'"-OH), 2.40 (bs, IH, C5"'-OH), 2.68 (d, J = 5.1 Hz, IH, NHMe), 3.50 (s, 3H, OCH3, 2'"), 3.55-3.75 (m, 4H, H3'"eq, H5" ' , H6' " ) , 3.60 (s, IH, Cl-OH, C8b-OH) , 3.70 (s, 3H, OCH3, 4'), 3.86(s, 3H, OCH3, 8), 3.91 (m, IH, H2), 4.16 (t, J = 11.1 Hz, IH, H3' ax 4.26 (m, IH, H4"'), 4.31 (d, J = 12.9 Hz, IH, H3; 4.61 (s, IH, H2"'), 4.96 (d, J = 5.7 Hz, IH, Hl), 5.35 (s, IH, Hl'") , 5.91 (d, J = 4.5 Hz, IH, NHMe), 6.27 (d, J = I. Hz, IH, H7) , 6.42 (d, J = 1.8 Hz, IH, H5) , 6.64 (br d, J = 8.7 Hz, 2H, H31 , H5 ' ) , 6.96-7.11 (m, 7H, H2", H3", H4", H5", H6", H21, H6') ; 13C NMR (500 MHz) δ 29.7, 30. , 945.9, 51.4, 55.1, 55.1, 55.8, 55.9, 59.1, 63.1, 68.1, 70.7, 79.4, 92.4, 92.9, 93.4, 94.0, 95.3, 101.9, 108.9, 112.6, 112.9, 126.6, 126.8, 127.9, 128.2, 128.9, 136.6, 142.1, 146.8, 157.4, 158.7, 159.9, 160.9, 168.9, 170.9, 171.0 HRMS (ESI) : Calcd for C34H39NNaOi2+ [M+Na]+ : 676.2370, found.

(b±ii; Amidation of acid (40) to dimethyl amide (4B)

To a solution of the acid (40) (21.5 itig, 0.0335 mmol) in dry CH2Cl2 (6.7 mL) was added at O0C, Me2NH-HCl (8.7 mg, 0.107 mmol), DCC (20.8 mg, 0.101 mmol) and DMAP (30.7 mg, 0.251 mmol) . The solution was warmed to room temperature and stirred for 2 d after which water and CH2Cl2 were added. The solution was cooled to 00C and 1% HCl was added slowly until the pH of the aqueous layer was 2. The solution was warmed to room temperature, stirred for 10 mins and extracted twice with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaHCO3, water, brine, dried (Na2SO4) , filtered and concentrated to give the crude residue which was purified using silica gel column chromatography eluting with 5%-10% methanol in chloroform to provide the dimethyl amide (4B) ( 5 . 5 rag, 77% ) as an amorphous solid :

[Ct] 23D -156. 8 ° ( c 0 . 98 , CH2Cl2 ) ; IR (thin film) 3435, 3055, 2988, 2956, 2841, 2098, 1623 cm"1; 1H NMR (300 MHz) δ.2.40 (bs, IH, C6'"-OH), 2.76 (bs, IH, C5'"-OH), 2.90 (s, 3H, NMe), 3.28 (s, 3H, NMe), 3.43. (s, 3H, OCH3, 2"'), 3.44-3.75 (m, 4H, H3'"eq, H5" ' , RS"'), 3.69 (s, 3H, OCH3, 4'), 3.82 (s, 3H, OCH3, 8), 3.98-4.16 (m, IH, H2), 4.16 (t, J = 11.1 Hz, 3H, H2, H3'"ax, H41"), 4.47 (d, J = 13.2 Hz, IH, H3), 4.50 (s, IH, H2 '") , 4.96 (d, J = 5.7 Hz, IH, Hl) 5.18 (s, IH, Hl1"), 6.24 (d, J = 1.8 Hz, IH, H7), 6.42 (d, J = 1.8 Hz, IH, H5) , 6.68 (br d, J = 8.7 Hz, 2H, H3', H5'), 6.84 (m, 2H, H2", H6") , 7.05 (m, 2H, H3", H5"), 7.10 (m, IH, H4"), 7.11 (br d, J = 9 Hz, 2H, H2 ' , H6') ; 13C NMR (400 MHz) δ 35.8, 37.0, 47.5, 54.9, 55.0, 55.8, 55.9, 59.0, 62.9, 67.9, 70.6, 78.8, 93.0, 93.6, 93.7, 94.1, 95.1, 101.6, 109.4, 112.7, 126.3, 126.9, 127.8, 128.8, 137.4, 157.2, 158.5, 159.7, 160.6, 169.7; HRMS (ESI) : Calcd for C35H4INNaO12+ [M+Na]+ : 690.2526, found 690.2512. Alternative reagents: ammonium chloride, DCC, EDC

Example 7 Preparation of cyσlopentabenzofuran core as shown in Scheme 10

( a ) Selective benzylation - 7-Benzyloxy-5-hydroxy-2~ (4- hydroxy-phenyl) -chr oman- 4 -one (44) 1

44 C22H18O5 Exact Mass: 362.12 MoI. Wt: 362.38 To a solution of 4' , 5, 7-trihydroxyflavanone (43) (1.1 g, 4.04 rtuαoles) in DMF (10 mL) under a nitrogen atmosphere was added lithium carbonate (306 mg, 4.14 mmoles) followed by benzyl bromide (524 μL, 4.4 mmoles) . The reaction was heated to 700C and left overnight . Next morning a small portion was worked up and checked by TLC which showed a 1:1 ratio of starting material to product. More benzyl bromide was added (524 μL, 4.4 mmoles) and the reaction left for a further 24 hours. After this time analysis by TLC showed the reaction was mostly complete. The reaction was worked up by partitioning between water (150 mL) and ethyl acetate (80 mL) . The aqueous was acidified with 10% HCl (50 mL) . The layers separated and the aqueous was extracted with ethyl acetate (80 mL) . The combined organic layer was washed with water (3 x 80 mL) , then dried over sodium sulphate, filtered and the solvent removed in vacuo. The material was azeotroped with toluene 2 x 10 mL to yield a yellow solid, compound (44) (1.67 g) which was used directly in the next step without further purification. Rf [petroleum spirit/ethyl acetate (2:1' 0.34; i1H NMR (500 MHz, CDCl3 + 10% CD3OD) δ 2.65 - 2.72 (m, IH), 2.99 - 3.07 (m, IH), 5.01 (s, 2H), 5.23 - 5.28 (m, IH), 6.06 (d, J = 12.0 Hz, IH), 6.80 (d, J = 8.2 Hz, 2H), 7.22 ( d, J = 8.2 Hz, 2H), 7.26 - 7.32 (m, 6H) ppm, OH signals not observed; ESMS, positive ion detection m/z 385.1 [M + Na]+.

(b) Oxidation - 7-Benzyloxy-5-hydroxy-2- (4-hydroxy-phenyl) - chromen-4-one (45)2

45 0.2H16O5 Exact Mass: 360.10 MoI. Wt: 360.36

The yellow solid from step (a) above (1.67 g) , under a nitrogen atmosphere was dissolved in pyridine (10 inL) and iodine (1.02 g, 4.04 mmoles) was added. The reaction was heated to reflux for 4 hours. After this time the pyridine was removed under a stream of nitrogen. The black residue was diluted with water (150 mL) acidified with 10% HCl (50 mL) then was extracted with ethyl acetate (2 x 80 mL) . The organic layer was washed with water (2 x 80 mL) , dried over sodium sulphate and filtered. Analysis by TLC showed a number of spots with some starting material but one major spot. The material was dried onto silica gel and purified by flash chromatography using petroleum spirit/ethyl acetate 2:1 - neat ethyl acetate as eluent. Three fractions were collected;

Fraction 1 - starting material, compound (44) (283 mg, 20%) a bright yellow oil . Basically unchanged starting material which is a mixture of compounds.

Fraction 2 - 7-Benzyloxy-5-hydroxy-2- (4-hydroxy-phenyl) - chromen-4-one (45) (854 mg, 58%), bright yellow solid. The desired target mixed with about 10% of some other impurity. Rf [petroleum spirit/ethyl acetate (2:1)] = 0.21; HPLC (211 nm) tR = 16.984 (84.7 %) min; UV λmax (acetonitrile/water) = 214.6, 267.7, 333.2 nm; 1H NMR (500 MHz, CDCl3 + 10% CD3OD) δ 5.03 (s, 2H), 6.32 (s, IH) , 6.44 (s, IH), 6.47 (s, IH), 6.83 (d, J = 8.5 Hz, 2H), 7.09 - 7.34 (m, 5H), 7.67 (d, J = 8.5 Hz, 2H) ppm, OH signals not observed; 13C NMR (126 MHz, CDCl3 + 10% CD3OD) δ 70.2, 93.3, 98.6, 103.2, 115.8, 121.8, 127.3, 128.0, 128.1, 128.4, 128.5, 135.5, 157.5, 160.8, 161.4, 164.4, 164.8, 182.4 ppm; ESMS, positive ion detection m/z 361.3 [M + H]+; ESMS, negative ion detection m/z 359.2 [M - H]-.

Fraction 3 - 4' ,5,7-trihydroxyflavone (272 mg, 24% yield) as a beige coloured solid A' , 5, 7-trihydroxyflavone [so no benzyl group has been incorporated but the flavanone has been oxidized up to the 4' , 5, 7-trihydroxyflavone. ( c) Dimethylation - 7-Benzyloxy-5-methoxγ-2- (4-methoxy- phenyl) -chromen-4-one (46) 3

46 C24H2OO5 Exact Mass: 388.13 MoI.Wt.:388.41

To a solution of compound 45 (1.35 g, 3.74 mmoles) in DMF (5 πiL) under an atmosphere of nitrogen was added potassium carbonate (1.55 g, 11.2 mmoles) followed by iodomethane (1.0 mL, 15 mmoles) . The reaction was left stirring overnight. Next morning the reaction was worked up by partitioning between dichloromethane (50 mL) and 2.5% HCl (450 mL) . The layers separated and the aqueous phase was extracted with DCM (2 x 20 mL) . The combined organic phase was washed with water (2 x 100 mL) . The organic phase was dried over sodium sulphate, filtered and the solvent removed in vacuo. The residue still contained some DMF which was removed by azeotroping with toluene (3 x 50 mL) and then dried under vacuum. The residue was immediately loaded onto a flash column and eluted with dichloromethane (1% - 5% methanol) using gradient elution. The first compound to elute from the column was some monomethylated material, followed by the desired target compound 46 (1.144 g, 79% yield) isolated as a golden oil. Rf [dichloromethane/5% methanol] = 0.54, strong blue fluorescence under UV light; HPLC (210 nm) tR = 11.665 (94.5 %) min; UV λraax (acetonitrile/water) = 214.6, 264.2, 326.0 nm; 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 3.95 (s, 3H) , 5.16 (s, 2H), 6.46 (s, IH), 6.65 (s, IH), 6.67 (s, IH), 7.00 (d, J = 8.0 Hz, 2H), 7.35 - 7.48 (m, 5H), 7.82 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 55.4, 56.4, 70.5, 93.7, 96.6, 107.7, 114.3, 123.8, 127.6, 127.6, 128.4, 128.8, 135.7, 159.7, 160.7, 160.9, 162.0, 162.9, 177.6 ppm; ESMS, positive ion detection m/z 389.3 [M + H]+, 411.2 [M + Na]+; ESMS, negative ion detection m/z 359.2 [M - H]"; LC-MS tR = 18.75 (389.25 [M + H]+) min.

(d) 3-Hydroxylation - 7-Benzyloxy-3-hydroxy-5-methoxy-2- (4- methoxy-phenyl) -chromen-4-one (47)4

47 C24H20O6 Exact Mass: 404.13 MoI. Wt: 404.41

A solution of chromone (46) (1.557 g, 4.0 mmoles) in THF (40 inL) was stirred under nitrogen at -78°C. To this solution was added a 2M solution of LDA (2.0 mL, 4.0 mmoles) drop-wise. The reaction solution turned very dark and was kept at -78°C for 5 mins . After this time a solution of trimethylborate (0.45 mL, 4.0 mmoles) in THF (5.0 mL) was added. The resulting solution was left for 40 mins at -780C, after which time a lot of the colour had dissipated. Reaction was then was quenched with glacial acetic acid (350 μL, 6.0 mmoles) the reaction stirred for 15 mins then 30% aqueous hydrogen peroxide (450 μL) was added drop-wise. The cold bath was removed and the reaction was left to slowly warm to room temperature over 1 hour. After this time the reaction was worked up by diluting with sat. sodium bicarbonate (50 mL) and extracting with ethyl acetate (3 x 80 mL) . The organic phase was dried over sodium sulphate, filtered and the solvent was removed in vacuo keeping the water bath temperature low (25 - 300C) to yield a bright orange solid. The solid was purified on silica gel using DCM/Et2θ 1:1 as eluent to yield the desired target, compound 47 (980 mg, 60% yield) as a dark greenish/brown crystalline solid. Analysis by IH and 13C NMR all confirmed this was the desired target compound and was very pure. Rf [petroleum spirit/ethyl acetate (1:1)] = 0.44, strong yellow fluorescence under UV light; HPLC (210 ran) tR = 17.595 (95.92%) min; UV λmax (acetonitrile/water) = 267.7, 333.2nm; 1H NMR (500 MHz, CDCl3) δ 3.898 (s, 3H), 3.97 (s, 3H), 5.16 (s, 2H), 6.44 (s, IH), 6.65 (s, IH), 7.03 (d, J = 8.5 Hz, 2H), 7.37 - 7.48 (m, 5H), 8.17 (d, J = 8.5 Hz, 2H) ppm OH signal not observed; 13C NMR (126 MHz, CDCl3) δ 55.4, 56.4, 70.6, 93.4, 96.2, 106.4, 114.0, 123.5, 127.7, 128.5, 128.8, 128.9, 135.6, 137.5, 142.3, 158.8, 160.6, 160.6, 163.3, 171.9 ppm; ESMS, positive ion detection m/z 405.1 [M + H]+, 427.1 [M + Na]+; ESMS, negative ion detection m/z 403.1 [M - H]"; LC-MS tR = 19.24 (405.31 [M + H]+) min.

Further elution from the column provided some starting material (46) (240 mg, 15% recovery) as an orange oil that slowly crystallized.

(e) Photolytic dipolar cycloaddition - - 5-Benzyloxy-l- hydroxy-3-methoxy-9- (4-methoxy-phenyl) -12-oxo-10-phenyl-8- oxa-tricyclo[7.2.1.02,7]dodeca-2,4,6-triene-ll-carboxylic acid methyl ester (48) and 5-Benzyloxy-8a-hydroxy-7-methoxy-2a- (4-methoxy-phenyl) -8- oxo-2-phenyl-2,2a,8,8a~tetrahydro-lH-3-oxa- cyclobuta[b]naphthalene-1-carboxylic acid methyl ester (49)

48 49 C34H3OO8 C34H30O8 Exact Mass: 566.19 Exact Mass: 566.19 MoI. Wt: 566.60 MoI. Wt: 566.60 To a cold finger apparatus containing a stirrer bar was added 7-Benzyloxy-3-hydroxy-5-methoxy-2- (4-methoxy-phenyl) - chromen-4-one (47) (150 mg, 0.37 mmoles) followed by anhydrous methanol (7 mL) , anhydrous acetonitrile (7 mL) and finally methyl trans cinnamate (904 mg, 5.6 mmoles) . Nitrogen was bubbled vigorously through the solution for about 15 mins to fully degas the solution. The reaction was kept under a nitrogen atmosphere by means of a balloon. Suspended chromone (47) was assisted into solution using limited sonication and gentle heating. The apparatus was fitted with the internal cooling finger and the reaction solution was cooled to -100C using an ethylene glycol cooling system connected to the internal cooling finger. The reaction mixture was then irradiated (Hanovia UV lamp, Pyrex filter) at -100C with stirring for 2 - 3 hours. Analysis by TLC indicated no starting material remained. The solvent was removed in vacuo. The reaction was repeated using 7-Benzyloxy-3-hydroxy-5- methoxy-2- (4-methoxy-phenyl) -chromen-4-one (47) (200 mg, 0.5 mmoles), anhydrous methanol (7 mL) , anhydrous acetonitrile (9 mL) and finally methyl trans cinnamate (910 mg, 5.6 mmoles) . The residues from both reactions were combined and purified by flash column on silica gel using petroleum spirit/ ethyl acetate, 3:2 as eluent to yield the desired mixture of compounds (48) and (49) (337 mg, 69% yield) as a bright orange foam. This material was used directly in the next step without further purification.

Partial data; Rf [petroleum spirit/ethyl acetate (2:1)] = 0.27 & 0.38; ESMS, positive ion detection m/z 589.5 [M + Na]+, 605.3 [M + K]+; ESMS, negative ion detection m/z 565.3 [M - H]". The 1H and 13C NMR spectra were very complex due to the number of compounds present, however, all key signals consistent with the desired target were present e.g. CO2Me, OMe groups, CH2Ph, and expected aromatic signals. Three major diagnostic peaks for compound 48 are presented below and correlate well to the work of Porco et al.5 1H NMR (500 MHz, CDCl3) δ 4.01 (s), 4.21 (d, J = 9.1 Hz), 4.51 (d, J = 9.1 Hz) . Porco5, 1H NMR (400 MHz, CDCl3) δ 3.94 (s, IH) , 4.18 (d, J = 9.2 Hz, IH), 4.48 (d, J = 9.2 Hz, IH) .

(f) α-Ketol Shift - 6-Benzyloxy-3a-hydroxy-4-methoxy-8a- (4- methoxy-phenyl) -3-oxo-l-phenyl-2,3,3a,8a-tetrahydro-lH-8- oxa-cyclopenta[a]indene-2-carboxylic acid methyl ester (50) , 6-Benzyloxy-3a-hydroxy-4-methoxy-8a- (4-methoxy-phenyl) -3- oxo-1-phenyl-2,3,3a,8a-tetrahydro-lH-8-oxa- cyclopenta[a] indene-2-carboxylic acid methyl ester (51) and 6-Benzyloxy-3,3a-dihydroxy-4-methoxy-8a- (4-methoxy-phenyl) - l-phenyl-3a,8a-dihydro-lH-8-oxa-cyclopenta[a] indene-2- carboxylic acid methyl ester (52)5

50 51 52 C34H30O8 C34H30O8 C34H30O8 Exact Mass: 566.19 Exact Mass: 566.19 Exact Mass: 566.19 MoI. Wt: 560.60 MoI. Wt.: 560.60 MoI. Wt.: 560.60

To a solution of the residue from step (e) above, containing compounds 48 and 49 (337 mg, assume 0.6 mmoles) dissolved in methanol (25 πiL) under nitrogen at room temperature was added 0.5 M sodium methoxide solution (3.0 mL, 1.5 mmoles) . The reaction was heated to reflux for 40 mins . After this time the reaction was quenched with saturated ammonium chloride (5 mL) and the solvent reduced in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL) . The layers were separated and the organic phase was washed with water (1 x 10 mL) then brine (1 x 10 inL) . The combined aqueous phase was back extracted with ethyl acetate (1 x 20 mL) . The combined organic phase was dried over sodium sulphate, filtered and the solvent removed in vacuo to yield compounds 50, 51 and 52 (350 mg) as a brown glassy solid. The mixture was taken through the next step without purification.

Partial data; Rf [petroleum spirit/ethyl acetate (3:2)] = 0.40; The 1H and 13C NMR spectra were very complex due to the number of compounds present, however, all key signals consistent with the desired target were present e.g. CO2Me, OMe groups, CH2Ph and expected aromatic signals. Five major diagnostic peaks for compounds 50, 51 and 52 are presented below and correlate well to the work of Porco et al.5 1H NMR (500 MHz, CDCl3) δ 4.06 (d, J = 13.3 Hz), 4.25 (d, J = 13.3 Hz), 4.37 (d, J = 14.2 Hz), 4.43 (d, J = 14.2 Hz) , 4.49 (S) . Porco5, 1H NMR (400 MHz, CDCl3) δ 4.04 (d, J = 13.6 Hz, IH), 4.22 (d, J = 13.6 Hz, IH), 4.36 (d, J = 14.8 Hz, IH), 4.42 (d, J = 14.8 Hz, IH), 4.46 (s, IH) .

(g) Selective Reduction - 6-Benzyloxy-3,3a-dihydroxy~4- methoxy-8a- (4-methoxy-phenyl) -l-phenyl-2 ,3,3a,8a-tetrahyd.ro- lH-8-oxa-cyclopenta[a]indene-2-carboxylic acid methyl ester (53) and (54)5

53 54 C34H32O8 C34H32O8 Exact Mass: 568.21 Exact Mass: 568.21 MoI. Wt: 568.61 MoI. Wt: 568.61 A solution of the tetramethylammonium triacetoxyborohydride (1.03 g, 3.91 mmoles) and acetic acid (370 μL, 6.46 πunoles) in acetonitrile (2OmL) was prepared and left stirring under nitrogen for 5 minutes. To this solution was added a solution of the ketone mixture, compounds 50, 51 and 52 from step (f) above (350 mg, 0.65 mmoles) in acetonitrile (10 mL) . This resulting yellow solution was left stirring under nitrogen overnight. Next morning the reaction was quenched with saturated ammonium chloride (11 mL) , and then was treated with IM aqueous solution of sodium tartrate (16 mL) and was left stirring for 30 mins. The aqueous solution was then extracted with DCM (2 x 50 mL) . The combined organic layer was dried over sodium sulphate, filtered and the solvent removed in vacuo to yield a golden brown oil (380 mg) . This was material was purified on silica gel using petroleum spirit/ethyl acetate 1:1 as eluent. First compound to elute from the column was, compound 53 (202 mg, 41.0 % yield over three steps starting from compound 47 obtained as a colourless oil. Rf [petroleum spirit/ethyl acetate (1:1)] = 0.52; 1H NMR (500 MHz, CDCl3) δ 1.82 (brs, IH), 3.65 (s, 3H), 3.67 (brs, IH), 3.71 (s, 3H) , 3.86 (s, 3H), 3.90 (dd, J = 14.2, 6.7 Hz, IH), 4.32 (d, J = 14.2 Hz, IH), 5.03 (d, J = 6.7 Hz, IH) , 5.08 (s, IH), 5.09 (s, IH), 6.21 (d, J = 2.0 Hz, IH), 6.36 (d, J = 2.0 Hz, IH), 6.67 (d, J = 9.0 Hz, 2H), 6.87 - 6.89 (m, 2H), 7.04 - 7.07 (m, 3H) , 7.11 (d, J = 9.0 Hz, 2H), 7.36 - 7.47 (m, 5H) ppm; 13C NMR (126 MHz, CDCl3) δ 50.4, 51.9, 55.0, 55.1, 55.8, 70.5, 79.5, 90.4, 93.3, 93.7, 101.9, 107.9, 112.7, 126.4, 126.5, 127.1, 127.6, 127.7, 127.7, 127.8, 128.2, 128.7, 128.8, 128.9, 136.4, 136.9, 157.0, 158.7, 160.8, 163.2, 170.5 ppm; ESMS, positive ion detection m/z 591.3 [M + Na]+; ESMS, negative ion detection m/z 567.9 [M - H]", 535.1 [M - CH5O]".

The second compound to elute from the column was compound 54 (68.3 mg, 13.9 % yield over three steps starting from compound 47 obtained as a colourless solid. Rf [petroleum spirit/ethyl acetate (1:1)] = 0.31; 1H NMR (500 MHz, CDCl3) δ 2.00 (brs, IH), 3.26 (dd, J = 12.8, 10.4 Hz, IH), 3.62 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 4.04 (d, J = 12.8 Hz, IH) , 4.79 (d, J = 10.4 Hz, IH), 5.03 (s, IH), 5.04 (s, IH), 6.18 (d, J = 1.7 Hz, IH) , 6.22 (d, J = 1.7 Hz, IH) , 6.90 (d, J = 8.8 Hz, 2H), 6.95 - 6.97 (m, 2H), 7.15 - 7.18 (m, 3H), 7.36 (d, J = 8.8 Hz, 2H), 7.39 - 7.47 (m, 5H) ppm; 13C NMR (126 MHz, CDCl3) δ 50.7, 52.2, 54.6, 55.2, 55.6, 70.4, 83.8, 89.5, 91.2, 93.2, 99.3, 105.1, 113.4, 113.8, 127.1, 127.2, 127.6, 127.8, 127.9, 128.2, 128.2, 128.6, 128.6, 128.8, 128.8, 128.9, 134.8, 136.3, 157.7, 159.2, 161.8, 163.0, 173.0 ppm; ESMS, positive ion detection m/z 591.5 [M + Na]+; ESMS, negative ion detection m/z 566.7 [M - H]".

(h) Deprotection - 3,3a, 6-Trihγdroxy-4-methoxy-8a- (4- methoxy-phenyl) -l-phenγl-2,3,3a,8a~tetrahydro-lH-8-oxa- cyclopenta[a]indene-2-carboxylic acid methyl ester (55) 6

55 C27H26O8 Exact Mass: 478.16 MoI. Wt: 478.49

To a solution of compound 53 (192 mg, 0.401 πtmoles) in ethanol (5 mL) was added 10% palladium on carbon (approximately 10 mg) . The reaction was stirred vigorously under a hydrogen atmosphere. After 3 hours TLC showed complete conversion of starting material to a new spot. Solution was filtered through a plug of Celite and the flask and pad washed with ethyl acetate (60 mL) . The combined solvent was removed to yield a golden oil (200 mg) . The material was dried onto silica gel and purified by flash column using petroleum spirit/ethyl acetate, 2:3 as eluent. The desired target, compound 55 (143 mg, 88% yield) was obtained as a pure white crystalline solid. This material was not very soluble in ethyl acetate and readily crystallized out. The low yield was attributed to the problems with solubility. Rf [petroleum spirit/ethyl acetate (1:2)] = 0.65; HPLC (254 nm) tR = 14.15 (74.12%) min; UV λmax (acetonitrile/water) = 243.0, 271.3 nm; 1H NMR (500 MHz, acetone -dβ) δ 2.90 (brs, IH), 3.56 (s, 3H), 3.66 (s, IH), 3.83 (s, 3H) , 3.94 (dd, J = 14.0, 6.5 Hz, IH) , 4.17 (s, IH), 4.29 (d, J = 14.0 Hz, IH), 4.93 (d, J = 6.5 Hz, IH), 6.12 (d, J = 1.5 Hz, IH), 6.17 (d, J = 1.5 Hz, IH), 6.63 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 7.3 Hz, 2H), 6.98 - 7.05 (m, 3H) , 7.13 (d, J = 9.0 Hz, 2H) ppm; 13C NMR (126 MHz, acetone-d6) δ 52.1, 52.2, 52.2, 55.9, 56.4, 56.5, 81.3, 92.5, 93.9, 103.2, 113.5, 127.5, 128.9, 129.5, 129.6, 130.6, 139.9, 159.4, 159.9, 162.4, 162.5, 162.7, 171.4 ppm; ESMS, positive ion detection m/z 501.4 [M + Na]+; ESMS, negative ion detection m/z All.3 [M - H]".

Example 8 Coupling of cyclopentabenzof-uran core to the side chain as shown in Scheme 15 (b) Coupling - 6-{6- [l-Benzyloxy-2- (tert-butyl-dimethyl- silanyloxy) -ethyl] -3-methoxy- [1,4]dioxan-2-yloxy}-3,3a- dihydroxy-4-methoxy-8a- (4-methoxy-phenyl) -1-phenyl- 2,3,3a,8a-tetrahydro-lH-8-oxa-cyclopenta[a]indene-2- σarboxylic acid methyl ester (56) and (57)

56 57 C47H58O13Si Exact Mass: 858.36 Exact Mass: 858.36 MoI. Wt.: 859.04 MoL Wt.: 859.04

To a stirred solution of compound 55(46 mg, 0.1 iranoles) in toluene (5 mL) was added a solution of compound 14 (194 mg, 0.49 mmoles) in dry toluene (5 mL) . Triphenylphosphine (127 mg, 0.48 mmoles) was added followed by MoI. Sieves (1.5 g) . The reaction was stirred under nitrogen for 20 mins then was cooled to 00C before the drop-wise addition of the DIAD (94 μL, 0.48 mmoles) . After 2 hours analysis by TLC showed some starting material and two new spots. The reaction was left for a further 2 hours then the solvent was removed in vacuo. The reaction was purified on silica gel using petroleum spirit/ethyl acetate, 3:2 - 1:2 using gradient elution. Two compounds were eluted off the column. The first compound to elute off the column was, compound 56 (56 mg, 65% yield) . The material was still contaminated with a bit of DIAD so was re-chromatographed to yield compound 56 (28.7 mg, 33.3 % yield) as a pure white foam. The sample was a mixture of diastereomers so both the 1H and 13C NMR spectra were very complicated with each signal being doubled. Rf [petroleum spirit/ethyl acetate (1:1)] = 0.75; 1H NMR (500 MHz, CDCl3) δ -0.08, -0.02, -0.01, 0.03 (4s, 6H), 0.80, 0.84 (2s, 9H), 3.48, 3.49 (2s, 3H), 3.64, 3.65 (2s, 3H), 3.70, 3.71 (2s, 3H), 3.84, 3.85 (2s, 3H), 3.45 - 4.00 (m, 6H) , 4.26 - 4.35 (m, 2H), 4.58 - 4.78 (m, 3H), 5.01 - 5.05 (m, IH), 5.25, 5.25 (2s, IH), 6.29 (brs, IH), 6.45 - 6.47 (m, IH) , 6.67 (d, J = 8.5 Hz, 2H), 6.85 - 6.90 (m, 2H), 7.05 - 7.08 (m, 3H), 7.11 (d, J = 8.5 Hz, 2H), 7.26 - 7.36 (m, 5H) ppm; 13C NMR (126 MHz, CDCl3) δ -5.5, -5.4, 18.1, 25.8, 50.4, 50.5, 51.9, 54.9, 54.9, 55.1, 59.8, 62.8, 67.0, 67.1, 72.9, 79.5, 79.6, 79.7, 79.7, 92.5, 92.6, 93.6, 93.6, 93.9, 94.1, 94.1, 94.2, 94.3, 95.3, 95.4, 95.5, 101.8, 102.0, 109.0, 109.2, 112.7, 112.7, 112.8, 112.9, 112.9, 126.5, 126.5, 127.6, 127.7, 127.7, 127.7, 127.8, 127.8, 128.3, 128.9, 129.0, 136.8, 136.9, 138.4, 138.4, 156.9, 156.9, 158.7, 160.6, 160.7, 160.1, 160.8, 170.4, 170.5 ppm; ESMS, positive ion detection m/z 881.7 [M + Na]+; ESMS, negative ion detection m/z 857.5 [M - H]".

The second compound to elute off the column was compound 57 (20.3 mg, 23 % yield) obtained as a pure white foam. The sample was a mixture of diastereomers so both the IH and 13C NMR spectra were very complicated with each signal being doubled. Rf [petroleum spirit/ethyl acetate (1:1)] = 0.70; 1H NMR (500 MHz, CDCl3) δ 0.05, 0.07, 0.08, 0.10 (4s, 6H), 0.92, 0.93 (2s, 9H), 3.53, 3.55 (2s, 3H), 3.64, 3.65 (2s, 3H), 3.70, 3.71 (2s, 3H), 3.83, 3.84 (2s, 3H), 3.45 - 4.05 (m, 5H), 4.10 - 4.19 (m, IH), 4.28 - 4.36 (m, IH), 4.56 - 4.63 (m, 2H), 4.73 - 4.78 (m, IH), 5.00 - 5.03 (m, IH), 5.16, 5.21 (2d, J = 1.5 Hz, IH), 6.28 - 6.30 m, IH), 6.40 (m, IH), 6.65 (m, 2H) , 6.86 - 6.90 (m, 2H), 7.04 - 7.06 (m, 3H), 7.10 (d, J = 9.0 Hz, 2H), 7.26 - 7.34 (m, 5H) ppm; 13C NMR (126 MHz, CDCl3) δ -5.4, -5.2, 18.2, 18.2, 25.9, 50.4, 50.6, 52.0, 55.0, 55.4, 55.8, 55.8, 59.8, 59.9, 61.7, 62.0, 72.6, 72.8, 73.5, 73.8, 79.1, 79.4, 79.5, 79.6, 92.0, 92.4, 93.6, 94.9, 95.0, 95.0, 95.0, 95.1, 96.2, 96.5, 102.0, 102.1, 109.4, 109.5, 112.6, 112.7, 126.2, 126.4, 126.5, 126.5, 127.7, 127.7, 127.8, 127.9, 128.0, 128.3, 128.9, 129.0, 136.8, 136.9, 138.2, 138.2, 156.8, 156.8, 158.7, 160.6, 160.7, 161.2, 161.3, 170.5, 170.5 ppm; ESMS, positive ion detection m/z 881.5 [M + Na]+; ESMS, negative ion detection m/z 857.3 [M - H]".

A third fraction was obtained that consisted of a mixture of compounds 56 and 57 (8.7 mg, 10.1 % yield) . (c) Deprotection - 6-[6- (1,2-Dihydroxy-ethyl) -3-methoxy- [1,4]dioxan-2-yloxy] -3,3a-dihydroxy-4-methoxy-8a- (4-methoxy- phenyl) -l-phenyl-2 ,3,3a,8a-tetrahydro-lH-8-oxa- cyclopenta[a]indene-2-carboxylic acid methyl ester 6

58 59 C34H38O13 C34H38O13 Exact Mass: 654.23 Exact Mass: 654.23 MoI. Wt: 654.66 MoI. Wt.: 654.66

Two, two step reactions were carried out exactly the same

(i) Solutions of compounds 56 and 57 in THF (2.5 mL) were cooled to 00C under an atmosphere of nitrogen before being treated with TBAF (3 eq. ) • The ice bath was removed and the reaction was left stirring at room temperature for 4 hours. After this time TLC showed that the reactions were complete. The reactions were worked up by partitioning between 10% citric acid (20 mL) and ethyl acetate (50 mL) . The organic phase was washed with brine (1 x 20 mL) . The combined aqueous phase was back extracted with ethyl acetate (2 x 20 mL) . The combined organic phase was dried over sodium sulphate, filtered and the solvent removed in vacuo to yield a crystalline solid. This residue was dissolved in ethyl acetate (10 mL) and passed through a short plug of silica gel using ethyl acetate as eluent to remove any salts. TLC analysis Rf [petroleum spirit/ethyl acetate (1:1)] = 0.25 α isomer, 0.45 β isomer.

(ii) To stirred suspension of the residue from Step A above in ethanol (3 mL) was added a catalytic portion of 10% palladium on carbon (about 0.1 eq. ) . The reaction was put under hydrogen atmosphere and left stirring vigorously for 3 hours. After this time analysis by TLC showed complete consumption of starting material and the appearance of a new spot. The solution was filtered through a plug of Ce lite and the flask and pad washed with ethyl acetate (30 mL) . Solvent was removed in vacuo to yield a colourless semi solid. This residue was dried onto silica gel and purified by flash chromatography using petroleum spirit/ethyl acetate, 1:9 - neat ethyl acetate as eluent.

Starting with compound 56 (28.7 mg, 0.033 imoles), compound 58 (8.9 mg, 41 % yield over two steps) was obtained as a slightly off white solid. This material required repeated chromatography to obtain sufficiently pure material resulting in the slightly low yield. The sample was a mixture of diastereomers so both the 1H and 13C NMR spectra were very complicated with each signal being doubled. Also an impurity from TBAF still remained. Rf [ethyl acetate] = 0.37; 1H NMR (500 MHz, CD3OD) δ 3.51, 3.51 (2s, 3H), 3.67 (s, 3H), 3.70 (s, 3H), 3.88 (s, 3H) , 3.40 - 4.13 (m, 7H), 4.29 - 4.32 (m, IH), 4.63 (m, IH), 5.31,5.32 (2s, IH), 6.37 - 6.39 (m,lH) , 6.46 - 6.47 (m, IH), 6.65 - 6.67 (m, 2H), 6.93 - 6.95 (m, 2H), 7.03 - 7.08 (m, 3H), 7.14 (d, J = 8.5 Hz, 2H) ppm, proton signal for position Z8 is obscured by solvent signal; 13C NMR (126 MHz, CD3OD) δ 44.0, 52.2, 52.5, 55.1, 55.4, 56.1, 56.4, 61.0, 64.3, 64.3, 68.8, 73.3, 74.1, 80.6, 93.3, 93.4, 95.0, 95.0, 95.1, 95.1, 95.5, 95.6, 96.9, 97.0, 103.0, 103.0, 110.8, 113.2, 127.2, 128.5, 129.1, 129.2, 130.0, 130.2, 159.4, 159.8, 161.4, 161.5, 162.0, 172.6, 173.8 ppm; ESMS, positive ion detection m/z 677.7 [M + Na]+; ESMS, negative ion detection m/z 653.4 [M - H]".

A further sample of compound 58 (2 mg, 13 %) was obtained.

Starting with compound 57 (20.3 mg, 0.023 mmoles) , compound 59 (10.0 mg, 65 % yield over two steps) was obtained as a slightly off white solid. The sample was a mixture of diastereomers so both the 1H and 13C NMR spectra were very complicated with each signal being doubled. Also an impurity from the TBAF still remained. Rf [ethyl acetate] = 0.37; 1H NMR (500 MHz, CD3OD) δ 3.60, 3.61 (2s, 3H), 3.68, 3.69 (2s, 3H), 3.70 (2s, 3H), 4.01 (s, 3H), 3.57 - 4.35 (m, 7H), 4.74 - 4.78 (m, 2H), 5.34 - 5.37 (m, IH), 6.65 - 6.80 (m, 3H), 6.81 - 6.82 (m, IH), 6.94 - 7.16 (m, 7H), proton signal for position Z8 is obscured by solvent signal; 13C NMR (126 MHz, CD3OD) δ 44.7, 53.2, 53.5, 56.3, 56.6, 56.9, 57.3, 57.5, 62.0, 63.1, 64.8, 73.8, 75.0, 76.8, 76.9, 81.4, 97.1, 97.4, 98.4, 98.8, 104.1, 114.1, 114.2, 114.6, 128.2, 129.5, 129.8, 130.0, 130.9, 131.0, 139.9, 160.7, 160.9, 173.4, 177.7 ppm; ESMS, positive ion detection m/z 677.4 [M + Na]+; ESMS, negative ion detection m/z 653.2 [M - H]".

Example 9 Coupling of cyclopentabenzofuran core to the side chain as shown in Scheme 16 (a) Coupling - 6-{6- [1,2-Bis- (tert-butyl-dimethyl- silanyloxy) -ethyl] -3-methoxy- [1,4]dioxan-2-yloxy}-3,3a- dihydroxy-4-methoxy-8a- (4-methoxy-phenyl) -1-phenyl- 2,3,3a,8a-tetrahydro-lH-8-oxa-cyclopenta[a]indene-2- carboxylic acid methyl ester (60) and (61) 7

60 61 C46H66θi3Si2 QoH66O13Si2 Exact Mass: 882.40 Exact Mass: 882.40 MoI. Wt: 883.18 MoI. Wt: 883.18 To a stirred solution of compound 55 (133 mg, 0.278 mmoles) in toluene (20 mL) was added a solution of compound 23 (350 mg, 0.826 mmoles) in dry toluene (21 mL) . Triphenylphosphine (233 mg, 0.886 mmoles) was added followed by MoI. Sieves (2.0 g) . The reaction was stirred under nitrogen for 20 mins then was cooled to O0C before the drop-wise addition of the DIAD (180 μL, 0.93 mmoles) . After 2 hours analysis by TLC showed a lot of starting material and one new spot corresponding to the desired product β-isomer with a very small trace of a second spot just under the first corresponding to the α-isomer. As the reaction was going so slowly, more sieves, triphenylphosphine (115 mg) and DIAD (90 μL) were added. The reaction was checked after another hour, when only a small amount of starting material and the two new product spots were observed. The higher Rf β-isomer was now the minor compound and the lower Rf spot the α- isomer was now the major compound. The solvent was removed in vacuo and the material purified on silica gel by flash chromatography using petroleum spirit/ethyl acetate, 2:1. The first compound to elute off the column was compound 60 (22.8 mg, 12% yield) as brown oil. The sample was a mixture of diastereomers so both the 1H and 13C NMR spectra were very complicated with each signal being doubled. Rf [petroleum spirit/ethyl acetate (2:1)] = 0.65; 1H NMR (500 MHz, CDCl3) δ 0.05, 0.06, 0.07, 0.08 (4s, 12H), 0.80, 0.83, 0.85, 0.85, 0.89 (5s, 18H), 1.75 (brs, IH), 3.46, 3.48 (2s, 3H), 3.63, 3.64 (2s, 3H), 3.70, 3.71 (2s, 3H), 3.86, 3.86 (2s, 3H), 3.30 - 4.11 (m, 6H), 4.24 - 4.36 (m, 2H), 4.57 - 4.58 (m, IH), 5.01 - 5.05 (m, IH), 5.31 (s, IH), 6.28 - 6.30 (m, IH), 6.49 - 6.52 (m, IH) , 6.67 (d, J = 8.6 Hz, 2H) , 6.84 - 6.94 (m, 2H) , 7.05 - 7.12 (m, 3H) , 7.11 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ -5.3, -4.9, -4.4, 1.0, 18.1, 18.1, 18.1, 21.9, 22.7, 25.8, 25.8, 29.3, 29.6, 29.7, 31.9, 50.4, 51.9, 54.8, 54.9, 55.1, 55.1, 55.8, 59.2, 63.6, 63.7, 69.0, 73.0, 73.0, 79.6, 92.8, 93.6, 93.6, 94.3, 94.4, 95.6, 101.7, 109.2, 112.6, 112.7, 126.2, 126.5, 126.5, 127.7, 127.7, 127.8, 128.9, 129.0, 136.8, 156.8, 158.7, 160.5, 160.8, 170.4, 170.5 ppm; ESMS, positive ion detection m/z 905.7 [M + Na]+; ESMS, negative ion detection m/z 881.5 [M - H]".

The second compound to elute off the column was compound 61 (84.0 mg, 43 % yield) obtained as a yellow solid. Rf [petroleum spirit/ethyl acetate (2:1)] = 0.46; 1H NMR (500 MHz, CDCl3) δ 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 (6s, 12H) , 0.86, 0.88, 0.89, 0.92 (4s, 18H), 3.50, 3.54 (2s, 3H), 3.64, 3.64 (2s, 3H), 3.69 (s, 3H), 3.84 (s, 3H), 3.39 - 4.09 (m, 7H), 4.28 - 4.33 (m, IH), 4.43, 4.59 (2s, IH) , 5.00 - 5.02 (m, IH), 5.15, 5.22 (2s, IH), 6.29 (s, IH), 6.43 - 6.46 (m, IH), 6.64 - 6.67 (m, 2H), 6.86 - 6.88 (m, 2H), 7.03 - 7.12 (m, 5H) ppm; 13C NMR (126 MHz, CDCl3) δ -5.5, -5.4, -5.3, - 4.7, -4.6, -4.5, 18.0, 18.1, 18.2, 18.2, 25.8, 25.9, 29.6, 50.4, 50.6, 51.9, 55.0, 55.2, 55.8, 58.7, 58.8, 63.8, 63.9, 72.7, 72.7, 77.2, 79.5, 79.6, 92.2, 92.3, 93.6, 93.6, 94.8, 94.8, 95.0, 95.2, 96.5, 96.6, 96.6, 96.6, 101.9, 102.0, 109.3, 109.4, 112.6, 112.6, 126.3, 126.4, 126.5, 127.6, 127.8, 127.8, 129.0, 136.8, 136.9, 156.7, 158.7, 160.5, 160.6, 161.3, 161.3, 170.4, 170.5 ppm; ESMS, positive ion detection m/z 905.7 [M + Na]+; ESMS, negative ion detection m/z 881.5 [M - H]".

(b) Deprotection - 6- [6- (1,2-Dihydroxy-ethyl) -3-methoxy- [1,4]dioxan-2-yloxy] -3,3a-dihydroxy-4-methoxy-8a- (4-methoxy- phenyl) -l-phenyl-2,3,3a,8a-tetrahydro-lH-8-oxa- cyclopenta[a]indene-2-carboxylic acid methyl ester (62) and (63) 6

62 63 C34H3SO13 C34H38O13 Exact Mass: 654.23 Exact Mass: 654.23 MoI. Wt: 654.66 MoI.Wt: 654.66

Two reactions were carried out exactly the same

Two reactions were set up by dissolving the starting material 60 or 61 in THF (2, 3 mL) cooling to O0C then adding the TBAF (3 eq. ) . The ice bath was removed and the reactions were left stirring at room temperature for 4 hours. After this time TLC showed both reactions were complete. They were worked up the same by portioning between 10% citric acid (20 mL) and ethyl acetate (50 mL) . The organic phase was washed with water (1 x 20 mL) then brine (1 x 20 mL) . The combined aqueous phase was back extracted with ethyl acetate (1 x 20 mL) . The combined organic phase was dried over sodium sulphate, filtered and the solvent removed in vacuo. Both reactions were purified by flash chromatography using ethyl acetate as eluent.

Starting with compound 60 (20.0 mg, 0.0226 mmoles), compound (62) (7.8 mg, 52 % yield) was obtained as a glassy oil. The sample was a mixture of diastereomers so both the 1H and 13C NMR spectra were very complicated with each signal being doubled, also this compound still contained some impurity from the reaction [a doublet of doublets around 3 ppm being a major impurity signal] . Rf [ethyl acetate] = 0.33; HPLC (210 nm) tR = 19.71 (45%), 20.48 (42%) min; UV λmax (acetonitrile/water) = 219.4/228.8, 271.3 nm; 1H NMR (500 MHz, CD3CN) δ 3.44 (s, 3H), 3.59, 3.60 (2s, 3H), 3.67, 3.68 (2s, 3H), 3.85, 3.86 (2s, 3H), 3.43 - 4.04 (m, 7H), 4.12 - - Ill -

4.20 (m, 2H), 4.58 (s, IH), 4.81 - 4.85 (m, IH), 5.32 (s, IH), 6.36 - 6.38 (m, IH) , 6.47 - 6.48 (m, IH), 6.64 - 6.67 (m, 2H) , 6.93 - 6.97 (m, 2H) , 7.05 - 7.11 (m, 5H) ppm; 13C NMR (126 MHz, CD3CN) δ 42.7, 51.0, 51.1, 51.7, 54.6, 54.6, 55.2, 55.5, 56.0, 59.3, 63.0, 68.7, 71.4, 73.2, 80.0, 93.0, 93.2, 94.1, 94.7, 95.0, 95.8, 95.8, 102.3, 102.4, 110.0, 112.6, 126.8, 128.1, 128.1, 128.5, 129.4, 138.4, 158.1, 159.0, 160.8, 161.0, 170.8, 174.4 ppm; ESMS, positive ion detection m/z 677.5 [M + Na]+; ESMS, negative ion detection m/z 653.1 [M - H]".

After collecting data, the sample above was mixed with an authentic sample of pure 2A (8 mg) obtained from natural sources. Analyses were re-run and one set of signals in each spectrum increased in intensity and correlated perfectly proving that one of the diastereomers in the synthetic mixture above was indeed the desired target 2A. HPLC (210 nm) tR = 19.77 (34%), 20.46 (55%) min; UV λmax (acetonitrile/water) = 219.4/228.8, 271.3 nm.

Starting with compound 61 (84.0 mg, 0.095 mmoles), compound (63) (46.7 mg, 75 % yield) was obtained as an off white solid. Rf [ethyl acetate] = 0.33; 1H NMR (500 MHz, CD3CN) δ 3.46, 3.47 (2s, 3H), 3.59, 3.60 (2s, 3H), 3.67, 3.67 (2s, 3H) , 3.85, 3.86 (2s, 3H) , 3.26 - 4.21 (m, 8H) , 4.16 - 4.21 (m, IH), 4.57 - 4.60 (m, IH), 4.81 - 4.85 (m, IH), 5.31 - 5.32 (m, IH) , 6.30 (s,lH), 6.39 - 6.40 (m, IH), 6.64 - 6.67 (m, 2H) , 6.95 - 7.00 (m, 2H) , 7.04 - 7.11 (m, 5H) ppm; 13C NMR (126 MHz, CD3CN) δ 51.0, 51.1, 51.7, 55.0, 55.1, 55.4, 55.5, 56.0, 58.9, 62.9, 71.2, 76.1, 76.2, 80.0, 92.3, 92.4, 94.0, 94.0, 94.1, 95.1, 96.4, 96.5, 96.5, 96.6, 102.3, 102.4, 110.1, 110.2, 112.6, 126.8, 128.1, 128.1, 128.5, 129.4, 138.3, 138.4, 158.1, 158.9, 160.9, 161.0, 161.1, 161.1, 170.8, 170.8 ppm; ESMS, positive ion detection m/z 677.4 [M + Na]+; ESMS, negative ion detection m/z 653.1 [M - H]-. References for Examples 7 to 9: 1. Wynαann, W. E.; Davis, R.; Patterson, Jr., J. W. ; Pfister, J. R. Synth Commun., 1988, 18, 1379. 2. Lee, Y. -J.; Wu, T. -D., J. Chinese Chem. Soc. 2001, 48, 201 - 206. 3. Bouktaib, M.; Lebrun, S.; Atmani, A.; Rolando, C. Tetrahedron 2002, 58, 10001 - 10009. 4. a. McGarry, L. W.; Detty, M. R. J. Org. Chem. 1990, 55, 4349 - 4356. b. Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.; Varma, R. S. J. Chem. Soc. Perkin Trans I 1985, 799 - 808. 5. Gerard, B.; Jones, II, G.; Porco, Jr., J. A. J. Am. Chem. Soc. 2004, 126, 13620 - 13621. 6. a. Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746. b. Srivastava, S. D.; Srivastava, S. K. Indian J. Chem. 1987, 26B, 57 - 58. 7. a. Roush, W. R.; Lin, X. -F. J. Am. Chem. Soc. 1995, 227, 2236 - 2250. b. Roush, W. R.; Lin, X. -F. J. Org. Chem. Soc. 1991, 56, 5740 - 5742. 8. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.