MXPA97000782A - Method for the preparation of the (+) - calanolida a and its intermed products - Google Patents

Abstract

The present invention relates to a method for preparing a (+) - calanolide A, a potent inhibitor of HIV reverse transcriptase, from chromene, a method for treating or preventing viral infections is provided, with the use of ( +) - calanolide or the (-) - calanoli

Description

METHOD FOR THE PREPARATION OF (±) -CAL-ANOLIDA A AND ITS INTERMEDIATE PRODUCTS RECIPROCAL REFERENCE This is a partial continuation of the Request for Patent of E. U. A., also pending, No. 08 / 285,655, filed on August 3, 1994.

FIELD OF THE INVENTION This invention relates to a method for the preparation of (±) -calanolide A, a potent inhibitor of HIV reverse transcriptase, and its intermediates. In particular, this invention relates to a method for the production, on a large scale, of (±) -calanolide A, its chiral resolution in its optically active forms and to the use of (±) -calanolide A and (-) ) -calanolide A for the treatment of viral infections.

BACKGROUND OF THE INVENTION The human immunodeficiency virus (HIV), which is also called human T-lymphotropic virus type III (HT V-III), virus associated with lymphadenopathy (AV) or retrovirus (ARV) associated with AIDS , was first isolated in 1982, and has been identified as the etiological agent of the acquired immunodeficiency syndrome (AIDS) and related diseases. Of course, AIDS chemotherapy has been one of the most exciting scientific endeavors. Thus, AZT, ddC, ddl and D4T, have been approved by the FDA and are being used clinically as drugs for the treatment of AIDS and AIDS-related complexes. Although these drugs approved by the FDA can prolong the lives of AIDS patients and improve their quality of life, none of these drugs is able to cure the disease. The toxicity of bone marrow and other side effects, as well as the emergence of viral strains resistant to the drug, limit the prolonged period of these agents1. On the other hand, the number of AIDS patients worldwide has increased dramatically in the past decade and it is estimated, in the cases reported, that in the very near future it will also continue to rise drastically. Therefore, it is evident that there is a great need for other promising drugs, which have improved selectivity and activity to combat AIDS1. Several approaches, including chemical synthesis, natural product research and biotechnology, have been used to identify compounds aimed at different stages of HIV replication for therapeutic intervention.2 Very recently, the research program at the National Institute del Cancer has discovered a class of remarkably effective anti-HIV natural products, called calanolides, derived from the tropical forest tree Calophyllum lanigerum, with the calanolide A, 1, being the most potent compound in the reported series.3 For example, calanolide A demonstrated 100% protection against the cytopathic effects of HIV-1; one of the two different types of HIV, in complete form at a concentration of 0.1 μM. This agent also stopped the replication of HIV-1 in human T-lymphoblastic cells (CEM-SS) (EC50 = 0.1 μM / IC5o = 20 μM) .3 Interestingly and importantly, calanolide A was found to be active against the strain G-9106 resistant to HIV AZT as well as the A173 virus resistant to pyridinone. Thus, the calanolides, known as inhibitors of HIV-1 specific reverse transcriptase, represent novel anti-HIV chemotherapeutic agents for the development of drugs. The only known natural source of the calanolida A, 1, was destroyed and other members of the same species do not contain the desired material.4 Consequently, a practical synthesis of the natural product must be developed to carry out further studies and developments in this active and promising series of compounds. Thus, we describe a method for the synthesis and resolution of (±) -calanolide A and some related compounds.

OBJECTS OF THE INVENTION Therefore, an object of the present invention is to provide a simple and practical method for preparing (±) -calanolide A, 1, from readily available starting materials, and solve them in their optically active forms by means of the chiral system of high performance liquid chromatography (HPLC) or enzymatic acylation and hydrolysis. Another object of the invention is to provide useful intermediate products for the preparation of (±) -calanolide A derivatives. A further object of the invention is to provide a simple and practical method for the large-scale preparation of (±) -calanolide A, with high yields, from the key intermediate chromene 4. A further object of the invention is to provide a method for treating or preventing viral infections with the use of (±) -calanolide A and (-) -Calanolide A.

These and other objects of the invention will become apparent from the following detailed description.

COMPENDIUM OF THE INVENTION The present invention relates to the synthesis of (±) -calanolide A and its intermediates, the chiral resolution of (±) -calanolide and methods for treating or preventing viral infections, with the use of (±) - and the (-) -Calanolides A. The method of the present invention for preparing the (±) -calanolide A, 1, uses chromene 4 as the key intermediate product. Chromen 4 is synthesized by the sequence illustrated in Scheme I. Thus, 5,7-dihydroxy-4-propylcoumarin, 2.5 is prepared quantitatively from ethyl butyrylacetate and phloroglucinol, under the Pechmann conditions.6 The yield and purity of the product are dependent on the amount of the sulfuric acid used. The 8-position of the 5,7-dihydroxy-4-propylcoumarin, 2, is then acylated selectively at 8-10fiC by the propionyl chloride and the AICI3, in a mixture of carbon disulfide and nitro-benzene, to supply the , 7-dihydroxy-8-propionyl-4-propylcoumarin, 3. In an alternative and preferred reaction, the intermediate cuyano 3 can be produced in large scale quantities and with minimal formation of the acylated product in the 6-position and the product acylated in the 6,8-bis position, undesired by the selective acylation of 5,7-dihydroxy-4-propylcoumarin 2 with a mixture of propionic anhydride and AICI 3, at a temperature of about 70-75 ° C. The chromene ring is introduced into the treatment of compound 3 with 4,4-dimethoxy-2-methylbutan-2-ol, 8 giving 4 in 78% yield (Scheme I). As shown in Scheme II, the reaction of Robinson-Kostanecki9 in 4, by the use of sodium acetate in refluxing acetic anhydride, produces enone 5 with a yield of 65%. This intermediate product failed to deliver the calanolide A in the reduction with borohydride reagents, such as NaBH4 CeCl3, NaBH / CuCl2, L ^ elec-triuro, 9-BBN and DIP chloride, and some transition metal reducing agents, such as Sml2 and [(Ph3P) CuH)] g, presumably due to the attack of the pyrone and the ring opening preferably occurred. The treatment of 5 with the Balcer yeast also results in the unfolding of the coumarin ring, while the tri-n-butyl-tin trihydride10 leads to the reduction of 5 to enol 6, with a modest yield. However, treatment of 4 with acetaldehyde diethyl acetal, in the presence of trifluoroacetic acid and pyridine, heating to 160 ° C, produced chromanone 7, which can then be reduced in the final product.

SCHEME SCHEME I I The large-scale production of chromanone 7 from chromene 4 can be carried out under two different reaction conditions. In a one-step reaction, chromene 4 is treated with paraldehyde, in place of acetaldehyde-diethylacetal, and cyclized in the presence of an acid catalyst, to supply chromanone 7 with a yield of 27%, together with 8% of the corresponding 7a-10,11-cis-dimethyl derivative, 7a. In a two-step reaction, under the condensation conditions of the aldol, chromene 4 is reacted with the acetaldehyde to form an open-chain aldol 7b product. This product of aldol 7b is then cyclized under acidic conditions, such as 50% of H2SO4 and TsOHf to form both chromanone 7 and the 7a derivative of 10,11-cis-dimethyl, in a ratio of 1: 1, with the previous leading to a purified yield of 16%. However, under the neutral conditions of Mitsunobu11, 7b is cyclized reproducibly to give chromanone 7 as the predominant product and with a yield of 48%. Finally, the (±) -calanolide A is successfully formed with the desired stereochemical arrangement, subjecting the chromanone 7 to the Luche12 reduction conditions (see Scheme (II) .The (±) -calanolide A was then resolved in the optically active forms, using a system of chiral separation of the preparative HPLC13. 7a 7b DESCRIPTION OF THE DRAWINGS Figures 1 (a) to 1 (e) illustrate the results of the in vitro gMM assay, as described in Example 15, using the viral strain G9106 HIV, which is resistant to AZT. Figures 2 (a) to 2 (e) illustrate the results of the in vitro MMT assay, as described in Example 15, using the viral strain H112-2 HIV, which was not previously treated with AZT. Figures 3 (a) to 3 (e) illustrate the results of the in vitro -MMT assay, as described in Example 15, using the viral strain A-17 HIV, which is resistant to non-nucleoside inhibitors, such like TIBO and pyridinone, but it is sensitive to AZT. Figures 4 (a) to 4 (e) illustrate the results of the in vitro MMT assay, as described in Example 15, which uses the cultured viral strain of IIIB.

Figures 5 (a) and 5 (e) illustrate the results of the in vitro MMT assay, as described in Example 15, which uses the cultured HIV viral strain of RF. Figure 6 is an HPLC chromatogram of (a) (+) - calanolide A in normal phase column; (b) (+) -Calanolide A on a chiral HPLC column; (c) (+) --calanolide A on a chiral HPLC column and (d) (-) --calanolide A on a chiral HPLC column. The conditions of HPLC are described in Example 13.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications and literature references cited herein are incorporated by reference in their entirety. According to the method of the present invention, chromene 4 is a key intermediate product in the preparation of (±) -calanolide A, 1. A preferred method for synthesizing chromene 4 from 5,7-dihydroxy- 4-propylcoumarin, 2, is shown in Scheme I. According to this synthetic scheme, 5,7-dihydroxy-4-propylcoumarin, 2, 5 is prepared quantitatively from ethyl butyrylacetate and phloroglucinol, under the conditions of Pechmann.6 In conducting this reaction, a volume of the concentrated acid is added, in drops, to a stirred mixture of ethyl butyrylacetate and phloroglucinol, with a molar ratio ranging from about 3: 1 to 1: 3, with a preferred range being from around 0.9: 1.0 The dropwise addition of an acid is carried out at a rate such that the temperature of the reaction mixture is maintained between 0 and 120 ° C, approximately, preferably around 90 ° C. Examples, suitable, but not limiting, of concentrated acids include sulfuric acid, trifluoroacetic acid and methanesulfonic acid. In the practice of this invention, concentrated sulfuric acid is particularly preferred. As the yield and purity of the product appear to be dependent on the amount of the concentrated sulfuric acid used, it is preferred that the amount of the concentrated sulfuric acid vary between about 0.5 and 10 moles, more preferably ranging between about 2 and 3.5 moles, per mole of the ethyl butyrylacetate. The reaction mixture is then heated to a temperature ranging from about 40 to 150 ° C, preferably about 90 ° C, until the reaction is complete, as determined by thin layer chromatography (TLC) analysis. The reaction mixture is then emptied onto ice and the precipitated product is collected by filtration and dissolved in an organic solvent. Suitable but not limiting examples of organic solvents include ethyl acetate, chloroform and tetrahydrofuran. A preferred solvent is ethyl acetate. The resulting solution is then washed with brine and dried over a suitable drying agent, for example sodium sulfate. The yields of this reaction are generally quantitative. Next, 5,7-dihydroxy-8-propionyl-4-propyl-coumarin, 3, is prepared by the selective acylation of the 8-position of 5,7-dihydroxy-4-propylcoumarin, 2, with the propionyl, in the presence of a Lewis acid catalyst. When carrying out this reaction, a solution of propionyl chloride, in a suitable solvent, for example, carbon disulfide, is added, in drops, to a vigorously stirred solution, of 5,7-dihydroxy-4-propylcoumarin, 2, a Lewis acid and an organic solvent, cooled in an ice bath. The droplet addition of propionyl chloride was carried out so that the temperature of the reaction mixture was maintained in a range between 0 and 30ac, approximately, preferably between about 8 and 102C. In the practice of the invention, the amount of the propionyl chloride used generally varies between about 0.5 and 6 moles, preferably between 1 and 2 moles, for each mole of the 5,7-dihydroxy-4-propylcoumarin, 2. Non-limiting examples of Lewis acid catalysts useful in the acylation reaction include AICI3, BF3, SnCl, ZnCl2, POCI3 and TiCl4. A preferred catalyst of Lewis acid is AICI3. The amount of the Lewis acid catalyst relative to the 5,7-dihydroxy-4-propyl-coumarin, 2, ranges from about 0.5 to 12 moles, preferably from about 2 to 5 moles per mole of the 5,7-dihydroxy- 4-propylcoumarin, 2. Non-limiting examples of organic solvents for use in preparing the solution of 5,7-dihydroxy-4-propyl-coumarin, 2, include nitrobenzene, nitromethane, chloro-benzene or toluene, and mixtures thereof . A preferred organic solvent for use in this invention is nitrobenzene. Upon completion of the addition of the propionyl chloride, the reaction mixture, vigorously stirred, is maintained at a temperature ranging from 0 to 120 ° C, approximately, preferably ranging from about 25 to 80 ° C, until the reaction is complete, as check by conventional means, such as TLC chromatography analysis. The reaction mixture is then emptied onto ice and extracted several times with a suitable solvent, such as ethyl acetate, chloroform, methylene chloride, tetrahydrofuran or a mixture of chloroform / methanol. A preferred solvent for this extraction is ethyl acetate. The extracts are then dried over a suitable drying agent, for example sodium sulfate, and the product can be purified by conventional means, such as silica gel column chromatography. On a smaller scale, the yield of 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3, produced by the reaction described above, is generally quantitative. However, on a larger scale, the reaction is very difficult to control and does not exclusively deliver the desired product. A route developed for the synthesis of Mammea coumarin was initially attempted for the preparation of compound 3, but proved too difficult to handle and of low yield. 7 Since the desired acylated product 3 in position 8 is always accompanied by the formation of the unwanted acylated product in position 6, and the 6,8-bis-acylated product, it is necessary to optimize the reaction conditions to reduce to a minimum the formation of the unwanted products and to develop a more efficient purification process to increase the purity and increase the amounts of the desired 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3. An alternative and preferred route for preparing 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3, in large scale amounts is then developed. The preparation of coumarin 3 8-acylated on a 5 gram scale as a single product (45% yield) has been achieved by adding a mixture of propionic anhydride, a Lewis acid, for example AICI3, and a suitable solvent, example 1,2-dichloroethane, in a previously heated, vigorously stirred mixture, of coumarin, a Lewis acid, for example, AICI3 and a suitable solvent, for example 1,2-dichloroethanol, at a temperature ranging from 40 to 160BC, approximately, preferably between about 70 and 752C. The droplet addition of the propionic anhydride solution is conducted at a rate such that the temperature of the reaction mixture is maintained within the desired range thereof. The amount of propionic anhydride used in the reaction generally varies between about 0.5 and 10 moles, preferably between 1 and 2 moles, approximately, per mole of 5,7-dihydroxy-4-propylcoumarin, 2. Non-limiting examples of the Lewis acid catalysts, useful in the acylation reaction, include A1C13, BF3, POCL3 , SnCl4, ZnCl2 and TiCl4. A preferred Lewis acid catalyst is AICI3. The amount of the Lewis acid catalyst in relation to the 5,7-dihydroxy-4-propyl-coumarin, 2, varies between about 0.5 and 12 moles, preferably between about 2 and about 4 moles, per mole of the 5,7- dihydroxy-4-propylcoumarin, 2. Examples suitable, but not limiting, of solvents for use in the invention include diglyme, nitromethane, 1,1,2,2-tetrachloroethane and 1,2-dichloroethane (the preferred). Upon completion of the addition of the propionyl anhydride, the reaction mixture, vigorously stirred, is maintained at a temperature ranging between about 40 and 160 ° C, preferably between about 70 and 75 ° C, until the reaction is completed, as verified by conventional, such as the analysis of TLC chromatography. The processing procedure is the same as described above. The product was purified without the use of column chromatography to deliver the desired product 3. This process has been increased to 1.7 kg of coumarin (for details, see experimental section) and yield for 8-acylated coumarin, 3, was 29% after recrystallization. This yield for 8-acylated coumarin, 3, can be further improved by changing the purification process. For example, the crude product can be recrystallized from one or more solvents, in addition to dioxane, or a simple wash with an appropriate solvent can lead to the product sufficiently pure for the next reaction step. Next, chromene 4 is prepared by introducing the chromene ring into 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3, using 4,4-dimethoxy-2-methylbutan-2-ol. According to the method of the present invention, a solution of 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3, and 4,4-dimethoxy-2-methylbutan-2-ol, in an organic solvent suitable, in the presence of a base, is reacted at a temperature ranging between 40 and 1802C, approximately, preferably between about 100 and 1202C, until the reaction is completed, as determined by conventional means, such as the analysis of TLC chromatography. The water and methanol formed during the reaction are azeotropically removed by means of a Dean-Stark trap. In the practice of this invention, the amount of 4,4-Dimethoxy-2-methylbutan-2-ol, used in the reaction, generally varies between about 0.5 and 8 moles, preferably between about 2 and 4 moles, per mole of the 5,7-dihydroxy-8-propionyl- 4-propylcoumarin, 3. Suitable but not limiting examples of organic solvents include pyridine, triethylamine, N, N-dimethylformamide (DMF), toluene, tetrahydrofuran (THF) or 1,2-dichloroethane. Suitable but not limiting examples of the bases include pyridine, 4-dimethylaminopyridine, triethylamine, N, N-diethylaniline, 1,5-diaza-bicyclo [4.3.0] -non-5-ene (DBN), 1, 8-diaza-bicyclo [5,4,0] undec-7-ene (DBU), sodium carbonate and sodium bicarbonate. Pyridine is used both as the base and the solvent in this invention, on a small scale, however, for larger scales, pyridine is used as the base and toluene as a solvent. Upon completion of the reaction, the solvent is removed under reduced pressure and the reaction products are dissolved in a suitable solvent, for example ethyl acetate. The solution is then washed in sequence with water and brine and dried over a suitable drying agent, for example sodium sulfate. Next, the crude chromene product, 4, can be purified by conventional means, such as silica gel column chromatography, using 25% ethyl acetate / hexane as the eluting solvent. The yield of chromene 4 is generally in the approximate range of 60 to 85%, usually resulting in a yield of approximately 78%. Next, chromanone 7 can be produced by the reaction of a solution of chromene 4, acetaldehyde-diethylacetal and an acid catalyst in an organic solvent, at a temperature ranging between about 60 and 140 ° C, preferably about 14 ° C, until complete the reaction. The amount of the acetaldehyde-diethylacetal used in the reaction generally varies between about 0.5 and 20 ms, preferably between about 3 and 5 moles, per mole of chromene 4. Suitable, but not limiting examples of the acid catalysts include trifluoroacetic acid, methanesulfonic acid , trifluoromethanesulfonic acid, p-tosylic acid, acetic acid, hydrofluoric acid and their pyridinium salts and mixtures thereof. A preferred acid catalyst for use in this invention is trifluoroacetic acid. The amount of the acid catalyst used generally varies between about 2 and 24 moles, preferably between about 17 and 22 moles, per mole of chromene 4.

Two alternative routes to prepare chromanone 7 from chromene 4 in large-scale quantities were developed and which involve either a one-step reaction process (reaction of a paraldehyde stage) of two-step reaction processes (process of LDA / sulfuric acid or LDA / Kitsunobu process). (a) Reaction of a paraldehyde stage: In place of acetaldehyde-diethylacetal, paraldehyde was used as the equivalent of acetaldehyde. In the presence of one or more acid catalysts, such as CF3SO3H, CF3C02H and pyridinium p-toluenesulfonate (PPTS), chromene 4 was reacted with the paraldehyde at an elevated temperature, in a suitable solvent, to provide the chromanone 7 as the main product and the corresponding 10, 11-cis-diraethyl derivative, 7a, as a minor product. According to this reaction, the para-aldehydes are added to a stirred solution of chromene 4 and an acid catalyst, for example the PPTS, at room temperature, in a suitable solvent. The resulting mixture is heated to a temperature ranging between about 40 and 140 ° C, preferably between about 60 and 100 ° C, for a period of time ranging between about 5 and 36 hours, preferably about 20 hours. Next, CF3CO2H, an additional equivalent of PPTS and paraldehyde, is added, and the resulting mixture is maintained at a temperature ranging from about 40 to 140 ° C, preferably between 60 and 100 °, overnight or until the completion of the reaction, as determined by conventional means, for example by TLC chromatography. The amount of the paraldehyde employed per mole of chromene 4 generally varies between 1 and 40 moles, approximately, preferably between about 20 and 30 moles. Acidic, non-limiting catalysts include trifluoromethanesulfonic acid, methanesulfonic acid, p-tosylic acid and their pyridinium salts. In the practice of this invention, the preferred acid catalyst is pyridinium p-toluenesulfonate (PPTS). The amount of the acid catalyst used in the reaction varies between 0.5 and 10 moles, approximately, preferably between about 1 and 2 moles. Representative solvents for use in the reaction include toluene, diglyme and 1,2-dichloroethane. In the practice of the invention, 1,2-dichloroethane is the preferred solvent. Upon completion of the reaction, it is neutralized with a saturated bicarbonate solution and extracted with a suitable solvent, for example ethyl acetate. The crude product is then purified as described above. The yields of chromanone 7 in this reaction generally vary between 20 and 60%, usually around 40%. (b) Reaction of two stages of LDA / sulfuric acid: Under the condensation conditions of aldol, chromene 4 is reacted with acetaldehyde to form an aldol, 7b, open chain product. According to the present invention, a solution of the LDA in THF is added dropwise to a solution of chromene 4 in THF, at a temperature ranging between about -78ac and oac, preferably between -30ac and -78ac. The amount of the added LDA per mole of chromene 4 varies between about 1 to 4 moles, preferably between about 2 and 3 moles per mole of chromene 4. The addition, in drops, of the LDA is conducted so that the reaction temperature is keep within the desired interval. The acetaldehyde is then added dropwise to the reaction mixture in amounts ranging from about 1 to 12 mol, preferably between 4 and 6 mol, per mol of chromene 4. The addition, in drops, of acetaldehyde it is conducted so that the reaction temperature remains within the aforementioned range. The reaction is monitored by conventional means, for example the analysis of TLC chromatography, until it is complete. One skilled in the art will appreciate that the reaction of aldol of chromene 4 with acetaldehyde to form the product 7b can be carried out under conditions employing other bases in addition to the LDA. For example, metal hydroxides, such as NaOH, KOH and Ca (0H) 2f metal alkoxides, such as MeONa, EtONa and t-BuOK, and amines, such as pyrrolidine, piperidine, diisopropylethylamine, , 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diaza-bicyclo [5.4.0] -undec-7-ene (DBU), LDA, NaNH2 and LiHMDS, Like hydrides, such as NaH and KH, they can all be used for aldol reactions.15 Similarly, aldol reactions can be mediated by metal complexes of Al, B, Mg, Sn, Ti compounds, Zn and Zr, such as TiCl2, (i-PrO) 3TiCl, (i-PrO) 4Ti, PhBCl2, (n-Bu) 2BCl, BF3SnCl, SnCl4, ZnCl2, MgBr2. Et2AlCl, with or without chiral auxiliaries, such as l, 1-binaphthol, nor-ephedrine sulfonate, camphor-diol, diacetone-glucose and dialkyl tartrate. ! 6-18 Next, the reaction mixture is rapidly cooled to -3oac to -10ac, with an aqueous saturated solution of ammonium chloride and extracted with a suitable solvent, for example ethyl acetate. The combined extracts are washed with brine and dried over a suitable drying agent, for example sodium sulfate. The yields of the aldol product, 7b, generally vary between 40 and 80%, usually around 70%.

It should be noted that there are two asymmetric centers in the product 7b. Therefore, this product 7b is a racemic mixture of two sets of enantiomers (four optimally active forms) which can be resolved by conventional resolution methods, such as fractional crystallization or chromatography of suitable diastereomer derivatives, such as salts or esters with optically active acids (for example, camphor-10-sulphonic acid, camphoric acid, methoxyacetic acid or dibenzoyltartaric acid) or the enzymatically catalyzed acylation or hydrolysis of racemic esters. Likewise, the aldol reaction, mediated by a transition metal, of chiral17'18 of chromene 4 with acetaldehyde, can directly produce one of the optically active enantiomers of 7b. The resulting or synthetic enantiomer can then be transformed to the enantioselective synthesis of the (+) - calanolide A and its congeners. The aldol, 7b, crude product is then cyclized under acidic conditions, to form a mixture of both the chromanone 7 and the 10,11-cis-dimethyl derivative, 7a, in a ratio of 1: 1. Suitable but not limiting acids include one or more acids, such as sulfuric acid, hydrochloric acid (aqueous or anhydrous), trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-tosylic acid, acetic acid or mixtures thereof. A preferred acid for use in the reaction is a mixture of 1: 1 volume / volume of acetic acid and 50% of H2SO4. The reaction mixture is cooled, ice water is added and the resulting mixture is extracted with a suitable solvent, for example ethyl acetate. The combined organic layers are washed with water, a saturated bicarbonate solution and brine. The crude product is concentrated in vacuo and purified by conventional means, for example by column of silica gel, using a solvent mixture of 2: 3 (v / v) ethyl acetate / hexane. The yields of chromanone 7 in this reaction generally vary between 10 and 40%, usually 20%, based on chromene 4. A person skilled in the art will also appreciate that 10, 11-cis-chromanone, 7a, it can be treated with a base, under thermodynamic (equilibrium) conditions, in order to supply the corresponding trans-chromanone, 7. Suitable bases, but not limiting, include metal hydroxides, such as NaOH, KOH and Ca (OH) 2. metal alkoxides, such as MeONA, EtONa and t-BuOK, amines, such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N, N-diethylaniline, pyrrolidine, piperidine, 1,5-diaza-bicyclo [4, 3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU), LD, and LiHMDS, as well as metal hydrides, such as NaH and KH. (c) Two-step reaction of LDA / Mitsunobu: In a preferred reaction, the aldol product, 7b, can be converted to the chromanone, 7, as the predominant product under the neutral reaction conditions of Mitsunobu. In this reaction, diethyl azodicarboxylate (DEAD) is added dropwise to a solution containing the product of aldol, 7b, crude, and triphenylphosphine, at a temperature ranging from about -10 to 40ac, preferably at environmental temperature. The amount of the DEAD used in the reaction generally varies between about 1 and 10 moles, preferably about 1 to 4 moles, per mole of the aldol, 7b. The amount of triphenylphosphine used in the reaction generally ranges from about 1 to 10 moles, preferably from about 1 to 4 moles, per mole of aldol, 7b. Instead of DEAD, other reagents reported in the literature may be used, such as diisopropyl azodicarboxylate (DIAD), dibutyl azodicarboxylate (DBAD), dipiperidinoazodicarboxcimide, bis- (N 4 -methylpiperazin-1-yl) azodicarboxamide, dimorpholinoazodicarboxamide, NJNJN 'JN'-tetramethylazodicarboxamide (TMAD) 19. Also, in addition to triphenylphosphine, tri-n-butylphosphine has been used, 19 triethylphosphine, trimethylphosphine and tris (dimethylamino) -phosphine. The reaction is then rapidly cooled with saturated ammonium chloride until complete and extracted with a suitable solvent, for example ethyl acetate. The combined organic layers are washed with brine, concentrated in vacuo and chromeinone, 7, crude is purified by conventional means, as discussed above. The yields of chromanone, 7, of the LDA / Mitsunobu reaction, generally vary between 30 and 60%, approximately, and in general it is 50%, based on chromene 4. Examples suitable, but not limiting , of the azo compounds for the Mitsunobu reaction, include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dibutyl azodicarboxylate (DBAD), dipiperidinoazodicarboxéimide, bis (N 4 -methylpiperazin-1-yl) -azodicarboxamide, dimorpholinoazodicarboxamide and N, N, N ', N'-tetramethylazodicarboxamide (TMAD). Suitable but not limiting examples of the phosphorus derivatives for the Mitsunobu reaction include triphenylphosphine, tri-n-butylphosphine, triethylphosphine, trimethylphosphine and tris (dimethylamino) phosphine. Finally, the moderate reduction of boron hydride of chromanone 7 in the presence of CeCl3 (H2?) 7, produces (±) -calanolide A with the desired stereochemical arrangement. When conducting the reduction reaction, a solution of the chromanone, 7, in a solution of the reducing agent, for example sodium borohydride, and a metal additive, for example CeCl 3 (H 2?), Is added dropwise. in ethanol. The addition rate is such that the temperature of the reaction mixture is maintained within a range between about -40 and 60ac, preferably between about 10 and about 30ac. Next, the reaction mixture is stirred at a temperature ranging between -40 and 60 ° C, approximately. In general, the amount of the metal additive, for example, CeCl3 (H2?) 7, present in the reaction mixture varies between about 0.1 and 2 moles, preferably between about 0.5 and 1 mole, per mole of the borohydride of sodium. In addition, the amount of the sodium reducing agent, for example borohydride, used in the reaction, generally ranges from about 0.1 to 12 moles, preferably from about 2 to about 4 moles, per mole of the chromanone 7. Suitable examples, but Non-limiting reducing agents include NaBH4, LiAlH4, (i-Bu) 2AlH, (n-Bu) 3SnH, 9-BBN, Zn (BH4) 2, BH3, DIP chloride, selectriides and enzymes, such as Baker's yeast Suitable but not limiting examples of metal additives include CeCl3, ZnCl2, AICI3, TiCl4, SnCl3 and LnCl3 and their mixtures with the tri-phenylphosphine oxide. In the practice of this invention, sodium borohydride co or reducing agent and CeCl3 (H20) are preferred as the metal additive. Then, the reduction mixture is diluted with water and extracted with a suitable solvent, for example ethyl acetate. The extract is dried over a suitable drying agent, for example sodium sulfate, and concentrated. The resulting residue is then purified by conventional means, such as silica gel chromatography, using solvent mixtures of ethyl acetate / hexane. Thus, (±) -calanolide A, 1, is successfully prepared with the desired stereochemical arrangement, by the treatment of the intermediate chromene, 4, key with acetaldehyde-diethyl acetal or paraldehyde, in the presence of trifluoroacetic acid and pyridine or a two-step reaction, which includes the reaction of aldol with acetaldehyde and cyclization under acidic conditions or Mitsunobu neutral conditions, to produce chromanone, 7, followed by reduction of Luche via chromanone, 7 ( see Scheme II). An alternative route to prepare the (±) -calanolide A from chromene 4. A Robinson-Kostanecki reaction was conducted in 4, with sodium acetate in refluxing acetic anhydride, and the enone, 5, is produced in a 65-70 yield % (see Scheme II). However, the enone, 5, failed to deliver the (±) -calanolide A, when reduced with borohydride reagents and some transition metal reducing agents, presumably because the attack of the pyrone and the ring opening they occur preferably. The treatment of compound 5 with Baker's yeast also resulted in the unfolding of the coumarin ring, while the tri-n-butyl-tin hydride reduces enone 5 in enol 6 with modest yield. In another embodiment of the invention, methods are provided for resolving (±) -calanolide A in its optically active forms, (+) --calanolide A and (-) --calanolide A. In one method, the (±) - Calanolide is resolved by high performance liquid chromatography (HPLC), with an organic solvent system, such as the mobile phase. HPLC chromatography is performed on a column packed with the chiral packaging material. Examples suitable, but not limiting, of. Chiral packing material include amylose carbamate, D-phenylglycine, L-phenylglycine, D-leucine, L-leucine, D-naphthylalanine, L-naphthylalanine or L-naphthyl-leucine. These materials can be either ionically or covalently bound to a silica sphere, with particle sizes ranging from about 5 to 20 μm. Suitable mobile phases, but not limiting, include hexane, heptane, cyclohexane, ethyl acetate, methanol, ethanol or isopropanol, or mixtures thereof. The mobile phase can be used in an isocratic stage gradient or continuous gradient systems, at flow rates ranging between 0.5 and 50 ml / min., Approximately. Another method for resolving (±) -calanolide A in its optically active forms involves acylation or hydrolysis catalyzed by enzymes. In the practice of this invention, acylation, catalyzed by (±) -calanolide A enzymes is preferred. The enzymatic resolution method uses enzymes, such as CC lipase (Candida Cylindracea), AK lipase (Candida Cylindracea), AY lipase (Candida Cylindracea), PS lipase (Pseudomonas species), AP lipase (Aspergillus niger), N lipase ( Rhizopus nieveuis), FAP lipase (Rhizopus nieveus), PP lipase (Porcine Pancrease), pork liver stearase (jporcine) (PLE), acetone powder from the liver of the pig (PLAP) or subtilisin. The preferred enzyme for use in the enzyme catalyzed acylation reaction is PS-13 lipase (Siptaa Corporation, St. Louis, MO, USA). Immobilized forms of the enzyme in Cellite, molecular sieves or ion exchange resins are also considered for use in this method. The amount of the enzyme used in the reaction depends on the desired chemical conversion rate and the activity of the enzyme. The enzymatic acylation reaction is carried out in the presence of an acylating agent. Suitable examples, but not limiting, of acylating agents include vinyl acetate, vinyl propionate, vinyl butyrate, acetic anhydride, propionic anhydride, phthalic anhydride, acetic acid, propionic acid, hexanoic acid or octanoic acid. The enzyme reaction employs at least one mole of the acylating agent per mole of the (±) -calanolide A. The acylating agent can be used as a solvent in the acylation reaction or as a co-solvent with another solvent, such as hexanes, chloroform, benzene and THF. One skilled in the art will appreciate that the racemic esters of the calanolide A can be obtained by conventional means of esterification and selectively hydrolyzed by the enzymes to thereby produce, in a high enantiomeric excess, the (+) - calanolide A or (-) -calanolide A, optically active, in free or esterified form. The esterified calanolide A can be hydrolyzed chemically or enzymatically in the free form. Suitable examples, but not limiting, of the solvents for use in the enzymatic hydrolysis reaction include water, suitable aqueous regulators, such as sodium phosphate regulators, or alcohols, such as methanol or ethanol. In yet another embodiment of The invention provides a method for treating or preventing viral infections with the use of (+) - calanolide and (-) - calanolide. (±) -calanolide A and (-) -calanolide A have not been reported before in their anti-HIV activity. It has been found that (±) -calanolide A inhibits type 1 human immunodeficiency virus (HIV-1), with an EC50 value of about half that for (+) - calanolide A. Although (-) ) -calanolide A is not active against HIV-1, does not exhibit a synergistic effect on the toxicity of (+) - calanolide A.

Therefore, one skilled in the art will appreciate the direct use of the synthetic (±) -Calanolide A or an antiviral agent, without further resolution in the optically active (+) - calanolide A, to inhibit the growth or replication of virus in a mammal. Examples of mammals include humans, primates, bovines, ovines, pigs, felines, canines, etc. Examples of viruses may include, but are not limited to, HIV-1, HIV-2, Herpes simplex virus (types 1 and 2) (HSV-1 and HSV-2), Varicella zoster virus (VZV) cytomegalo-virus (CMV) , papilloma virus, HTLV-1, HTLV-2, feline leukemia virus (FLV), avian sarcoma viruees, such as rous sarcoma virus (RSV), hepatitis AE viruses, equine infections, influenza virus, arboviruses, measles , mumps and rubella viruses. More preferably, the compounds of the present invention will be used to treat humans infected with a retrovirus. Preferably, the compounds of the present invention will be used to treat an exposed or infected human (i.e., in need of such treatment) with the human immunodeficiency virus, or prophylactically or terapeutically. An advantage of certain compounds of the present invention is that they retain the ability to inhibit certain mutants of HIV RT, which are resistant to other non-nucleoside inhibitors, such as TIBO and nevirapine, or resistant to nucleoside inhibitors. This is advantageous over current AIDS drug therapy, where biological resistance often develops analogous to those used in the inhibition of RT. Therefore, the compounds of the present invention are particularly useful in the prevention or treatment of infections by the human immunodeficiency virus and also in the treatment of consequent pathological conditions, associated with AIDS. The treatment of AIDS is defined as including, but not limited to, the treatment of a wide range of HIV infection states: AIDS, ARC, both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating HIV infections after suspecting an exposure to HIV, for example in a blood transfusion, exposure to patients' blood during surgery or an accidental needle prick. The (±) -calanolide A and antiviral (-) -calanolide A can be formulated as a solution of lyophilized powders for parenteral administration. The powders can be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable carrier, before use. The liquid formulation is generally an aqueous, isotonic, regulated solution. Examples of suitable diluents are a normal isotonic saline solution, standard 5% dextrose in water or a sodium acetate or regulated ammonium solution. Such a formulation is suitable especially for parenteral administration, but may also be used for oral administration . It may be convenient to add excipients, such as polyvinylpyrrolidone, gelatin, hydroxy-cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, the compounds of the present invention can be prepared in capsules, tablets or prepared in an emulsion syrup (oil-in-water or water-in-oil) for oral administration. Pharmaceutically acceptable solid or liquid carriers, which are generally known in the pharmaceutical formulating art, may be added to increase or stabilize the composition, or to facilitate the preparation of the composition. Solid carriers include starch (corn or potato), lactose, calcium sulfate dihydrate, magnesia, cros-carmalose sodium, magnesium stearate or stearic acid, talc, pectin, acacia, agar, gelatin or colloidal silica . Liquid carriers include syrups, pooch-huate oil, olive oil, saline and water. The carrier can also include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of the solid carrier varies but, preferably, it will be between about 10 mg and 1 g, per unit dose.

The dose ranges for the administration of the (±) -calanolide A and the antiviral (-) -calanolide A are those to produce the desired effect, which improve the symptoms of the infection. For example, as used herein, a pharmaceutically effective amount for HIV infection refers to the amount administered in order to maintain an amount which suppresses or inhibits secondary infections by the formation of syncytia or by the circulation of viruses throughout the period during which is evident HIV infection, such as by the presence of anti-HIV antibodies, the presence of culturable viruses and the presence of the p24 antigen in the patient's serum. The presence of anti-HIV antibodies can be determined by the use of standard ELISA or Western blot assays, for example, for anti-gpl20, anti-gp41, anti-tat, anti-p55, anti-p17, antibodies, etc. . The dose will generally vary with age, extent of infection, body weight and counter-indications, if any, for example, immunological tolerance. The dose will also be determined by the existence of any adverse side effects that may accompany the compounds. It is always convenient, when possible, to keep adverse side effects to a minimum. A person skilled in the art can easily determine the appropriate dose, schedule and method of administration for the exact formulation of the composition that is used, in order to achieve the desired effective concentration in the individual patient. However, the dose may vary between about 0.001 to 50 mg / kg / day, but preferably it will be between about 0.01 to 1.0 mg / kg / day. The pharmaceutical composition can contain other pharmaceutical products in conjunction with the (±) -calanolide A and the antiviral (-) -Clanolide A, to treat (therapeutically or prophylactically) AIDS. For example, other pharmaceutical products may include, but are not limited to, other antiviral compounds (eg, AZT, ddC, ddl, D4T, 3TC, acyclovir, gancyclovir, fluorinated nucleosides and non-nucleoside analogues2 *?, Such as derivatives TIBO, nevirapine, a-interferon and recombinant CD4), immunostimulants (for example pyridinones, BHAP, HEPTs, TSAOs, α-APA, various interleukins and cytokines), immunomodulators and antibiotics (for example antibacterial, antifungal agents, anti-pneumocisitis ). The administration of the inhibitory compounds with other anti-retroviral agents that act against other HIV proteins, such as protease, integrase and TAT will generally inhibit most or all of the replication stages of the viral life cycle. In addition, the compounds of the present invention are useful as tools and / or reagents for studying the inhibition of retroviral reverse transcriptases. Thus, for example, the present compounds selectively inhibit HIV reverse transcriptase. Therefore, the present compounds are useful as a tool of the structure-activity relationship (SAR), to study, select and / or design other molecules to inhibit HIV. The following examples are illustrative and not to limit the scope of the invention, as claimed, EXPERIMENTAL All the chemical reagents and solvents mentioned herein are readily available from a number of commercial sources, including Aldrich Chemical Co., or Fischer Scientific. The Nuclear Magnetic Resonance Spectrum ("NMR") was carried out on a Hitachi NMR spectrometer, 60 MHz R-1200 or on an NMR Varian VX-300 spectrometer. The infrared (IR) spectra were obtained using a Midac M series FT-IR instrument. The mass spectrum data were obtained using a Finnegan MAT 90 mass spectrometer. All melting points are corrected.

EXAMPLE lt 5,7-dihydroxy-4-propylcoumarin5 (2) Concentrated sulfuric acid (200 ml) was added to a mixture of floroglucinol dihydrate (150 g, 0.926 mol) and ethyl butyrylacetate (161 g)., 1.02 mol). The resulting mixture was stirred at 90 ° C for two hours and then emptied onto ice. The solid product was collected by filtration and then dissolved in ethyl acetate. The solution was washed with brine and dried over Na2SO4. After removing the solvent in vacuo, the residue was triturated with hexane to give essentially pure compound 2 (203 g), in quantitative yield, melting point: 233-235ac (Lit.5: 236-238ac). iH-NMR5 (DMS0-d6) d 0.95 (3H, t, J = 6.9 Hz, CH3); 1. 63 (2H, apparent sextet, J = 7.0 Hz, CH2); 2.89 (2H, t, J = 7.5 Hz, CH2); 5.85 (1H, s, H3); 6.22 (1H, d, J = 2.0 Hz, H6); 6. 31 (1H, d, J = 2.0 Hz, H8); 10.27 (1H, s, OH); 10.58 (1H, s, OH); Mass Spectrum (MS) (El); 220 (100, M +); 205 (37.9, M-CH3); 192 (65.8, M-C2H4); 177 (24.8, M-C3H7); 164 (60.9, M-CHC02 + 1); 163 (59.6 M-CHC02); Infrared Spectrum (IR) (KBr): 3210 (vs and width, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1); Analysis, calculated for Ci2H24 ° 4: > 65.45; H, 5.49; Found C, 65.61; H, 5.44.

EXAMPLE 2: 5/7-dihydroxy-8-propionyl-4-propylcoumarin (3) A three neck flask (500 ml), equipped with an efficient mechanical stirrer, thermometer and addition funnel, was charged with the 5.7- dihydroxy-4-propylcoumarin, 2, (25.0 g, 0.113 mol), aluminum chloride (52.1 g, 0.466 mol) and nitro-benzene (150 ml), and the mixture was stirred until a solution was obtained, which was cooled to oac in an ice bath. A solution of propionyl chloride (15.2 g, 0.165 mol) in carbon disulfide (50 ml) was added dropwise at such a rate that the reaction temperature was maintained at 8-10ac. The addition was completed in a period of 1 hour, with vigorous agitation. The reaction was monitored by TLC chromatography using a mobile phase of 50% ethyl acetate / hexane. After three hours, an additional portion of propionyl chloride (2.10 g, 0.0227 mol) in carbon disulfide (10 ml) was added. Immediately after the analysis of TLC chromatography indicated the total consumption of the starting material, the reaction mixture was emptied on ice and allowed to stand overnight. The nitrobenzene was removed by steam distillation, and the remaining solution was extracted several times with ethyl acetate. The extracts were combined and dried over Na2 so4 * E1 crude product, obtained by evaporation in vacuo, purified by chromatography on a column of silica gel, eluting with 50% ether / hexane to give coumarin 3, treated with propionyl, desired PF (corrected): 244-246ac. '-H-NMR (DMSO-d6) d 0.96 (3H, t, J = 7.3 Hz, CH3); 1.10 (3H, t, J = 7.2 Hz, CH3); 1.60 (2H, m, CH2); 2.88 (2H, t, J = 7.7 Hz, CH2); 3.04 (2H, q, J = 7.2 Hz, CH2), * 5.95 (1H, s, H3); 6.31 (1H, s, H6); 11.07 (1H, s, OH); 11.50 (1H, s, OH); MS (The); 277 (6.6, M + l); 276 (9.0, M +); 247 (100, M-C2H5); IR (KBr): 3239 (s and width, OH), 1693 (s, C = 0), 1625 and 1593 (s) cm "" 1; Analysis, calculated for C? 5Hi 05 i C, 65.21; H 5.84; Found: C, 64.92; H, 5.83. The assignment of isomers was made by analogy to the preceding one. EXAMPLE 3: 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H, 8H-benzo [1, 2-: 3, '] dipiran-8-one () A mixture of 3 (2.60 g, 9.42 mmol) and 4,4-dimethoxy-2-methylbutan-2-ol (5.54 g, 37.7 mmol) was dissolved in anhydrous pyridine (6.5 mL). The mixture was refluxed under nitrogen for three days. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate. The ethyl acetate was washed several times with IN HCl and brine. Then it was dried over Na2SO4. The crude product obtained by evaporation in vacuo was purified by silica gel column chromatography, eluting with 25% ethyl acetate / hexane to give 2.55 g of product 4 with 76.6% yield, PF: 96-98ac * H- NMR (CDC13) d 1.05 (3H, t, J = 7.3 Hz, CH3); 1.22 (3H, t, J = 7.5 Hz, CH3); 1.53 (6H, s, 2 CH3); 1.75 (2H, m, CH2), * 2.92 (2H, t, J = 7.1 Hz, CH2); 3.35 (2H, q, J = 7.1 Hz, CH2); 5.56 (1H, d, J = 10.0 Hz, H3); 5.98 (1H, s, H9); 6.72 (1H, d, J = 10.0 Hz, H4); MS (El): 343 (5.7, M + 1); 342 (22.5, M +); 327 (100, M-CH3) IR (KBr): 1728 (vs, C = 0) cm "1; Analysis, calculated for C2oH22 ° 5: C, 70.16; H, 6.48; Found: C, 70.45; H, 6.92 .

EXAMPLE 4: 10, 11-didehydro-12-oxocalanolide A (5) A mixture of product 4 (1.76 g, 5.11 mmol) and sodium acetate (0.419 g, 5.11 mmol) in acetic anhydride (12 ml) was refluxed for 10 hours, after which the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel, eluting first with 25% ethyl acetate / hexane, followed by 50% ethyl acetate / hexane to give 1.16 g (62% yield) of enone 5 ( 6,6, 10, 11-tetramethyl-4-propyl-2H, 6H, 12H-benzo [1,2-b: 3,4-b ': 5,6-b "] - tripiran-2, 12-dione ) as a white solid, with a melting point of 209-209.5BC. "-H-NMR (CDC13) d 1.05 (3H, t, J = 6.6 Hz, CH3); 1.56 (5H, S, 2CH3); 1.73 (2H, m, CH2); 1.98 (3H, s, CH3); 2.38 (3H, s, CH3); 2.91 (2H, t, J = 7.5 Hz, CH3); 5.69 (1H, d, J = 10.0 Hz, H7); 6.11 (1H, s, H3); 6.71 (1H, d, J = 10 Hz, H8); MS (El): 366 (29.6, M +); 351 (100, M-CH3); 323 (16.5, M-C3H7); IR (KBr): 1734 (vs, C = 0), 1657, 1640, 1610 and 1562 cm "1; Analysis, calculated for C22H22 ° 5: c, 72.12; H, 6.05; Found: C, 72.14; H, 6.15 .

EXAMPLE 5: 10,11-didehydrocalanolide A (6) A mixture of enone 5 (160 mg, 0.437 mmol) and tri-n-butyl tin hydride (0.318 g, 1.09 mmol) in dry dioxane (2.0 ml) it was refluxed under nitrogen for 12 hours. The solvent was then removed in vacuo and the residue was purified by preparative TLC chromatography, using 25% ethyl acetate in hexane as the mobile phase. The product exhibited an Rf of approximately 0.4. Enol 6 (12-hydroxy-6,6,10,1-tetramethyl-4-propyl-2H, 6H, 12H-benzo- [1,2-b: 4-b1: 5, 6-b "] - tripiran -2-one) (23.3 mg, 8%) was isolated as an oil from the plate by elution of ethyl acetate.This elution may have been inefficient and the actual yield increased, as indicated by analytical TLC chromatography of the product crude. xH-NMR (CDC13) d 0.92 (3H, t, J = 6.0 Hz, CH3), 1.26 (3H, s, CH3), 1.39 (3H, s, CH3), 1.63 (2H, m, CH2); 1.96 (3H, S, CH3), 2.36 (3H, s, CH3), 2.45 (2H, t, J = 6.0 HZ, CH2), 3.65 (1H, s, H12), 5.51 (1H, d, J = 10.0 Hz, H7), 6.67 (1H, d, J = 10.0 Hz, H8), 13.25 (1H, br, s, OH), MS (El): 369 (3.9 (M + l), 368 (4.4 (M +) , 367 (8.3, Ml) 366 (28.4, M-2), 351 (100, M-OH), IR (KBr): 1651 (s), 1589 (m) cm-1.

EXAMPLE 6: 12-oxocalanolide A (7) A solution containing chromene 4 (344 mg, 1.0 mmol), acetaldehyde-diethylacetal (473 mg, 4.0 mmol), trifluoroacetic acid (1.5 ml, 19.4 mmol) and anhydrous pyridine (0.7 ml), was heated to 140 ° C under N2. The reaction was monitored by the analysis of TLC chromatography. After 4 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed several times with 10% aqueous NaHC 3 and brine. The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane (2: 4). Chromanone 7, (10, 11-trans-dihydro-6,6,10, 11-tetramethyl-4-propyl-2H, 6H, 12H-benzo [1,2-b: 3,4-b ': 5, 6-b "] -tripyran-2,12-dione) (110 mg, 30% yield) was obtained, PF: 176-177BC (Lit.5: 130-132BC) .IH-NgMR5 (CDC13) d 1.02 ( 3H, t, J = 7.5 Hz, CH3), 1.21 (3H, d, J = 6.8 Hz, CH3), 1.51 (3H, d, J = 7.0 Hz, CH3), 1.55 (6H, 2s, 2 CH3); 1.63 (2H, sextet, J = 7.0 Hz, CH2), 2.55 (1H, dq, J = 6.9 Hz, J = 11.0 Hz, J = 11.0 Hz, H10), * 5.60 (1H, d, J = 9.9 Hz, H8), 6.04 (1H, s, H3), 6.65 (1H, d, J = 11.8 Hz, H7), MS (Cl): 369 (100, M + l).

EXAMPLE 7: (±) -calanolide A (1): To a solution of chromanone 7 (11 mg, 0.03 mmol) in EtOH (0.4 ml) was added sodium borohydride (2.26 g, 0.06 mmol) and CeCl3 (H 0 7) (11.2 mg, 0.03 mmol) in EtOH (5 ml) at room temperature. After stirring for 45 minutes, the mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over Na 2 SO and concentrated. The crude product was purified by preparative TLC chromatography, eluting with ethyl acetate / hexane (1: 1) to give the (±) -calanolide A (1) (10.5 mg, 94%), MP: 51-54 c, which increased to 102ac after drying completely (Lit.5: 56-58CC). iH-NMR (CDCl 3): d 1.03 (3 H, t, J = 7.3 Hz, CH 3), 1.15 (3 H, d, J = 6.8 HZ, CH 3), 1.46 (3 H, d, J = 6.8 Hz, CH 3), 1.47 (3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, m, CH2), 1-93 (1H,, Hn), 2.89 (2H,, CH2), 3.52 (1H, broad) -s, OH), 3.93 (1H, m, H10), 4.72 (1H, d, J = 7.8 Hz, H12), 5.54 (1H, d, J = 10.0 Hz, H7), 5.94 (1H, s, H3) ), 6.62 (1H, d, J = 9.9 Hz, H8); MS (Cl): 371 (75.4, M + 1), 370 (16.1, M +), 353 (100, M-OH); Analysis, calculated for C 22 H 25 O 5: C, 71.33; H, 7.07; Found: C, 71.63; H, 7.21.

EXAMPLE 8: 5,7-dihydrox: L-4-propylcoumarin (2): In this example, the preparation of intermediate 2 on a kilogram scale is described. In a stirred suspension of phloroglucinol (3574.8 g, 28.4 mol, previously dried at a constant weight) and ethyl butyrylacetate (4600 ml, 28.4 mol), concentrated sulfuric acid was added dropwise at such a rate that the internal temperature did not exceeded 40ac. After adding 100 ml of sulfuric acid, the temperature rose to 70ac and the suspension became a yellow solid. Analysis of TLC chromatography indicated that the reaction had preceded to completion. The reaction mixture was diluted with water (10 1) and stirred at room temperature overnight. The precipitated product was collected by filtration and then rinsed with water until the filtrate was neutral. An amount of 4820 g (77% yield) of the 5,7-dihydroxy-4-propylcoumarin 2 was obtained after drying, which was identical to an authentic sample by comparison of TLC chromatography, melting point and the spectroscopic data.

EXAMPLE 9: 5,7-Dihydroxy-8-propionyl-4-propylcoumarin 3 In this example, kilogram-scale quantities of intermediate 3 were synthesized using propionic anhydride in place of propionyl chloride. The 5,7-dihyd ?. Í-4-propyl-coumarin, 2, (1710 g, 7.77 moles) and the AICI3 (1000 g, 7.77 moles) were mixed in 1,2-dichloro-ethane (9 liters). The resulting orange suspension was stirred and heated to 70 ° C until a solution was obtained. Next, a mixture of propionic anhydride (1010 g, 7.77 mol) and AICL3 (2000 g, 15.24 mol) in 1,2-dichloroethane (3.4 liters) was added in 3 hours. The reaction was stirred at 70 ° C for an additional hour. After cooling to room temperature, the reaction mixture is evacuated in a rapidly stirred mixture of ice water and IN HCl. The precipitated product was taken up in ethyl acetate (30 liters) and the aqueous solution was extracted with the same solvent (10 liters x 2). The combined extracts were washed successively with IN HCl (10 liters) saturated NaHC 3, aqueous (10 liters) and water (10 liters). After drying over MgSO4 and concentrating in vacuo, a solid product (1765 g) was obtained which was washed with ethyl acetate (15 liters) and dioxane recrystallized (9.5 liters) to give 514 g of pure compound 3 . From the ethyl acetate washes, an additional 100 g of the compound was obtained, after recrystallization of the dioxane. A) Yes. the combined yield for compound 3, which was identical with an authentic sample by comparison of TLC chromatography, melting point and spectroscopic data, was 29%.

EXAMPLE 10; 2 2-dimethyl-5-hiajL? XI-6-propionyl-10-propyl-2H 8H-benzo [l, 2-b: 3,4-b '] -dipyran-8-one (4): In this example , intermediate 4 was prepared in amounts of half a kilogram from 3, by means of the modification of the reaction conditions described in Example 3. A mixture of compound 3 (510.6 g, 1.85 mol) and 4.4 dimethoxy-2-methylbutan-2-ol (305.6 g, 2.06 moles) was dissolved in a mixture of toluene (1.5 liters) and dry pyridine (51 ml). This mixture was stirred and refluxed; the water and MeOH formed during the reaction were azeotropically removed by means of a Dean-Stark trap. The reaction was monitored by TLC chromatography. After 6 days, the reaction proceeded to completion. The mixture was then cooled to room temperature and diluted with ethyl acetate (1 liter) and IN HCl (1 liter). The ethyl acetate solution was separated and washed with IN HCl (500 ml) and brine (1 liter). After drying over Na 2 SO 4 and evaporating in vacuo, an amount of 590 g (93% yield) of compound 4 was obtained, which was greater than 95% pure without further purification and compared with an authentic sample by chromatography TLC and spectroscopic data. No traces of the 6-acylated or 6,8-bis-acylated product were observed, although a small amount formed the 7-monoester.

EXAMPLE 11: 12-oxacalene Lide A (7): In this Example, chromanone 7 was prepared from two alternative routes involving either a one-step reaction process (process A) or a two-step reaction process (procedures B and C). Procedure A. One-step reaction of Paraldehyde: To a stirred solution of chromene 4 (350 mg, 1.0 mmol.) And PPTS (250 mg, 1.0 mmol) in 1,2-dichloroethane (2 ml) at room temperature, under N2, 3 ml of paraldehyde (22.5 mmol) was added. The resulting mixture was refluxed for 7 hours. Next, CF3CO2H (1 ml), an additional equivalent of PPTS and 1 ml of paraldehyde were added; the mixture was refluxed overnight. The reaction mixture was neutralized with saturated aqueous NaHC 3 and extracted with ethyl acetate (50 ml x 3). The crude product obtained by evaporation, under reduced pressure, was washed with hexane. The residue was purified by column chromatography, eluting with ethyl acetate / hexane (1: 2) to deliver 100 mg (27% yield) of chromanone 7 and 30 mg (8% yield) of 7a. Chromanone 7 (10, 11. Trans-dihydro-6,6, 10-tetramethyl-4-propyl-2H, 6H, 12H-benzo [1,2,2-b: 3,4-b ': 5,6-b] "[Tripiran-2, 12-dione], obtained by this method, was identical to an authentic sample by comparison of TLC chromatographies, HPLC and spectroscopic data.

Procedure B Two-Stage Reaction of LDA / Sulfuric Acid: To a stirred solution of chromene 4 (5.0 g, 14.6 mmol) in THF (75 mL) at -30 ° C, under N2, 18.3 mL (36.5 mmol) of 2M LDA were added in THF After 15 minutes at the same temperature, acetaldehyde (5.0 ml, 89.5 mmol) was added via syringe, the reaction was monitored by TLC chromatography analysis. After 1 hour, the reaction mixture was rapidly cooled to -10 ° C with saturated aqueous NH 4 Cl (75 mL) and extracted with ethyl acetate (125 mL x 3). The combined extracts were washed with brine (125 ml) and dried over Na2SO4. Removal of the solvents in vacuo gave a reddish oil of the product 7b (8.5 g). The crude product 7b was dissolved in acetic acid (100 ml) and then 50% H2SO (100 ml) was added with stirring. The resulting mixture was heated at 75 ° C for 2.5 hours and then at 50 ° C for 4 hours. Analysis of TLC chromatography indicated that the starting material had been consumed. The reaction mixture was determined to contain both chromanone 7 and derivative 7a of 10, 11-cis-dimethyl, in a ratio of 1: 1. After cooling to room temperature, the reaction mixture was poured into a mixture of ice water (500 ml) and ethyl acetate (500 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (200 ml x 3). The ethyl acetate solutions were combined and washed with aqueous NaHC03 and saturated with urea salt. After concentration in vacuo, the product was purified by chromatography on a column of silica gel, eluting with ethyl acetate / hexane (2: 3) to give 850 mg (16% yield) of chromanone 7, which was purified subsequently by recrystallization from ethyl acetate / hexane and was identical with an authentic sample by comparison of TLC chromatographies, HPLC and spectroscopic data.

Procedure C »Two-Stage Reaction of LDA / Mitsunobu: Within a stirred solution of THF (10 ml), containing triphenylphosphine (1.27 g, 4.80 mmol) and crude product 7b, obtained from chromene 4 (1.0 g, 2.34 mmole), 2.5 equivalents of LDA and 6.0 equivalents of acetaldehyde, by the procedure described above, was added, in drops, diethyl azodicarboxylate (DEAD, 0.77 ml, 4.89 mmoles). The resulting reddish solution was stirred at room temperature under N2, for 1 hour, after which the reaction mixture was quenched with saturated aqueous NH C1 and extracted with ethyl acetate (50 ml x 3). The extracts were washed with brine and dried over Na 2 SO 4: After removing the solvents, the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane (2: 3), to give 412 g ( 48% yield, based on chromene 4) of chromanone 7, the predominant product of the reaction, which was identical with an authentic sample by comparison of TLC chromatographies, HPLC and spectroscopic data.

EXAMPLE 12: (±) -calanolide A (1): In this Example, (±) -calanolide A was prepared on a multi-gram scale, using the procedure described in Example 7. To a stirred solution of chromanone 7 (51.5 g, 0.14 mol) in EtOH (1.5 liters) was added CeCl3 (H2?) 7 (102 g, 274 mmol). The mixture was stirred for 1.5 hours at room temperature, under N2, and then cooled to -30ac with a dry ice bath in ethylene glycol / H2? (1: 2, weight / weight). After the temperature was equilibrated to -30ac, NaBH4 (21.3 g, 563 mmol) was added and equilibrated at the same temperature for 8.5 hours, during this time the reaction was quickly cooled with H2O (2 liters) and extracted with ethyl acetate (2 liters x 3). The extracts were combined, washed with brine (2 liters) and dried over Na 2 SO 4. The crude product obtained by the removal of the solvent, under reduced pressure, was passed through a short column of silica gel, to supply 53 g of the mixture, which contained 68% of the (±) -calanolide A, 14 % of calanolide B and 13% of chromanone 7, as shown by HPLC chromatography. This material was subjected to a further purification by preparative HPLC chromatography to deliver the pure (±) -calanolide A (1).

EXAMPLE 13: Chromatographic Resolution of Synthetic (±) -Calanolide A Synthetic (±) --calanolide A (1) was resolved in the enantiomers, the (+) - calanolide A and the (-) --calanolide A, by the preparative HPLC chromatography. Thus, using a normal-phase silica gel HPLC column (250 mm x 4.6 mm internal diameter: Zorbasil, particle size 5 / xm, MAC-MOD Analytical, Inc., PA, USA), Synthetic (±) -calanolide A (1) appeared as a ridge with a retention time of 10.15 minutes, when hexane / ethyl acetate (70:30) was used as the mobile phase, at a flow rate of 1.5 ml / min and a wavelength of 290 nm, as the adjustment of the UV light detector. However, in a chiral HPLC column, packed with amylose carbamate (250 mm x 4.6 mm internal diameter: Chiralpak AD, particle size 10 μm, Chiral Technologies, Inc., PA, USA), two were observed. crests with retention times of 6.39 and 7. 15 minutes, in a ratio of 1: 1, at a flow rate of 1.5 ml / min. The mobile phase was hexane / ethanol (95: 5) and the UV light detector was adjusted to a wavelength of 254 nm. These two components were separated using the column of Chiral, semi-preparative HPLC, which supplied pure enantiomers of the calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the natural product reported, were characterized by spectroscopic data.

HPLC chromatograms of (±) -calanolide A and their optical forms are shown in Figure 6. < + * - Calanolidc # A (l): mp 47-50'C (Lit. 45-48ßC); [a] aD- + 68.8 * »(CHClj, c 0.7) (Lit.14 [o] V +« 6.6 * (CHC1: >, c 0.5); lH NMR (CDClj) S 1.03 (3H, t, J-7.3 Hz, CH,), 1.15 (3H, d, J-6.8 HZ, CH,), 1.46 (3H , d, J-6.4 Hz, CH,), 1.47 (3H, s, CH,), 1.51 (3H, s, CH,), 1.66 (2H, m, CH,), 1.93 (1H, p, H " ), 2.89 (2H, ffl, CH2), 3.52 (1H, d, J-2.9 HZ, OH), 3.93 (1H, m, H, 0), 4.72 (1H, dd, J-7.8 Hz, J-2.7) Hz, H "), 5.54 (1H, d, J-9.9 HZ, H7), 5.94 (1H, s, H,), 6.62 (1H, d, J-9.9 HZ, Hg);, 3C NMR (CDCl, ) S 13.99 (CH,), 15.10 (CH,), 18.93 (CH,), 23.26 (CH2), 27.38 (CH,), 28.02 (CH,), 38.66 (CH2), 40.42 (CH), 67.19 ( CH-OH), 77.15 (CH-O), 77.67 (CO), 104.04 (CJ, 106.36 (C and CI2, 110.14 (C,), 116.51 (Ct) * 126.97 (C,), 151.14 (C «.) 153.10 (C »), 154.50 (CIJk), 158.88 (C4), 160.42 (CO), CIMS: 371 (100, M + l), 370 (23.6, M *), 353 (66.2, M-OH); IR: 3611 (w) and 3426 (m, broad, OH), 1734 (v. CO), 1643 (m), 1606 (m) and 1587 (vss) car1; UV? ^ (MeOH): 204 (32,100) , 22 8 (23,200), 283 (22,200), 325 (12,700) n; Anal, caled, for CJJHMO, 1 / 4H20: C, 70.47; H, 7.12; Found: C, 70.64; H, 7.12.

(-) - Calanolidci A (1): mp 47-50'C; [a] 2 * 0-75.6ß (CHC1, c 0.7) Lit .- 'üa] 250-66 »(CHC1" c 0.5); ? NMR (CDCl,) = 1.03 (3H, t, J-7.4 Hz, CH,), 1.15 (3H, d, J-6.8 Hz, CH,), 1.46 (3H, d, J-6.3 HZ, CH,) , 1.47 (3H, S, CH,), 1.51 (3H, ß, CH,), 1.66 I (2H, a, CH,), 1.93 (1H, m, H "), 2.89 (2H, m, CHj) , 3.50 (1H, d, J-2.9 HZ, OH), 3.92 (1H, m, H) 0), 4.72 (1H, dd, J-7.8 HZ, J-2.7 HZ, H, 2), 5.54 (1H , d, J-10.0 Hz, H7), 5.94 (1H, S, H,), 6.62 (1H, d, J-10.0 Hz, H,); 13C NMR (CDCl,) i i 13.99 (CH,), 15.10 (CH,), 18.93 (CH,), 23.36 (CH2), 27.38 j (CH,), 28.02 (CH,), 38.66 (CH2) , 40.42 (CH), 67.19 (CH-OH), 1 77.15 (CH-O), 77.67 (CO), 104.04 (CJ, 106.36 (C "and C), 110.14 (C,), 116.51 (C,), 126.97 (C7), 151.14 (C, *), | 153.11 (Ctl), 154.50 (C12b), 158.90 (C4), 160.44 (CO); CIMS: 371 (95.2, M + l), 370 (41.8, MT) , 353 (100, M-OH), IR: 3443 I (m, broad, OH), 1732 (vs, CO), 1643 (), 1606 (m) and, 1584 (vs) cm1; UV? ^, ( MβOH): 200 (20,500), 230 (19,400), '283 (22,500), 326 (12,500) not; Anal, caled, for (C ^ HjßOjl HjO: C, 70.47; H, 7.12; Found: C, 70.27; H, 7.21 EXAMPLE 14: Enzymatic Resolution of the (±) -Calanolide AA a suspension, magnetically stirred, of the (±) -Calanolide A, prepared by the method of the present invention, and the vinyl butyrate (0.1 ml ) in hexane (0.5 ml), at room temperature, 1 mg of PS-13 lipase (Pseudomonas Species) was added (Sigma Corporations, St. Louis, MO, USA). The reaction mixture was stirred and monitored by conventional means, such as the TLC chromatography analysis: At 10 days, an additional 1 mg of PS-13 lipase was added. After stirring for a total of 20 days, the reaction was stopped because there was no obvious increase in ester formation. The enzyme was filtered and separated and the filtrate was concentrated to dryness. The residue was analyzed by HPLC (Example 13), and showed that 21% of the (-) --calanolide A had been converted to its butyrate ester form (Scheme IV). The enriched (+) --calanolide A and the (-) - calanolide A butyrate ester were easily separated by conventional means, such as column chromatography. The enriched (±) -calanolide A was repeatedly treated with the vinyl butyrate and the lipase PS-13, as described above, and thus obtain high yield of the (+) - calanolide A. EXAMPLE 15 In vitro evaluation of the ( +) - and (-) calanolides A This example illustrates the viral anti-HIV activity of the synthetic (±) -calanolide A and its pure enantiomers, the (+) --calanolide A and the (-) --calanolide A were evaluated using the published MTT-tetrazolium method.20 Retroviral agents, AZT and DDC were used as controls for comparison purposes. The cells used for the research were the MT-2 and the human T4-lymphoblastoid cell line, CEM-S, and grew in RPMI 1640 medium supplemented with 10% (v / v) heat inactivated fetal calf serum and also contained 100 units / ml of penicillin, 100 μg / ml streptomycin, 25 mM HEPES and 20 μg / ml gentamicin. The medium used for the dilution of the drugs and maintenance of the cultures, during the test, was the same as before.

The HTLV-IIIB and HTLV-RF were propagated in CEM-SS. Appropriate amounts of the pure compounds for anti-HIV evaluations were dissolved in DMSO, then diluted in the medium to the desired initial concentration. The concentrations (μg drug / ml of medium) used were 0.0032 μg / ml, 0.001 μg / ml, 0.0032 μcf / ml, 0.01 μg / ml, 0.032 μg / ml, 0.1 μg / ml, 0.32 μg / ml, 1 μg. / ml, 3.2 μg / ml, 10 μg / ml, 32 μg / ml and 100 μg / ml. Each dilution was added to the plates in an amount of 100 μl / well). The drugs were tested in wells triplicated by dilution with the infected cells, while the wells duplicated, by dilution with uninfected cells for cytotoxicity. On day 6 (CEM-SS cells) and on day 7 (MT-2 cells), after infection, viable cells were measured with a tratrazolium salt, MTT (5 mg / ml), added to the plates. proof. A solution of 20% SDS in 0.001 N HCl was used to dissolve the MTT-formazan produced. The value of the optical density was a function of the amount of the formazan produced, which is proportional to the number of viable cells. The percentage of inhibition of CPE by concentration of the drug was measured as a control on test and expressed in percent (T / C%). The data is summarized in Figures 1 (a-e), 2 (a-e), 3 (a-e), 4 (a-e) and 5 (a-e). Figures 1 (a) to 1 (e) illustrate the results of the in vitro MMT assay using a viral strain 21 G9106 HIV, isolated, which is resistant to AZT. The data show that (-) -calanolide A was relatively non-toxic at concentrations of 1 μg / ml, but exhibited very little antiviral effect. Also, (±) -calanolide A was effective as (+) - calanolide A in reducing viral CPE. As expected, AZT has little or no effect in reducing viral CPE and increasing the viability of cells. Figures 2 (a) to 2 (e) illustrate the results of the in vitro MMT assay, using the viral strain H112-2 HIV, which was not previously treated with AZT. As expected, the viral strain was sensitive to AZT. The data also show that (-) - calanolide A was relatively non-toxic at concentrations of 1 μg / ml, but exhibits very little antiviral effect. (±) -calanolide A was almost as effective as (+) -calanolide A in reducing viral CPE. Figures 3 (a) to 3 (e) illustrate the in vitro MMT assay with the use of viral strain 22 A-17 HIV, which is resistant to non-nucleoside inhibitors, such as TIBO and pyridinone, but is sensitive to AZT . The results here are parallel to those shown in Figures 2 (a) -2 (e). Figures 4 (a) - (e) and 5 (a) - (e) illustrate the results of the in vitro MMT assay with the use of the viral strains HIV, cultured in the laboratory, IIIB and RF, respectively. The results here are also parallel to those shown in Figures 2 (a) -2 (e).

REFERENCES la. Brookmeyer, R., Reconstruction and Future Trends of the AIDS Epidemic in the United States, Science, 1991, 253, 37-42. b. Brain, M.M.; Heyward, W.L .; Curran, J.W. , The Global Epidemiology of HIV Infection and AIDS, Annu. Rev.

Microbiol. , 1990, 44, 555-577. 2a. Weislow, O.S .; Kiser, R.; Fine, D.L .: Bader, J.

Shoemaker, R.H .; Boyd, M.R. , New Soluble-formazan Assay for HIV-1 Cytopathic Effets: Application to High-Flux Screening of Synthetic and Natural Products of AIDS-Antiviral Activity. J. Nati. Cancer Inst. , 1989, 81, 577-586. b. Mitsuya, H.; Yarchoan, R.; Broder, S., Molecular Targets for AIDS Therapy. Science, 1990, 249, 1533-1544. C. Petteway, S.R. , Jr.; Lambert, D.M.; Metcalf, B.W. , The Chronically Infected Cells: A Target for the Treatment of HIV Infection and AIDS. Trends Pharmacol. Sci. , 1991, 12, 28-34. d. Ric-hman, D.D., gAntiviral Therapy of HIV Infection, Annu. Rev. Med., 1991, 42, 69-90. and. Haden, J.H., Immunotherapy of Human Ineficiency Virus Infection. Trends Pharmacol Sci. , 1991, 12, 107-111. F. Huff, J.R. , HIV Protease: A Novel Chemotherapeutic Target for AIDS. J. Med. Chem., 1991, 34, 2305-2314. g. De Clercq, E., HIV Inhibitors Targeted at the Reverse Transcriptase. AIDS Research and Human Retroviruses, 1992, 8, 119-134. 3. Kashman, Y .; Gustafson, K.R.; Fuller, R.W.; Cardellina, J.H., II; McMahon; J.B .; Currens, M.J.; Buckheit, R.W. , Jr .; Hughes, S.H .; Cragg, G.M.; Boyd, M.R., The Calanolides, to Novel HlV-Inhibitory Class of Coumarin Derivatives from the Tropical Rainforest Tree, Calophyllu lanigerum. J. Med. Chem. 1992, 35, 2735-2743. Boyd, M.R. , National Cancer Institute, Personal Communication. Chenera, B.; West, M.L .; Finkelstein, J.A .; Dreyer, G.B., Total Synthesis of (±) -Calanolide A, to Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase. J. Org. Chem. 1993, 58, 5605-5606. Sethna, S.; Phadke, R., The Pechmann Reaction. Organic Reactions, 1953, 7, 1-58 and references cited therein. Crombie, L.; Jones, R.C.F .; Palmer, C.J. , Synthesis of the Mam and Coumarin. Part 1. * The Coumarin of the Mammea A, B, and C Series. J. Chem. Soc, Perkin Trans. 1, 1987, 317-331. Barton, D.H.R .; Donnelly, D.M.X.; Finet, J.P .; Guiry, P.J., Total synthesis of Isorobustin. Tetrahedron Lett. 1990, 31, 7449-7452. Kovacs, T.S .; Zarandy, M.S .; Erdohelyi, A., Cyclization of the Enol Esters of o-Acyloxyphenyl Alkyl Ketones, IV. A Kenetic Study of the Steps of the Kostanecki-Robinson Reaction. Helv. Chim. Acta, 1969, 52, 2636-2641. Fung, N.Y.M .; de Mayo, P.; Schauble, J.H .; Weedon, A.C, Reduction by Tributyltin Hybride of Carbonyl Compounds Absorbed on Silica Gel: Selective Reduction of Aldehydes, J. Org. Chem. 1978, 43, 3977-3979. Hughes, D.L., The Mitsunobu Reaction. Organic Reaction, 1992, 42, 335-656 and references cited therein. Gemal, A.L .; Luche, J.L., Lanthanoids in Organic Synthesis. 6. The Reduction of -Enons by Sodium Borohydride in the Presence of Lanthanoid Chlorides: Synthetic and Mechanistic Aspects. J. Am. Chem. Soc. , 1981, 103, 5454-5459.

Very recently, a similar work has been published in the literature; Cardellina, J. H., II; Bokesch, H. R.; McKee, T. C.; Boyd, M.R., Resolution and Comparative Anti-HIV Evaluation of the Enantiomers of Calanolides A and B. Bioorg. Med. Chem. Lett. 1995, 5, 1011-1014. Deshpande, P. P., Tagliaferri, F.; Victory, S.F .; Yan, S .; Baker, D.C., Synthesis of Optically Active Calanolides A and B. J. Org. Chem. 1995, 60, 2964-2965. For a review, see Nielsen, A.T.; Houlihan, W.J., The aldol Condensation. Org. React. 1968, 16, 1-438. For reviews, see: (a) Mukaiyama, T., The Directed Aldol Reaction. Org. Rßact. 1982, 28, 203-331. (b) Reetz, M.T., Chelation or Non-Chelation Control in Addition Reactions of Chiral a- and 0-Alkoxy Carbonyl Compounds, Angew. Chem. Int. Ed. Eng. 1984, 23, 556-569. (c) Shibata, I .; Baba, A., Organotin Enolates in Organic Synthesis. Org. Prep. Proc. Int. 1994, 26, 85-100. For a review on chiral titanium complexes, see Duthaler, R.O.; Hafner, A., Chiral Titanium Complexes for Enantioselective Addition of Nucleophiles to Carbonyl Groups. Chem. Rev., 1992, 92, 807-832 and reference cited therein. For a review on chiral boron complexes, see Paterson, L.; Goodman, J.M.; M., Aldol Reactions in Polypropinonatc Synthesis: High tr-Face Selectivity of Enol Borinates from a-Chiral Methyl and Ethyl Ketones under Substrate Control. Tetrahedron Lett. 1989, 30, 7121-7124 and references cited therein. Tsunoda, T.; Yamamiya, Y .; Kawamura, Y.,; Ito, S., Mitsunobu Acylation of Sterically Congested Secondary Alcohols by N, N, N ', N'-Tetramethylazodicarboxamide-Tributylphosphine Reagents, Tetra edron Lett. 1995, 36, 2529-2530. Gulakowski, R.J.; McMahon, J.B .; Staley, P.G .; Moran, R.A.; Boyd, M.R., A Semiautomated Multiparameter Approach for Anti-HIV Drug Screening, J. Virol. Methods, 1991, 33, 87-100. Larder, B.A .; Darby, G .; Richman, D.D., HIV with reduced Sensitivity to Zidovudine (AZT) isolated during Prolonged Therapy. Science, 1989, 243, 1731-1734. Nunberg, J.H .; Schleif, W.A.; Boots, E.J .; O'Brien, J.A .; Quintero, J.C .; Hoffman, J.M .; < Emini, E.A.; Goldman, M.E. , Viral Resistance to Human Immunodeficiency Virus Type 1-specific Pyridinone Reverse Transriptase, J.Virol. , 1991, 65, 4887-4892.-

Claims (46)

1. CLAIMS 1. A method for the preparation of (±) -calanolide A, which comprises the following steps: (a) condensing ethyl butyrylacetate and phloroglucinol, in the presence of an acid catalyst, to form the 5.7 -dihydroxy-4-propylcoumarin; (b) acylating 5,7-dihydroxy-4-propylcoumarin with propionyl chloride, in the presence of a Lewis acid, to form 5,7-dihydroxy-8-propionyl-4-propylcoumarin; (c) reacting 5,7-dihydroxy-8-propionyl-4-propylcarina with 4,4-dimethoxy-2-methylbutan-2-ol, to produce 5-hydroxy-2,2-dimethyl-6 -propionyl- 10-propyl-2H, 8H-benzo [l, 2-b: 3, 4-b '] -dipyran-8-one; (d) reacting 5-hydroxy-2, 2-dimethyl-6-propionyl-10-propyl-2H, 8H-benzo [1,2-b: 3, 4-b '] -dipyran-8-one with acetaldehyde diethyl acetal, in the presence of an acid catalyst, to form 12-oxocalanolide A; and (e) reducing the 12-oxocalanolide A, to thereby form the (±) -calanolide A.
2. 2. The method according to claim 1, wherein the acid catalyst comprises the sulfuric acid, trifluoroacetic acid or methanesulfonic acid.
3. 3. The method according to claim 1, wherein the step (e) is carried out with a reducing agent, comprising sodium borohydride, zinc borohydride, borane or selec-triures, in the presence of a metal additive including the CeCl3 (H20) 7, ZnCl2, A1C13, TiCl, SnCl3 or LnCl3, or mixtures thereof with triphenylphosphine oxide.
4. 4. The method according to claim 1, wherein the acid catalyst of step (a) comprises sulfuric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
5. The method according to claim 1, wherein the Lewis acid of step (b) comprises AICI3, ZnCl2, TiCl4, BF3, POCI3 or SnCl4.
6. 6. 5-Hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H, 8H-benzo [1,2-b: 3, 4-b '[-dipyran-8-one].
7. 7. 5,7-Dihydroxy-8-propionyl-4-propylcoumarin.
8. 8. A method for the preparation of (±) -calanolide A, which comprises the steps of: (a) reacting chromene 4 with paraldehyde, in the presence of an acid catalyst, to form chromanone 7; (b) reducing chromanone 7, to thereby form (±) - calanolide A.
9. 9. The method according to claim 8, wherein the acid catalyst of step (a) comprises trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid or its pyridinium salts.
10. The method according to claim 8, wherein step (b) is carried out with a reducing agent, comprising sodium borohydride, zinc borohydride, borane or selec-triuretes, in the presence of a metal additive, which includes CeCl3 (H20) 7, ZnCl2, A1C13, TiCl4, SnCl3, LnCl3 or their mixtures with triphenylphosphine oxide.
11. 11. A method for the preparation of chromene 4, comprising the steps of: (a) acylating 5,7-dihydroxy-4-propylcoumarin with propionic anhydride, in the presence of a Lewis acid, to thereby produce 5, 7-dihydroxy-8-propionyl-4-propyl-coumarin; (b) reacting this 5,7-dihydroxy-8-propyl-4-propylcoumarin with 4,4-dimethoxy-2-methylbutan-2-ol, in the presence of a base, to thereby produce chromene 4
12. 12. The method according to claim 11, wherein the Lewis acid of step (a) comprises AIC
13. I3, ZnCl2, TiCl, BF3, POCI3 or SnC
14. l4. The method according to claim 11, wherein the base of step (b) comprises pyridine, 4-dimethyl-aminopyridine, triethylamine, N, N-diethylaniline, 1,5-diaza-bicyclo [4.3, 0] non-5-ene (DBN), 1,8-diazabicyclo [5, 4, Ojundec-7-ene (DBU), sodium carbonate or sodium bicarbonate. The method according to claim 11, wherein step (b) is conducted in the presence of a solvent, comprising N, N-dimethylformamide (DMF), toluene, 1,2-di-chloroethane and THF.
15. 15. A method for the preparation of the aldol 7b product, which comprises reacting chromene 4 with acetaldehyde, in the presence of a metal base or complex, to thereby produce the product of aldol 7b.
16. 16. The method, according to claim 15, wherein the base comprises a metal hydroxide, a metal alkoxide, a metal hydride, a metal amide, an amine or the LiHMDS.
17. The method according to claim 15, wherein the metal complex comprises TiCl, (i-PrO) 3TiCl, (i-PrO) 4) Ti, PhBCl, (n-Bu) 2BCl, BF3, (n- Bu) 3SnCl, SnCl 4, ZnCl 2, MgBr 2 or Et 2 AlCl.
18. 18. The method according to claim 17, further comprising a chiral auxiliary, which includes 1,1'-binaphthol, norephedrine sulfate, canfandiol, diacetone-glucose or dialkyl tartrate.
19. 19. A method for the preparation of chromanone 7, comprising the cyclization of the aldol product 7b, in the presence of an acid or in the presence of an azo compound, and a phosphorus derivative.
20. The method according to claim 19, wherein the acid comprises sulfuric acid, hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-tosylic acid, acetic acid or mixtures thereof.
21. The method according to claim 19, wherein the azo compound comprises diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dibutyl azodicarboxylate (DBAD), dipiperidinoazodi-carboxy ida, bis- (N 4 -methylpiperazine- 1-yl) azodicarboxamide, dimorpholinoazodicarboxamide or N, N, N ', N' -tetramethylazodi-carboxamide (TMAD).
22. 22. The method according to claim 19, wherein the phosphorus derivative comprises triphenylphosphine, tri-n-butylphosphine, triethylphosphine, trimethylphosphine and tris (dimethylamino) phosphine.
23. 23. A method for the preparation of chromanone 7, which comprises treating cis-chromanone 7a with a base, so as to form chroman 7.
24. 24. The method according to claim 23, wherein the base comprises a metal hydroxide. , a metal alkoxide, a metal hydride, a metal amide, an amine or the LiHMDS.
25. 25. A method for the chiral resolution of (±) -calanolide A in its optically active forms, the (+) - calanolide A and the (-) --calanolide A, this method comprises passing the (±) -calanolide A through a column that includes a chiral solid phase, which uses an organic solvent system, as a mobile phase.
26. 26. The method according to claim 25, wherein the chiral solid phase comprises the amylose carbamate, D-phenylglycine, L-phenylglycine, D-leucine, L-leucine, D-naphthylalanine, L-naphthylalanine or L-naphthylleucine.
27. 27. The method according to claim 25, wherein the column comprises a column of HPLC chromatography.
28. 28. The method according to claim 25, wherein the chiral solid phase comprises the amylose carbamate.
29. 29. The method according to claim 25, wherein the mobile phase comprises hexane, heptane, cyclohexane, ethyl acetate, methanol, ethanol, isopropanol or mixtures thereof.
30. 30. The method according to claim 29, wherein the mobile phase comprises a mixture of hexane and ethyl acetate.
31. 31. A method for the chiral resolution of (±) -calanolide A, comprising the steps of: (a) contacting (±) -calanolide A with an enzyme and an acylating agent, to thereby form a diastereomeric mixture of calanolide A, esterified and not esterified; and (b) separating the esterified calanolide A from the mixture.
32. 32. The method according to claim 31, wherein the enzyme comprises the lipase CC (Candida Cylindracea), lipase AK (Candida Cylindracea), lipase AY (Candida Cylindracea), PS lipase (Pseudomonas Species), AP lipase (Aspergillus niger), N lipase (Rhizopus nieveuis), FAP lipase (Rhizopus nieveus), PP lipase (Porcine Pancrease), Pig liver stearase (porcine) (PLE), Acetone powder Liver of the Pig (PLAP), or subtilisin. The method according to claim 32, wherein the enzyme is immobilized on Cellite, molecular sieves or an ion exchange resin. 34. The method according to claim 31, wherein the acylating agent comprises vinyl acetate, vinyl propionate, vinyl butyrate, acetic anhydride, propionic anhydride, phthalic anhydride, acetic acid, propionic acid, hexanoic acid or acid. octanoic 35. 5-Hydroxy-2,2-dimethyl-6- (l-methyl-2-hydroxy-butyro) -10-propyl-2H, 8H-benzo [l, 2-b: 3, 4-b1] dipyran -8-ona. 36. The 10, 11-cis-dihydro-6,6, 10, 11-tetramethyl-4-propyl-2H, 6H, 12H-benzo [1,2-b: 3, 4-b1: 5, 6-b "] -tripiran-2,12-dione. 37- The (-) -Calanolide A. 38. An antiviral composition, which comprises a non-toxic, antiviral effective amount of the (±) ~ calanolide A or the (-) -calanolide A, and a pharmaceutically acceptable. 39. The composition according to claim 38, which further comprises an antiviral effective amount of at least one additional antiviral compound. 40. The composition according to claim 39, wherein the additional antiviral compound is AZT or DDC. 41. A method for preventing or treating a viral infection in a mammal, this method comprises administering to the mammal an antiviral, non-toxic, effective amount of the (±) -calanolide A or (-) -calanolide A. 42. The method according to claim 41, further comprising co-administering an antiviral effective amount of at least one additional antiviral compound. 43. The method according to claim 42, wherein the antiviral compound comprises the AZT or the DDC .. 44. The method according to claim 37, wherein the viral infection is by the retrovirus. 45. The method according to claim 44, wherein the retrovirus is a human immunodeficiency virus (HIV). 46. The method according to claim 41, wherein the mammal is a human being.