MXPA01003772A - Method and composition for treating and preventing tuberculosis - Google Patents

Abstract

Calanolides and analogues thereof that demonstrate potent mycobacterium activity are provided. Also provided is a method of using calanolides and analogues thereof for treating or preventing mycobacterium infections. The calanolides and analogues thereof provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Description

METHOD AND COMPOSITION FOR THE TREATMENT AND PREVENTION OF TUBERCULOSIS FIELD OF THE INVENTION The present invention relates to a method and composition for the treatment and / or prevention of mycobacterium infections (mycobacteria) in patients.

BACKGROUND OF THE INVENTION Infectious diseases are still the largest cause of death in the world today, greater than cardiovascular disease or cancer.1 Among infectious diseases, tuberculosis (TB) is the leading cause of death.2 The emergence of strains resistant to various drugs (MDR) and the pandemic of the global human immunodeficiency virus (HIV) widens the incidence of TB. Tuberculosis mainly affects the lungs but can also complicate other organs. TB attacks people of all ages but is more common among the elderly. The disease can also afflict animals, especially livestock such as cattle, pigs and poultry. The bacteria that make up the bacilli, bacilli tuber discovered by the physicist REF: 128625 German Robert Koch in 1882, causes the disease. The bacilli tuber belongs to a genus of bacteria called Mycoba c teri um. This disease once figured among the most common causes death in the world. Nowadays, improved methods for prevention, detection, diagnosis, and treatment have greatly reduced both the number of people who contract the disease and the number of people who die from it. However, in the last decade, the MDR TB epidemics (MDRTB) and TB expanded by the global HIV pandemic make TB an urgent global issue. One third of the world population is infected with Mycobacterium tuberculosis (Mtb), 3 an intracellular facultative bacillus. After infection with Mtb, the lifetime risk of developing TB is approximately 10%, while 90% of infected people have latent infection with viable bacilli. This 10% TB cup explains the 8 million people reported annually with active TB, and the resulting 3 million die. However, TB is a serious problem apparent for patients with hemodialysis, 4 and TB is the No. 1 killer of women of childbearing age around the world with 1.2 million women who are dying of the disease in 1997 according to the reports by the World Death Organization.113 a. Tuberculosis and AIDS TB infection is a serious problem for patients with acquired immunodeficiency syndrome (AIDS). Individuals infected with HIV are particularly susceptible to infection with Mtb and the development of TB. Compared to an individual who is not infected with HIV, an individual infected with HIV has a 10-fold greater risk of developing TB. In an individual infected with HIV, the presence of other infections, including TB, may allow HIV to multiply more rapidly. This can result in a faster progression of HIV infection and AIDS.5 As HIV infection progresses, CD4 + lymphocytes decrease in number and function. The immune system is less able to prevent the growth and local extension of Mtb. Even in patients infected with HIV, pulmonary TB (PTB) is still the most common form of TB. The presentation depends on the degree of immunosuppression. As in adults, the natural history of TB in a child infected with HIV depends on the stage of HIV disease. Prematurely in HIV infection, when the immunity is stronger, the signs of TB are similar to those in a child without HIV infection. As HIV infection progresses and immunity decreases, the spread of TB becomes more common. Tuberculous meningitis, miliary tuberculosis, and spread tuberculosis occur in lymphadenopathy. Positive HIV patients and staff in health units face daily exposure to TB. The risk of exposure is greatest in medical wards for adults and TB rooms where there are many cases of PTB. Since 1990-1992, the Centers for Disease Control and Prevention (CDC) investigates TB epidemics resistant to various drugs (MDRTB) in several hospitals and in a state reformatory system. Almost 300 cases of MDRTB were identified in these epidemics: the majority of patients are HIV positive. The mortality rate was 80% -90% and the average diagnosis interval from tuberculosis to death varies from 4-16 weeks.6 In 1995, approximately one third of the 17 million people globally infected with HIV were also co-infected with Mtb. 5 (TB is _ the leading cause of death in patients with AIDS). b. TB treatment Isoniazid (isonicotinic acid hydrazide) was first reported to be effective against Mtb and M. bovi s in 1952 7-9 Isoniazid, still in a first line therapy against TB, has been shown to be an effective anti-tubercular prophylaxis10, and modern short-course chemotherapy is initiated with three drugs: isoniazid, rifampin and pyrazinamide (PZA), often with the inclusion of a fourth drug, usually ethambutol. Recently, rifapentine, a derivative of rifamycin, was approved by the FDA for the treatment of tuberculosis.1113 The American Thoracic Society and the CDC in the United States now recommend a treatment regimen of isoniazid, rifampin and pyrazinamide for 2 months, followed by isoniazid and rifampin for about 4 additional months, as the standard 6-month regimen. The isoniazid, cheap and safe, has a wide therapeutic margin and high early bactericidal activity so that it quickly kills the growth of bacilli in lesions, but is inefficient in finally sterilizing these lesions. Rifampin and PZA are crucial in achieving sterilization by persistent semi-dormant bacilli at slaughter, and are thus responsible for shortening the treatment duration from the previous standard of 12-18 months to the current standard of 6 months. 2 However, many people discontinue prolonged therapy altogether, treatment suspensions are high, and MDR is increased. Some 4 years of study, carried out by the World Organization of Death, shows that of the people who have been treated for TB for less than a month, 36 percent harbor microbes that support at least one of the four main antituberculosis drugs. In addition, 10% of infected people who have not been treated for the disease, carry a strain of Mtb that supports at least one drug. d. Mechanism of Drug Action Isoniazid is a prodrug that requires activation by the enzyme catalase-mycobacterial peroxidase. { Ka tG) for an active form that then exerts a lethal effect on an intracellular target or targets.14"16 The lethal or deadly effect is found in the biosynthetic pathway by mycolic acids, 14 '17' 19 alpha-branched fatty acids and beta -hydroxylates found in the development of mycobacteria.Rifamycins (eg, rifampin, rifabutin, and rifapentine) are potent inhibitors of RNA polymerase that depend on prokaryotic DNA, with little activity against the equivalent mammalian enzymes. Antimicrobials are compounds composed of aromatic rings linked by an aliphatic bridge.Lipophilic properties of the molecule are most likely important for the binding of the drug to the polymerase and aids in the penetration of the drug through the mycobacterial cell wall. Pyrazinamide (PZA) is a synthetic derivative (pyrazine analogue) of nicotinamide and in combination with isoniazid it is rapidly bacterial. ricida to replicate Mtb forms, with an MIC average of 20 μg / ml. The activity of PZA depends on the presence of a bacterial amidase that converts PZA to pyrazinoid acid (PZOA), the active antibacterial molecule.21 Amidase activity is present in sensitive PZA but not in PZA-resistant species such as M. bovi s , opportunistic mycobacterium and Mtb resistant to PZA as a result of drug therapy. The Gen . { pn cA) that encodes the PZA amidase (and nicotinamide) that is responsible for the processing of PZA in its bactericidal form has been identified, and mutations in pn cA that confers resistance of PZA to the bacilli tuber have been recently reported.22 Ethambutol it is active against Mtb, with MICs in the range of 1 to 5 μg / ml. The drug has much more variable activity against the other slowly growing mycobacterial species and is significantly less active against rapidly growing mycobacteria. In general, ethambutol is inactive against other microorganisms. The mechanisms of action of ethambutol are focused on two objectives: polyamine function and metabolism and cell wall synthesis. Ethambutol inhibits the transfer of mycolic acid into the cell wall and stimulates the synthesis of trehalose dimycolate. e. Resistance to various drugs The importance of Ka rG mutations in isoniazid resistance is well established, although the extent to which such mutations account for the spectrum of resistance observed in clinical isolates is debatable.24 Better estimates indicate that > 50% of isoniazid-resistant clinical isolates are Ka rG mutants. 2 Mycobacteria have a similar enzyme, InhA, required for mycolic acid biosynthesis.26 A genetic approach reveals that InhA appears for a function as a component of a Type II fatty acid synthase system responsible for the final reduction in elongation stage of the chain to form conventional fatty acids.27"28 Clinical isolation sequencing of Mtb has revealed mutations in putative regulated regions upstream of the InhA gene and mutations in the sequence encoding potential that can be directly implicated in resistance to isoniazid, but this occurs only in a subpopulation of isolates of catalase-wild-type peroxidase resistant to isoniazid.24"25 '29 ~ 31 Thus, although the InhA protein may be involved in resistance to isoniazid, it probably does not represent the target whose inhibition results in the accumulation of hexacosanoic acid, and the mutations in InhA and Ka tG do not seem be sufficient to explain all of the observed resistance.32 Recently, a species of purified Mtb protein treated with INH was shown to consist of a covalent complex of isoniazid, a 12 kilodalton acyl carrier protein (AcpM), and a protein synthase. carrier of beta-ketoacylacil, Ka sA. Mutations that alter the amino acid in the Ka sA protein were identified in isolates of isoniazid-resistant patients lacking other mutations associated with resistance to this drug.33 More recently, the complete genome sequence of the best-characterized strain of Mtb, H37Rv, has been determined and analyzed.34 This will improve our understanding of the biology of this slowly growing pathogen and to assist in the conception of new prophylactic and therapeutic interventions. f. The significance of the Renaissance of the Recent TB The registration number of new cases of global TB correlates with economic conditions, the highest incidence is observed in Africa, Asia and Latin America. In the industrialized nations, including Europe, the regular decline in the incidence of TB began to stabilize in the mid-1980s and then stagnated or even reversed. Much of this increase can be attributed to an influx of migrants from countries with a higher incidence of TB.35 Another element in this tendency to increase is HIV. The particular susceptibility and increased mortality of the disease among individuals infected with HIV presents a serious threat to TB control programs.36 In addition, the emergence of strains resistant to various drugs of M. t ubercul osi s (MDR-Mtb) has resulted in fatal epidemics in many countries, including the United States.37 Strains of MDR-? ftJ, some of which are resistant to more than seven drugs, are deadly for both HIV-negative and HIV-positive individuals.38 The event of MDRTB in patients with AIDS has led to significant changes in the direction of tuberculosis in these patients, compared with tuberculosis in patients without AIDS. g. Prophylactic treatment The prophylactic treatment of children with strongly positive tuberculin skin test by isoniazid and rifampicin has led to a marked reduction in the incidence of pediatric TB in geographic areas of high incidence.39 Controlled clinical studies have shown that isoniazid preventive treatment reduces the incidence of pediatric TB. risk of TB disease in HIV positive individuals also infected with Mtb. 6 Since (+) - calanolide A could be used in the clinic as an anti-AIDS drug in the near future, a prophylactic and therapeutic effect in TB for AIDS patients could be demonstrated when used in the treatment of AIDS.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a composition and method for the treatment and / or prevention of mycobacterium infections, especially in patients with tuberculosis infections. The method is useful for the treatment or prevention of mycobacterium infections in immunocontained patients, particularly patients infected with HIV. Accordingly, an object of the invention is a method for the treatment or prevention of mycobacterium infection in a patient comprising administering an effective amount of anti-mycobacterium of calanolide or analogues thereof. Representative mycobacterial organisms include the Mycobacterium avium (MAC) complex, Mycobacterium kansaii, Mycobacterium marinum, Mycobacterium phlei, Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium gordonae, Mycobacterium terrea complex, Mycobacterium haemophilum, Mycobacterium fortuitum, Mycobacterium tuberculosis, Mycobacterium laprae, Mycobacterium scrofulaceum and Mycobacterium smegmatis. Another object of the invention is to provide an anti-mycobacterium composition comprising calanolide or analogs thereof, particularly (+) - calanolide A, (-) - calanolide A, (-) - calanolide B, also called costatolide), (+ ) -catanolide A, sulatrolide, and (-) -7,8-dihydrosoulatrolide. The Applicants discovered the anti- tuberculosis activity of these compounds, especially (+) - Calanolide A and (-) - Calanolide A, whose inhibitory activity is manifested against Mtb H37Rv in a BACTEC 12B medium, using the BACTEC 460 radiometric system with inhibition of 96% and 98%, respectively, at a concentration of 12.5 μg / ml. The current minimum inhibitory concentration (MIC) for (+) - calanolide A, defined as the lowest concentration that inhibits 99% of the inoculum, was 8 μM (3.13 μg / ml). The composition of ant i-mycobacterium may include one or more other pharmaceutically active agents such as ant i-viral agents. The present invention provides analogs of calanolide obtained by means of synthesis employing chromene 4 and chromanone 7 as key intermediates, which is described in US Patent Applications Serial Nos. 09 / 173,143, filed October 15, 1998; 08 / 609,537, filed on March 1, 1996; and 08 / 510,213, presented on August 2, 1995, as well as U.S. Patent No. 5,489,697, issued February 6, 1996, incorporated herein by reference in its entirety. Chromen 4 is synthesized by the sequence depicted in Reaction Scheme I. Thus, 5,7-dihydroxy-4-propylcoumarin 2.55 was prepared quantitatively from ethyl butylacetatate and phloroglucinol under Pechmann conditions.56 Product yield and purity are dependent on the amount of sulfuric acid used. The 8-position of 5,7-dihydroxy-4-propylcoumarin, 2, was then selectively acylated at 8-10 ° C by propionyl chloride and A1C13 in a mixture of carbon disulfide and nitrobenzene to produce 5,7-dihydroxy- 8-propionyl-4-propi 1cumariña, 3. In an alternative and preferred reaction, coumarin intermediate 3 can be produced in large-scale quantities and with minimal formation of the acylated product in the undesirable 6-position and the product 6, 8- bis-acylated by selective acylation of ,7-dihydroxy-4-propylcoumarin 2 with a mixture of propionic anhydride and A1C13 at about 70-75 ° C. The chromene ring was introduced with treatment of compound 3 with 4,4-dimethoxy-2-methylbutan-2-ol, yielding 4 in 78% yield (Reaction Scheme I). The reaction of chlorotitanium-mediated aldol of chromene 4 with acetaldehyde leads to the formation of. { + _) -8a and (+) -8b in a ratio of 95: 5. The product [ . { + _) -8a] of aldol syn racemic is resolved by the catalyzed acylation of the enzyme. In this way, in the presence of lipase and vinylacetate, (-) - 8a is selectively acylated and the desired (+) - 8a enantiomer was not reacted. The purified (+) - 8a was subjected to a Mit sunbubu_a reaction, leading exclusively to (+) - trans-chromanone [(+) - 7], Finally, the Luche 58 reduction in (+) - 7 leads to the formation of (+) -calanolide A [(+) - l] containing 10% (+) - calanolide B (see Reaction Scheme III). (+) - Calanolide A [(+) - 1] of (+) - Calanolide B was also separated by preparative normal phase CLAP and identified with an authentic sample. If desired, the racemic [(+ _) -8b] aldol an ti product can also be resolved by catalyzed acylation of the enzyme in (-) - 8b and ester 10 of (-) - 8b (Reaction Scheme IV) . The Mitsunobu reaction in (+) - 8b would lead to the formation of cis-chromanone 7a which could then be reduced to produce calanolide C. The synthetic sequence for (+) - calanolide A was extended to the synthesis of the calanolide analogues. In this way, the Pechmann reaction of phloroglucinol with several β-ketodes teres produced substituted 11-dihydroxycoumarin 11 (Reaction Scheme V).

The Friedel-Crafts acylation of substituted 5,7-dihydroxycoumarin 11 leads to the formation of 8-acylated 5,7-dihydroxycoumarin. The chromenylation of 12 can be achieved by reacting with substituted β-hydroxyaldehyde dimethylacetal, producing chromenocoumarin 13. The aldol reaction of cromenocoumarin 13 with carbonyl compounds in the presence of LDA with or without metal complexing agents forms the product (^.) -14 aldol racemic The cyclization of (+ _) -14 under Mitsunobu conditions, using triphenylphosphine and diethyl azodicarboxylate (DEAD), leads to the formation of the chromanone analogue (-15) The reduction of (+ _) -15 with sodium borohydride with or without cerium chloride it produces the analogous 12-hydroxy (+ _) -16 (Reaction Scheme V) The catalytic hydrogenation of both (+ _) -15 and (-16 produces 7,8-dihydro (+ _) - derivatives 17 and (+) - 18 (Reaction Scheme VI) The treatment of (-15 with hydroxylamine or alkoxyamine produces oxime derivatives (+ _) -19 (Reaction Scheme VI) The reduction of (_ +) -19 under Different conditions 59 should selectively produce hydroxylamino or amino compounds (20 and 21) Optically active forms of 14-21 should be obtained using enzymatic acylation, as described in Reaction Scheme III (for (+) - calanolide A [(+ ) -l] In this way, the catalyzed acylation of the racemic (+) -14 aldol product enzyme must selectively acylating an enantiomer [ie (-) - 14] and leaving the other enantiomer [ie (+) - 14] unreacted, which must be easily separated by conventional methods such as column chromatography on silica gel. The acylated enantiomer [ie (-) - 14] can be hydrolyzed to form the pure enantiomer [i.e. (-) - 14]. The optically pure enantiomers obtained in this way [(+) - 14 and (-) - 14] will be cyclized to (+) - 15 and (-) - 15, respectively, by reaction of Mitsunobu The reduction of (+) - 15 and (-) - 15 would lead to the formation of (+) - 16 and (-) - 16. Hydrogenation of optically active forms of 15 and 16 would provide pure enantiomers of 17 and 18 [(+) - and (-) - 17; (+) - and (-) - 18]. The treatment of pure enantiomers of 15 with hydroxylamine and alkoxylamine produces 19 [(+) - and (-) - 19] oxime enantiomerically pure. If desired, (+) - 19 and (-) - 19 can be reduced to produce 20 and 21 [(+) - and (-) - 20; (+) - and (-) - 21] enantiomerically pure. The 12-hydroxyl group in compound 1, 16, and 17 as well as their optically active forms can be epimerized by a number of methods including acidic conditions, Mitsunobu neutralus 57a_d conditions, or with DAST .57d An example showing the conversion of (-) -calanolide A [(-) - l ] a (-) -calanolide B is represented in Reaction Scheme VII. The process can be used to prepare a wide variety of calanolide analogues such as Formulas i -v shown in Reaction Scheme VIII and Formulas vi -vi i shown in Reaction Scheme IX. Additional exemplary calanolide analogs include, but are not limited to, Formulas 15 and 16. For Formula i, Ri and R2 are independently -mullí O "" "^ ß * For Formula II, Ri, R2 and R3 are independently H or CH3 For Formula III, Ri is linear or branched alkyl of C? -C6 For Formula IV, Ri is propyl or phenyl and For the formula VI, Ri is linear or branched alkyl of C? -C6 For the formula vii, Ri is propyl or phenyl and R2 is -MiiiiOH or - ^^ OH, shown in Reaction Scheme V, and Formulas 17 and 18 shown in Reaction Scheme VI.

Methods for the treatment and / or prevention of viral infections using compounds of the invention are also described. Representative viral infections include HIV, hepatitis B, herpes simplex type 1 and 2, cytomegalovirus, varicella zoster virus, Epstein Barr virus, influenza A and B, parainfluenza, adenovirus, measles, and respiratory syncytial virus. Accordingly, it is an object of the invention to provide calanolide analogs obtained by means of the synthesis employing chromene 4 and chromanone 7 as key intermediates. A further object of the invention is to provide a method for the treatment or prevention of mycobacterium infections using calanolide analogs of the formula I: where Ri is H, halogen, hydroxyl, amino, C? -6 alkyl, C? _6-alkyl aryl, mono- or poly-fluorinated C? -6 alkyl, C? -6-alkyl hydroxy, C? -6, C? _6 aminoalkyl, C? _6 alkylamino, C? _6) amino, C? -8-alkyl-C? _8 alkyl, di (C? _6 alkyl) amino-C-8 alkyl, cyclohexyl, aryl, or heterocycle, wherein aryl or heterocycle can each be substituted or unsubstituted with one or more of the following: C? -6 alkyl, C? _6 alkoxy, hydroxy-C? -4 alquiloalkyl, hydroxyl, amino, alkylamino, di (Ci-β) amino, amino-C alquilo-8alkyl, C?-8alkylamino-C alquilo-8alkyl, di (alkyl) of C? -6) amino-C? _8 alkyl, nitro, azido or halogen; R 2 is H, halogen, hydroxyl, C 1-6 alkyl, aryl C 1-6 alkyl, C 1-6 mono- or poly-fluorinated alkyl, aryl or heterocycle, R 3 and R 4 are independently selected from the group consisting of H , halogen, hydroxyl, amino, C? _6 alkyl, aryl-C? _6 alkyl, mono- or poly-fluorinated C? _6 alkyl, C? -6 hydroxyalkyl, C? _8-alkyl amino-alkyl, C? _8 alkylamino C? _8 alkyl, di (C? _6 alkyl) amino C? _8 alkyl, cyclohexyl, aryl or heterocycle; and R3 and R can be taken together to form a 5-7 membered saturated cyclic heterocyclic ring or ring; R5 and R6 are independently selected from the group consisting of H, C? -6 alkyl, aryl-C? -6 alkyl, mono- or poly-fluorinated C? _6 alkyl, aryl or heterocycle; and R5 and R6 can be taken together to form a 5-7 membered heterocyclic ring or cyclic saturated ring; R7 is H, halogen, methyl, or ethyl; R8 and R9 are independently selected from the group consisting of H, halogen, C6-6 alkyl, arylC1-6 alkyl, mono- or poly-fluorinated C1-6 alkyl, hydroxyC1-6 alkyl, amino C 1 8 alkyl, C 8 alkyl alkylamino C 8 alkyl, C 1 8 alkylamino C 1 8 alkyl, cyclohexyl, aryl or heterocycle; and R8 and R9 can be taken together to form a 5-7 membered saturated cyclic heterocyclic ring or ring; Rio is halogen, O, ORn, NORn, NHORn, NOR12, NHOR? 2, NRnR? 2, NRi2, or NR12NRi3; wherein Rn is H, acyl, P (0) (OH) 2, S (0) (OH) 2, CO (C? _ 0 alkyl) CO2H, (C? -8 alkyl) C02H, CO ( C1-10 alkyl) NR? 2R13, (C? -8 alkyl) NR12R13; Ri2 and R13 are independently selected from the group consisting of H, C? -6 alkyl, aryl, and aryl-C? -6 alkyl; and R 2 and R 13 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen; or a pharmaceutically acceptable salt thereof. These and other objects of the invention will be clear from the detailed descriptions below: C.HjCOCl or (tHfioyfi REACTION SCHEME I (D-7 (D-l REACTION SCHEME II 10 fifteen twenty í * M REACTION SCHEME lll REACTION SCHEME IV twenty REACTION SCHEME V 16 16 17 REACTION SCHEME VI:? (-) - Calanolide A (-) - Calanolide B REACTION DIAGRAM Vil REACTION SCHEME IX DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a representative example of inventive compounds that are evaluated in the test results under example 38 and the MTT in vi t ro test, as described in Example 37, using a viral strain of HIV G910-6 that is resistant to AZT. These and other objects of the invention would be clear in the light of the detailed description below.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications, and references cited herein are incorporated by reference in their entirety. (+) - Calanolide A, an anti-HIV agent currently suffering from Phase I / II clinical trials, was originally isolated from the tropical forest tree, Ca l ophyl l um lan igerum, in Sara a, Malaysia. Due to the scarce supply of (+) --calanolide A from natural resources, the applicants developed synthetic routes for both (+ _) and (+) -calanolide A.40-43 The processes have been used for the production in kilogram scale of (+) -calanolide A. See, for example, U.S. Patent No. 5489697, O96 / 04263, U.S. Patent Applications Nos. 08/510213 and 08 / 609,537, which are incorporated herein by reference in their entirety. The synthetic material has been used for several studies that include virological, pharmacological, toxicological and pharmacokinetic evaluations in animals, as well as humans. The (-) calanolide A, an enantiomer of (+) - calanolide A, of strong anti-tuberculosis activity exposed with 98% inhibition against Mtb H37Rv at a drug concentration of 12.5 μg / ml. Since both (+) - and (-) -calanolide A demonstrate potent antituberculosis activity, (+) --calanolide A could result in a stronger activity than (+) - and (-) --calanolide A due to its positive synergistic effect . In addition, (+ _) -calanolide A has the advantage of being more easily synthesized. The present invention relates to calanolide and analogues thereof and methods for using such compounds for the treatment or prevention of mycobacterium infections. In one embodiment, the invention provides calanolide analogs obtained by means of the synthesis employing chromene 4 and chromanone 7 as key intermediates, as shown in Reaction Schemes I and III. According to this synthetic reaction scheme, chromene 4 can be prepared from 5,7-dihydroxy-4-propylcoumarin, 2, as shown in Reaction Scheme I. According to this synthetic reaction scheme, 5, 7-dihydroxy-4-propylcoumarin, 2.55 was quantitatively prepared from ethyl butyrylacetate and phloroglucinol under Pechmann conditions.56 In the conduct of this reaction, a volume of a concentrated acid in a dropwise form of a mixture was added. of agitation of ethyl butyrylacetate and phloroglucinol with a molar ratio ranging from about 3: 1 to about 1: 3, with a preferable range that is about 0.9: 1.0. The dropwise addition of an acid was conducted at a rate such that the temperature of the reaction mixture was maintained at a temperature ranging from about 0 ° C to about 120 ° C, preferably about 90 ° C. Suitable but not limiting examples of concentrated acid include sulfuric acid, trifluoroacetic acid, and methanesulfonic acid. In the manufacture of compounds of the invention, concentrated sulfuric acid is particularly preferred. When the yield and purity of the product appear to be dependent on the amount of concentrated sulfuric acid used, it is preferred that the amount of concentrated sulfuric acid vary between about 0.5 and 10 moles, more preferably ranging between about 2 and about 3.5 moles, per mol of ethyl butyrylacetate. The reaction mixture was then heated to a temperature ranging from about 40 ° C to about 150 ° C, preferably about 90 ° C, until the reaction reaches completion as determined by TLC analysis. The reaction mixture was then poured into ice and the precipitated product was 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 was then washed with brine and dried over a suitable drying agent, for example sodium sulfate. The yields of this reaction are generally quantitative. Therefore, 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3 was prepared by selectively acylating the 8-position of 5,7-dihydroxy-4-propylcoumarin, 2, with propionyl chloride in the presence of a Lewis acid (Friedal-Crafts acylation). In the conduct of this reaction, a solution of propionyl chloride in a suitable solvent, for example carbon disulfide, was added in a dropwise fashion to a vigorously stirred solution of sodium hydroxide., 7-dihydroxy-4-propylcoumarin, 2, a Lewis acid and an organic solvent cooled in an ice bath. The dropwise addition of propionyl chloride was conducted in such a way that the temperature of the reaction mixture was maintained at a temperature ranging from 0 ° C to about 30 ° C, preferably from about 8 ° C to 10 ° C. .

In manufacturing compounds of the invention, the amount of propionyl chloride used generally ranges from about 0.5 to about 6 moles, preferably ranging from about 1 to about 2 moles, per mole of 5,7-dihydroxy-4-propylcoumarin, 2. Non-limiting examples of Lewis acid catalysts useful in the acylation reaction include A1C13, BF3, SnCl4, ZnCl2, POCl3 and TiCl. A preferred Lewis acid catalyst is A1C13. The amount of the Lewis acid catalyst relative to 5,7-dihydroxy-4-propylcoumarin, 2, ranges from about 0.5 to about 12 moles, preferably ranging from about 2 to about 5 moles, per mole of 5, 7-dihydroxy-4-propylcoumarin, 2. Non-limiting examples of organic solvent for use in the preparation of the solution 5,7-dihydroxy-4-propylcoumarin, 2 include nitrobenzene, nitromethane, chlorobenzene, or toluene and mixtures thereof. A preferred organic solvent for use in this invention is nitrobenzene. Upon completion of the addition of propionyl chloride, the vigorously stirred reaction mixture was maintained at a temperature ranging from about 0 ° C to about 120 ° C, preferably ranging from about 25 ° C to 80 ° C, until that the reaction reached completion as monitored by conventional means such as CCF analysis. The reaction mixture was then poured into 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 column chromatography on silica gel. In a small scale (<1 gram), the yield of 5,7-dihydroxy-8-propionyl-propylcoumarin 3, produced by the reaction described in the above is generally quantitative. However, a larger scale (> 1 gram), the reaction was very difficult to control and did not exclusively produce the desired product as the product 3 acylated in the desired 8-position, was accompanied by the formation of the acylated product in the 6-position unwanted and the 6,8-bis-acylated product. In this way, an alternative and preferred route was prepared for preparing 5,7-dihydroxy-8-propionyl-4-propylcoumarin 3 in large-scale quantities. The preparation of coumarin 3 8-acylated on a scale of 5 grams as a simple product (45% yield) has been achieved by adding a mixture of propionic anhydride, a Lewis acid, for example AICI 3 and a suitable solvent, for example 1 , 2-dichloroethane, in a vigorously stirred pre-heated mixture of coumarin, a Lewis acid, for example A1C13, and a suitable solvent, for example 1,2-dichloroethane, at a temperature ranging between about 40 ° C and about 160 ° C, preferably ranging from about 70 ° C to about 75 ° C. The dropwise addition of the propionic anhydride solution was conducted at a rate such that the temperature of the reaction mixture remained within the desired temperature range. The amount of propionic anhydride used in the reaction usually ranges from about 0.5 to about 10 moles, preferably ranging from about 1 to about 2 moles, per mole of 5,7-dihydroxy-4-propylcoumarin 2.

Non-limiting examples of Lewis acid catalysts useful in the acylation reaction include A1C13, BF3, P0C13, SnCl4, ZnCl2 and TiCl4. A preferred Lewis acid catalyst is A1C13. The amount of the Lewis acid catalyst relative to 5,7-dihydroxy-4-propylcoumarin, 2, ranges from about 0.5 to about 12 moles, preferably ranging from about 2 to about 4 moles., per mole of 5, 7-dihydroxy-4-propylcoumarin, 2. Suitable but not limiting examples of solvents for use in manufacturing compounds of the invention include diglyme, nitromethane, 1,1,2,2-tetrachloroethane and 1, 2-dichloroethane (preferred). Upon completion of the addition of propionic anhydride, the vigorously stirred reaction mixture was maintained at a temperature ranging from about 40 ° C to about 160 ° C, preferably ranging from about 70 ° C to 75 ° C, until that the reaction reached completion as monitored by conventional means such as CCF analysis. The manufacturing process is the same as described above. The product was purified without the use of column chromatography to produce the desired product 3. This procedure has been progressively increased to 1.7 kg of coumarin (for details see experimental section) and the yield for coumarin 3 8-acylated was 29% after recrystallization. The yield for coumarin 3 8-acylated can be further improved by changing the purification processing. For example, the crude product may be recrystallized from solvent or solvents other than dioxane, or a simple wash with a suitable solvent may result in sufficient pure product for the next reaction step. Therefore, chromene 4 was prepared by introducing the chromene ring into 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3, using 4,4-dimethoxy-2-methybutan-2-ol. A solution of 5,7-dihydroxy-8-propionyl-4-propylcoumarin, 3 and 4,4-dimethoxy-2-methybutan-2-ol in a suitable organic solvent was reacted in the presence of a base at a temperature which it varies between about 40 ° C and about 180 ° C, preferably ranging from about 100 ° C to about 120 ° C, until the reaction reached completion as determined by conventional means such as TLC analysis. The water and methanol formed during the reaction were removed azeotropically by means of a Dean-Stark trap. In manufacturing compounds of the invention, the amount of 4,4-dimethoxy-2-methylobutan-2-ol used in the reaction usually ranges from about 0.5 to about 8 moles, preferably ranging from about 2 to about 4 moles, per mole of 5, 7-dihydroxy-8-propionyl-4-propylcoumarin 3. Examples suitable, but not limiting, 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-diazabicyclo- [4, 3, 0] -non-5-ene (DBN), 1.8 -diazabicyclo- [5, 4, 0] undec-7-ene (DBU), sodium carbonate and sodium bicarbonate. Pyridine was used as both base and solvent in this invention on a small scale; to progressively increase, however, pyridine was used as a base and toluene was used as a solvent. Upon completion of the reaction, the solvent was removed under reduced pressure and the reaction product was dissolved in a suitable solvent, for example, ethyl acetate. The solution was then washed sequentially with water and brine and dried over a suitable drying agent, for example sodium sulfate. Therefore, the crude chromene 4 product can be purified by conventional means such as column chromatography on silica gel using 25% ethyl acetate / hexane as the eluting solvent. The chromene 4 yields generally fall within the range of about 60% and about 85%, usually resulting in about 78% yield. Chromen 4 was then used to prepare chromanone 7. A number of alternative routes were planned to prepare chromene 4 chromanone 7 in large scale quantities. These routes are described in U.S. Patent Application Serial No. 08 / 510,213, filed on August 2, 1995, the disclosure of which is hereby incorporated in its entirety. For example, U.S. Patent Application Serial No. 08 / 510,213 discloses a single-step reaction process (single-step paraldehyde reaction), shown in the US Pat.

Reaction II, and a two-stage reaction process (LDA process / sulfuric acid or Mitsunobu LDA process) to prepare chromene 4 chromanone 4.

Examples of these reactions are provided in the following Examples. In this invention, a new way to prepare chromene 4 chromanone 7 was planned, shown in Reaction Scheme III, which introduces a chiral resolution step between the two-stage process LDA / Mi tsunobu described in application 08 / 510,213 and illustrated below. One of the benefits to include the step of acylation / resolution of the enzyme in this stage of the process is that it provides a more practical and economical means to produce large-scale quantities of chromanone (+) - 7, which would lead to the formation of ( +) -calanolide A after reduction without the subsequent need for the resolution of chiral CLAP of the racemic A calanolide. According to Reaction Scheme III, (+) - chromanone 7 was prepared by an aldol condensation reaction mediated with chlorotitanium chromene 4 with acetaldehyde leading to the formation of aldol (+) - 8a and (+ _ ) -8b in a ratio of 95: 5, respectively. In the conduct of the aldol condensation reaction, a solution of LDA was added dropwise to a solution of chromene 4 dissolved in a solvent at a temperature ranging from about -78 ° C to about 0 ° C, preferably from approximately -30 ° C and approximately -78 ° C. Therefore, a solution of titanium tetrachloride was added dropwise to the stirring reaction mixture. The resulting solution was then heated to a temperature ranging from about -78 ° C to about 40 ° C, preferably about -40 ° C, and allowed to stir for about 45 minutes to account for transmetalation. Therefore, the solution was re-cooled to -78 ° C. The amount of added LDA per mole of chromene 4 ranges from about 1 to about 4 moles, preferably ranging from about 2 to about 3 moles per mole of chromene 4. The dropwise addition of LDA is conducted in such a way that the The reaction temperature was kept within the desired range. The amount of titanium tetrachloride ranges from about 0.5 to about 10 moles, preferably ranging from about 2 to about 4 moles per mole of chromene 4. Examples suitable, but not limiting, of solvent include methylene chloride, THF, diethyl ether, dioxane, etc.

The acetaldehyde is then added dropwise to the reaction mixture in amounts ranging from about 1 to about 12 moles, preferably ranging from about 4 to about 6 moles per mole of chromene 4. The dropwise addition of acetaldehyde is conducted in such a manner that the reaction temperature remained within the aforementioned range. The reaction was monitored by conventional means, for example CCF analysis, until it reached completion. The aldol reaction of chromene 4 with acetaldehyde can be carried out under conditions employing bases other than LDA. For example, metal hydroxides such as NaOH, KOH and Ca (OH) 2, metal alkoxides such as MeONa, EtONa and t-BuOK, and amines such as pyrrolidine, piperidine, diisopropylethylamine, 1,5-diazabicyl [4, 3 , 0] non-5-ene (DBN), 1,8-diazabicyclo [5, 4, 0] undec-7-ene (DBU), NaNH2 and LiHMDS as well as also hydrides such as NaH and KH can all be used for the reactions of aldol.60 Also, aldol reactions can be mediated by metal complexes of Al, B, Mg, Sn, Zn, Zr and other Ti compounds such as (i-PrO) 3TiCl, (i-PrO) Ti, PhBCl2, (n-Bu) 2BCl, BF3, (n-Bu) 3SnCl, SnCl4, ZnCl2, MgBr2, Et2AlCl with or without chiral auxiliaries such as 1,1'-binaphthol, norephedrine sulfonate, cannanediol, diacetone glucose and tartrate of dialkyl.61-63 Therefore, the reaction mixture was rapidly cooled from -30 ° C to -10 ° C with aqueous ammonium chloride solution, saturated and extracted with a suitable solvent, for example ethyl acetate. The combined extracts were washed with brine and dried over a suitable drying agent, for example sodium sulfate. The yields of the aldol product generally vary between about 40% and about 80%, usually about 70%. It should be noted that the aldol reaction of chromene 4 results in a product having two asymmetric centers which in turn would result in a diastereomeric mixture of two groups of enantiomers (four optically active forms). The mixture can be separated by conventional means to produce the racemic (+ _) -8a product of aldol syn and the racemic (+) -8b product of racemic aldol which can be resulted in optically active forms. Conventional resolution methods may be used such as chromatographic or fractional crystallization of suitable diastereoisomeric derivatives such as salts or esters with optically active acids (for example camphor-10-sulfonic acid, camphoric acid, methoxyacetic acid, or dibenzoyltartaric acid) or acylation or enzymatically catalyzed hydrolysis of racemic esters. The resulting or synthetic enantiomer can then be transformed into enantioselective synthesis of (+) - calanolide A and its congeners. In one method, the racemic aldol product can be resolved by high pressure liquid chromatography (CLAP) with organic solvent system as a mobile phase. CLAP is performed on a column packed with chiral packaging material. Suitable but not limiting examples of packaging material include amylose carbamate, D-phenylglycine, L-phenylglycine, D-leucine, L-leucine, D-naphthylalanine, L-naphthylalalin, or L-naphthyl-leucine. These materials can be combined, either ionically or covalently, to silica sphere whose particle sizes vary between about 5 microns and about 20 microns. The suitable mobile phase, but not limiting, includes hexane, heptane, cyclohexane, ethyl acetate, methanol, ethanol, or isopropanol and mixtures thereof. The mobile phase can be used in gradient systems of continuous gradient or step, isocratic at flow rates that vary generally between approximately 0.5 ml / minute and approximately 50 ml / minute. In the manufacture of compounds of the invention, the racemic product, ie the product [(+) - 8a] of aldol syn, is preferably resolved by the catalyzed acylation of the enzyme. Enzyme resolution can employ enzymes such as CC lipase. { Candida cyl indra cea), AK lipase. { Candida cyl indra cea), lipase AY. { Candida cyl indra cea), PS lipase (Pseudomonas species), AP lipase. { Aspergillus us Ní ger), lipase N. { Rhi zopus ni eveui s), lipase FAP. { Rhizopus ni eveus), liapsa PP (Porcine Pancreasa), stearase of pig liver (porcine) (PLE), acetone powder of pig liver (PLAP), or subtilisin. Immobilized forms of the enzyme on celite, molecular sieve, or ion exchange resin are also contemplated for use in this method. The amount of enzyme used in the reaction depends on the desired chemical conversion rate and the activity of the enzyme. The preferred enzyme for use in the catalyzed acylation reaction of the enzyme is lipase. The enzymatic acylation reaction is carried out in the presence of an acylating agent. Suitable but not limiting examples of acylating agents include vinyl acetate, vinyl propionate, vinyl butyrate, vinyl stearate, acetic anhydride, propionic anhydride, phthalic anhydride, acetic acid, propionic acid, hexanoic acid or octanoic acid. The enzymatic reaction employs at least one mole of acylating agent per mole of aldol product. The acylating agent can be used as a solvent in the acylation reaction or in solution with another solvent such as hexanes, chloroform, benzene, tert-butylmethylether, and THF. The preferred solvent and acylating agent for use in the catalyzed acylation of the enzyme are tert-butyl methyl ether and vinyl acetate, respectively. Suitable but not limiting examples of solvents for use in the enzymatic hydrolysis reaction include water, suitable aqueous buffers such as sodium phosphate buffers, or alcohols such as methanol or ethanol. One skilled in the art will appreciate that the racemic esters of aldol products can be made by conventional esterification and selectivity hydrolyzed by enzymes to produce, in high enantiomeric excess, optically active aldol product, i.e., (+) - 8, in free form or esterified. The purified (-) - 8a was subjected to a neutral Mitsunobu reaction, selectively carrying (+) - trans-chromanone [(+) - 7]. In carrying out this reaction, diethyl azodicarboxylate (DEAD) was added dropwise to a solution containing (+) - 8a and triphenylphosphine at a temperature ranging from about -10 ° C to about 40 ° C, preferably about the room temperature. The amount of DEAD used in the reaction usually ranges from about 1 mole to about 10 moles, preferably about 1 mole and about 4 moles, per mole of aldol (+) - 8a. The amount of triphenylphosphine used in the reaction usually ranges from about 1 mole to about 10 moles, preferably ranging from about 1 mole to about 4 moles, per mole of aldol (+) - 8a. In place of DEAD, other suitable azo reagents reported in the literature may be employed such as diisopropyl azodicarboxylate (DIAD), dibutyl azodicarboxylate (DBAD), dipiperidino-azodicarboxamide, bis (N4-methylpiperazin-1-yl) azodicarboxamide, dimorpholinoazodicarboxamide, N, N, N ', N'-tet ramethylazo-dicarboxamide (TMAD) 64. Also, in addition to triphenylphosphine, other phosphine derivatives such as tri-n-butylphosphine, 64, triethylphosphonyl, tri-ethylphosphine and tris (dimethylamino) phosphine can be used.

Therefore, the reaction was quenched with saturated ammonium chloride with the termination and extracted with a suitable solvent, for example ethyl acetate. The combined organic layers were washed with brine, concentrated in vacuo, and the crude (+) - 7 chromanone was purified by conventional means as discussed above. Chromanone (+) - 7 yields of the Mitsunobu reaction usually vary between about 60% and about 80%, usually about 70%. Finally, the reduction of soft borohydride of chromanone (+) - 7 in the presence of (+) --calanolide A of CeCl3 (H20) 7 (Luche reduction) produced with the desired stereochemical disposition. In the conduction of the reduction reaction, a solution of chromanone (+) - 7 was added dropwise in a solution of reducing agent, for example sodium borohydride and a metal additive, for example CeCl3 (H20) 7 in ethanol. The rate of addition is such that the temperature of the reaction mixture is maintained within a range of between about -40 ° C to about 60 ° C, preferably ranging from about -10 ° C to about -30 ° C. ° C. Therefore, the reaction mixture was stirred at a temperature ranging from about -40 ° C to about 60 ° C. In general, the amount of metal additive, for example CeCl3 (H20) 7 present in the reaction mixture, ranges from about 0.1 to about 2 moles, preferably ranging from about 0.5 to about 1 mole, per mole of sodium borohydride. . In addition, the amount of reducing agent, for example sodium borohydride employed in the reaction usually ranges from about 0.1 to about 12 moles, preferably ranging from about 2 to about 4 moles, per mole of chromanone (+) - 7 Suitable but not limiting examples of reducing agents include NaBH4 LiAlH4, (i-Bu) 2AlH, (rl-Bu) 3SnH, 9-BBN, Zn (BH4) 2, BH3, DIP chloride, selectrides and enzymes such as baking yeast. Suitable but not limiting examples of metal additives include CeCl3, ZnCl2, A1C13, TiCl4, SnCl3 and LnCl3 and their mixture with triphenylphosphine oxide. In the practice of this invention, sodium borohydride is preferred as the reducing agent and CeCl3 (H20) 7 as the metal additive. Therefore, the reduction mixture was diluted with water and extracted with a suitable solvent, for example, ethyl acetate. The extract was dried over a suitable drying agent, for example sodium sulfate, and concentrated. The resulting residue was then purified by conventional means such as chromatography on silica gel, using solvent mixtures of ethyl acetate / hexane. The Luche reduction in (+) - 7 leads to the formation of (+) --calanolide A [(+) - 1] which contains 10% (+) - calanolide B. The (+) --calanolide A [(+) -l] was further separated from (+) - calanolide B by means of preparative normal phase CLAP and was identical with an authentic sample. In this way, the (+) --calanolide A, 1, was successfully prepared with the desired stereochemical arrangement by means of treatment of the key intermediate of chromene 4 with aldol reaction catalyzed with chlorotitanium to produce (+ _) -8a, resolution of racemate enzyme to produce (+) - 8a, and reaction of (+) - 8a of neutral Mitsunobu to produce chromanone (+) - 7, followed by reduction of Luche by means of chromanone (+) - 7 (see Scheme of Reaction III). The resolution of the trans (+ _) -8b racemate enzyme with vinyl acetate and lipase takes into account the separation of (+) - 8b, which follows the treatment under the neutral reaction of Mitsunobu with triphenylphosphine and DEAD and subsequent reduction of Luche, would result in calanolide C (Reaction Scheme IV). In another embodiment of the invention, calanolide analogs A are provided by extension of the synthetic sequence mentioned above for (+) - calanolide A. The Pechmann reaction of phloroglucinol with substituted β-ketoesters produces substituted 5,7-dihydroxycoumarin. as shown in Reaction Scheme V. The conditions and reagents used in the Pechmann reaction are described in the foregoing. ß-Suitable keto esters, but not limiting includes those of the formula a: O, CO, Et wherein Ri is H, halogen, hydroxyl, amino, C? -6 alkyl, C? _6-alkyl aryl, mono- or poly-fluorinated C? _6 alkyl, Ci-e-alkyl hydroxy, C-alkoxy ? -6, amino-C-alkyl? , C? _6 alkylamino, di (C? _6) amino alkylamino, C? -8 alkylamino of C? _8 alkyl, di (C? _6 alkyl) amino-C? _8 alkyl, cyclohexyl, aryl, or heterocycle, wherein aryl or heterocycle can each be unsubstituted or substituted with one or more of the following: C? _6 alkyl, C? -6 alkoxy, hydroxy-C? _4 alkyl, hydroxyl, amino, alkylamino of Ci-β, di (C ?_6 alkyl) amino, C amino-8 aminoalkyl, C ?_8 alkylamino of C ?_8 alkyl, di (C ?_6 alkyl) amino-C alquilo-8 alkyl , nitro, azido or halogen; and R 2 is H, halogen, hydroxyl, C 1-6 alkyl, aryl C 1-6 alkyl, C 1-6 mono- or poly-fluorinated alkyl, aryl or heterocycle. The Friedel-Craft acylation of substituted 5,7-dihydroxycoumarin leads to the formation of 8-acylated 5,7-dihydroxycoumarin. The conditions and reagents used in the Friedel-Crafts acylation reaction are described in the foregoing. Non-limiting examples of carboxylic acid anhydrides and halides include carboxylic acid anhydrides and halides of the formula b: wherein X is halogen (for example chloro) or OCOCHR3R4, wherein R3 and R4 are independently selected from the group consisting of H, halogen, hydroxyl, C6-6alkyl, arylCi-βalkyl, C-alkyl? _6 mono- or poly-fluorinated, hydroxy-C de-6 alkyl, C?-8 aminoalkyl, C?-8-alkylamino of C? _8 alkyl, di (C?-6 alkyl) amino-alkyl of C? _8, cyclohexyl, aryl or heterocycle; and R3 and R4 can be taken together to form a 5-7 membered heterocyclic ring or cyclic saturated ring. The chromenylation of 12 can be achieved by reacting with substituted β-hydroxyaldehyde dimethylacetal, producing chromenocoumarin 13. The conditions and amounts of reagents are described above. Representative examples of substituted β-hydroxyaldehyde dimethyl acetals of formula c comprise: wherein R5 and Re are independently selected from the group consisting of H, C? _6 alkyl, C? _6 aryl alkyl, mono- or poly-fluorinated C? _6 alkyl, aryl or heterocycle; R5 and R6 can be taken together to form a 5-7 membered saturated cyclic heterocyclic ring or ring; and R7 is H, halogen, methyl, ethyl. The condensation reaction of aldol of chromene 13 with carbonyl compounds in the presence of LDA forms the racemic (+ _) -14 aldol product. In accordance with the present invention, a solution of LDA in THF was added dropwise to a solution of chromene 13 in THF at a temperature ranging from about -78 ° C to about 0 ° C, preferably about -30 ° C. and approximately -78 ° C. The amount of added LDA per mole of chromene 13 ranges from about 1 to about 4 moles, preferably ranging from about 2 to about 3 moles per mole of chromene 13. The dropwise addition of LDA was conducted in such a way that the The reaction temperature was kept within the desired range. A carbonyl compound of the formula IV is then added dropwise to the reaction mixture in amounts ranging from about 1 to about 12 moles, preferably ranging from about 4 to about 6 moles per ol of chromene 13. The drop addition The drop of the carbonyl compound was conducted in such a way that the reaction temperature remained within the aforementioned range. The reaction was monitored by conventional means, for example CCF analysis, until it reached completion. Representative examples of carbonyl compounds of the formula d comprise: Rs' R * R8 and R9 are independently selected from the group consisting of H, halogen, C6-6alkyl, arylC6-6alkyl, C6-6 mono- or poly-fluorinated alkyl, hydroxyC1-6alkyl , C amino _8 amino-alkyl, C? _8-alkylamino of C? _8alkyl, di (C?-6alkyl) amino-C de-alkyl, cyclohexyl, aryl or heterocycle; and R8 and R9 can be taken together to form a 5-7 membered saturated cyclic heterocyclic ring or ring. One skilled in the art will appreciate that the reaction of aldol of chromene 13 with carbonyl compounds of formula d to form 14 can be carried out under conditions employing bases other than LDA. For example, metal hydroxides such as NaOH, KOH and Ca (OH) 2, metal alkoxides such as MeONa, EtONa and t-BuOK, and amines such as pyrrolidine, piperidine, diisopropyl-ylamine, 1,5-diazabicylo - [4, 3, 0] non-5-ene (DBN), 1, 8-diazabicyclo [5, 4, 0] undec-7-ene (DBU), NaNH2 and LiHMDS as well as hydrides such as NaH and KH they can all be employed for aldol reactions.10 Also, aldol reactions can be mediated by metal complexes of Al, B, Mg, Sn, Ti, Zn and Zr compounds such as TiCl4, (i-PrO) 3TiCl, (i-PrO) 4Ti, PhBCl2, (n-Bu) 2BCl, BF3, (n-Bu) 3SnCl, SnCl 4, ZnCl 2, MgBr 2, Et 2 AlCl with or without chiral auxiliaries such as 1, 1'-bifol, norefedrinsul fonate, cannediol , diacetone glucose and dialkyl tartrate.11-13 Therefore, the reaction mixture was rapidly cooled from -30 ° C to -10 ° C with saturated aqueous ammonium chloride solution and extracted with a suitable solvent, for example ethyl acetate. The combined extracts were washed with brine and dried over a suitable drying agent, for example sodium sulfate. The yields of the aldol product (+ _) -14 generally vary between about 40% and about 80%, usually about 70%. The cyclization of (+ 0-14 under neutral Mitsunobu conditions, using triphenylphosphine and diethyl azodicarboxylate (DEAD), leads to the formation of the chromanone analogue (+ -15.) The reduction of (+ _) - 15 with sodium borohydride with or without metal additives such as cerium chloride produces the analogue 12-hydroxy (+ _) -16 (Reaction Scheme V) The conditions and amounts of reagents used in the reduction reactions of Mitsunobu and borohydride are described in the above The catalytic hydrogenation of both (+ -15 and (+ _) -16 produces derivatives 7,8-dihydro (+ _) -17 and (+ _) -18 (Reaction Scheme VI). It was added to a solution of (+ _) -15 or (+ _) -16 in ethanol or mixtures of ethanol / methylene chloride in a conventional Parr apparatus under H2, a hydrogenation catalyst at room temperature. The mixture was stirred under hydrogen for a sufficient time to complete the hydrogenation reaction. The solution was then filtered by gravity to remove the catalyst and the solvent was evaporated. Suitable hydrogenation catalysts, but not limiting for use in the invention include Pd / C, Pt02 and Rh / C, Raney-Ni. In the manufacture of compounds of the invention, 10% palladium / carbon is preferred. The amount of catalysts employed generally ranges from about 0.01 to about 0.5 moles, preferably ranging from about 0.05 to about 0.1 moles per mole of (+ _) -15 or (+) - 16. In still another embodiment of the invention, the intermediary chromanones. { +) -T, (+) - 7, (+) - 7a and (+ _) - 15 can be used to prepare oxime, hydroxyamino, alkoxyamino or amino calanolide derivatives. Treatment of the chromanones with hydroxylamine or alkoxyamine produces oxime derivatives (+ -19 (Reaction Scheme VI) Representative amines for the preparation of oxime derivatives comprise NH2OR10, wherein R10 is H, C? _8 alkyl, phenyl, benzyl , acyl P (O) (OH) 2, S (0) (OH) 2, CO (C? .10 alkyl) CO2H, (C? _8 alkyl) C02H, CO (C -? 0 alkyl) NR12R13 , (C 8 alkyl) NR 12 R 13, wherein R 12 and R 3 are independently selected from the group consisting of H, C 1 -β alkyl, and R 2 and R 3 can be taken together to form a heterocyclic ring 5-7-membered saturated nitrogen containing solvent Examples of useful alkoxyamines include methoxyamine and benzyloxyamine The oxime derivatives can be prepared by refluxing a methanolic solution of the chromanone with hydroxylamine or alkoxyamine in the presence of a metal carbonate such as carbonate. of potassium or pyridine until the reaction reaches completion.The amount of amine at The general amount ranges from about 1 to about 20 moles, preferably from about 3 to about 6 moles, per mole of chromanone. With the completion of the reaction, the filtration of the solution to remove solids and elimination of the solvent results in an oil which is purified by chromatography on silica gel. Yields of oximes usually vary between about 30% and about 80%, usually about 50%. If desired, the oxime derivatives (+ _) -19 can be reduced under different conditions to produce hydroxyamino or amino compounds (20 and 21). In this way, the optically active forms of 14-21 (Reaction Scheme V and VI) must be obtained using enzymatic acylation, as described above, in the procedure described in Reaction Scheme III for (+) -calanolide A [(+) - l]. The catalyzed acylation of the racemic (+ _) -14 aldol product enzyme must selectively acylate an enantiomer [ie (-) - 14] and leave the other enantiomer [ie (+) - 14] unreacted, which must be easily separated by conventional methods such as column chromatography on silica gel. The acylated enantiomer [ie (-) - 14] can be hydrolyzed to form the pure enantiomer [ie (-) - 14]. The optically pure enantiomers obtained in this way [(+) - 14 and (-) - 14] will be cyclized to (+) - 15 and (-) - 15, respectively, by the Mitsunobu reaction as described above. The subsequent reduction of (+) - 15 and (-) - 15 would lead to the formation of (+) - 16 and (-) - 16, respectively. Hydrogenation of optically active forms of 15 and 16 would provide pure enantiomers of 17 and 18 [(+) - and (-) - 17; (+) - and (-) - 18], respectively. The treatment of pure enantiomers of 15 with hydroxylamine and alkoxyamine, as described above, should produce the enantiomerically pure 19 ((+) - and (-) - 19] oxime. The reduction of (+) - 19 and (-) - 19 would lead to the formation of 20 and 21 [(+) - and (-) - 20; (+) - and (-) - 21] enantiomerically pure. The 12-hydroxyl group in compound 1, 16, and 17 as well as their optically active forms can be epimerized by a number of methods including acidic conditions, neutral Mitsunobu573"0 conditions, or with DAST.57d. An example showing the conversion of (-) -calanolide A [(-) -!] to (-) - calanolide B using DAST57d is represented in the Reaction Scheme VII. In this way, the process used to produce compounds of the present invention can be used to prepare a wide variety of calanolide analogues such as Formulas i -v shown in Reaction Scheme VIII and Formulas vi -vi i shown in Reaction Scheme IX. For Formula I, Rx and R2 are independently for Formula I, Rx, R2 and R3 independently on H or CH3. For Formula II i, Rx is linear or branched alkyl of C -C6- For Formula IV, Rx is propyl or phenyl and R2 is MIOH or - ^ "OH For Formula VI, Rx is linear or branched alkyl of C? ~ C6 For Formula VI i, Rx is propyl or phenyl and R2 is miOH or - ^ * OH.

Additional exemplary calanolide analogs include but are not limited to Formulas 15 and 16 shown in Reaction Scheme V, and Formulas 17 and 18 shown in the Reaction Scheme.

In another embodiment of the invention, the (-) --calanolide B, obtained by means of the conversion of (-) --calanolide A, is provided. It has been discovered that (-) --calanolide A can be easily converted to (-) - calanolide B using diethylamidosulfide trifluoride (DAST) or the Mistsunobi reaction, for example diethyl azodicarboxylate and triphenylphosphine, under the conditions and ranges described in the foregoing. The amount of DAST employed in the inversion reaction usually ranges from about 0.5 to about 5.0 moles, preferably ranging from about 1 to about 2.0 moles, per mole of (-) --calanolide A. Suitable reaction solvents, but non-limiting for use in the invention, include methylene chloride, THF, diethyl ether, or chloroform. In the practice of the invention, the preferred solvent is methylene chloride. The reaction can be conducted at a temperature ranging from about -78 ° C to about 50 ° C, preferably about -78 ° C, until the reaction is complete as determined by usual methods such as thin layer chromatography.

The calanolide compounds of the invention can be formulated as a solution of lyophilized powders for parenteral administration. The powders can be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier before use. The liquid formulation is usually an aqueous, isotonic, buffered solution. Examples of suitable diluents are normal isotonic saline, standard 5% dextrose in water or buffered ammonium or sodium acetate solution. Such a formulation is especially suitable for parenteral administration, but can also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, the compounds of the present invention may be encapsulated, compressed or prepared in an emulsion syrup (oil in water or water in oil) for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added, which are generally known in pharmaceutical formulating techniques, to increase or stabilize the composition, or to facilitate the preparation of the composition. Solid carriers include starch (corn or potato), lactose, calcium dihydrate sulfate, alba earth, croscarmellose sodium, magnesium stearate or stearic acid, talc, pectin, acacia, agar, gelatin, maltodextrins and microcrystalline cellulose, or silicon dioxide colloidal Liquid carriers include, syrup, peanut oil, olive oil, corn oil, sesame 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 solid carrier varies but, preferably, it will be between about 10 mg to about 1 g per unit dose. The dose ranges for the administration of the calanolide compounds of the invention are those to produce the desired effect, whereby the symptoms of infection are improved. For example, as used herein, a pharmaceutically effective amount for a mycobacterium infection refers to the amount administered "to maintain an amount that suppresses or inhibits mycobacterium infection as evidenced by the standard assay. the dosage for the existence of any adverse side effects that may accompany the compounds.It is always desirable, whenever possible, to maintain adverse side effects to a minimum.An expert in the art can easily determine the appropriate dose, schedule, and method of administration for the exact formulation of the composition which is used to achieve the desired effective concentration in the particular patient.However, the dose may vary from about 0.001 mg / kg / day to about 150 mg / kg / day, but preferably between about 0.01 to about 20.0 mg / kg / day.The pharmaceutical composition The pharmaceutical composition may contain other pharmaceuticals together with the calanolide antimicrobial analogues of the invention. For example, other pharmaceuticals may include, but are not limited to, antiviral compounds (e.g., AZT, ddC, ddl, D4T, 3TC, acyclovir, gancyclovir, fluorinated nucleosides and non-nucleoside analog compounds such as TIBO and nevirapine derivatives, α-interferon and recombinant CD4), protease inhibitors (for example indinavir, saquinavir, ritonavir and nelfinavir), immunostimulants (for example various interieucins and cytokines), immunomodulators, (antimicrobials such as anti-TB agents, rifampin, rifabutin, rifapentine, pyrazinamide, and ethambutol, antibacterials, antifungals, anti-pneumocystitis agents) and chemokinesis inhibitors. The administration of the inhibitory compounds with antiretroviral agents that act against other HIV proteins such as protease, intergrase and TAT will generally inhibit most or all of the replicative stages of the viral life cycle. The calanolides and analogues thereof described herein may be used either alone or in combination with other pharmaceutical compounds to effectively fight a simple infection. For example, the calanolides and analogues of the invention can be used either alone or in combination with acyclovir in combination therapy to treat HSV-1. The calanolides and analogues can also be used either alone or in combination with other pharmaceutical compounds to combat multiple infections. For example, the calanolides and analogs thereof can be used in combination with one or more anti-mycobacterial agents such as anti-TB agents such as Isoniazid, rifamycins (eg, rifampin, rifabutin and rifapentine), pyrazinamide, and ethambutol as a prophylactic or therapeutic treatment. The calanolides and analogs thereof can also be used in combination with Intron A and / or a biflavonoid for the treatment of Hepatitis B; with gancyclovir, progancyclovir, famcyclovir, foscarnet, vidarabine, cidovir, and / or acyclovir for the treatment of herpes virus; and with ribavarin, amantidine, and / or rimantidine for the treatment of the respiratory virus. The following example is illustrative of the invention but does not serve to limit its scope.

EXPERIMENTAL OR TESTING All chemical reagents and solvents referred to herein are readily available from a number of commercial sources including Aldrich Chemical Co., or Fischer Scientific. The NMR spectrum was run on a Hitachi 60 MHz R-1200 NMR spectrometer or on a Varian VX-300 NMR spectrometer. The IR spectrum was 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 rectified.

EXAMPLE 1: 5, 7-Dihydroxy-4-propylcoumarin55 (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 after which it was poured 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 removal of the in va cuo solvent, the residue was triturated with hexane to provide essentially pure compound 2 (203 g) in a quantitative yield, m.p. 233-235 ° C (Lit.55 236-238 ° C). NMR ^ H55 (DMSO-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 = 7.5Hz, 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); In the); 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); IR (KBr): 3210 (broad vs, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1; Analysis calculated for C12H2404: C, 65.45; H, 5.49; Found: C, 65.61; H, 5.44; EXAMPLE 2: 5, 7-Dihydroxy-8-propionyl-4-propylcoumarin (3) A three-necked flask (500 ml) equipped with an efficient mechanical stirrer, thermometer and addition funnel was charged with 5,7-dihydroxy-4 -propyl-coumarin, 2, (25.0 g, 0.113 mol), aluminum chloride (62.1 g, 0.466 mol), and nitrobenzene (150 ml) and the mixture was stirred until a solution was obtained, which was cooled to 0 ° C 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 8-10 ° C. The addition was completed for a period of 1 hour with vigorous stirring. The reaction was monitored by TLC 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 TLC analysis indicated the total consumption of starting material, the reaction mixture was poured onto 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 Na2SO4. The crude product obtained by in va evaporation was purified by chromatography on a column of silica gel eluting with 50% ether / hexane to provide the desired propionylated coumarin 3, m.p. 244-246 ° C. RMN-1 !! (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 (El): 277 (6.6, M + 1); 276 (9.0, M +); 247 (100, M-C2H5); IR (KBr): 3239 (s and broad, OH); 1693 (s, C = 0), 1625 and 1593 (s) cm "1; Analysis calculated for C? 5H16? 5; C, 65.21; H, 5.84; Found: C, 64.92; H, 5.83. The evaluation of the isomer was made by analogy to precedent.65 EXAMPLE 3: 2, 2-Dimethyl-5-hydroxy-6-propionyl-10-propyl-2ff-8H-benzo [l, 2-b: 3,4-b '] dipyran-8-one (4) A mixture of 3 (2.60 g, 9.42 mmol) and 4,4-dimethoxy-2-methylobutan-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 the elimination of the solvent in va cuo, the residue was dissolved in ethyl acetate. The ethyl acetate was washed several times with NHC1 IN and brine. It was then dried over Na2SO4. The crude product obtained by evaporation in va cuo was purified by column chromatography on si gel, eluting with 25% ethyl acetate / hexane to yield 2.55 g of 4 in a yield of 78.6%, m.p. 96-98 ° C. NMR-1H (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 C2oH2205; 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 4 (1.76 g, 5.11 mmol) and sodium acetate (0.419 g, 5.11 mmol) in acetic anhydride (12 ml) was brought to reflux by 10 hours after which the solvent was removed in va cuo. The residue was purified by column chromatography on silica gel, eluting first with 25% ethyl acetate / hexane followed by 50% ethyl acetate / hexane to provide 1.16 g (62% yield) of enone 5 (6, 6, 10, 1 l-tetramethyl-4-propyl-2i, ßH, 12 H-benzo [1, 2-b: 3, 4-b ': 5, 6-b "] tripiran-2, 12-dione) as a white solid, mp 209-209.5 ° C. NMR- ^? (CDC13) d 1.05 (3H, t, J = 6.6 Hz, CH3); 1.56 (6H, s, 2 CH3); 1.73 (2H, m, CH2), 1.98 (3H, s, CH3), 2.38 (3H, s, CH3), 2.91 (2H, t, J = 7.5 Hz, CH2), 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 C22H2205: 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-butyltin hydride (0.318 g, 1.09 mmol) and dry dioxane (2.0 ml) was brought to reflux under nitrogen for 12 hours. The solvent was then removed in vacuo and the residue was purified by preparative TLC 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, 11-tetramethyl-4-propyl-2H, 6H, 12H-benzo [l, 2-b: 3,4-b ': 5, 6-b was isolated "] tripiran-2-one) (13.3 mg, 8%) as an oil from the plate by elution of ethyl acetate This elution may have been inefficient, and the current highest yield, as indicated by analytical TLC of the crude product, NMR-XH (CDC13), 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, H? 2), 5.51 (1H, d , J = 10.0 Hz, H7), 6.06 (1H, s, H3), 6.67 (1H, d, J = 10.0 Hz, H8), 13.25 (1H, broad s, OH), MS (El): 369 (3.8 , 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 ) crn "1.

EXAMPLE 6: 12-Oxocalanolide A [(+) - 7) A solution containing chromene 4 (344 mg, 1.0 mmol), acetaldehyde diethyl acetal (473 mg, 4.0 mmol), trifluoroacetic acid (1.5 ml, 19.4 mmol) and pyridine Anhydrous (0.7 ml) was heated to 140 ° C under N2. The reaction was monitored by CCF analysis. After 4 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed several times with 10% aqueous NaHCO 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: 3). Chromanone (+ _) -7 (10.1 l-trans-dihydro-4-propyl-6,6,10,1 l-tetramethyl-2H, 6H, 12H-benzo [l, 2-b: 3, 4-b ': 5, 6-b "] -tripyran-2, 12-dione) (110 mg, 30% yield), mp 176-177 ° C. (Lit.55 130-132 ° C). ^ H55 (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. O 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, Hn), 2.88 (2H, t, J = 7.6 Hz, CH2), 4.28 (1H, dq, J = 6.3 Hz, J = 11.0 Hz, H? 0), 5.60 (1H, d, J = 9.9 Hz, H7), 6.04 (1H, s, H3) 6.65 (1H, d, J = 11.8 Hz, H8); MS (Cl): 369 (100, M + 1).

EXAMPLE 7: (+) -Calanolide A (1): To a solution of chromanone (+ _) -7 (11 mg, 0.03 mmol) in ethanol (0.4 ml) was added sodium borohydride (2.26 g, 0.06 mmol) and CeCl3 (H20) 7 (11.2 mg, 0.03 mmol) in ethanol (5 ml) at room temperature. After stirring for 45 minutes, the mixture was diluted with H20 and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by preparative TLC eluting with ethyl acetate / hexane (1: 1) to give (+ _) - calanolide A (1) (10.5 mg, 94%), m.p. 52-54 ° C, which increases to 102 ° C after it has completely dried (Lit 55, 56-58 ° C). NMR-1H (CDC13): d 1.03 (3H, t, J = 7.3 Hz, CH3), 1.15 (3H, d, J = 6.8 Hz, CH3), 1.46 (3H, d, J = 6.8Hz, CH3), 1.47 (3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, m, CH2), 1.93 (1H, m, H1X), 2.89 (2H, m, CH2), 3.52 (1H, s broad, OH), 3.93 (1H, m, H10), 4.72 (1H, d, J = 7.8Hz, H? 2), 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 C22H2505: C, 71.33; H, 7.07; Found: C, 71.63; H, 7.21.

EXAMPLE 8: 5, 7 -Dihydroxy-4-propylcoumarin (2): In this Example, the scale preparation in kilogram of intermediate 2 was described. To a stirring suspension of phloroglucinol (3574.8 g, 28.4 moles, pre-dried to constant weight) and ethyl butyrylacetate (4600 ml, 28.4 moles) was added dropwise of concentrated sulfuric acid at a rate that the internal temperature does not exceed 40 ° C. Then 100 ml of sulfuric acid was added, the temperature increased to 70 ° C and the suspension turned to a yellow solid. The CCF analysis indicated that the reaction has proceeded 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 filter became neutral. An amount of 4820 g (77% yield) of 5,7-dihydroxy-4-propylcoumarin 2 was obtained, then dried, which was identical with an authentic sample by comparison of TLC, melting point and spectroscopic data.

EXAMPLE 9: 5, 7-Dihydroxy-8-propionyl-4-propylcoumarin (3) In this Example, kilogram quantities of intermediate 3 were synthesized using propionic anhydride in place of propionyl chloride. 5, 7-Dihydroxy-4-propylcoumarin 2 (1710 g, 7.77 moles) and A1C13 (1000 g, 7.77 moles) were mixed in 1,2-dichloroethane (9 1). The resulting orange suspension was stirred and heated to 70 ° C until a solution was obtained. Then, a mixture of propionic anhydride (1010 g, 7.77 mol) and A1C13 (2000 g, 15.54 mol) in 1,2-dichloroethane (3.4 1) was added dropwise over 3 hours. The reaction was allowed to stir at 70 ° C for an additional hour. After it was cooled below room temperature, the reaction mixture was poured into a mixture rapidly under stirring of ice water and IN HCl. The precipitated product was taken in ethyl acetate (30 1) and the aqueous solution was extracted with the same solvent (10 1 x 2). The combined extracts were washed successively with IN HCl (10 1), aqueous NaHCO 3, saturated (10 1), and water (10 1). After it was dried over MgSO4 and concentrated in vacuo, a solid product (1765 g) was obtained which was washed with ethyl acetate (15 l) and recrystallized from dioxane (9.5 l) to give 514 g of the compound 3. After washing with ethyl acetate, an additional 100 g of the compound was obtained after recrystallization of dioxane. In this way, the combined yield for compound 3, which is identical with an authentic sample by comparison of TLC, melting point and spectroscopic data, was 29%.

EXAMPLE 10: 2, 2-Dimethyl-5-hydroxy-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 of 3 by means of modifying the reaction conditions described in Example 3. A mixture of compound 3 (510.6 g, 1.85 moles) and 4,4-dimethoxy-2 -met ilbutan-2-ol (305.6 g, 2.06 mol) was dissolved in a mixture of toluene (1.5 1) and dry pyridine (51 ml). This mixture was stirred and brought to reflux; the water and methanol formed during the reaction were azeotically removed by means of a Dean-Stark trap. The reaction was monitored by CCF. After 6 days, the reaction has proceeded to completion. The mixture was then cooled to room temperature and diluted with ethyl acetate (2 1) and IN HCl (11). The ethyl acetate solution was separated and washed with IN HCl (500 ml) and brine (11). After it was dried over Na2SO4 and evaporated 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 TLC and spectroscopic data. .

EXAMPLE 11: 12-Oxocalanolide A ((+) - 7): In this Example, chromanone (+ _) -7 was prepared from two alternative routes involving either a one-stage paraldehyde reaction (process A) or a two-stage reaction process (procedures B and C).

Procedure A. One Step Paraldehyde Reaction: To a stirring 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 was added. added 3 ml of paraldehyde (22.5 mmol). The resulting mixture was refluxed for 7 hours. Then, CF3C02H (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 NaHCO 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 yield 100 mg (27% yield) of chromanone (±) ~ 7 Y 3 ° m9 (8% yield) of (; +) - 7a. L chromanone (+ _) -7 (10, 11-t-rans-dihydro-4-propyl-6, 6, 10, 11-tetramethyl-2H, 6H, 12H-benzo [1,2-b: 3,4- b ': 5,6-b "] tripiran-2,12-dione) obtained by this method was identical with an authentic sample by comparison of TLC, CLAP and spectroscopic data.

Procedure B Two-Stage Reaction of LDA / Sulfuric Acid: To a stirring solution of chromene 4 (5.0 g, 14.6 mmol) in THF (75 mL) at -30 ° C under N2 was added 18.3 mL (36.5 mmol) of LDA 2 M 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 CCF 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. The elimination of the solvents in va cuo produced a reddish oil of (+ _) -8a and (+ _) -8b (8.5 g). The crude (+) - 8a and (+ _) - 8b were dissolved in acetic acid (100 ml) and then 50% H 2 SO 4 (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. The CCF analysis indicated that the initial material has been consumed. The reaction mixture was determined to contain both chromanone (+ _) -7 and (+ _) -7a derived from 10, 11-cis-dimethyl in a 1: 1 ratio. 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 saturated aqueous NaHCO3 and brine. After being concentrated in vacuo, the product was purified by chromatography on a column of silica gel eluting with ethyl acetate / hexane (2: 3) to provide 850 mg (16% yield) of chromanone. { +) -! , which was further purified by recrystallization from ethyl acetate / hexane and was identical with an authentic sample by comparison of TLC, CLAP and spectroscopic data.

Procedure C Two-Stage Reaction of LDA / Mitsunobu: In a stirred solution of THF (10 ml) containing triphenylphosphine (1.27 g, 4.80 mmol) and the crude mixture of. { + _) -8a and (+ _) -8b, obtained from chromene 4 (1.0 g, 2.34 mmoles), 2.5 equivalents of LDA and 6.0 equivalents of acetaldehyde by the procedure described in the above, diethyl azodicarboxylate was added dropwise (DEAD, 0.77 ml, 4.89 mmol). The resulting reddish solution was stirred at room temperature under N2 for 1 hour, after which the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate (50 ml x 3). The extracts were washed with brine and dried over Na2SO4. After removal of solvents, the crude product was purified by column chromatography on silica gel eluting with ethyl acetate / hexane (2: 3) to provide 412 mg (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, CLAP 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 ethanol (1.5 1) was added CeCl3 (H20) 7 (102 g, 274 mmol). The mixture was stirred for 1.5 hours at room temperature under N2 and then cooled to -30 ° C with a dry ice bath of ethylene glycol / H20 (1: 2 w / w). After the temperature was equilibrated to -30 ° C, NaBH4 (21.3 g, 563 mmol) was added and stirred at the same temperature for 8.5 hours, at which time the reaction was quenched with H20 (2 1) and extracted with ethyl acetate (2 1 x 3). The extracts were combined, washed with brine (2 1) and dried over Na 2 SO 4. The crude product obtained by solvent removal under reduced pressure was passed through a short silica gel column to provide 53 g of mixture containing 68% (+) - calanolide A, 14% (+) -calanolide B and 13% chromanone (+ _) -7 as shown by CLAP. This material was subjected to another purification by preparative CLAP to produce (+ _) -calanolide A pure (1).

EXAMPLE 13: Chromatographic Resolution of Synthetic (+) -Calanolide A Synthetic (+) -1 was resolved into enantiomers, (+) -calanolide A and (-) -calanolide A, by preparative CLAP66. Using in this way a normal column phase of silica gel CLAP (250 mm x 4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analitical, Inc., PA, USA), the synthetic (+ _) -1 appears as a peak with a retention time of 10.15 minutes when hexane / ethyl acetate was used (70:30) as the mobile phase at a flow rate of 1.5 ml / minute and a wavelength of 290 nm was used as the uv fixation detector. However, they were observed on a column of chiral CLAP packed with amylose carbamate (250 mm x 4.6 mm ID Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., PA, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1: 1 at a flow rate of 1.5 ml / minutes. The mobile phase was hexane / ethanol (95: 5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral CLAP column, providing the pure enantiomers of 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. The CLAP chromatograms of (+ _) -calanolide A and their optical forms were shown in Figure 6.

(+) -Calanolide A (1): p.f. 47-50 ° C (Lit.67 45-48 ° C); [a] 25D = + 68.8 ° (CHC13, c 0.7) (Lit67 [a] 25D = + 66.6 °) (CHC13; c 0.5); 1N NMR (CDC13) d 1.03 (3H, t, J = 7.3 Hz, CH3), 1.15 (3H, d, J = 6.8 Hz, CH3), 1.46 (3H, d, J = 6.4 Hz, CH3), 1.47 ( 3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, m, CH2), 1.93 (1H, m, Hn), 2.89 (2H, m, CH2), 3.52 (1H, d, J = 2.9 Hz, OH), 3.93 (1H, m, H10), 4.72 (1H, dd, J = 7.8 Hz, J = 2.7 Hz, Hi2), 5.54 (1H, d, J = 9.9 Hz, H7), 5.94 (1H, s, H3), 6.62 (1H, d, J = 9.9 Hz, H8); 13 C NMR (CDC13) 13.99 (CH3), 15.10 (CH3), 18.93 (CH3), 23.26 (CH2), 27.38 (CH3), 28.02 (CH3), 38.66 (CH2), 40.42 (CH), 67.19 (CH-OH ), 77.15 (CH-O), 77.67 (CO), 104.04 (C4a), 106.36 (C8a and C? 2a), 110.14 (C3), 116.51 (C8), 126.97 (C7), 151.14 (C4b), 153.10 ( C8b), 154.50 (C? 2b), 158.88 (C4), 160.42 (C = 0); CIMS: 371 (100, M + l), 370 (23.6, M "), 353 (66.2, M-OH), IR: 3611 (w) and 3426 (m, broad, OH), 1734 (vs C = 0) ), 1643 (m), 1606 (m) and 1587 (vs) cm "1; UV? Max (methanol): 204 (32,100), 228 (23,200), 283 (22,200), 325 (12,700) nm; Analysis calculated for C22H2605 1 / 4H20: C, 70.47; H, 7.12; Found: C, 70.64; H, 7.12.

(-) -Calanolide A (1) p.f 47-50 ° C, [a] "D = -75.6 (CHC13, c 0.7) Lit 6 ° 7 '[a] DD = -66.6? (CHC13; c 0.5 NMR XH (CDCI3) d 1.03 (3H, t, J = 7.4 Hz, CH3), 1.15 (3H, d, J = 6.8 Hz, CH3), 1.46 (3H, d, J = 6.3 Hz, CH3), 1.47 (3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, m, CH2), 1.93 (1H, m, H ??), 2.89 (2H, m CH2), 3.50 (1H, d, J = 2.9 Hz, OH), 3.92 (1H, m, H10), 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, H3), 6.62 (1H, d, J = 10.0 Hz, H8); 13 C NMR (CDC13) d 13.99 (CH3), 15.10 (CH3), 18.93 (CH3), 23.36 (CH2), 27.38 (CH3), 28.02 (CH3), 38.66 (CH2), 40.42 (CH), 67.19 (CH-) OH), 77.15 (CH-O), 77.67 (CO), 104.04 (C4a), 106.36 (C8a and C? 2a), 110.14 (C3), 116.51 (C8), 126.97 (C7), 151.14 (C4b), 153.11 (C8b), 154.50 (C12b), 158.90 (C4), 160.44 (C = 0); CIMS: 371 (95.2, M + l), 370 (41.8, M +), 353 (100, M-OH); IR: 3443 (m, broad, OH), 1732 (vs, C = 0), 1643 (m), 1606 (m) and 1584 (vs) cm "1; UV? max (methanol): 200 (20,500), 230 (19,400), 283 (22,500), 326 (12,500) nm; Analysis calculated for C22H26? S 1 / 4H20: C, 70.47; H, 7.12; Found: C, 70.27; H, 7.21.

EXAMPLE 14: Enzymatic Resolution of (+) -Calanolide AA a magnetically stirred suspension of (_ +) --calanolide A, prepared by the method of the present invention, and vinylbutyrate (0.1ml) in hexane (0.5ml) at temperature environment, 1 mg of PS-13 lipase was added. { Pseudomonas Species) (Sigma Corporations, St. Louis, MO, USA). The reaction mixture was stirred and monitored by conventional means such as TLC analysis. An additional 1 mg of PS-13 lipase was added in 10 days. 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 out and the filtrate was concentrated to dryness. The residue was analyzed by CLAP (see Example 13), which showed that 21% of (-) - calanolide A has been converted to its butyrate ester form. The enriched (+) --calanolide A and the (-) --calanolide A butyrate ester can be easily separated by conventional means such as column chromatography. The enriched (+) - catalanide A can be repeatedly treated with vinyl butyrate and lipase PS-13 as described above to obtain high e.e. of (+) -calanolide A.

EXAMPLE 15 Reaction of Aldol (Reaction Scheme III) of Chromeno 4 in the Presence of LDA To a stirring solution of chromene 4 (1.0 g, 2.9 mmol) in THF (15 mL) at -78 ° C under N2 was added LDA 2M in THF (3.2 ml, 6.4 mmol). After 1 hour at the same temperature, acetaldehyde (1.0 ml, 17.5 mmol) was added via syringe. The reaction was monitored by CCF analysis. After 1 hour, the reaction mixture was quenched with 2N HCl pre-cooled in methanol (15 ml) and extracted with ethyl acetate (30 ml x 3). The combined extracts were washed with brine and dried over Na2SO4. Removal of solvents in vacuo yielded a reddish oil, which was purified by column chromatography on silica gel eluting with a discontinuous gradient of 5%, 10%, 15%, 25% and 30% ethyl acetate in hexane for obtain 780 mg (70% yield) of a mixture of (+ _) -8a and (+) - 8b in a ratio of 1: 1, as indicated by 1 H NMR. Pure samples of (+ _) -8a and. { + _) -8b were obtained by carefully collecting the frontal fractions and previous fractions from the column chromatography, analytical data of which are described in the following: 6,6-Dimethyl-9-hydroxy-10- [2 (S *) -methyl-3 (R *) -hydroxybutyl] -4-propyl-2H, 6H-benzo [1,2-b: 3,4- b '] dipiran-2-one [syn-. { + _) 8a] • p.f. 66-67 ° C; XH NMR (CDC13): 1.05 (3H, t, J = 7.3 Hz, CH3), 1.30 (3H, d, J = 6.0 Hz, CH3), 1.33 (3H, d, J = 6.6 Hz, CH3), 1.54 ( 6H, s, 2 CH3), 1.67 (2H, m, CH2), 2.62 (1H, broad s, OH), 2.91 (2H, t, J = 7.7 Hz, CH2), 3.98 (1H, dq, J = 2.7 Hz, J = 7.0 Hz, H2), 4.29 (1H, m, H3), 5.59 (1H, d, J = 10.0 Hz, H7), 6.01 (1H, s, H3), 6.73 (1H, d, J = 10.0 Hz, H8), 14.11 (1H, s, OH); XH NMR (DMS0-d6): 1.00 (3H, t, J = 7.3 Hz, CH3), 1.13 (3H, d, J = 6.6 Hz, CH3), 1.16 (3H, d, J = 6.8 Hz, CH3), 1.49 (3H, s, CH3), 1.50 (3H, s, CH3), 1.60 (2H, apparent sextet, J = 7.6 Hz, CH2), 2.88 (2H, apparent dd, J = 6.3 Hz, J = 9.0 Hz, CH2), 3.39 (1H, broad s, OH), 3.68 (1H, dq, J = 5.2 Hz, J = 6.7 Hz, H2), 3.97 (1H, apparent quintet, J = 5.8 Hz, H3), 5.78 (1H , d, J = 10.1 Hz, H7), 6.11 (1H, s, H3), 6.63 (1H, d, J = 10.1 Hz, H8), 13.25 (1H, s, OH); MS (Cl): 388 (36.5, M + 2), 387 (100, M + 1), 386 (6.6, M +), 369 (21.6, M-OH), 343 (50.7, M-C 3 H 7); UV? Max (methanol) nm: 199 (41,000), 270 (25,700), 306 (21,900); IR (KBr) cm "1: 3395 (broad, m, OH), 1734 (s) and 1707 (vs) (C = 0), 1644 (m), 1608 (vs), 1578 (vs) and 1547 (vs ): Calculated Analysis for C22H2606 1 / 3H20: C, 67.33; H, 6.84; Found: C, 67.43; H, 6.93. 6,6-Dimethyl-9-hydroxy-10- [2 (S *) -methyl-3 (R *) -hydroxybutyl] -4-propyl-2H, 6H-benzo [1,2-b: 3,4- b '] dipiran-2-one [anti- (+ _) 8b]. p.f. 115 ° C; XH NMR (CDC13): 1.05 (3H, t, J = 7.4 Hz, CH3), 1.25 (3H, d, J = 6.4 Hz, CH3), 1.29 (3H, d, J = 6.9 Hz, CH3), 1.54 ( 6H, s, 2 CH3), 1.66 (2H, apparent sextet, J = 7.6 Hz, CH2), 2.92 (2H, t, J = 7.8 Hz, CH2), 2.95 (1H, d, J = 5.5 Hz, OH) , 3.98 (1H, dq, J = 6.1 Hz, J = 6.8 Hz, H2), 4.22 (1H, apparent sextet, J = 6.2 Hz, H3), 5.59 (1H, d, J = 10.1 Hz, H7), 6.03 (1H, s, H3), 6.73 (1H, d, J = 10.1 Hz, H8), 14.25 (1H, s, OH); 1 H NMR (DMSO-de): 1.00 (3H, t, J = 7.3 Hz, CH3), 1.11 (6H, d, J = 6.7 Hz, 2 CH3), 1.49 (3H, s, CH3), 1.50 (3H, s, CH3), 1.60 (2H, apparent sextet, J = 7.3 Hz, CH2), 2.85, 2.90 (2H, type t-AB, J = 7.7 Hz, JAB = 21.4 Hz, CH2), 3.59 (1H, apparent quintet , J = 7.1 Hz, H2), 3.96 (1H, apparent quintet, J = 7.0 Hz, H3), 4.97 (1H, broad s, OH), 5.78 (1H, d, J = 10.1 Hz, H7), 6.10 ( 1H, s, H3), 6.63 (1H, d, J = 10.0 Hz, H8), 12.69 (1H, s, OH); MS (El): 387 (2.8, M + 1), 386 (9.4, M +), 371 (5.3, M-CH 3), 369 (1.5, M-OH), 353 (54.0, M-CH3-H20), 342 (22.5, M-C3H7-1), 327 (100, M-C3H7-OH + 1); UV? Max (methanol) nm: 199 (41,000), 270 (25,700), 306 (21,900); IR (KBr) cm "1: 3478 (broad, m, OH), 1736 (vs) and 1707 (vs) (C = 0), 1645 (m), 1603 (vs), 1584 (vs, sh): Analysis Calculated for C22H2606 1 / 3H20: C, 67.33; H, 6.84; Found: C, 67.34; H, 6.45.

EXAMPLE 16 Reaction of Aldol (Reaction Scheme III) of Chromeno 4 in the Presence of LDA / TiCl4 In this Example, two procedures are provided for effecting the Aldol reaction. Process B was found to be more suitable to progressively increase due to the simplification of temperature control.

Procedure A. To a stirring solution of chromene 4 (200 mg, 0.58 mmol) in dry methylene chloride (10 ml) at -78 ° C under N2 was added a 2 M solution of LDA in heptane / THF / ethylbenzene (0.64). ml, 1.28 mmol). The reaction mixture was stirred at -78 ° C for 30 minutes and then TiCl 4 (0.13 mL, 1.17 mmol) was added. The resulting yellow solution was warmed to -40 ° C and stirred for 45 minutes. The mixture was re-cooled to -78 ° C, and acetaldehyde (150 mg, 3.5 mmol) was added via syringe. After 4 hours, the reaction was rapidly quenched by slow addition of NH4C1 saturated, pre-cooled (10 ml). Water was added (3 ml) to dissolve the oily solid. The mixture was extracted with ethyl acetate (50 ml x 3). The combined extracts were washed with brine (100 ml) and dried over MgSO4. The crude product obtained by evaporation was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (5: 1) to yield unreacted chromene 4 (30 mg, 15% yield) and syn- (+) -8a (140 mg, 61% yield), which contained 7% of an t i- (+ _) -8b as shown by CLAP.

Procedure B. To a stirring solution of chromene 4 (20 g, 58.4 mmol) in dry methylene chloride (300 ml) at -40 ° C under N2 was added TiCl 4 (19 ml, 175 mmol). The mixture was then cooled to -78 ° C, followed by slow addition of 2 M solution of LDA in heptane / THF / et il-benzene (64 mL, 128 mmol). After 30 minutes at the same temperature, acetaldehyde (9 ml, 175 mmol) was added via syringe. The reaction mixture was stirred at -78 ° C for 2 hours. Analysis of TLC (hexane / ethyl acetate, 5: 1) indicated that about 90% of chromene 4 has been converted. The mixture was then poured into saturated, pre-cooled NH C1 (240 ml). Water (120 ml) was added to dissolve the oily solid and the mixture was stirred for 20 minutes. The layers were separated and the aqueous solution was extracted with ethyl acetate (600 ml x 3). The combined extracts were washed with brine (600 ml) and dried over MgSO4. The solvent removal in va cuo produced a reddish oil (23 g), which was extracted into ether (250 ml). The undissolved residue was filtered and the ether solution was concentrated to half the volume and then added slowly with stirring of rapidly-cooled hexane at -78 ° C. In this way the formed precipitates were collected by filtration to produce syn - (+) - 8a (11.1 g, 49% yield), which contained 4% of (+ _) -8b as shown by CLAP.

EXAMPLE 17: Enzymatic Resolution of syn- (+) -8a (Reaction Scheme III) To a stirred solution of syn-. { + _) -8a (7.6 g, 19.7 mmol) in tert-butyl methyl ether (130 ml) at room temperature under N2 was added successively vinyl acetate (33 ml), molecular sieve of 4 Á (17 g) and Lipase PS-30 (3.8 g) (Amano Enzyme USA Co., Ltd., Troy, VA). The resulting mixture was stirred vigorously at room temperature for 4 days, after which it was filtered through celite and the celite was washed with ethyl acetate (20 ml). The crude product obtained from the evaporation was subjected to column chromatography on silica gel eluting with a discontinuous gradient of 5%, 10%, 15%, 25%, 30% and 40% ethyl acetate in hexane to yield 4.8 g. (63% yield) of acetate (9), which was contaminated by over-acylation of the product of (+) - 8a, and 2.8 g (37% yield) of pure syn- (+) - 8a. 6,6-Dimethyl-9-hydroxy-10- [2 (R) -methyl-3 (S) -hydroxybutyl] -4-propyl-2H, 6H-benzo [l, 2-b: 3,4-b ' ] dipiran-2-one [syn- (+) 8a]. p.f. 82-85 ° C; [a] 25D = 0 ° (CHC13, c 0.7; [a] 25D = 0 ° (CHC13, c 0.35); XH NMR (CDC13): 1.05 (3H, t, J = 7.4 Hz, CH3), 1.31 (3H , d, J = 5.6 Hz, CH3), 1.33 (3H, d, J = 6.9 Hz, CH3), 1.54 (6H, s, 2 CH3), 1.67 (2H, apparent sextet, J = 7.6 Hz, CH2), 2.75 (1H, broad s, OH), 2.91 (2H, t, J = 7.8 Hz, CH2), 3.98 (1H, dq, J = 2.7 Hz, J = 7.0 Hz, H2), 4. 30 (1H, dq, J = 2.7 Hz, J = 6.5 Hz, H3), 5.59 (1H, d, J = 10.2 Hz, H7), 6.01 (1H, s, H3), 6.72 (1H, d, J = 10.3 Hz, H8), 14.10 (1H, s, OH); 13 C NMR (CDC13); 10.42 (CH3), 14.00 (CH3), 20.61 (CH3), 23.32 (CH2), 28.31 (2 CH3), 39.05 (CH2), 50.93 (CHCO), 68.03 (CH-O), 79.92 (C-O), 102.95 (C8a), 103.69 (C4a), 106.12 (C10), 110.60 (C3), 115.80 (C8), 126.51 (C7), 157.03 and 157.11 (C9 and C? Oa), 158.58 (C4b), 159.01 (C4), 163.13 (C02), 210.61 (C = 0); MS (Cl): 388 (33.4, M + 2), 387 (100, M + 1), 386 (8.5, M +), 369 (36.3, M-OH), 343 (97.2, M-C3H7); Analysis Calculated for C22H2606: C, 68.38; H, 6.78; Found: C, 68.02; H, 6.62.

EXAMPLE 18: 10 (R), 11 (R) -trans-Dihydro-6, 6, 10, 11-tetramethyl-4-propyl-2H, 6H, 12H-benzo- [1, 2- b: 3,4- b ': 5,6-b "] tripiran-2, 12-dione [Reaction Scheme III, (+) -7] To a stirring solution of syn- (+) - 8a (2.0 g, 5.2 mmol) in THF (50 mL) was added triphenylphosphine (1.9 g, 7.2 mmol) and diethyl azodicarboxylate (DEAD, 1.2 mL, 7.6 mmol) The resulting reddish solution was stirred at room temperature under N2 for 5 hours, after which it was cooled The reaction mixture was rapidly quenched with saturated aqueous NH4C1 (20 ml) and extracted with ethyl acetate (50 ml x 3) The combined extracts were washed with brine (50 ml) and dried over Na2SO.The crude product (5.8 g. ) obtained by evaporation was purified by column chromatography on silica gel eluting with a discontinuous gradient of 10%, 20%, 30% and 40% ethyl acetate in hexane to yield 1.2 g (63% yield) of (+ ) -7 pure, Mp 171-175 ° C; [a] 25D = + 37.9 ° (CHC13, c 0.73); XH NMR [CDCI3 / CD3OD (3: 1)]: 1.06 (3H, t, J = 7.3 Hz, CH3), 1.22 (3H, d, J = 7.0 Hz, CH3), 1.54 (3H, s, CH3), 1.57 (3H, d, J = 6.0 Hz, CH3), 1.58 (3H, s, CH3), 1.67 (2H, apparent sextet, J = 7.6 Hz, CH2), 2.59 (1H, dq, J = 6.9 Hz, J = ll.l Hz, Hn), 2.92 (2H, t, J = 7.8 Hz, CH2), 4.37 (1H, dq, J = 6.3 Hz, J = ll.l Hz, H? 0), 5.66 (1H, d, J = 10.1 Hz, H7), 6.05 (1H, s, H3), 6.67 (1H, d, J = 10.1 Hz, H8); 13 C NMR [CDC13 / CD30D (3: 1)]: d 9.87 (CH3), 13.34 (CH3), 18.97 (CH3), 22.85 (CH2), 27.40 and 27.73 (2 CH3), 38.38 (CH2), 46.82 (CHCO) ), 79.17 (CH-0 and C-0), 102.91 (C8a), 104.11 (C4a), 105.46 (C? 2a), 111.09 (C3), 115.21 (C8), 126.90 (C7), 154.83 and 155.86 (C8b) and C12b), 157.89 (C4b), 158.99 (C4), 160.27 (C02), 190.50 (C = 0); MS (Cl): 370 (49.0, M + 2), 369 (100, M + 1), 368 (17.2, M +); Analysis Calculated for C22H2405: C, 71.72; H, 6.57; Found: C, 71.46; H, 6.60.

(+) -Calanolide A: To a stirring solution of (+) - 7 (660 mg, 1.79 mmol) in ethanol (18 ml) were added CeCl3 (H20) 7 (2.7 g., 7.17 mmole) and triphenylphosphine oxide (2.0 g, 7.17 mmole). The mixture was stirred for 1 hour at room temperature under N2 and then cooled to -30 ° C with a dry ice bath of ethylene glycol / H20 (1: 2 w / w). After the temperature was equilibrated to -30 ° C, NaBH4 (271 mg, 7.17 mmol) was added and stirred at the same temperature for 5.5 hours, at which time the reaction was rapidly quenched with saturated NH4C1 (20 ml) and extracted with ethyl acetate (30 ml x 3). The combined extracts were washed with brine (50 ml) and dried over Na2SO4. The crude product obtained by solvent removal under reduced pressure was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield 520 mg (78% yield) of a mixture containing 90% of ( +) -calanolide A [(+) - l] and 10% (+) - calanolide B. The (+) -Calanolide A [(+) - l] was further separated from (-) -calanolide B by CLAP from normal phase and was identical with an authentic sample.

EXAMPLE 19: Enzymatic Resolution (Reaction Scheme IV) of anti- (+) - 8b To a stirred solution of an- ti- (+ _) -8b (3.0 g, 7.8 mmol) in tert-butyl methyl ether (78 mL) a At room temperature under N2, vinyl acetate (26 ml), a molecular sieve 4 Á (3.0 g) and Lipase PS-30 (1.5 g) were added successively (Amano Enzyme USA Co., Ltd., Troy, VA). The resulting mixture was stirred vigorously at room temperature for 41 hours, after which it was filtered through celite and the celite was washed with ethyl acetate (20 ml). The crude yellow solid product (3.2 g) obtained from the evaporation was purified by column chromatography on silica gel eluting with a discontinuous gradient of 5%, 10%, 15%, 25%, 30% and 40% ethyl acetate in hexane to yield 1.68 g (50% yield) of acetate (10) and 1.37 g (46% yield of an ti- (+) - 8b. 6,6-Dimethyl-9-hydroxy-10- [2 (S) -methyl-3 (S) -hydroxybutyl] -4-propyl-2H, 6H-benzo [l, 2-b: 3,4-b ' ] dipiran-2-one [an ti- (+) 8b]. p.f. 131-134 ° C; [a] 25D = + 45.3 ° (CHC13, c 0.72); TR NMR (CDCl3): 1.06 (3H, t, J = 7.3 Hz, CH3), 1.25 (3H, d, J = 6.6 Hz, CH3), 1.29 (3H, d, J = 6.7 Hz, CH3), 1.55 ( 6H, s, 2 CH3), 1.67 (2H, apparent sextet, J = 7.6 Hz, CH2), 2.92 (2H, t, J = 7.8 Hz, CH2), 2.96 (1H, d, J = 7.1 Hz, OH) , 3.98 (1H, apparent quintet, J = 6.1 Hz, H2), 4.22 (1H, apparent sextet, J = 6.0 Hz, H3), 5.60 (1H, d, J = 10.1 Hz, H7), 6.03 (1H, s , H3), 6.73 (1H, d, J = 10.1 Hz, H8), 14.25 (1H, s, OH); MS (Cl): 388 (41.4, M + 2), 387 (100, M + 1), 386 (13.0, M "), 369 (42.8, M-OH), 343 (63.8, M-C3H7); calculated for C22H2606: C, 68.38; H, 6.78; Found: C, 68.50, H, 6.91. 6, 6-Dimethyl-9-hydroxy-10- [2 (R) -methyl-3 (R) -ace toxibu iro] -4-propyl-2H, 6H-benzo [1,2-b: 3,4- b '] dipiran-2 -one [anti-. { +) -10]. p.f. 61-64 ° C; [a] 25D = + 30.0 ° (CHC13, c 0.73); XH NMR (CDC13): 1.06 (3H, t, J = 7.2 Hz, CH3), 1.29 (3H, d, J = 6.2 Hz, CH3), 1.32 (3H, d, J = 6.7 Hz, CH3), 1.54 ( 6H, s, 2 CH3), 1.67 (2H, apparent sextet, J = 7.6 Hz, CH2), 1.93 (3H, s, CH3CO), 2.91 (2H, m, CH2), 4.18 (1H, dq, J = 8.3 Hz, J = 6.9 Hz, H2), 5.34 (1H, dq, J = 8.2 Hz, J = 6.4 Hz, H3), 5.59 (1H, d, J = 10.1 Hz, H7), 6.02 (1H, s, H3) ), 6.73 (1H, d, J = 10.1 Hz, H8), 14.02 (1H, s, OH); MS (Cl): 430 (37.1, M + 2), 429 (95.2, M + 1), 428 (7.2, M +), 369 (100, M-AcO); Analysis calculated for C24H2807: C, 67.28; H, 6.59; Found: C, 67.75, H, 6.90.

EXAMPLE 20: 5, 7-Dihydroxy-4-trifluoromethylcoumarin (Reaction Scheme V, lia, R? = CF3, R2 = H) To a mixture of anhydrous floroglucinol (8 g, 63.0 mmol) and 4, 4, 4-trifluoroacetoacetate of ethyl (12 g, 65.0 mmol) was added concentrated H2SO4 (11 mL). The resulting mixture was heated to 100 ° C and stirred for 2 hours, after which the reaction mixture was cooled to room temperature. Ice (100 g) and H20 (150 ml) were then added while cooling with an ice bath. The precipitated product was collected and dissolved in AcOEt (100 ml), which was washed with H20 and dried over Na2SO4. The crude product (16 g) obtained by evaporation under vacuum was subjected to chromatography in methylene chloride-ethanol (95: 5) to provide lia (6 g, 39% yield) together with another unidentified product. lia: p.f. 250-252 ° C after recrystallization from methylene-hexane chloride. 1 H NMR (DMSO-d6): 6.30 (1H, s, H3), 6.33 and 6.54 (2H, 2 s, H7 and H8), 10.68 and 10.99 (2H, 2 s, 2 OH); MS (Cl) m / z: 246 (100, M +), 226 (14.6, M-HF), 218 (10.0, M-CO), 198 (59.6, M-HF-CO); IR (KBr) cm "1: 3537 (m, sh) and 3384 (s, broad, OH), 1709 (s, C = 0), 1618 (s, C = CC = 0), 1154 (s, CF); Calculated Analysis for C? 0H5F3? 4: C, 48.80; H, 2.05; Found, C, 48.83; H, 2.10.

EXAMPLE 21: 5, 7-Dihydroxy-8-isobutyryl-4-propylcoumarin (Reaction Scheme V, 12a, R? = N-Pr, R2 = H, R3 = R4 = Me) It was placed on a round-bottomed matrass of 3 cue l l of 500 ml of flame s 5, 7-dihydroxy-4-propylcoumarin (2, 10.0 g, 48.1 mmoles) and A1C13 (12.0 g, 90 mmoles) under N2. Then dichloroethane (120 ml) was added, and the solution was heated to 75 ° C with a water bath with mechanical stirring. After 15 minutes of stirring at 75 ° C, a homogeneous solution was obtained. To this solution was added a mixture of isobutyric anhydride (7.61 g, 48.1 mmol) and A1C13 (12.0 g) in dichloroethane (60 ml) dropwise over 1 hour. After the addition was complete, the solution was stirred for an additional 1 hour at 75 ° C, then cooled to room temperature. The solution was poured into a mixture of crushed ice (100 g) and 2 N HCl (100 ml), at which point a white precipitate formed. The mixture was diluted with ethyl acetate (1.8 1), and the organic layer was separated. The organic solution was washed sequentially with 1 N HCl (500 ml) and saturated brine (500 ml), dried over magnesium sulfate, filtered and evaporated to give an orange powder. The powder was triturated with acetone (80 ml), collected on a Büchner funnel, rinsed with diethyl ether (80 ml) and dried to give a cream colored solid (4.22 g). The product was then purified by recrystallization from ethanol (200 ml) to give colorless plates (3.63 g, 26.0%); p.f. 263-265 ° C, with softening at 250 ° C (Lit.65 272-273 ° C); XH NMR (DMSO-d6): 0.95 (3H, t, J = 7.4 Hz, CH3), 1.08 (6H, d, J = 6.9 Hz, 2 CH3), 1.59 (2H, sextet, J = 7.4 Hz, CH2) , 2.87 (2H, t, J = 7.4 Hz, CH2), 3.24 (1H, heptet, J = 6.9 Hz, CH), 5.93 (1H, s, H3), 6.37 (1H, s, H6), 11.16 and 11.44 (2H, 2 s, 2 OH); EMEI: 290 (23.2, M +), 247 (100, M-C3H7), 219 (11.1, M-C3H7CO); IR (KBr) cm "1: 3216 (s, OH), 1684 (s, C = 0); Analysis calculated for C? 6H1805: C, 66.20; H, 6.25. Found: C, 66.15; H, 6.21.

EXAMPLE 22: 6, 6-Dimethyl-9-hydroxy-10-isobutyryl-4-propyl-2H, 6H-benzo [1, 2-b: 3, 4-b '] dipyran-2-one (Reaction Scheme V , 13a, R? = N-Pr, R2 = R7 = H, R3 = R4 = R5 = Me) To a solution of 12a (2.90 g, 10.0 mmol) in pyridine (5 ml) was added 4, 4-dimethoxy- 2-methylbutan-2-ol (1.49 g, 10.1 mmol), and the solution was heated to reflux. After heating for 40 hours, the CCF indicated the complete consumption of the initial material. The reaction was cooled to room temperature and the pyridine was removed in vacuo. The dark colored residue was dissolved in ethyl acetate (50 ml) and washed sequentially with 2 N HCl (50 ml x 2), 5% NaHCO 3 (50 ml) and saturated brine (50 ml). The solution was dried over magnesium sulfate, filtered and evaporated to give a dark orange solid, which was chromatographed on a column of silica gel (125 g) and eluted with ethyl acetate / hexane (1: 4). ) to produce the pure product as a bright orange crystalline solid (2.51 g, 70.5%); p.f. 70-72 ° C; NMR? H (CDC13): 1.05 (3H, t, J = 7.3 Hz, CH3), 1.26 (6H, d, J = 6.7 Hz, 2 CH3), 1.54 (6H, s, 2 CH3), 1.66 (2H, sextet, J = 7.7 Hz, CH2), 2.91 (2H, t, J = 7.7 Hz, CH2), 4.06 (1H, heptet, J = 6.7 Hz, CH), 5.58 (1H, d, J = 9.9 Hz, H7 ), 6.01 (1H, s, H3), 6.73 (1H, d, J = 9.9 Hz, H8), 14.45 (1H, s, OH); EMEI: 356 (48.0, M +), 341 (100, M-CH3), 313 (65.0, M-C3H7); IR (KBr) cm "1: 1732; Analysis calculated for C2? H240s: C, 70.77; H, 6.79. Found: C, 70.73; H, 6.78.

EXAMPLE 23: (+) - 6, 6-Dimethyl-10- (2,2-dimethyl-3-hydroxybutyl) -9-hydroxy-4-propyl-2H, 6H-benzo [1,2-b: 3, 4 -b '] dipyran-2-one (Reaction Scheme V, 14a, R? = n-Pr, R3 = R4 = R5 = R6 = R9 = Me) To a solution of 13a (1.25 g, 3.51 mmol) in Anhydrous THF (20 ml) under N2 at -78 ° C was added LDA (2.0 M in heptane / THF / ethylbenzene, 4.39 ml, 8.78 mmol) dropwise, and the resulting red solution was stirred for 1 hour. A solution of acetaldehyde (1.54 g, 35.1 mmol) in THF (6 mL) was added dropwise, and the reaction mixture was stirred at -78 ° C for 3 hours after which the reaction was rapidly quenched by slowly adding Ethanolic HCl 2.5 M (10 ml), and the solution was then allowed to warm to room temperature. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and saturated NaHCO 3 (100 ml). The organic layer was collected and washed with saturated brine (100 ml), dried over magnesium sulfate, filtered and evaporated to give a brown solid. The product was triturated with ethyl acetate / hexane (1: 1, 15 ml), collected on a Büchner funnel, rinsed with fresh solvent and dried by air to give the desired product as a white powder (6.54 mg, 46.6%). An analytical sample was obtained by recrystallization from ethyl acetate / hexane (1: 1); p.f. 190-191 ° C; NMR? R (CDC13): 1-04 (3H, t, J = 7.4 Hz, CH3), 1.25 (3H, s, CH3), 1.29 (3H, d, J = 6.4 Hz, CH3), 1.33 (3H, s, CH3), 1.48 (3H, s, CH3), 1.52 (3H, s, CH3), 1.66 (2H, sextet, J = 7.5 Hz, CH2), 2.39 (1H, broad s, OH), 2.88 (m, 2H, CH2), 4.47 (1H, q, J = 6.4 Hz, CH), 5.56 (1H, d, J = 10.0 Hz, H7), 5.92 (1H, s, H3), 6.64 (1H, d, J = 10.0 Hz, H8), 8.99 (1H, s, OH): 400 (1.1, M "), 356 (37.5, M -C2H40), 341 (100, M-CH3-C2H40), 313 (68.2, M-C3H7-C2H40); IR (KBr) cm "1: 3246 (s broad, OH), 1686 (s, C = 0); Analysis calculated for C23H28? 6; C, 68.98; H, 7.05; Found, C, 69.03; H, 6.99.

EXAMPLE 24: (+) - 6,6-Dimethyl-10- (2,3-dimethyl-3-hydroxybutyl) -9-hydroxy-4-propyl-2H, 6H-benzo [1, 2-b: 3, 4 -b '] dipyran-2-one (Reaction Scheme V, 14b, R? = n-Pr, R2 = R3 = R7 = H, R4 = sR5 = R6 = R8 = R9 = Me) To a suspension of 4 ( 1.2 g, 3.50 mmol) in THF (16 mL) at -78 ° C was added a solution of LDA in heptane / THF / et il-benzene (2 M, 5.0 mL, 10.0 mmol) dropwise under N2. The solution was stirred at -78 ° C for 1 hour and acetone (2.0 ml, 27.2 mmol) was added rapidly via syringe. The solution was stirred at -78 ° C for 3 hours, cooled rapidly with methanolic HCl (2M, 15 ml) at -78 ° C, then allowed to warm to room temperature. The reaction mixture was concentrated and partitioned between ethyl acetate (150 ml) and saturated NaHCO 3 (100 ml). The organic layer was collected and washed with saturated brine (50 ml), dried over magnesium sulfate, filtered and concentrated to give a red oil (1.36 g), an analytical sample of which was obtained by means of column chromatography. on silica gel (ethyl acetate / hexane, 1: 4) as an off-white solid: mp 99-102 ° C; XH NMR (CDC13): 1-05 (3H, t, J = 7.3 Hz, CH3), 1. 29 (3H, s, CH3), 1.32 (3H, s, CH3), 1.39 (3H, d, J = 6.8 Hz, CH3), 1.55 (6H, s, 2 CH3), 1.67 (2H, sextet, J = 7.7 Hz, CH2), 2.91 (2H, t, J = 7.7 Hz, CH2), 3.52 (1H, s broad, OH), 4.03 (1H, q, J = 6.8 Hz, CH), 5.60 (1H, d, J = 9.9 Hz, H7), 6.03 (1H, s, H3), 6.73 (1H, d, J = 10.1 Hz, H8), 13.81 (1H, s, OH); EMEI: 401 (5.1, M + l), 400 (21.5, M +), 385 (6.2, M-CH3), 342 (38.9, M-C3H70 + 1), 327 (100, M-CH3-C3H70 + 1); IR (KBr) cm "1: 3547 (w, OH), 3449 (vw, broad, OH), 1734 (vs, C = 0); Analysis calculated for C23H2806: C, 68.98; H, 7.04. Found: C, 68.98; H, 7.04.

EXAMPLE 25: (+) -syn and (+) -ant ± - 6,6-Dimethyl-9-hydroxy-10- (2-methyl-3-hydroxypentanoyl) -4-propyl-2H, 6H-benzo [l, 2-b: 3, 4-b '] dipyran-2-one (Reaction Scheme V, 14c, R? = N-Pr, R2 = R3 = R7 = R8 = H, R4 = R5 = R6 = Me, R9 = Et) To a solution of 4 (1.75 g, 5.11 mmol) in THF (27.0 ml) at -78 ° C was added dropwise a solution of LDA in heptane / THF / et il-benzene (2 M, 7.0 ml, 14. 0 mmole) under N2. The solution was stirred at -78 ° C for 1 hour, and propionaldehyde was added quickly (2.2 ml, 31.2 mmol) by means of a syringe. The solution was stirred at -78 ° C for 3 hours, quenched with methanolic HCl (2 M, 25 ml) at -78 ° C, then warmed to room temperature. The mixture was extracted with ethyl acetate (350 ml), washed sequentially with 150 ml of each saturated NaHCO 3 and saturated brine, dried over magnesium sulfate, filtered and concentrated to provide a diastereomeric mixture of the product as a red oil ( 2.44 g, 100%), which was not further purified and used for the next stage.

EXAMPLE 26: (+) -10, 11-Dihydro-6, 6, 10, 11, 11-pentamethyl-4-propyl-2H, 6H, 12H-benzo [1,2-b: 3, 4-b ': 5, 6-b "] tripiran-2, 12-dione (Reaction Scheme V, 15a, R? = N-Pr, A solution of 14a (0.5 g, 1.25 mmol) and triphenylphosphine (492 mg, 1.88 mmol) in THF (10 ml), a solution of diethyl azodicarboxylate was added (327 mg, 1.88 mmol) in THF (2 ml) dropwise under N2. The reaction mixture was stirred for 2.5 hours, after which it was poured into saturated NH4C1 (100 ml). The solution was extracted with ethyl acetate (100 ml), and the separated organic layer was washed sequentially with H20 (100 ml) and saturated brine (100 ml). After drying over magnesium sulfate, the solution was filtered and concentrated in vacuo to give a yellow oil. Column chromatography through 75 g of silica gel (ethyl acetate / hexane, 1: 2) gave the desired product as a white crystalline solid (449 mg, 94.0%). An analytical sample was obtained by recrystallization from ethyl acetate / hexane (2: 1): m.p. 157 ° C, NMR? H (CDC13): 1.03 (3H, t, J = 7.3 Hz, CH3), 1.09 (3H, s, CH3), 1.19 (3H, s, CH3), 1.43 (3H, d, J = 6.5 Hz, CH3), 1.53 (3H, s, CH3), 1.55 (3H, s, CH3), 1.64 (2H, sextet, J = 7.7 Hz, CH2), 2.88 (2H, t, J = 7.7 Hz, CH2), 4.34 (1H, q, J = 6.4 Hz, H10), 5.60 (1H, d, J = 10.0 Hz, H7), 6.04 (1H, s, H3), 6.66 (1H, d, J = 10.0 Hz , H8); MSEI: 382 (60.8, M +), 367 (100, M-CH3), 312 (50.3 M-C5H10), 297 (74.5 M-CH3-C5H? 0); IR (KBr) cm "1: 1730 (vs, C = 0); Analysis calculated for C23H2605: C, 72.23; H, 6.85, Found: C, 72.35; H, 6.90.

EXAMPLE 27: (+) -10, 11-Dihydro-6, 6, 10, 10, 11-pentamethyl-4-propyl-2H, 6H, 12H-benzo [1, 2-b: 3, 4-b ': 5, 6-b "] tripiran-2, 12-dione (Reaction Scheme V, 15b, R? = N-Pr, R2 = R3R7 = H, R4 = 5 = Rg = Rg = Rg = M) To one solution of crude 14b (980 mg, 2.19 mmol) and triphenylphosphine (859.0 mg, 3.28 mmol) in THF (15 ml) was slowly added diethyl azodicarboxylate (DEAD, 0.50 ml, 3.17 mmol) under N2 The red solution was stirred for 2.5 hours at room temperature, then quenched with saturated NH4C1 (10 ml) The solution was extracted with ethyl acetate (200 ml), washed sequentially with 50 ml of each H20 and saturated brine, dried over magnesium sulfate, it was filtered and concentrated to give a yellow residue (2.37 g). Purification by column chromatography on silica gel (ethyl acetate / hexane, 1:10) provided, after drying overnight under high vacuum in the presence of P20s. , the desired product as a white solid uecino (373.7 mg, 44.6%): p.f. 140-141 ° C; XH NMR (CDC13): 1-03 (3H, t, J = 7.3 Hz, CH3), 1.19 (3H, d, J = 7.0 Hz, CH3), 1.34 (3H, s, CH3), 1.53 (6H, s , 2 CH3), 1.55 (3H, s, CH3), 1.65 (2H, sextet, J = 7.8 Hz, CH2), 2.72 (1H, q, J = 7.0 Hz, H ??), 2.85-2.91 (2H, m, CH2), 5.60 (1H, d, J = 10.1 Hz, H7), 6.03 (1H, s, H3), 6.65 (1H, d, J = 10.0 Hz, H8); MSEI: 382 (61.2, M +), 367 (82.0, M-CH3), 312 (46.0, M-C5H10), 297 (100, M-CH3-C5H10); IR (KBr) cm "1: 1728 (vs, C = 0); Analysis calculated for C23H2605: C, 72.23; H, 6.85, Found: C, 71.95; H, 6.88.

EXAMPLE 28: (+) -10, 11-trans-10, 11-Dihydro-10-ethyl-4-propyl-6, 6, 11-trinyl-ethyl-2H, 6H, 12H-benzo [1, 2- b : 3, 4-b "] tripiran-2, 12 -dione (15c) and (+) - 10, ll-cis-10, 11-Dihydro-10-ethyl-4-propyl- 6,6, 11-trimethyl -2H, 6H, 12H-benzo [1, 2-b: 3, 4- b ': 5, 6-b "] tripiran-2, 12-dione (15d, Reaction Scheme V) To a solution of 14c ( 2.44 g, 5.11 mmol) and triphenylphosphine (1.96 mg, 7.48 mmol) in THF (30.0 mL) was slowly added diethyl azodicarboxylate.

(DEAD, 1.16 ml, 7.37 mmol) under N2. The red solution was stirred for 2.5 hours at room temperature, then quenched with saturated NH C1 (22 ml). The solution was warmed to room temperature and extracted with ethyl acetate (400 ml), washed with H20 (100 ml) and brine (100 ml) and dried over magnesium sulfate. After filtration, the solution was concentrated in vacuo to give a yellow residue (5.75 g). The crude product was purified by repetitive silica gel column chromatography (3X) using ethyl acetate / hexane (1: 4.5) as eluent. The desired fractions were combined, concentrated in vacuo and dried under high vacuum overnight in the presence of P20s to yield 15c (765.4 mg, 39.2%) and 15d (350.4 mg, 17.9%). 15c (R? = N-Pr, R2 = R = R7 = R8 = H, R3 = R5 = R6 = Me, R9 = Et): p.f. 155-158 ° C; XH NMR (CDC13): 1-03 (3H, t, J = 7.4 Hz, CH3), 1.13 (3H, t, J = 7.4 Hz, CH3), 1.22 (3H, d, J = 6.9 Hz, CH3), 1.53 (3H, s, CH3), 1.56 (3H, s, CH3), 1.64 (2H, sextet, J = 7.6 Hz, CH2), 1.78-1.95 (2H, m, CH2), 2.62 (1H, dq, J = 10.4 Hz, J = 7.0 Hz, Hn), 2.88 (2H, t, J = 7.7 Hz, CH2), 4.14 (1H, ddd, J = 3.5 Hz, J = 7.8 Hz, J = 10.7 Hz, H10), 5.61 (1H, d, J = 10.0 Hz, H7), 6.04 (1H, s, H3), 6.66 (1H, d, J = 10.0 Hz, H8); MSEI: 382 (37.2, M +), 367 (100, M-CH3), 297 (47.2, M-CH3-C5H? O); IR (KBr) cm "1: 1738 (vs, C = 0); Analysis calculated for C23H2605: C, 72.23; H, 6.85, Found: C, 71.75; H, 7.02. 15d (R? = N-Pr, R2 = R3 = R7 = R8 = H, R4 = R5 = R6 = Me, R9 = Et): p.f. 100-102 ° C; XH NMR (CDC13): 1.03 (3H, t, J = 7.3 Hz, CH3), 1.07 (3H, t, J = 7.4 Hz, CH3), 1.14 (3H, d, J = 7.3 Hz, CH3), 1.54 ( 3H, s, CH3), 1.55 (3H, CH3), 1.65 (2H, sextet, J = 7.6 Hz, CH2), 1.83-1.98 (2H, m, CH2), 2.70 (1H, dq, J = 3.2 Hz, J = 7.3 Hz, Hu), 2.88 (2H, t, J = 7.6 Hz, CH2), 4.39 (1H, ddd, J = 3.4 Hz, J = 5.3 Hz, J = 8.8 Hz, H? O), 5.60 ( 1H, d, J = 10.0 Hz, H7), 6.05 (1H, s, H3), 6.66 (1H, d, J = 10.0 Hz, H8); MSEI: 382 (55.0, M +), 367 (100, M-CH3), 297 (52.7, M-CH3-C5H10); IR (KBr) c "1: 1732 (vs, C = 0); analysis calculated for C23H2605: C, 72.23; H, 6.85, Found: C, 71.80; H, 6.97.

EXAMPLE 29: (+) -10, ll-cis-10, 11-Dihydro-12-hydroxy-6, 6, 10, 11, 11-pentamethyl-4-propyl-2H, 6H, 12H-benzo [1, 2 -b: 3, 4-b ': 5, 6-b "] tripiran-2-one (16a) and (+) - 10, 11-trans-10, 11-dihydro-12-hydroxy-6,6, 10, 11, 11-pentamethyl-4-propyl-2H, 6H, 12H-benzo [1, 2-b: 3, 4-b ': 5, 6-b "] - tripyrhan-2-one (16b, Scheme Reaction V) To a solution of 15a (252 mg, 0.661 mmol) in ethanol / THF (1: 1, 8 ml) was added sodium borohydride (25.1 mg, 0.661 mmol) and the solution was stirred at room temperature for 30 minutes. minutes The reaction was quenched by the addition of water (1 ml), and the solvent was then removed in vacuo. The residue was partitioned between 20 ml of each of ethyl acetate and 1 M HCl, and the organic phase was separated and washed sequentially with 50% NaHCO 3 and saturated brine. After drying over magnesium sulfate, the solution was evaporated to give the product as a pale yellow foam. The analysis of CCF (ethyl acetate / hexane, 1: 2) showed the two epimeric alcohols 16a and 16b at Rf 0.30 and 0.25, as well as a minor impurity at Rf 0.55. Separation by column chromatography (75 g of silica gel, ethyl acetate / hexane, 1: 2) provided 16a (127.7 mg, 50.3%) and 16b (18.8 mg, 7.4%) as a white foam and a whitish waxy solid, respectively. 16a (R? = N-Pr, R2 = R7 = R8 = H, R3 = R4 = R5 = R6 = R9 = Me): 1H NMR (CDCl3): 1-04 (3H, t, J = 7.3 Hz, CH3 ), 1.06 (6H, s, 2 CH3), 1.40 (3H, d, J = 6.7 Hz, CH3), 1.47 (3H, s, CH3), 1. 50 (3H, s, CH3), 1.66 (2H, sextet, J = 7.3 Hz, CH2), 2.80-2.99 (2H, m, CH2), 3.39 (1H, d, J = 3.2 Hz, OH), 3. 99 (1H, q, J = 6.7 Hz, H? 0), 4.70 (1H, d, J = 3.2 Hz, H? 2), 5.54 (1H, d, J = 9.9 Hz, H7), 5.94 (1H, s, H3), 6.63 (1H, d, J = 9.9 Hz, H8, EMEI: 384 (59.0, M ") , 369 (100, M-CH3), 314 (44.7, M-C5H? 0), 299 (88.8, M-CH3-C5H? O); IR (KBr) cm "1: 3432 (broad s, OH), 1734 (vs, C = 0); Analysis calculated for C23H2805: C, 71.85; H, 7.34.

Found: C, 71.74; H, 7.43. 16b (R? = N-Pr, R2 = R7 = R8 = H, R3 = R4 = R5 = R6 = R9 = Me): RMN ^ H (CDCl3): 0.78 (3H, s, CH3), 1.04 (3H, t, J = 7.3 Hz, CH3), 1.11 (3H, s, CH3), 1.36 (3H, d, J = 6.5 Hz, CH3), 1.49 (6H, s, 2 CH3), 1.64 (2H, m, CH2 ), 2.47 (1H, broad s, OH), 2.89 (2H,, CH2), 4.35 (1H, q, J = 6.5 Hz, H? O), 4.63 (1H, broad s, H? 2), 5.54 ( 1H, d, J = 9.8 Hz, H7), 5.96 (1H, s, H3), 6.65 (1H, d, J = 9.8 Hz, H8); EMEI: 384 (40.7, M +), 369 (100, M-CH3), 314 (13.5, M-C5H10), 299 (48.4, M-CH3-C5H? 0); Analysis calculated for C23H2805: C, 71.85; H, 7.34. Found: C, 71.79; H, 7.49.

EXAMPLE 30: (+) - 11, 12-cis-10, 11-Dihydro-12-hydroxy-6,6,10,10, 11-pentamethyl-4-prqpil-2H, 6H, 12H-benzo [1, 2 -b: 3, 4-b ': 5, 6-b "] tripiran-2-one (16c) and (+) - ll, 12-trans-10, 11-dihydro-12-hydroxy-6,6, 10, 10, 11-pentamethyl-4-propyl-2H, 6H, 12H-benzo [1, 2-b: 3, 4-b ': 5, 6-b "] - tripyrn-2-one (16d, Scheme Reaction V) To a solution of 15b (289.7 mg, 0.75 mmol), triphenylphosphine oxide (927.0 mg, 3.33 mmol) and CeCl3 (H20) 7 (842.0 mg, 2.25 mmol) in ethanol (15 ml) at 0 ° C NaBH4 (195.0 mg, 5.15 mmol) was added slowly under N2. The suspension was stirred for one hour at room temperature, then quenched with saturated NH 4 Cl (30 ml). The solution was extracted with ethyl acetate (200 ml), washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated to yield a pink crystalline solid (1.38 g). Column chromatography on silica gel (ethyl acetate / hexane, 1: 5) gave 16c (100.0 mg, 34.3%) as off-white foam and 16d which was further purified by preparative TLC (silica gel, diethyl ether / hexane, 2). : 1) as whitish foam (56.0 mg, 19.2%). 16c (Rx = n-Pr, R2 = R3 = R7 = H, R4 = R5 = R6 = R8 = R9 = Me): p.f. 44-45 ° C; XH NMR (CDC13): 1.04 (3H, t, J = 7.3 Hz, CH3), 1.24 (3H, d, J = 7.1 Hz, CH3), 1.38 (3H, s, CH3), 1.45 (3H, s, CH3), 1.47 (3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, sextet, J = 7.3 Hx, CH2), 1.96-2.04 (1H, m, HX1), 2.8- 3.0 ( 2H, m, CH2), 3.02 (1H, d, J = 4.0 Hz, OH), 4.94 (1H, t, J = 4.2 Hz, H? 2), 5.53 (1H, d, J = 10.0 Hz, H7) , 5.94 (1H, s, H3), 6.65 (1H, d, J = 9.9 Hz, H8); EMEI: 385 (22.1, M + l), 384 (61.8, M "), 369 (71.1, M-CH3), 351 (29.5, M-CH3-H20), 299 (100, M-CH3-C5H? O); (KBr) cm "1: 3451 (broad m, OH), 1709 (s, C = 0); Analysis calculated for C23H2805: C, 71.85; H, 7.33. Found: C, 71.63; H, 7.64. 16d (R? = N-Pr, R2 = R4 = R7 = H, R3 = R5 = R6 = R8 = R9 = Me): p.f. 40-42 ° C; X H NMR (CDCl 3): 1.04 (3 H, t, J = 7.3 Hz, CH 3), 1.13 (3H, d, J = 7.0 Hz, CH3), 1.21 (3H, s, CH3), 1.46 (3H, s, CH3), 1.48 (3H, s, CH3), 1.52 (3H, s, CH3), 1.67 (2H, sextet, J = 7.6 Hz, CH2), 2.03 (1H, quintet, J = 7.2 Hz, H ??), 2.8-3.0 (2H, m, CH2), 3.66 (1H, s, OH), 4.69 (1H, d, J = 7.4 Hz, H? 2), 5.54 (1H, d, J = 10.0 Hz, H7), 5.94 (1H, s, H3), 6.63 (1H, d, J = 9.9 Hz, H8); EMEI: 385 (8.7, M + l), 384 (36.0, M +), 369 (65.8, M-CH3), 351 (17.6, M-CH3-H20), 299 (100, M-CH3-C5H? O); IR (KBr) cm "1: 3437 (w, OH), 1734 (s, C = 0); Analysis calculated for C23H2805: C, 71.85; H, 7.33. Found: C, 71.70; H, 7.56.

EXAMPLE 31: (+) -10, 11-trans-ll, 12-cis-10, 11-Dihydro-10-ethyl-12-hydroxy-4-propyl-6,6, ll-trimethyl-2H, 6H, 12H -benzo [l, 2-b: 3,4-b ': 5,6-b "] - tripiran-2-one (16e) and (+) -10, 11-trans-11, 12-trans-10 , 11-dihydro-10-ethyl-12-hydroxy-4-propyl-6,6, 11-trimethyl-2H, 6H, 12H-benzo [1, 2-b: 3, 4-b ': 5, 6 b "] -tripiran-2-one (16f, Reaction Scheme V) To a suspension of 15c (454.7 mg, 1.19 mmol), triphenylphosphine oxide (1.38 g, 4.96 mmol) and CeCl3 (H20) 7 (1.21 g, 3.25 mmol) in ethanol (10 ml) at 0 ° C NaBH4 (312.0 mg, 8.25 mmol) under N2 was slowly added. The suspension was stirred for 3 hours at room temperature. The reaction mixture was quenched with saturated NH4C1 (15 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give pink crystals (1.97 g). Column chromatography on silica gel (ethyl acetate / hexane, 1: 4) yielded a yellow oil, which consisted of the mixture of 16e and 16f (261.0 mg). Compounds were separated using preparative CLAP (normal phase, ethyl acetate / hexane, 3: 7). The desired fractions were combined and concentrated in vacuo and dried overnight under high vacuum in the presence of P205 to yield 16e (yellow oil, 46.5 mg, 10.1%) and 16f (white solid, 137.6 mg, 30.1%). 16e (R? = N-Pr, R2 = R4 = R7 = R8 = H, R3 = R5 = R6 = Me, R9 = Et): NMR: H (CDC13): 1.03 (3H, t, J = 7.3 Hz, CH3), 1.10 (3H, t, J = 7.6 Hz, CH3), 1.13 (3H, d, J = 6.8 Hz, CH3), 1.48 (3H, s, CH3), 1.49 (3H, s, CH3), 1.65 (2H, sextet, J = 7.4 Hz, CH2), 1.76-1.98 (3H, m, CH2 + H ??), 2.80-2.92 (3H, m, CH2 + 0H), 4.10 (1H, ddd, J = 2.9 Hz, J = 7.9 Hz, J = 10.7 Hz, H? 0), 4.98 (1H, d, J = 3.3 Hz, H? 2), 5.54 (1H, d, J = 9.9 Hz, H7), 5.94 (1H, s, H3), 6.63 ( 1H, d, J = 9.9 Hz, H8); EMEI: 385 (10.5, M + l), 384 (35.8, M "), 369 (78.4, M-CH3), 366 (43.1, M-H20), 351 (39.0, M-CH3-H20), 337 ( 100, M-H20-C2H5), 299 (37.7, M-CH3-C5H10); IR (thin, pure film) cm "1: 3432 (w, OH), 1709 (s, C = 0); Analysis calculated for C23H2805.l / 4 H20: C, 71.02; H, 7.38. Found: C, 71.10; H, 7.40. 16f (R? = N-Pr, R2 = R4 = R7 = R8 = H, R3 = R5 = R6 = Me, R9 = Et): p.f. 103-105 ° C; XH NMR (CDC13): 1.04 (3H, t, J = 7.3 Hz, CH3), 1.07 (3H, t, J = 7.4 Hz, CH3), 1.13 (3H, d, J = 6.9 Hz, CH3), 1.47 ( 3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, sextet, J = 7.6 Hz, CH2), 1.79-1.90 (2H, m, CH2), 2.05 (1H, m, H ?? ), 2.90 (2H, m, CH2), 3.53 (1H, s, OH), 3.78 (1H, dt, J = 4.1 Hz, J = 8.1 Hz, H? 0) 4.73 (1H, d, J = 6.7 Hz , H? 2), 5.54 (1H, d, J = 10.0 Hz, H7), 5.95 (1H, s, H3), 6.63 (1H, d, J = 9.9 Hz, H8); EMEI: 385 (7.6, M + l), 384 (31.1, M +), 369 (100, M-CH3), 351 (9.5, M-CH3-H20), 337 (11.5, M-H20-C2H5), 299 (36.9, M-CH3-C5H10); IR (KBr) cm "1: 3493, 3435 and 3250 (w, OH), 1699 (s, C = 0); Analysis calculated for C23H2805: C, 71.85; H, 7.33, Found: C, 71.46; H, 7.34 .

EXAMPLE 32: (+) - 10, 11-cis-ll, 12-trans-10, 11-Dihydro-10-ethyl-12-hydroxy-4-propyl-6,11-trimethyl-2H, 6H, 12H-benzo [l, 2-b: 3,4-b ': 5,6-b "] - tripiran-2-one (16g) and (+) -10, 11, 12-cis- 10, ll- dihydro-10-ethyl-12-hydroxy-4-propyl-6,6, 11-trimethyl-2H, 6H, 12H-benzo [1,2-b: 3, -b ': 5, 6-b "] - tripiran-2-one (16h, Reaction Scheme V) To a solution of 15d (290.5 mg, 0.76 mmol) in ethanol (15 ml) at 25 ° C was added NaBH4 (269.0 mg, 7.11 mmol) in portions under N2. The suspension was stirred for 1 hour at room temperature, then quenched with saturated NH4C1 (6 mL). The solution was extracted with ethyl acetate (200 ml), washed with brine (80 ml), dried over magnesium sulfate, filtered and concentrated to give 16h (R? = N-Pr, R2 = R3 = R7 = R8 = H, R4 = R5 = R6 = Me, R9 = Et): NMR aH (CDCI3): 0.79 (3H, d, J = 7.3 Hz, CH3), 1.04 (3H, t, J = 7.3 Hz, CH3), 1.11 (3H, t, J = 7.3 Hz, CH3), 1.49 (3H, s, CH3), 1.51 (3H, s, CH3), 1.67 (2H, sextet, J = 7.4 Hz , CH2), 1.92 (2H, m, CH2), 2.10 (1H, tq, J = 2.0 Hz, J = 7.3 Hz, H ??), 2.79 (1H, s, OH), 2.81-2.90 (2H, m, CH2), 4.23 (1H, ddd, J = 1.9 Hz, J = 5.4 Hz, J = 8.7 Hz, H? O), 4.87 (1H, d, J = 1.9 Hz, H12), 5.54 (1H, d, J = 10.0 Hz, H7), 5.96 (1H, s, H3), 6.66 (1H, d, J = 9.9 Hz, H8); EMEI: 385 (6.1, M + l), 384 (26.0, M "), 369 (100, M-CH3), 351 (9.8, M-CH3-H20), 337 (8.2, M-H20-C2H5), 299 (17.6, M-CH 3 -C 5 H 10); IR (thin film, pure) cm "1: 3410 (w, OH), 1732 (s, C = 0).

EXAMPLE 33: (+) - 10, 11-trans-4-Propyl-7, 8, 10, 11-tetrahydro-6, 6, 10, 11-tetramethyl-2H, 6H, 12H-benzo [1,2- b : 3, 4-b ': 5, 6-b "] tripiran-2, 12-dione (Reaction Scheme VI, 18a, R? = N-Pr, R2 = R = R7 = R8 = H R3 = R5 = R6 = R _? = Me) To a solution of { +) - 7 (534 mg, 1.45 mmol) in ethanol / methylene chloride (1: 1, 50 ml, Parr apparatus) under N2 was added 10% palladium carbon (53.4 mg) at room temperature The mixture was stirred under hydrogen (2 atm) for 1 hour, then filtered by gravity through Whatmann filter paper The solvent was evaporated to give a white crystalline solid which was filtered through a short plug of silica gel, eluting with methylene chloride / methanol (97: 3) Pure compound (+ _) -18a (441 mg, 82.2%) was obtained as white plates by recrystallization of ethyl acetate. ethyl: mp 165 ° C; RMN? R (CDC13): 1.01 (3H, t, J = 7.3 Hz, CH3), 1.21 (3H, d, J = 6.8 Hz, CH3), 1.42 (3H, s, CH3) , 1.44 (3H, s, CH3), 1.53 (3H, d, J = 6.2 Hz, CH3), 1.61 ( 2H, sextet, J = 7.5 Hz, CH2), 1.84 (2H, apparent dt, J = 2.4 Hz, J = 6.7 Hz, CH2), 2.53 (1H, dq, J = 11.2 Hz, J = 6.8 Hz, Hn) , 2.69 (2H, apparent dt, J = 3.4 Hz, J = 6.7 Hz, CH2), 2.88 (2H, t, J = 7.5 Hz, CH2), 4.28 (1H, dq, J = 11.2 Hz, J = 6.2 Hz , Hio), 6.02 (1H, s, H3); EMEI: 371 (40.8, M + l), 370 (100, M "), 314 (99.3, M-C4H8), 299 (21.6, M-C5H? 0-1), 286 (65.0, M-CH3-C5H ? 0 + 1), 271 (20.5, M-CH3-C5H80), 259 (47.5, M-C4H8-C3H40 + 1), IR (KBr) cm "1: 1740 (vs, C = 0); Analysis calculated for C22H2605: C, 71.33; H, 7.07; Found: C, 71.00; H, 7.22.

EXAMPLE 34: (+) -10, 11-trans-10, 11-Dihydro-4-propyl-6,6,10, 11-tetramethyl-2H, 6H, 12H-benzo [1, 2-b: 3, 4 -b ': 5, 6-b "] tripiran-2, 12-dione-12-oxy a (Reaction Scheme VI, 19a, Rx = n- Pr, R2 = 4 = R7 = R8 = H, R3 = R5 = R6 = R9 = Me, R? O = H) Was placed in a one-neck round bottom flask of 100 ml (+) -7 (1.47 g, 4.00 mmol) and NH20HHC1 (1.39 g, 20.0 mmol). Methanol was added to this mixture (60 ml), and the solution was heated to reflux with magnetic stirring until the ketone dissolved.

Carefully added K2C03 powder was then added (1.38 g, 10.0 mmol), and the reaction was allowed to stir at reflux for 4 hours. The solution was cooled to room temperature, filtered to remove K2C03 and evaporated in vacuo to give a yellow solid. The residue was divided between 150 ml each of H20 and ethyl acetate. The organic phase was collected and washed sequentially with 1 N HCl and saturated brine, then dried over magnesium sulfate, filtered and evaporated to yield a thick yellow syrup, which was purified by column chromatography on silica gel. (75 g), eluting with methylene chloride / methanol (97: 3) to yield the desired product as a white solid (657 mg, 43%). An analytical sample was obtained by recrystallization from acetone / hexane (1: 3) as colorless prisms; p.f. 200-201 ° C; XH NMR (CDC13): 1.04 (3H, t, J = 7.4 Hz, CH3), 1.23 (3H, d, J = 7.0 Hz, CH3), 1.33 (3H, d, J = 6.5 Hz, CH3), 1.51 ( 3H, s, CH3), 1.54 (3H, s, CH3), 1.67 (2H, sextet, J = 7.4 Hz, CH2), 2.82-3.01 (2H, m, CH2), 3.79 (1H, dq, J = 2.0 Hz, J = 7.0 Hz, Hn), 4.46 (1H, dq, J = 2.0 Hz, J = 6.5 Hz, H? 0), 5.57 (1H, d, J = 9.9 Hz, H7), 6.02 (1H, s , H3), 6.67 (1H, d, J = 9.9 Hz, H8), 9.46 (1H, broad s, OH); EMEI: 384 (12.9, M + 1), 383 (49.22, M +), 368 (100, M-CH 3), 366 (21.1, M-OH), 352 (15.2, M-NOH); IR (KBr) cm "1: 3223 (broad, OH), 1740 (C = 0); Analysis calculated for C22H25N05.1 / 4 H20): C, 68.11; H, 6.63; N, 3.61. Found: C, 68.40; H, 6.59; N, 3.58.

EXAMPLE 35: (+) -10, 11-trans-10, 11-Dihydro-4-propyl-6,6,10, 11-tetrame-2H, 6H, 12H-benzo [1,2-b: 3, 4-b ': 5, 6-b "] tripiran-2, 12-dione-12-methoxime (Reaction Scheme VI, 19b, R? = N-Pr, R2 = R4 = R7 = R8 = H, R3 = R5 = R6 = R9 = Me, R? 0 = Me) Was placed in a one-neck round neck flask of 100 ml (+) -7 (1.47 g, 4.00 mmol) and NH20CH3 HCl (1.67 g, 20.0 mmol) To this mixture was added methanol (60 ml), and the solution was heated to reflux with magnetic stirring until the ketone was dissolved, then solid K2C03 powder (1.38 g, 10.0 mmol) was carefully added, and the reaction was left The mixture was cooled to room temperature, filtered to remove K2C03 and evaporated in vacuo to give a yellow oil.The residue was divided between 150 ml of H20 and 150 ml of ethyl acetate. The organic phase was collected and washed sequentially with 1 N HCl and saturated brine, then dried over magnesium sulfate, filtered or and evaporated to produce a thick yellow syrup. The product was purified by column chromatography on silica gel (75 g), eluting with ethyl acetate / hexane (1: 3) to produce the desired product as a faintly yellow oil which, firmly, forms a white solid (598 mg, 38%). An analytical sample was obtained by recrystallization from acetone / hexane (1: 3) as white plates; p.f. 143-144 ° C; 1N NMR (CDC13): 1.01 (3H, t, J = 7.3 Hz, CH3), 1.16 (3H, d, J = 7.0 Hz, CH3), 1.28 (3H, d, J = 6.4 Hz, CH3), 1.49 ( 3H, s, CH3), 1.50 (3H, s, CH3), 1.64 (2H, sextet, J = 7.3 Hz, CH2), 2.79-2.99 (2H, m, CH2), 3.57 (H, dq, J = 1.9 Hz, J = 7.0 Hz, Hn), 4.06 (3H, s, 0CH3), 4.37 (1H, dq, J = 1.9 Hz, J = 6.4 Hz, Hio), 5.54 (1H, d, J = 10.0 Hz, H7 ), 6.00 (1H, s, H3), 6.62 (1H, d, J = 10.0 Hz, H8); EMEI: 397 (61.2, M "), 382 (100, M-CH3), 366 (12.9, M-0CH3), IR (KBr) cm" 1: 1728 (vs, C = 0); Analysis calculated for C23H27N05: C, 69.50; H, 6.85; N, 3.52. Found: C, 69.39; H, 6.90; N, 3.59.

EXAMPLE 36: Conversion of (-) -Calanolide A to (-) - Calanolide B To a solution of (-) -calanolide A (341 mg, 0.922 mmol) in anhydrous methylene chloride (5 ml) at -78 ° C under N2 was added a solution of diethylamidosulfide trifluoride (DAST, 178 mg, 1.11 mmol) in methylene chloride (1 ml) and the resulting yellow solution it was stirred at -78 ° C for 4 hours. The reaction was quenched with 0.5 ml of methanol, then warmed to room temperature. The solution was diluted with methylene chloride (20 ml), then washed with water (50 ml) and saturated brine (50 ml). After drying over magnesium sulfate, the solution was filtered and evaporated to give a light yellow solid. The analysis of TLC (silica gel, 3% methanol in methylene chloride) showed two components, one with fast movement and one slow. The material was subjected to chromatography through 80 g silica gel, eluting with 1% methanol in CH2C12, and the fractions containing the respective components were combined and evaporated to yield 198 mg (61% yield) of compound 22 and 75.3 mg (22%) of (-) - calanolide B.

(S) -4-propyl-6, 6, 10, 11-tetramethyl-2H, 6H, lOH-benzo- 1, 2-b: 3, 4-b ': 5,6-b "] tripiran-2 -one (22): XH NMR (CDC13): 1.03 (3H, t, J = 7.4 Hz, CH3), 1.39 (3H, s, J = 6.6 Hz, CH3), 1.47 (3H, s, CH3), 1.51 (3H, s, CH3), 1.66 (2H, sextet, J = 7.4 Hz, CH2), 1.85 (3H, s, CH3), 2.88 (2H, m, CH2), 4.89 (1H, q, J = 6.6 Hz , H? 0), 5.55 (1H, d, J = 10.0 Hz, H7), 5.93 (1H, s, H3), 6.62 (1H, s, J = 10.0 Hz, H8), 6.64 (1H, s, Hi2 ); EMEI: 353 (15.5, M + 1), 352 (53.2, M +), 337 (100, M-CH 3). IR (KBr) cm "1: 1724 (s, C = 0); Analysis calculated for C22H240: C, 74.98; H, 6.86. Found: C, 74.87; H, 7.00. (-) -Calanolide B: XH NMR (CDC13): 1.03 (3H, t, J = 7.3 Hz, CH3), 1.14 (3H, d, J = 7.0 Hz, CH3), 1.43 (3H, d, J = 6.4 Hz, CH3), 1.48 (3H, s, CH3), 1.49 (3H, CH3), 1.66 (2H, sextet, J = 7.6 Hz, CH2), 1.72-1.79 (1H, m, Hn), 2.60 (1H, d, J = 3.8 Hz, OH), 2.89 (2H, m, CH2), 4.26 (1H, dq, J = 10.7 Hz, 6.3 Hz, H? 0), 4.97 (1H, J = 3.8 Hz, H12), 5.53 (1H, d, J = 10.0 Hz, H7), 5.95 (1H, s, H3), 6.63 (1H, d, J = 10.0 Hz, H8); ESI: 370 (31.1, M +), 355 (100, M-CH 3), 299 (29.7, M-CH 3 -C 4 H 8); IR (KBr) cm "1: 3478 (s, acute, OH), 1703 (s, C = 0).

EXAMPLE 37: Activity of (+) -Calanolide A against Tuberculosis In the primary screen assay in vi tro against H37Rv of Mycoba cteri um t ubercul osi s in a BACTEC 12B medium using the radiometric system BACTEC 460, 44 both the (+ ) - as (-) -calanolide A showed 98% inhibition at a concentration of 12.5 μg / ml. The (+) -Calanolide A was also tested at low concentrations against H37Rv of M. t ubercul osi s in BACTEC 460 to determine the current minimum inhibitory concentration (MIC), the lowest concentration that inhibits 99% of the inoculum. It was found that (+) - calanolide A presented moderate anti-TB activity, with MIC value being 3.13 μg / ml (8.4 μM), compared to the positive control of the drug rifampicin which had MIC value of 0.06 μg / ml .

EXAMPLE 38: Screening of Calanolide Analogs In the primary screen test in vi tro against H37Rv of Mycoba cteri um t ubercul osi s in a BACTEC 12B medium using the radiometric system BACTEC 460, 44 Figure 1 analogues of calanolide (- ) -soulatrolide, (-) - costatolide and (-) - 7, 8-dihydrosoulatrolide showed 99% inhibition at a concentration of 12.5 μg / ml. The calanolide analogs were further tested at low concentrations against M. tuberculosis tuberculosis in BACTEC 460 to determine the minimum inhibitory concentration (MIC), the lowest concentration that inhibits 99% of the inoculum. It was found that calanolide showed moderate anti-TB activity, compared to the positive control of the drug rifampicin, which had a MIC value of 0.06 μg / ml. Soulatrolide can be prepared using the digest procedures for (+) - caralanide A or extracted from natural sources. See Lin et al., Pha rema ceu ti ca l Bi olgy 1999, Vol. 37 (1), p. 71-76.

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It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (14)

CLAIMS Having described the invention as above, property is claimed as contained in the following rei indications:

1. A method for the prevention or treatment of an infection of mycobacterium (mycobacterium), characterized in that it comprises administering to a mammal, an effective amount of at least one compound of the formula I: wherein Ri is H, halogen, hydroxyl, amino, C? -6 alkyl, C? _6-alkyl aryl, mono- or poly-fluorinated C? -6 alkyl, C? -6-alkyl hydroxy, alkoxy of C? _6, C? -8-aminoalkyl, C? -6-alkylamino, C? _6) amino, C? _8-alkyl-C? -8 / di alkyl (C? _6) amino-Ci-β alkyl, cyclohexyl, aryl, or heterocycle, wherein aryl or heterocycle can each be substituted or unsubstituted with one or more of the following: C?-6 alkyl, Ci-alkoxy , hydroxy-C de4 alkyl / hydroxyl, amino, C?-6 alkylamino, di (C? -6) alkyl amino, C amino _ amino amino-alkyl, C? _8-alkylamino C alquilo-alkyl 8, di (C? _6 alkyl) aminoalkyl of C? -8, nitro, azido or halogen; R2 is H, halogen, hydroxyl, C? -6 alkyl, aryl-C? -6 alkyl, mono- or poly-fluorinated C? _6 alkyl, aryl or heterocycle, R3 and R4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C? -6 alkyl, aryl-C? -6 alkyl, mono- or poly-fluorinated C? _6 alkyl, hydroxy-C? _6 amino-alkyl of C? _8 -alkyl, C 1-8 alkylamino-C 8 -alkyl, di (C 6 -alkyl) amino-C 8 alkyl, cyclohexyl, aryl or heterocycle; and R3 and R4 can be taken together to form a heterocyclic ring or 5-7 membered saturated cyclic ring; R5 and R6 are independently selected from the group consisting of H, C6_6 alkyl, arylC6 alkyl, C6_6 mono- or poly-fluorinated alkyl, aryl or heterocycle; and R5 and R6 can be taken together to form a heterocyclic ring or 5-7 membered saturated cyclic ring; R7 is H, halogen, methyl, or ethyl; R8 and R9 are independently selected from the group consisting of H, halogen, C6-6 alkyl, aryl-C6-6alkyl mono- or poly-fluorinated alkyl, hydroxy-C6-6alkyl, amino -Ci-β alkyl, Ci-β-alkylamino of Cβ-, di (Ci-e alkyl) aminoalkyl of Cβ-8, cyclohexyl, aryl or heterocycle; and R8 and Rg can be taken together to form a heterocyclic ring or 5-7 membered saturated cyclic ring; Rio is halogen, O, ORn, NORn, NHORn, NORi2, NHORi2, NRnR? 2, NRi2, or NR12NRX3; wherein Rn is H, acyl, P (0) (OH) 2 S (O) (OH), CO (C? -? 0 alkyl) CO2H, (C? _8 alkyl) C02H, CO (C) alkyl ? _? 0) NRi2R? 3, (C? _8 alkyl) NR? 2R? 3; R12 and. R 3 are independently selected from the group consisting of H, C 6 alkyl, aryl, and aryl C 1 -β alkyl! and R 2 and R 3 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen; or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, characterized in that the infection of mycobacterium is selected from the group consisting of complex of Mycobacterium avium (MAC), Mycobacterium kansaii, Mycobacterium marinum, Mycobacterium phlei, Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium gordonae, complex of Mycobacterium terrea, Mycobacterium haemophilum, Mycobacterium fortuitum, Mycobacterium tuberculosis, Mycobacterium laprae, Mycobacterium scrofulaceum and Mycobacterium smegmatis.

3. The method according to claim 1, characterized in that the compound is selected from the group consisting of (+) - calanolide A, (-) --calanolide A, (+ _) -calanolide A, (-) -calanolide B, soulatrolide , and (-) - 7, 8-dihydrosoulatrolide.

4. The method according to claim 1, characterized in that it further comprises co-administering an effective therapeutic amount of at least one compound selected from the group consisting of an anti-microbial agent, an antiviral compound, an immunostimulant, an immunomodulator, a antibiotic, or a chemokinesis inhibitor. 5. The method according to claim 4, characterized in that the antimicrobial agent is an anti-mycobacterial agent. 6. The method according to claim 5, characterized in that the mycobacterial agent is an anti-TB agent. 7. The method according to claim 6, characterized in that the anti-TB agent comprises isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide or ethambutol. 8. The method according to claim 4, characterized in that the antiviral compound is a protease inhibitor. 9. The method according to claim 8, characterized in that the protease inhibitor is selected from the group consisting of indinavir, saquinavir, ritonavir, and nelfinavir. 13. The method according to claim 4, characterized in that the antiviral compound is a biflavanoid.

5. The method of conformance with rei indication 4, characterized in that the antimicrobial agent is an antimicrobial agent.

6. The method according to claim 5, characterized in that the mycobacterial agent is an anti-TB agent.

7. The method according to claim 6, characterized in that the anti-TB agent comprises isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide or ethambutol.

8. The method according to claim 4, characterized in that the antiviral compound is a protease inhibitor.

9. The method according to claim 8, characterized in that the protease inhibitor is selected from the group consisting of indinavir, saquinavir, ritonavir, and nelfinavir.

10. The method according to the rei indication 4, characterized in that the antiviral compound is a biflavanoid.

11. The method according to the indication 10, characterized in that the biflavanoid is selected from the group consisting of robus taflavone, flavone catnip, and a derivative or salt thereof.

12. The method according to rei indication 4, characterized in that the antiviral compound is selected from the group consisting of AZT, ddC, ddl, D4T, 3TC, acyclovir, gancyclovir, fluorinated nucleosides and non-nucleoside analog compounds such as delavirdine and nevirapine. , and efavirenz, a- inter feron, recombinant CD4, amantadine, rimantadine, ribavirin, and vidarabine.

13. The method according to claim 4, characterized in that the immunostimulant is an interleukin or cytosine.

14. The method according to the rei indication 4, characterized in that the antibiotic is an antibacterial agent, an antifungal agent or an anti-pneumocyst agent.