NZ619726B2 - Synthesis of cleistanthin a and derivatives thereof - Google Patents

Abstract

Disclosed is a method for preparing Cleistanthin A (the compound of formula I), a diphyllin glycoside, and derivatives and intermediates thereof. In particular the present invention provides a method for synthesis of compound of formula D a key intermediate of diphyllin, which can be carried out in a shorter duration and at an ordinary temperature between 0 - 25 degree centigrade or at a room temperature. a shorter duration and at an ordinary temperature between 0 - 25 degree centigrade or at a room temperature.

Description

TITLE SYNTHESIS OF CLElSTANTHlN A AND TIVES THEREOF FIELD OF THE INVENTION The present invention relates to methods for synthesizing anthin A, derivatives thereof, and to intermediates thereto.

BACKGROUND OF THEINVENTION Cleistanthin A (I) is a diphyllin glycoside isolated from the tropical plant ‘10 Cleistanthus collinus: OCH3 Hob.\\OCH3 o o anthin A is a diphyllin glycoside having anticancer potential. it. is found to arrest growth by inhibiting DNA synthesis and cancer cell on and by g cancer cells to apoptosis. These properties of cleistanthin A renders it ing agent useful in regimens for treating cancer. The conventional process for the isolation of cleistanthin A comprises the steps of treating the dried leaves of Cleistanthus collinus with petroleum ether to obtain a defatted powder, which is subsequently extracted with acetone and treated with benzene and chloroform to ' afford a black residue. Pure cleistanthin A is then isolated ing recrystallization with acetone. Because such a process is lengthy and not sufficient for gramscale quantities, synthetic procedures have been developed which culminate in the glycosylation of diphyllin (ll): Diphyllin (II) is thus a key ediate in the synthesis of cleistanthin A. The synthesis of diphyllin as well as anthin A is reported in , the ty of which is herein incorporated by reference. This synthesis of diphyllin, while accomplished in only five linear steps from commercially available starting material, es a metallation step requiring ely low temperatures. Such temperatures, while may be easy to carry out on small laboratory scale, are exponentially problematic on a commercial scale, requiring the use of hazardous reagents and long reaction times.

Further, such conditions limit the scale on which a compound can be manufactured, ultimately increasing the production cost of the active pharmaceutical ingredient (API).

Hence, there remains a need for a more robust, of shorter duration and commercially viable synthesis of diphyllin, its analogs and ediates thereof.

SUMMARY OF THE INVENTION A first aspect of the invention provides for a method for preparing a compound of formula D: (R1)n (R2)m wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -NO2, -CN, or -L-R; (10871759_1):KZA each L is independently a covalent bond or a bivalent C1-6 hydrocarbon chain, wherein one or two methylene units of L is optionally and ndently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, (O)O-, -OC(O)N(R)-, , -S(O)2-, -S(O)2N(R)-, -N(R)S(O)2-, -OC(O)- or -C(O)O-; each R is independently hydrogen or selected from a group consisting of C1-6 aliphatic, phenyl, a 3-8 membered clic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or ic carbocyclic ring, a 3-8 membered monocyclic saturated or lly unsaturated heterocyclic ring having 1-2 atoms independently selected from nitrogen, oxygen, or , a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, , or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and PG is selected from -CH(OR3), 2-(1,3-dioxolanyl) or 2-(1,3-dioxanyl); and R3 is an aliphatic group; comprising the steps of: (a) providing a solution of a compound of formula C: (R1)n wherein n is 0-4; each R1 is independently selected from halogen, -NO2, -CN, or -L-R; each L is independently a nt bond or a bivalent C1-6 hydrocarbon chain, n one or two methylene units of L is optionally and independently replaced by -O-, -S-, - N(R)-, -C(O)-, -C(S)-, -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, -S(O)-, -S(O)2-, -S(O)2N(R)-, (O)2-, -OC(O)- or -C(O)O-; (10871759_1):KZA each R is independently hydrogen or selected from a group ting of C1-6 aliphatic, , a 3-8 membered clic saturated or partially unsaturated yclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 atoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated, or ic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur; PG is selected from -CH(OR3), 2-(1,3-dioxolanyl) or 2-(1,3-dioxanyl); R3 is an aliphatic group; and LG is halogen; (b) sonicating said solution; and (c) reacting said solution with an aryl aldehyde solution and an alkyl lithium reagent under sonication to form a compound of formula D.

A second aspect of the invention provides for a compound of formula D prepared by the method of the first aspect of the invention.

A third aspect of the invention provides for a nd of formula F prepared by the method of the first aspect of the invention.

A fourth aspect of the invention provides for a nd of formula III prepared by the method of the first aspect of the invention.

A fifth aspect of the invention es for a compound of formula IV prepared by the method of the first aspect of the invention.

A sixth aspect of the invention provides for Cleistanthin A prepared by the method of the first aspect of the invention. (10871759_1):KZA Accordingly, in one aspect the present invention provides a method for sis of an intermediate compound of diphyllin, which can be carried out in a shorter duration and at an ordinary temperature.

In one embodiment the present invention provides a method for synthesis of compound of a D: (R1)n (R2)m (10871759_1):KZA comprising the steps of: (a) providing a solution of a compound of formula C: (mamLG (b) sonicating said solution; and (c) reacting said. solUtion with an aryl aldehyde solution and an alkyl lithium reagent under sonication to form ‘a nd of formula D. The compounds of formula D and C are described in detail herein below.

In another aspect, the present invention provides'a method for synthesisof a lin (ll) or its derivatives, which can be carried out in a shorter duration and at an ordinary temperature.

In some embodiments the t invention provides a method for synthesis of nds of formula III: ' Ill comprising the steps of: (a) reacting nd of formula D with a compound of formula E: R3020 : C02R3 under conditions effective to form a compafiund of formula F; and (b) reacting said compound F with a metal hydride to form a compound of formula III The compounds of formula E, F and III are described in detail herein below.

In one embodiment said intermediate compound F is dimethyl 1- (benzo[d][1,3]dioxo|y|)-‘4—hydroxynaphtha|ene-2,3—dicarboxylate, the reduction of said . yl zo[d][1,3]dioxol-S-y|)hydroxynaphtha|ene—2,3- 'dicarboxylate with lithium aluminum hydride provides diphyllin (II).

In still another aspect the present invention provides a method for synthesis of'an improved method for preparing an acetate derivative of Cleistanthin A.

In an embodiment, the present ion provides a method for preparing a compound of formula IV: sing the steps of: (a) providing a compound of formula Ill: (b) reacting said compound of formula III with a pyranose of formula V: HO 0 under conditions effective to form a compound of formula IV. The nds of formula III, IV and V are described in detail herein below.

In yet another aspect the'present invention provides an improved method for preparing anthin A, which can be carried out in a shorter duration and wherein the metallation step is carried out at an ordinary ature.

In one of the embodiment, the present invention provides a method for preparing anthin A (I): OCH3 HObMOCHg O O under conditions effective to form cleistanthin A (I). In one specific ment, the effective conditions include treating Compound of a IV with an alkali and a solvent to form compound of formula I.

DETAILED DESCRIPTION OF'THE INVENTION In general aspects the present invention provides methods for synthesizing cleistanthin A, derivatives thereof, and intermediates thereof. Cleistanthin A is a diphyllin glycoside and one of the main step in synthesizing it, is glycosylation of an intermediate diphyllin. One key step in the synthesis~ of diphyllin is the condensation of an aryl lithium anion, formed from the reaction of an aryl lithium and an aryl aldehyde. Such aryl lithium anions are readily generated in situ via a lithium-halogen exchange from the treatment of an aryl halide with a lithium reagent. Lithium reagents are moisture-sensitive and/or pyrophoric, requiring the reactions to be conducted at very low atures. Moreover, because the reactivity of lithium reagents is in part due to their high nucleophilicity, they are prone to unwanted side reactions. Such side reactions include the SNAr addition of the alkyl lithium to the aryl halide, ing in an alkylated aryl species rather than the desired aryl lithium anion. Alkylated aryl species account for the majority of byproducts associated with lithium—halogen exchange and render the starting material le. While the generation of such byproducts may be acceptable at the first step of a synthesis, it is particularly undesirable at later ‘15 stages of a synthesis when advanced intermediates are converted to unusable materials. Thus, low atures are necessary to minimize both the hazards associated with the. use of lithium reagents as well as the potential for side reactions. As discussed above, such temperatures, though may appear trivial on small scale, are much more ult to reach, maintain and/or control at small as well as on a larger, commercial scale, thus rendering such reactions inefficient and costly.

It has now been surprisingly found that such condensations may be performed at higher temperatures. Moreover, such condensations run at higher temperatures result in fewer side ons. ingly, the present invention es methods of preparing compounds of formula III: or a pharmace‘utically acceptable salt thereof, wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, j-NOZ, —CN, or -L-R; each L is independently a nt bond or an ally substituted bivalent CH; hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by -—O—, —S—, —N(R)—, —C(O)—, —C(S)—, —C(O)N(R)— , -N(R)C(O)NlR)-, -N(R)C(O)-, -N(R)C(OlO-, N(Rl-, -S(O)-, -S(O)2—, -S(O)2N(R)—, —N(R)S(O’)2—, —OC(O)— or -—C(O)O—; and each R is independently hydrogen or an ally substituted group selected from CH; aliphatic, phenyl, 'a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 membered ic saturated, lly unsaturated, or aromatic carbocyclic ring, a 3:8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 ed heteroaryl ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur, or an 8—10 membered bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or , or: , two R groups on the same nitrogen are taken together with their ening 'atoms to form. a 3-8 membered saturated, partially unsaturated, or ic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. in particular, the present invention provides methods of preparing synthetic intermediates useful for preparing such compounds.

‘In certain embodiments, the present compounds are generally prepared according to Scheme I set forth below: Scheme l _ PG (R1in———':Ajj\HS—:—> (R )n LG -—->(R1)r©:LG wherein each of R1, R2, R3, n, m, PG, and LG are as defined and bed in embodiments herein.

In one . aspect, ,the present invention provides s for preparing benzo[d][1,3]dioxolyl(pheny|)methanol compounds of formula D according to the steps depicted in Scheme l, above. At step 5-1, a leaving group, LG, is orated into intermediate A to form intermediate B. One of ry skill in the art will recognize that a variety of g groups are suitable for use in provided methods. As used herein, the term ”leaving group” refers to a chemical moiety that is readily displaced by a desired incoming chemical moiety. Suitable leaving groups are well knowni'to a person having ordinary skill in the art and can be selected suitably. Such leaving groups include halogens. In certain embodiments,,LG is Bromine. In some embodiments, LG is iodine.

In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, R1 is L-R. In some embodiments, R1 is L-R, wherein L is a covalent bond.

In some embodiments, R1 is L-R, wherein L is an optionally substituted bivalent C1- hydrocarbon chain, wherein one or two methylene units of L is optionally and . independently replaced by -o—, —s—, -N(R)’-, —C(O)—, —C(S)—, —C(O)N(R)—, -N(R)C(O)N(R)-. -.N(R)C(0)—i -N(R)C(0)0-, -0C(0)N(R)-, —S(0)-, -S(O)2—, -S(O)2N(R)—, —N(R)S(O)2—, —OC(O)—-'or —C(O)O-. In some embodiments, R1 is L-R, wherein L is an ally substituted bivalent C1_5 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O—, —S—-, , —C(O)—, —C(S)-, —C(O)N(R)—, -N(R)C(O)N(R)—, —N(R)C(O)—, 4N(R)C(Q)O— , —OC(O)N(R)—, —5(0)—, —5(,0)2—, -S(O)2N(R)—, -—N(R)S(O)2—, —oc(0)— or —C(O)O—. In some embodiments, R1 is L-R, wherein L is an optionally substituted bivalent C14 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —-O—,‘ —S—-, —, —C(O)—, , -C(O)N(R)—, ' (O)N(R)-i (O)-i -N(R)C(0)0-, -OC(O)N(R)-, -S(O)-, -S(O)2-, -—S(O)2N(R)—, —N(R)S(O)2-, —OC(O)— or —C(O)O—. In some embodiments, R1 is L-R, wherein L is an optionally substituted bivalent C13 arbon chain, wherein one or two ene units of L is optionally and independently replaced by —O—, —S—, -N(R)—, —C(O)—, -, —C(O)N(R)—, -N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O— ,-OC(O)N(R)—, -S(O)—, -—S(O)2—, N(R)—, -N(R)S_(O)2—, —OC(O)— or —C(O)O—.

In some ments, R1 is L-R, wherein L is an optionally substituted bivalent C1- 2 hydrocarbon chain, wherein one or both methylene units of L is ally and independently replaced by -o—,' —s—, -N(R)—, ‘—C(O)—, —C(S)—, —C(O)N(R)—, -N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, :OC(O)N('R)—-, , “5(0)“, . -S(O)2N(R)-, (O)2—, —OC(O)— or —-C(O)O—.

In some embodiments, R1 is L-R, n L is an optionally subStituted bivalent C1- 2 hydrocarbon chain, wherein One methylene unit of L is optionallyv'and independently replaced by —O—, -—S-, —N(R)—, —C(O)—, '—C(S)—, —C(O)N(R)—, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(0)Q-, -0Cl0)N(R)—, ‘—S(O)-, -S(0)2-, -S(O)2N(R)—,—N(R)S(O)2—,—OC(O)—or—C(O)Of. 2012/001296 In some embodiments, R1 is L-R, wherein L is —O—.

In some embodiments, R1 is L-R, wherein R is hydrogen or an optionally substituted group selected from C1_5 aliphatic, phenyl, a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 ed monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially _10 unsaturated, or aromatic cyclic ring having 1-4 heteroatoms ndently selected from en, oxygen, or sulfur.

In some embodiments, R1 is L-R, wherein R is hydrogen. In some embodiments, R1 is L-R, wherein L is a covalent bond and R is hydrogen.

In some ments, R1 is L-R, wherein R is an optionally substituted group '15 selected frOm C1-5 aliphatic. in some ments, R1 is L-R, wherein R is an optionally substituted group selected from C1_5 aliphatic. In some embodiments, R1 is L—R, wherein R is an optionally substituted group selected from C14 aliphatic. in some embodiments, R1 is L-R, wherein L is a covalent bond and” R is n~butyl, sec- butyl or tert—butyl. In some embodiments, R1 is L-R, wherein L is a covalent bond and R is —CH2CH2CH2CH3.

In some embodiments,»R1 is L—R, wherein R is an optionally substituted group selected from C13 tic. In some embodiments, R1 is 'L-R, wherein L is a nt bond and R is propyl or isopropyl. In some embodiments, R1 is L-R, wherein L is a covalent bond and R is —CH2CH2CH3.

In some embodiments, R1 is L—R, n R is an optionally substituted group selected from Cm aliphatic. In some embodiments, R1 is L-R, wherein L is a covalent bond and R is —CH2CH3. ‘In some embodiments, R1 is L-R, wherein L is - O— and R is —CH2CH3.

In some embodiments, R1 is L—R, wherein R is an ally substituted methyl group. In some embodiments, R1 is L—R, wherein L is a covalent bond and R is - CH3.

In some embodiments, R1 is L-R, 'wherein L is —O— and R is -CH3.

In some embodiments, intermediate A is selected from: O ' o . O /\oADD/H /o©/ILH O/H . \O O O In some embodiments of‘ 5-1, such LG may be incorporated via an electrophilic aromatic substitution on. In some embodiments of 5-1, a halogen LG is incorporated into intermediate A via an electrophilic aromatic substitution reaction. In some such embodiments of 5-1, nds of intermediate B are prepared by reacting intermediate A with X2. In some embodiments, X2 is Clz, Brz or I2. In some embodiments of 5-1, compounds of intermediate B are prepared by reacting ediate A with X2 in the presence of an acid. Suitable acids for use in step S-l include, but are not d to, l acids such as hydrochloric acid, as well as organic acids such as acetic acid. In some embodiments of step S-1, intermediate A is treated with X2 in the presence of acetic acid. In certain embOdiments, the electrophilic aromatic substitution of 3,4- ' dimethoxybenzaldehyde in the presence of brOmine and acetic acid provides 2- bromo-4,5-dimethoxybenzaldehyde.

At step 5-2, the aryl aldehyde is converted to a protecting group PG. The PG of intermediate C is a suitable carbonyl protecting group. Suitable carbonyl protecting groups are well known to a person having ordinary skill in the art and can be selected ly by such a person. Suitable carbonyl protecting groups include, but are not limited to, cyclic and dialkyl acetals, monothioacetals or ' cetals. Cyclic acetals include 1,3-dioxolanes and 11,3'-dioxanes. Cyclic thioacetals include 1,3-dithianes and 1,3-dithiolanes. in some embodiments of step 5-2, the PG moiety of intermediate C is a 1,3-dioxolanyl moiety. In some embodiments of step 5-2, the PG moiety of ediate C is a 1,3~dioxany| moiety. In some embodiments of step 5-2, the PG moiety of intermediate C is a 1,3-dithiolanyl moiety. In some embodiments of step, 5-2, the PG moiety of intermediate C is a thianyl moiety. In some ments of step 5—2, the PG moiety is -—CH(OCH3)2. In some ments of step S-2, the’PG moiety is — CH(SCH3)2. In some embodiments of step 5-2, the PG mOiety is —CH(OC2H5)2. In . some. embodiments of step 5-2, the PG moiety is —CH(OC3H7)2. In certain- embodiments, the present invention provides a method of preparing intermediate C by treating benzaldehyde B with ethylene glycol, or’an equivalent thereof. In some embodiments, the present invention provides a method of preparing intermediate C by treating benzaldehyde B with a catalytic amount of ' acid and ethylene glycol, or an equivalent thereof. Suitable acids for catalyzing the condensation of ne glycol and an aldehyde include both mineral acids, such as hydrochloric acid, and organic acids, such as p-toluenesulfonic acid. in certain embodiments, the condensation of 2-bromo-4,5—dimethoxybenzaldehyde and ethylene glycol in the presence of catalytic p-toluenesulfonic acid provides 27 (2—bromo-4,5-dimethoxyphenyl)-1,3—dioxolane. One of ordinary skill will appreciate that the oxidation state of the aldehyde moiety in intermediate A can be modified so as to permit access to other ng materials of formula A. For example, in some embodiments, an appropriately substituted c acid is subjected to electrophilic aromatic substitution conditions to provide the c acid analog of intermediate B. The benzoic acid moiety is then protected as, for example, an orthoester to enable aryl lithium ion at step 5-3. The orthoester PG is then deprotected and/or converted to an aldehyde or aldehydic ion state prior to or during step 5-4.

At step 5-3, the aryl ring of intermediate, C is metallated with an alkyl lithium to form an aryl lithium anion in situ. Suitable alkyl lithiums for use in the present invention e n-butyllithium, sec-butyllithium and tert-butyllithium. in some embodiments, the aryl ring of formula C is treated with n—butyllithium.

The aryl anion formed from treating intermediate C_with an alkyl lithium is thereby reacted with an aryl aldehyde to form intermediate D. In some ments, the aryl aldehyde is optionally substituted pipronal. As discussed " above, such nucleophilic additions are lly performed at low temperatures, for example, at -70 °C. Typically, reactions run at such low temperatures take 3 or more hours to ed the desired temperature. Once the reaction has reached the target ature, such as -70‘ bC, the reaction ature. must -be ' carefully maintained by slow addition of or to the electrophile.

Temperatures of about -60 °C to about -80 °C are generally achieved h the use of solid carbon dioxide (e.g., dry ice) or liquid nitrogen. Both of these reagents are hazardous on small scale, and the hazards which is only ied on larger scales. For example, both dry-ice and liquid nitrogen rapidly freeze or burn unprotected skin, resulting in frostbite. r, dry ice readily sublimes at room temperature, releasing carbon dioxide gas into the air and displacing the oxygen in confined locations. Similarly,‘ liquid nitrogen evaporates below room temperature and can also displace gen in the air. Thus, both dry ice and liquid nitrogen can act as asphyxiates when used in poorly ventilated spaces.

Further, both carbon dioxide and nitrogen are odorless, colorless and tasteless, and can asphyxiate a subject without any sensation or prior warning.

At temperatures of about -60 °C to about -80 ”C, a nucleophilic on reaction such as step 5-3 can require reaction times of at least 8-9 hours or longer, depending on the scale, as larger volumes require longer cooling times. Further, ‘ the temperature of larger volumes is more difficult maintain and control. Due to the difficulties in maintaining such a temperature, side reactions are common and result in higher percentages of impurities. Such impurities render the ion of the product difficult and contribute'to overall low yields. tion is the agitatation of. particles in a sample through the application: of sound energy (i.e., ultrasound). lthas now been surprisingly found that the use of sonication'in the nucleophilic addition of the aryl m anion to the aryl aldehyde results in a cleaner reaction profile. ‘Thus, in some ments, the present invention provides method of preparing a compound of intermediate D comprising a nucleophilic addition reaction of. an aryl lithium anion to an aryl aldehyde, wherein the nucleophilic on reaction is performed under sonication. It has further been surprisingly found that such a nucleophilic on reaction can be run at room temperature, thereby decreasing the reaction times and eliminating the hazards associated with the use of dry ice and/or liquid nitrogen. Moreover, the impurities formed during sonication are minimal, thus demonstrating the enhanced selectivity of the reaction.

Accordingly, in some embodiments, the present ion provides a method of preparing intermediate D comprising the nucleophilic addition of an aryl anion to ‘ an aryl de, wherein the nucleophilic addition is performed under tion at room temperature. In certain embodiments, the nucleophilic addition of (2- (1,3-dioxolanyl)4,5-dimethoxyphenyl)lithium anion to pipronal provides (2— (1,3—dioxolanyl)4,5-dimethoxyphenyl)(benzo[d][1,3]dioxol-S—yl)methanol, wherein the nucleophilic addition is performed under sonication and at room temperature as per Scheme ll.

‘Scheme ll: Sonicator n BuLi & THF —_‘—_———————,——> Piperonal In some embodiments, such a sonication reaction is complete within. 1-3 .hours.

Further, the use of tion is environmentally friendly and doesn’t generate ' waste (such as s emissions and/or solvent waste) d to temperature control.

At step 5-4, intermediate D is converted to an isobenzofuran moiety in situ, which then undergoes a cycloaddition reaction with dicarboxylacetylene ediate E to afford intermediate F. $ee,for example, Charlton et a/.,'”‘Hindered Rotation in Arylnaphthalene Lignans," J. Org. Chem. 1996, 61(10), 3452-3457. In some embodiments of step 5-4, the ddition reaction is a Alder reaction.

One of ordinary skill will recognize that a cycloaddition reaction such as step 5—4 requires removal or unmasking of the PG (i.e. the aldehyde) to enable the. formation of the isobenzofuran intermediate. Suitable conditions for removing the PG moiety in intermediate D are well known in the art. In some embodiments of 4, ediate D is treated with an acid. Suitable acids for removing P6 in step S-4 include organic acids and mineral acids. In some embodiments, intermediate D is treated with an c acid. In some such embodiments, intermediate D is treated with acetic acid. In some embodiments, intermediate D is treated with a mineral acid. In some such embodiments, intermediate D is treated with hydrochloric acid. Thus, in some embodiments, the ddition of an isobenzofuran and a dicarboxylacetylene moiety E in the presence of'acetic acid provides the alkyl 1-(benzo[d][1,3]dioxolyl)—4-hydroxynaphthalene—2,3- .- 20 dicarboxylate F.

In some embodiments, ediate D is treated with acid and heated to effect in situ generation of an isobenzofuran. One of ordinary skill in the art would recognize that a wide variety of acids are useful for deprotecting acid-sensitive acetal groups. In some such embodiments, intermediate D is treated with a ‘ mineral acid and heated.- In some embodiments, intermediate D is treated with an organic acid and heated. In some embodiments, the Diels—Alder reaction of step 5—4 is heated to a temperature of at least 100°C in the presence of an organic acid. In some embodiments, the Diels-Alder reaction of step 5-4 is heated to a temperature of at least 100°C in the ce of acetic acid. In some embodiments, the Diels-Alder reaction of step 5-4 is heated to a temperature of - at least 120°C in the presence of acetic acid. In some embodiments, the Diels- Alder reaction of step 5-4 is heated to a temperature of at least 140 °C in the presence of acetic acid.

In some embodiments, each R3 of intermediate E is independently an optionally substituted C16 aliphatic. In some embodiments, each R3 of intermediate E is independently an optionally substituted C1-5 aliphatic. In some embodiments, each R3 of intermediate E is independently an optionally substituted C1_4 aliphatic.

In some embodiments, each R3 of intermediate E is independently an optionally substituted C1_3 aliphatic. In some embodiments, each R3 of intermediate E is an optionally substituted propyl group: In some' embodiments, each R3 of ediate E is ndently an optionally substituted C1_2 aliphatic. 'In some embodiments, each R3 of intermediate E is an optionally substituted ethyl group.

In some embodiments, each R3 of intermediate E is an optionally substituted methyl group. In some embodiments, each R3 of intermediate E is —CH_:,. In some embodiments, each R3 of intermediate E is —CH2CH3. In some embodiments, each R3 of intermediate E is ~CH3. In some embodiments, each R3 of intermediate E is -' CH2CH2CH3.

In certain embodiments, the Diels-Alder reaction of '5-(5,6- dimethoxyisobenzofuranyl)benzo[d][1,3]dioxo|e and diethyl ene— dicarboxylate in the presence‘of acetic acid and at 140 °C es yl 1- (benzo[d][1,3]dioon—S-yl)—4-hydroxynaphthalene-2,3-dicarboxylate.

At step 5-5, the naphthylenedicarboxylate _F is treated with a metal hydride to effect the condensation—cyclization of the lactone moiety of intermediate III. One of ordinary skill in the art would recognize that the hydroxyl group of ediate F controls the ivity of the reduction through a six-membered coOrdination of the metal, directing reduction of the proximal carboxylate ester.

Suitable metal hydrides useful in the ed reduction of intermediate F include borohydrides, boranes and aluminum es. In some embodiments of step 5- , the metal hydride is selected frdm lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, m borohydride, zinc dride and borane. In certain embodiments, the reduction of dimethyl 1— (benzo[d][1,3]dioxol—5—yl)hydroxynaphthalene-2,3-dicarboxylate with lithium aluminum hydride provides lin (ll).

According to another , the present invention provides a method for preparing a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein: m is 0-3; n is 0—4; each of R} and R2 is independently selected from halogen, ~N02, ——Cl\l, or -L-R;, each L is independently a covalent bond or an optionally substituted bivalent C145 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O—, -S—, -N(R)—, , -—_C(S)—, —C(O)N(R)—, -N(R).C(0)N(R)-, -N(R)C(0)—, -N(R)C(0)0-, -0C(0)N(R)—, -5(0)-, —5(0)2-, -S(O)2N(R)—, (O)2—, —OC(O)— or -; each R is independently hydrogen or an ally substituted group selected from €1.16 aliphatic, phenyl, a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3—8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- membered bicyclic saturated, partially unsaturated, or aromatic cyclic ring having 1—4 heteroatoms independently selected from nitrogen, , or sulfur, or: two R groups on the same nitrogen are taken together with their intervening- atoms to form a 3-8 membered Saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R3, R4 and R5 is independently hydrogen, R6, or —C(O)R6;' each R6 is independently an optionally substituted CH, tic group or a suitable yl protecting group; comprising the steps of: (a) providing a compound of formula lll: wherein each of n, m, R1, and R2 is as defined above and described herein, and (b) reacting said compound of formula ill with a pyranose of formula V: HO 0 V wherein each of R3, R4 and R5 is independently hydrogen, R6, or —C(O)R6; and each R6 is independently an optionally tuted CH; aliphatic group or a suitable yl protecting group; under conditions ive to form a compound of formula W.

The synthesis of compounds of a V is set forth in , the entirety of which is herein incorporated by reference.

According to one embodiment, conditions effective to form a compound of formula Ill include a base. One of ordinary skill will recognize that a variety of bases are le for use in step (b) above. Suitable bases include inorganic or mineral bases, such as hydroxides, and organic bases such as alkyl amines and aikoxides. In some embodiments, a compound of formula III is reacted with a compound of formula V in the presence of sodium hydroxide. In some such embodiments, the sodium hydroxide is aqueous. In some embodiments, a compound of formula Ill is reacted with a compound of formula V in the presence of a 2 molar aqueous on of sOdium hydroxide.

One of ry skill will recognize that a compound of formula ill is not soluble in an aqueous on of sodium hydroxide. One of ordinary skill in the art will further recognize that the use of aqueous sodium hydroxide in step (b) above requires a phase transfer t. Thus, in some embodiments, one or more phase transfer reagents are utilized in step (b) above. Suitable phase transfer reagents include tetraalkylammonium salts such astetrabutylammonium salts. In some embodiments, a compound of formula ill is reacted (with a compound of formula V in the presence of aqueous sodium hydroxide and tetrabutylammonium bromide.

In some embodiments, the t invention provides a'method for preparing a compound of formula ill: wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -N02, ~CN, or —L-R; ' each L is independently a covalentbond or an optionally tuted bivalent CH; hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O—,- —S—, —N(R)—, , —C(S)—-, —C(O)N(R)~—, -N(R)C(0)N(R)-, —N(R)C(0)-, —N(R)C(O)O—, -0C(0)N(R)—. -S(O)-, -, -S(O)2N(R)—, —N(R)S(O)2—, — or -C(O)O—; each R is independently hydrogen or an optionally substituted group selected from C14; aliphatic, , a 3-8 memberedmonocyclic saturated or partially unsaturated carbocyclic ring, an 8—10 membered bicyclic saturated, partially unsaturated, or aromatic carb0cyclic ring, a 3-8 ed monocyclic saturated or partially unSaturated heterocyclic ring having 1-2 atoms independently ed from en, oxygen, or sulfur, a 5—6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- 10 ed bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3—8 membered saturated, lly unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; comprising the steps of: (a) ing a compound of formula F: ' wherein m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -—N02, —CN, or -L-R; each L is independently a covalent bond or an optionally substituted bivalent C14; hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O—-, 55—, -N(R)-, —C(O)—, —-C(S)—, I—C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)—, —N(R)C(.0)O-, N(R)-, _-S(O)—, -S(O)2—, -S(O)2N(R)-, —N(R)S(O)2—, —OC(O)— or —C(O)O—; each R is independently hydrogen or an optionally tuted group selected from C16 aliphatic, phenyl, a 3—8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3—8 membered monocyclic saturated or lly unsaturated 'heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- 10'membered bicyclic saturated, partially unsaturated, or aromatic cyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur; each R3 is an optionally tuted aliphatic; and (b) reacting said compound F with a metal hydride. to form a compound of formula lll.

As bed above, suitable metal es for use in step (b) above include aluminum hydrides, borohydrides and boranes. in some embodiments, the metal hydride is selected from lithium um hydride, diisobutylaluminum hydride, sodium borohydride, lithium dride, zinc borohydride and borane. in some embodiments, the metal hydride for use in step (b) is lithium um hydride.

One of ordinary" skill will recognize that two molar equivalents of hydride are necessary to effect the ion of the carboxylateproximal to droxyl group on the naphthalene ring (”the proximal carboxylate”). One of ordinary skill will further recognize that many metal hydride reagents have two or more hydrides which may be‘transferred to a compound of formula F. Thus, in some embodiments, less than two molar_equivalents of a metal e reagent is required to completely reduce the proximal carboxylate. 2012/001296 One of ordinary skill in the art will also appreciate that the ent of a compound of formula F with a base such 'as a metal e will result in the immediate deprotonation of the hydroxyl group. .Accordingly, in some ments of step (b) above, a compound of formula F is treated with at least two molar equivalents of a metal hydride to provide a compound of formula iii.

In some embodiments of step (b) above, a compound of formula F is d with at least two molar equivalents of lithium aluminum’hy'dride, wherein the first equivalent of the metal hydride is consumed by the deprotonation ofthe hydroxyl group and the second equivalent is effective to reduce the proximal carboxylate.

One of Ordinary skill in the art will recognize that reactive reagents such as metal hydrides e the use of a non aprotic solvent.' Suitable non polar, aprotic solvents for use in ‘step (b) above include ethers such as diethyl ether, tetrahydrofuran, dioxane and MTBE and hydrocarbon solvents such as hexanes or cyclohexane.

‘ In some embodiments, step 5-5 is performed at a temperature range of about -10 °C to about 0 °C. In some embodiments, step'S-5 is performed at room temperature. in some embodiments, the present‘ invention provides a method for preparing a compound of formula F: wherein: m is 0-3; n is 0-4 each of R1 and R2 is independently selected from halogen, —N02, -CN, or -L-R; each L is independently a covalent bond or an ally substituted bivalent C1_5 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O—, -S—, —N(R)—, —C(O)—, —C(S)—, —C(O)N(R)- , -N(R)C(O)N(R)-, -N(R)C(0)-, 4N(R)C(0)O—, -0C(O)N(R)—, -S(0)-, -5(0)2-.

-S(O)2N(R)—, -N(R)S(O)2—, —OC(O)— or -C(O)O—-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-8 membered clic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 ed monocyclic saturated or partially unsaturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1—4 atoms independently selected from nitrogen, oxygen, or , or an 8-10 membered bicyclic saturated, lly unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms _ ndently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 ed ted, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or ; and each R3 is independently an optionally substituted C1-6 aliphatic; comprising the steps of: (a) providing a compound of formula D: wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, —N02, —CN, or -L—R; each L is independently a covalent bond or an optionally substituted bivalent CM, hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by -O—, —S—, —N(R)—, -C(Q)—, —-C(S)—, ——C(O)N(R)— , -N(R)C(O)N(R)-, *NlR)C(O)—, -N(R)C(0)0—, -0C(O)N(R)-, ~S(0)-. —$(O)2-, . -S(O)2N(R)—, -N(R)S(O)2—, —OC(O)— or —C(O)O—; each R is independently hydrogen or an optionally tuted group selected from C16 aliphatic, phenyl, a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or ic carbocyclic ring, a 3-8 membered . monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently ed from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1—4 heteroatoms. independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated, ’or aromatic heterocyclic ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, or sulfur, or: two 'R groups on the same en are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently ed from nitrogen,oxygen, or sulfur; [and PG is—CH(OR3), -dioxolanyl) or -dioxanyl); (b) reacting said compound of formula D with a compound of formula E: R3020 : 002R3 ‘ wherein each R3 is an optionally substituted Cm aliphatic; .. (c) under ions effective to form a nd of formula F}.

As described above, the reaction of a compound of formula D and a compound of formula E is a cyclization reaction. In particular, such a reactionis a Alder reaction. As further bed above, one of ordinary skill will ize that-the diene component of the Diels-Alder reaction is an isobenzofuran, which is generated in situ from a compound of formula D. In some embodiments, conditions effective to generate an isobenzofuran in situ from a compound of .formula D include heating a compound of formula D in the presence of an acid.

One of ordinary skill in the art will recognize that a variety of acids are. useful to promote and/or facilitate such a reaction. Suitable acids include, t limitation, acetic acid, hloric acid, p-toluenesulfonic acid, and the like. In some embodiments, a compound of formula D is treated with acetic acid.

One of ordinary skill in the art will recognize that a reaction such as the Diels- Alder reaction described above is performed at a temperature range of about 100 °C to about 200°C. In some embodiments, step (c) above is performed using acetic acid at a temperature of about 100 °C. In some embodiments, step (c)‘ above is performed using acetic acid at a temperature of about 120 °C. In some embodiments, step (c) above is performed using acetic acid at a temperature of about 140 °C. In' some embodiments, step (c) above is med using acetic acid at a ature of at least 140 °C.

One of ordinary skill will appreciate that suitable ts for use in step (c) above include those which have a boiling point at or greater than 100 °C. Suitable ts useful in the present invention include polar, protic solvents such acetic acid and oiling alcohols, benzene and its derivatives (e.g. toluene, xylenes), dimethylformamide, dimethylacetamide and diglyme. in some embodiments, step (c) above is performed in acetic acid. ’ _2O In some embodiments, a suitable solvent es halogenated arbon solvents such as chloroform or methylene chloride, ethers such as diethyl ether or tetrahydrofuran and hydrocarbon solvents such as hexanes or cyclohexane.

In some embodiments, one or more reagents may perform as a suitable solvent.

In certain embodiments, the present invention provides a method for preparing a compound of formula D: WO 01352 wherein: m is 0—3; n is 0-4 each of R1 and R2 is independently selected from halogen, —N02, ~CN, or -L—R; each L is independently a covalent bond or an optionally substituted bivalent CH; hydrocarbon chain, wherein one or two eneunits of L is optionally - and independently ed by —O—, —S—, -N(R)—, —-C(O)-, —-C(S)—-, —C(O)N(R)— , -N(R)C(0)N(Rl-. -N(R)C(0)—, -N(R)C(0)0-, -0C(0)N(R)-, -S(0)—, .~S(0)2-.

-S(O)2N(R)—, —N(R)S(O)2—, ~OC(O)— or -C(O)O—; each R is ndently hydrogen or an optionally substituted group selected from CH; aliphatic,’ phenyl, a 3—8 membered monocyclic saturated or partially unsaturated yclic ring, an 8—10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3—8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 atoms independently selected from nitrogen, oxygen, or , a 5-6 membered heteroaryl ring having'1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, Or sulfur; and P16 is selected from —CH(OR8)2, 8)2, 2-(1,3.-dioxolany|),2-(1,3-dioxany|), 2- (1,3-dithiolanyl) or 2-(1,3-dithianyl); and R8 is an optionally substituted CH; tic group; comprising the steps of: (a) providing a on of: . a compound of formula C: (RUn’Ej:/ PG n is 0—4; each R1 is independently selected from halogen, —N02, —CN, or ~L-R; each L is independently a covalent bond or an optionally substituted biValent CH; hydrocarbon. chain, wherein one or two methylene units of L is optionally and independently replaced by —0—, -s—, —N(R)-, -—C(O)—, —C(S)——, -—C(O)N(R)— , -N(R)C(0)N(R)-, 'NlR)C(0)-, ~N(R)C(0)O-, -0C(0)N(R)-, -S(0)-, -S(0)2-, -S(O)2N(R)-, (O)2—,——OC(O)— or—C(O)O—; - each R is independently hydrogen or an optionally substituted group selected from CH; tic, phenyl, a 3-8 membered clic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic ted, partially unsaturated, or aromatic carbocyclic ring, a 3-8 membered clic saturated or partially unsaturated heterocyclic ring having 1—2 heteroatoms independently ed from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 atoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 ed bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 144 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: ' two R groups on the same nitrogen are taken together with their intervening atoms to form a 3—8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; PG is selected from —CH(OR8)2, ~CH(SR8)2, —dioxolanyl), 2-(1,3-dioxanyl), 2— (.1,3—dithiolanyl) or 2-(1,3-dithiany|); R8 is an optionally substitutedCLs aliphatic group; and LG is halogen; (b) sonicating said solution; and (c) reacting said solution with an aryl aldehyde solution and an alkyl m reagent under sonication to form a compound of formula D.

As described above, the reaction of an aryl halide of formula C with an alkyl lithium reagent to form an aryl lithium anion is generally performed at low temperatures to avoid unWanted side reactions. Such temperatures are typically - 65°C to‘ about -80°C. In some embodiments, step (c) above is performed at temperatures above 65°C. In some embodiments, step (c) above under sonication is performed at atures within the range of about 0°C to about °C. In some embodiments, step (c) above Is performed at room temperature for example about 25°C to about 35°C under sonication. cribed above, le alkyl lithium reagents include n-butyllithium, sec— ithium and tert-butyllithium. In some embodiments, the alkyl lithium reagent n-butyllithium.

In some ments, the present invention provides a method of preparing a compound of formula D comprising the steps of (a) providing a solution of a compound of formula C, (b) sonicating said on, and (c) reactingsaid solution with an aryl aldehyde solution and an alkyl lithium reagent to form a-compound of formula D. In some embodiments, the aryl aldehyde is pipronal.

One of ordinary skill will appreciate that such ons require the use of non polar, aprotic solvents. le non polar, aprotic solvents inClude ethers such as diethyl ether, Methyl Tertiary Butyl Ether (MTBE), tetrahydrofuran or dioxane or hydrocarbon solvents such as hexanes or cyclohexane.

In some embodiments, the present invention provides a method for preparing a compound of formula C: (wk—g/ PG LG 'wherein: each R1 is independently selected from n, :NOZ, -CN, or -L—R; each L is independently a nt bond or an optionally substituted bivalent CH, hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O-, -S—,-—N(R)—, —-C(O)-, —C(S)—, —C(O)N(R)— , -N(R)C(O)N(R)-. -N(R)C(O)-, (0)0-. -OC(O)N(R)-., -S(0)-, —S(0)2¥, —S(O)2N(R)—, —-N(R)S(O)2—, —OC(O)— or —-C(O)O—; each R is independently hydrogen or an optionally tuted group selected from C1_5 aliphatic, phenyl, a 3—8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8—10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 membered , monocyclic saturated or partially rated heterocyclic ring having 1-2 heteroatoms independently ed from nitrogen, oxygen, or sulfur, a 5—6 membered heteroaryl ring having 1—4 heteroatoms independently selected from_ nitrogen, oxygen, or , or an 8-10 ed bicyclic satUrated,’ partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur, or: two R- groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4‘heteroatoms ndently" selected from nitrogen, oxygen, or ; PG is selected from —CH(OR8)2, -—CH(SR8)2, 2—(1,3—dioxolany|), 2-(1,3-dioxanyl), 2- (1,3-dithiolanyl) or 2_-(1,3-dithianyl); R8 is C1_5 tic; and LG is halogen; comprising the steps of: (a) providing a compound of formula B: \ H (R1)n_:©:U\/ wherein: nisO-4; each R1 is independently selected from n, —N02, ~CN, or —L-R; each L is independently a covalent bond or an optionally substituted bivalent C1_5 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by —O—, -S—-, , —C(O)—-, -C(S)—, —C(O)N(R)— , -N(R)C(0)N(R)-, -N(R)C(O)-, -N(R)C(O)0-, -OC(O)N(R)-, -S(O)-, -S(C)2—, -S(O)2N(R)—, -N(RiS(O)2—, —OC(O)- or —C(O)O-—; each R is independently hydrogen 'or an optionally substituted group selected from CH; aliphatic, phenyl, a 3-8 membered monocyclic saturated or partially unsaturated carboCyclic ring, an 8—10 membered bicyclic saturated, partially rated, or aromatic carbocyclic ring, a 3-8 ' membered monocyclic saturated or lly unsaturated heterocyclic ring having 1—2 heteroatoms independently selected from nitrogen, , or sulfur, a 5—6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8—10 membered "bicyclic saturated, partially rated, or aromatic heterocyclic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3:8 membered saturated, partially unsaturated, or aromatic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LG is halogen, and (b) ng said compound of formula B with an alcohol to form a compound of formula C, wherein the alcohol is selected from: HORB, ethylene glycol, HSRB, .1,3-propanediol, - 1,2-ethan'edithiol or 1,3— propanedithiol, wherein R8 is C14; aliphatic. in some embodiments, step (b) above is performed using a catalytic amount of an acid. Suitable catalytic acids include both mineral acids, such as hydrochloric acid, and organic acids, such as p-toluenesulfonic acid. In some embodiments, step (b) is performed using p-toluenesulfonic acid.

In some embodiments, step (b) above is performed using methanol or ethanol.

Thus, in some embodiments,.a compound of formula B is d with ol or l to provide a nd of formula C wherein PG is -CH(OCH3)2 or — 2CH3)2, respectively. in some embodiments, a compound of formula B is reacted with ethylene glycol to provide a nd of formula C wherein PG is - 2-(1,3-dioxolany|). In some ments, a compound of formula B is reacted with 1,3-propanediol to provide a compound of formula C n PG is ~2-(1,3- dioxanyl). In some embodiments, a compound of formula B is reacted With CH3$H to e a compound of formula C wherein PG is —CH(SCH3)2. In some embodiments, a compound of formula B is reacted with CH3CHZSH to’ provide a compound of formula C wherein PG is —CH(SCH2CH3)2.

In some embodiments, a compound of formula B is d with 1,2-ethanedithiol to provide a compound of formula C wherein PG is thiolanyl. In some embodiments, a compound of formula B is d with 1,3-propanedithiol to provide a compound of formula C wherein PG is 1,3—dithianyl.

A suitable solvent or solvent mixture is selected such that the solveht solubilizes the reaction components and/or facilitates the ss of thevreaction. Suitable solvents include halogenated hydrocarbon ts (e.g. chloroform or methylene chloride), benzene and derivatives thereof (e.g., toluene, xylenes), ethers (e.g; MTBE, tetrahydrofuran and dioxane), and the like. In some ments, a suitable solvent is a polar, aprotic t such as tetrahydrofuran or dioxane.

According to one embodiment, the alcohol of step (b). above performs as the reaction solvent. When ethylene glycol or 1,3-propanediol is used as a solvent, one of ordinary skill in the art will appreciate that the reaction mixture is poured into a non-miscible organic solvent such as ethyl acetate Or methylene chloride.

The non-miscible organic layer is then washed with water to remove the excess alcohol.

In some embodiments, the reaction of a compound of formula B with an l in the presence of catalytic acid is . In some embodiments, the reaction mixture is refluxed. In some embodiments, step 5-2 is heated to about 90°C to about 95°C.

In some embodiments, the'present invention provides a method for preparing a compound of formula B: . H (Rm—l , LG wherein n is 0-4; each R1 is independently selected from halogen, —N02, —CN, or -L-R; each L is independently a covalent bond or an optionally substituted nt C14; arbon chain, wherein one or two methylene units of L is optionally and ndently replaced by ‘0? —s—, -N(R)—, —C(O)—, -C(S)—, -C(O)N(R)— , -N(R)C(O)N(R)-, -N(R)C(O)-, ~--N(R)C(0)O-, -0C(0)N(R)-, -S(0)-. -S(0)2-, -S(O)2N(R)—, -—N(R)S(O')2——, —OC(O)— or —C(O)O—; each R is independently hydrogen or an optionally substituted group selected from C14; aliphatic, phenyl, a 38 membered monocyclic saturated or partially unsaturated yclic ring, an 8—10 membered bicyclic saturated, partially unsaturated, or ic carbocyclic ring, a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ringhaving 1-2 .. heteroatoms independently ed from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, , or sulfur, or an 8-10 membered bicyclic saturated, lly unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken er With their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, or sulfur; and LG is halogen, comprising the steps of: (a) providing a compound of formula A: (R1)n—©/U\\ H (b) reacting said compound of formula A With a dihalogen to form a nd of formula B.

WO. 2013/001352 In some embodiments, a compound of formula A is reacted with chlorine gas, bromine or iodine. In some embodiments, a compound of formula A is reacted with bromine. In some embodiments, a compound of formula A is reacted with hydrobromic acid. lnsome embodiments, a compound of formula A is reacted with N-bromosuccinimide. In some embodiments, step (b) is performed in a polar, protic t. Suitable polar, protic solvents include alcohols (e.g. methanol, ethanol, isopropanol), organic acids (acetic acid, formic acid, propionic acid) and water. In some embodiments, a nd of formula A is dissolved in acetic acid and d with bromine.

One of ordinary skill in the art will recognize that, in some circumstances, electrophilic aromatic substitutions require elevated temperatures. In some embodiments, a compound of formula A is ved ~in acetic acid and d with bromine at room temperature.

In one of the ment, the present invention provides a'method for preparing Cleistanthin A '(l): OCH3 Ho:(5,\OCH3 o o under conditions effective to form Cleistanthin A (I). In one specific embodiment, the effective conditions include treating compound of formula W with an alkali and a solvent to form compound of a l. One of ordinary skill will further ize that many alkalis and ts can be used in this reaction. In a preferred embodiment alkali is potassium carbonate and solvent is methanol.

The present invention provides an improved method for preparing Cleistanthin A, derivatives f and ediates thereto, which can be carried out in a shorter duration and wherein the' metallation step is carried out at an ordinary temperature. The metallation step is carried out in much shorter on of 1-3 hours, preferably metallation step is d out in 0.5 - 1 hour, thus shortening the period ofthe entire synthesis method and rendering it efficient.

The following es serve to illustrate the invention without liming the scope EXAMPLES Synthesis of (2-(1,3-dioxolanyl)4,5—dimethoxyphen-yl)(benzo[d][1,3] dioxol-5~ yl)methanol - General Procedure: A clean and dry four necked round bottom flask equipped with a thermometer pocket, water condenser and dropping funnel was placed in a sonicator. The flask was d with dry tetrahydrofuran and 2-(2—bromo-4,5—dimethoxy)—1,3— dioxolane. The reaction was sonicated at room temperature. Pipronal dissolved in tetrahydrofurna was slowly charged via dropping funnel. n-Butyllithium was simultaneously ”charged to the reaction. The reaction was maintained 'at room temperature for 15 minutes and red by TLC. Oncelthe reaction was complete, water was added and the reaction mixture was stirred. The organic layer was separated and concentrated under vacuum. Methanol was added to the sticky residue and the flask was scratched to initiate crystallization. The solid was filtered, washed with methanol and dried in a vacuum oven at 50°C. The isolated product was obtained in 36.9% yield.

Comparative Example 1A Synthesis of (2—(1, 3-Dioxolane — 2~y|) — 4, 5 — dimethoxy phenyl.) (d) (1,3) dioxol — 5 — yl) — methanol (carried out as per known method): To a flame dried -four necked round bottom flask (100mL) were added 2-(2— bromo-4, 5-dimethoxyphenyl)—1, 3-dioxolane (formula Vll; 1.0 g, 0.9934 mole) and anhydrous tetrahydrofuran (25mL) under nitrogen atmosphere. The flask was cooled to -78°C in dry ice-acetone bath; n- Butyllithium (5.3mL, 0.005 mole) was added drop wise with stirring at -78°C and stirred .for 15 minutes. A separate flame dried flask was charged with Piperona|'(0.517g, 1.0034 mole) and dry tetrahydrofuran (6mL). The Piperonal solution was cannulated to the reaction mixture during 30 minutes and after the addition, reaction mixture was slowly warmed to room temperature and further stirred for - 2.5 hours. After the consumption of all bromine compound, as confirmed 'by TLC‘(50:50, EtOAc: Hexane), reaction e was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3 x”20mL). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 80% of crude product. The crude product was purified (by column tography using column of 2 meter length, diameter 2.5 cm and filled with silica (gel 60—120. (column tographic grade). Finally column eluted with EtOAC: Hexane (50:50), to get pure product (2-(1, olane — 2—yl) - 4, 5 — dimethoxy phenyl ) (benzo(d) (1,3) dioxol — yl) — methanol with 30% yield. The total time required was about 7 hours.

The NMR s of compound (2—(1, 3-Dioxolane — 2—yl) — 4, 5 - dimethoxy phenyl ) (benzo(d) (1,3) dioxol — 5 — yl) 4- methanol were as follows: lHNMR (300 MHz, CDCI3): 5 = 7.14 (s, 1H), 6.90-6.78(m,4H), , ,1H),5.96(s,2H),5.90(s,1H),4.19(t,2H,J=6.6HZ), 4.16(t,2H,J=6.8Hz),4.02(s,3H),3.81(s,3H,3.17(s, 1H). 13CNMR (300 MHz, CDCI3): :14942, 148.11, 147.57, 146.58,136.95, 135.43, 126.83,121.04, 119.69, 111.48, , 107.92, 107.26, , 100.93, 71.34, 65.05, 55.94, 55.89.

Example 1 Synthesis of (2-(1, 3-Dioxolane - 2-y|) — 4, 5 — dimethoxy phenyl ) (benio(d) (1,3) dioxol — 5 — yl) — methanol (carried out as per the present invention): A clean, dry four neck round bottom flask equipped with mechanical stirrer, ,thermometer pocket, condenser, guard tube and dropping funnel was arranged on sonicator. It was charged with dry tetrahydrofuran (120 mL) and 2-(2-bromo—4, —dimethoxy)-1,3—dioxalane (5 gm, 0.017 mol). Said reaction mass was sonicated at temperature 25°C. Pipronal (3g, 0.019 mol) previously dissolved in 10 mL tetrahydrofuran, was added by dropping , simultaneously n—Butyllithium (20 g, 0.3125 mol) was slowly added to the reaction mixture under sonication at room temperature within 45 minutes. Following the addition, the reaction was monitored by TLC (50:50, EtOAc: Hexane), saturated um chloride on was added and extracted with ethyl acetate (2 X 30mL). After completion of the reaction, 20 mL water was added, all organic layers were separated dried over anhydrous sodium sulphate, ed and concentrated under-vacuum to afford a sticky solid. ol (10 mL) was added and the flask was scratched to initiate crystallization; 2.3 g, solid was isolated and dried under vacuum at 50 °C. The isolated t was ed in 37.55% The NMR details of compound (2- (1, 3-Dioxolane —- 2-yl) - 4,5 — dimethoxy phenyl ) (benzo(d) (1,3) dioxol —— 5 — y|) — methanol were as below: 1HNMR. (300 MHz, CDCI3): 5 = 17.14 (s, 1H), 6.90-6.78(m,4H), 6.11(s,1H),5.96(s,2H),5.90(s,1H),4.19(t,2H,J=6.6Hz), 4.16(t,2H,J=6.8Hz),4.02(5,3H),3.81(s,3H,3.17(s, 1H). 13CNMR (300 MHz,,CD‘Cl3): 6: 149.42, 148.11, , 146.58, 136.95, 135.43, 126.83, 121.04, 119.69, 111.48, 109.50, , 107.26, 101.65, 100.93, 71.34, 65.05, 55.94, 55.89.

Example 2 Synthesis of (2-(1, 3-Dioxolane - 2—yl) — 4, 5 — dimethoxy phenyl ) (benzo(d) (1,3) dioxol — 5 — yl) — methanol (carried out as per the present invention): A clean, dry four neck round bottom flask equipped with ical stirrer, thermometer pocket, condenser, guard tube and dropping-funnel was arranged on sonicator. lt'was charged with dry tetrahydrofuran (120 mL) and 2-(2-bromo—4, -dimethoxy)-1,3-dioxalane (5 gm, 0.0172 mol). Said reaction mass was sonicated at temperature 25°C. Piprona|»(2.55 g, 0.0169 mol) previously dissolved in 10 mL tetrahydrofuran, was added by dropping funnel, simultaneously n-Butyllithium (3.96 g, 0.061 mole) was slowly added to the on mixture under sonication at room temperature within 60 minutes.

. Following the addition, the reaction was monitored by TLC (50:50, EtOAc: Hexane), after the consumption of all bromine compound, saturated ammonium chloride solution was added and extracted with ethyl acetate (3 X 30 mL). After completion of the reaction, 20 mL water was added, all organic layers were separated dried over anhydrous sodium' sulphate, ed and concentrated under vacuum to afford a sticky solid. ol (30 mL) was added and the flask was scratched to initiate crystallization. 2.3 g solid was ed and dried under vacuum at 50°C. The isolated product was obtained in 36.55% yield.

The NMR s of compound (2-(1, 3—Dioxolane — 2-yl) —- 4, 5 — dimethoxy phenyl )(benzo(d) (1,3) dioxol — 5 f— yl) - methanol were as below: 1HNMR " (300 MHz, CDCI3): 5 = 7.14 (s, 1H), 6.90-6.78(m,4H), 6.11(s,1H),5.96(s,2H),5.90(s,1H),4.19(t,2H,J=6.6Hz), 4.16(t,2H,J=6.8Hz),4.02(s,3H),3.81(s,3H,3.17(s, 1H). 13CNMR (300 MHz, : ' 8: 149.42, 148.11, 147.57, , , 135.43, 126.83, 121.04, 119.69, 111.48, 109.50, 107.92, 107.26, 101.65, 100.93, 71.34, 65.05, 55.94, 55.89.

Example 3 Synthesis of (2-(1, 3-Dioxolane — 2-yl) — 4, 5 — dimethoXy phenyl ) (benzo(d) (1,3) dioxol — 5 — yl) — methanol (carried out as per the t invention); Aclean, dry four neck round bottom flask equipped with mechanical stirrer, thermometer pocket, condenser, guard tube and dropping funnel was arranged on sonicator. It was chargedwith dry tetrahydrofuran (120 mL) and 2-(2-bromo—4, -dimethoxy)—1,3—dioxaiane (5 gm, 0.0172 mol). Said reaction mass Was sonicated at temperature 30°C. 'Pipronal (2.55 g, 0.0169 mol) previously dissolved in 10 mL tetrahydrofuran, was .added by dropping funnel, simultaneously n—Butyllithium (3.96 g, 0.061 mole) was slowly added to the on mixture under sonication at room temperature within 50 minutes. Following the addition, the reaction was monitored by TLC (50:50, EtOAc: Hexane), after the consumption of all bromine compound, saturated um chloride solution was added and extracted with ethyl acetate (3 X 30 mL). After completion of the reaction, 20 mL water was added, all organic layers were separated dried over anhydrous sodium sulphate, filtered and concentrated'under vacuum to afford a sticky solid. Methanol (30 mL) was added and the flask was scratched to initiate crystallization. 2.3 g solid was ed and dried under vacuum at 50°C. The isolated t was obtained in 37% yield.

The NMR details of compound (2-(1, 3-Dioxolane — 2-yl) — 4, 5—dimethoxy phenyl) (benzo(d) (1,3) dioxol — 5 — yl) —- methanol were as below; 1HNMR (300 MHz, c003): 5 % 7.14 (s, 1H), 6.90-6.78(m,4H), 6.11(s,1H),5.96(s,2H),5.90(s,1H),4.19(t,2H,J=6.6Hz), ,2H,J=6.8Hz),4.02(s,3H),3.81(s,3H,3.'17(s, 1H). 13CNMR (300 MHz, CDCl3): : 149.42, 148.11, , 146.58, 136.95, 135.43, 126.83, , 121.04, 119.69, 111.48, 109.50, 107.92, 107.26, 101.65, 100.93, 71.34, 65.05, 55.94, 55.89.

Example 4 Synthesis of Cleistanthin A using (2-(1, 3-Dioxolane —'2—yl) — 4, 5 — dimethoxy phenyl ) (benzo(d) (1,3) dioxol — 5 — yl) — methanol (prepared as per the present '20 invention): Sealed tube was charged with (2-(1, 3-Dioxolane — 2-yl) — 4, 5 - dimethoxy phenyl ) (benzo(d) (1,3)‘dioxol — 5 — yl) — methanol (prepared as per any one of the es 1-3),(0_.30 g, 0.833 mmole), diethyl acetylinedicarboxylate (0.141 g, 0.833 mole), dichloromethane (0.4 mL) and glacial acetic acid (0.242 mL) and mixurewas heated at 140°C for 1 hour. After completion of reaction as judged by TLC (50:50, EtOAc: ), reaction mixture was cooled to room temperature, d with dichloromethane (10 shed with 5 % sodium bicarbonate solution (3 x 10 mL), organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude reaction mass Was purified by flash column. chromatography over silica gel using} EtOAczhexane (15:85) to afford l 1- (3’,4’-methylenedioxyphenyl)hydroxy-6,7-dimethoxynaphthalene-2,3- dicarboxylate as white solid 0.3 g (75 %).

Two necked round bottom flask was charged with 'lithium aluminium hydride (0.032 g, 0.852 mmol) and ous tetrahydrofuran (,4 mL) and the mixture was cooled to 0°C with stirring. To this suspension, a solution of diethyl 1-(3’,4’- methylenedioxyphenyl)-4—hydroxy-6,7-dimethoxynaphthalene-2,3—dicarboxylate (0.200 g, 0.426 mmol) in tetrahydrofuran (4 mL) was added drop wise and stirring was continued for 2 hours. After completion of reaction as judged by TLC (1:9, MeOH:DCM), reaction mixture was quenched with saturated sodium sulfate solution and extracted with nol (4 x 20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

The crude e was purified by flash column chromatography over silica gel to give yellow solid 9-(3’,4‘-Methylenedioxyphenyl)hydroxy-6,7- dimethoxynaphtho[2,3—c]furan-1(3H)-one 0.07 g (85 %).

To a flame dried three necked round bottom flask (250 mL), 9-(3’,4’— methylenedioxyphenyl) - 4-hydroxy — 6,7—dimethoxynaptho[2, 3-c] furan-1(3H)- one compound (1.2 g 0.0031 mole), and methylene dichloride (100 mL) were added and stirred to dissolve completely. Then ,2Acetyl—3,4-—dimethoxy—a-D- bromoxylopyranose (1.8 g , 0.0063 mole), tetra butyl um bromide (0.49 g and 1 N sodium ide solution (4 mL) were added , 0.00151 mole) in above on. Reaction mass was kept for digestion under'stirring for 2 hours, conversion was checked by TLC (MeOH:MDC, 0.5:9.5) and the conversion if'found unconverted then digestion continued till conversion was complete. After completion of reaction, the" onvmass was washed with 1% sodium bicarbonate solution. After layer separation, methylene dichloride was concentrated to give solid 1.62 gms (yield 55%) of Cleistanthin A acetate.

In a clean dry three necked round bottom flask cleistanthin A acetate (1.26g, 0.0027 mole), potassium carbonate catalytic amount (0.1g, 0.00072 mole) and methanol ( 100 mL) were added & stirred well for 1 Hr at ature 25°C.

Reaction was monitored by TLC and HPLC. After completion of reaction, the reaction mass was quenched by water and extracted with ethyl acetate (2 X 30 mL) to get the final product. Ethyl e was concentrated to get pure 1.2 gm (yield 97%) of cleistanthin A; Tlle NMR details cleistanthir) A were as follows: 1HNMR (CDCI3, 300 MHz); = 7.92 (s, 1H), 7.05 (d, .1H, J = 1.5 Hz), 6.94 (dd, 1H, J = 1.2, 7.8 Hz), 6.83-6.78 (m, 2H), 6.07 (d, 1H, J = 14.1 Hz), 6.06 (d, 1H, J = 14.4 Hz), .49 (d, 1H, J : 14.7 Hz), 5.42 (d, 1H, J = 14.7 Hz), 5.10 (d, 1H, J = 5.7 Hz), 4.10 (dd, 1H, J = 2.4, 12.0 Hz), 4.04 (s, 3H), 3.95-3.88 (m, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.49 (s, 3H), 3.45 (dd, 1H, J = Hz), 3.93-3.30 (m, 3H). 13CNMR (300 MHz, com): 5 = 169.75, 151.77, 150.15, 147.41, 144.09, 135.84, 130.61,-128.90, 128.87, 128.35, 126.79, 123.55, 119.13, 110.68, , 106.04, , 101.16, 101.02, 82.10, 78.20, 71.13., 71.11‘, 67.26, 61.13, 60.01, 57.91, 56.15, 55.76.

Claims (22)

We Claim:

1. A method for preparing a compound of formula D: (R1)n (R2)m wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -NO2, -CN, or -L-R; each L is ndently a nt bond or a bivalent C1-6 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, -S(O)-, -S(O)2-, -S(O)2N(R)-, -N(R)S(O)2-, -OC(O)- or -C(O)O-; each R is independently hydrogen or selected from a group consisting of C1-6 aliphatic, phenyl, a 3-8 membered monocyclic saturated or lly rated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 membered clic saturated or partially unsaturated heterocyclic ring having 1-2 atoms ndently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their ening atoms to form a 3-8 membered saturated, partially unsaturated, or ic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and PG is selected from -CH(OR3), 2-(1,3-dioxolanyl) or 2-(1,3-dioxanyl); and R3 is an aliphatic group; (10871759_1):KZA comprising the steps of: (a) providing a on of a compound of formula C: (R1)n n is 0-4; each R1 is independently selected from halogen, -NO2, -CN, or -L-R; each L is independently a covalent bond or a bivalent C1-6 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently ed by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, -S(O)-, -S(O)2-, -S(O)2N(R)-, -N(R)S(O)2-, -OC(O)- or -C(O)O-; each R is independently hydrogen or selected from a group consisting of C1-6 tic, , a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or ic carbocyclic ring, a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 atoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic ted, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 ed saturated, partially unsaturated, or aromatic ring having 1-4 atoms independently selected from nitrogen, oxygen, or sulfur; PG is selected from -CH(OR3), 2-(1,3-dioxolanyl) or 2-(1,3-dioxanyl); R3 is an aliphatic group; and LG is halogen; (b) sonicating said solution; and (c) reacting said on with a substituted piperonal solution and an alkyl lithium reagent under sonication to form a compound of formula D.

2. The method according to claim 1, wherein the reaction is performed at 0-25 degree centigrade or at a room temperature. 11268229

3. The method according to claim 1 or claim 2, wherein LG is bromine or iodine.

4. The method according to any one of claims 1 to 3, wherein the alkyl lithium reagent is n-butyllithium.

5. The method ing to any one of claims 1 to 4, wherein the aryl aldehyde is pipronal .

6. The method ing to any one of claims 1 to 5, wherein the solution of compound of formula C and aryl aldehyde is prepared in a non polar, aprotic solvent selected from but not d to the ether such as diethyl ether, MTBE, tetrahydrofuran or e or hydrocarbon solvent such as hexane or cyclohexane.

7. The method according to any one of claims 1 to 6, wherein PG is 2-(1,3-dioxolanyl).

8. The method according to any one of claims 1 to 7, further comprising the steps of: (a) reacting said compound of formula D with a compound of formula E: R3O2C CO2R3 wherein each R3 is a C1-6 aliphatic; under conditions ive to form a compound of formula F: CO2R3 (R1)n CO2R3 (R2)m wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -NO2, -CN, or -L-R; (10871759_1):KZA each L is independently a covalent bond or a bivalent C1-6 hydrocarbon chain, wherein one or two methylene units of L is optionally and independently replaced by -O-, -S-, -N(R)-, -C(O)-, -C(S)-, -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, N(R)-, -S(O)-, -S(O)2-, -S(O)2N(R)-, (O)2-, -OC(O)- or -C(O)O-; each R is independently hydrogen or selected from C1-6 aliphatic, phenyl, a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, an 8-10 ed bicyclic saturated, lly unsaturated, or aromatic carbocyclic ring, a 3-8 ed monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms ndently selected from nitrogen, oxygen, or sulfur, a 5-6 ed heteroaryl ring having 1-4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur, or an 8- 10 membered bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same en are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 atoms independently selected from nitrogen, oxygen, or sulfur; and each R3 is C1-6 aliphatic.

9. The method according to claim 8, wherein each R3 is ethyl.

10. The method according to claim 8 or claim 9, wherein PG is 2-(1,3-dioxolanyl).

11. The method according to any one of claims 8 to 10, wherein the compound of formula D and the compound of formula E are heated in acetic acid.

12. The method according to any one of claims 8 to 11, wherein the compound of formula D and the nd of formula E are heated to about 120 °C to about 140 °C.

13. The method according to any one of claims 8 to 12, further comprising the step of reacting said compound F with a metal hydride to form a compound of formula III: (10871759_1):KZA wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -NO2, -CN, or -L-R; each L is independently a covalent bond or a bivalent C1-6 hydrocarbon chain, wherein one or two ene units of L is optionally and independently replaced by -O-, -S-, - N(R)-, , -C(S)-, -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, -S(O)-, -S(O)2-, -S(O)2N(R)-, -N(R)S(O)2-, -OC(O)- or -C(O)O-; and each R is independently hydrogen or selected from a group ting of C1-6 aliphatic, phenyl, a 3-8 membered monocyclic saturated or lly rated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 ed monocyclic saturated or partially rated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic saturated, partially unsaturated, or ic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, , or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

14. The method according to claim 13, wherein the metal hydride is lithium aluminum hydride.

15. The method according to claim 13 or claim 14, further comprising the step of: reacting said nd of formula III with a pyranose of formula V: wherein each of R4, R5 and R6 is independently hydrogen, R7, or -C(O)R7; and each R7 is independently a C1-6 aliphatic group or a suitable hydroxyl protecting group; (10871759_1):KZA under conditions effective to form a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein: m is 0-3; n is 0-4; each of R1 and R2 is independently selected from halogen, -NO2, -CN, or -L-R; each L is independently a covalent bond or a bivalent C1-6 hydrocarbon chain, wherein one or two methylene units of L is optionally and ndently ed by -O-, -S-, -N(R)-, -C(O)-, , -C(O)N(R)-, -N(R)C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, -S(O)-, -S(O)2-, -S(O)2N(R)-, -N(R)S(O)2-, -OC(O)- or -C(O)O-; and each R is independently hydrogen or ed from a group ting of C1-6 aliphatic, phenyl, a 3-8 membered monocyclic saturated or lly unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aromatic carbocyclic ring, a 3-8 membered monocyclic saturated or partially unsaturated cyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered ic saturated, partially unsaturated, or aromatic heterocyclic ring having 1-4 heteroatoms independently selected from en, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 3-8 membered saturated, lly unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. (10871759_1):KZA

16. A method for preparing cleistanthin A (I): sing a step of reacting compound of formula IV obtained by method of claim 15 with an alkali and a solvent to form Cleistanthin A (I).

17. The method according to claim 16, wherein the alkali is potassium carbonate and solvent is methanol.

18. A compound of formula D prepared by the method of any one of claims 1 to 7.

19. A compound of formula F prepared by the method of any one of claims 8 to 12.

20. A compound of formula III prepared by the method of claim 13 or claim 14.

21. A compound of formula IV prepared by the method of claims 15.

22. Cleistanthin A prepared by the method of claim 16 or claim 17. Godavari Biorefineries Ltd. By the eys for the ant SPRUSON & FERGUSON Per: (10871759_1):KZA