Calanolides

In the realm of natural product synthesis, Kepler and Rehder utilized the K-R reaction to synthesize ( )-calanolide A (56), a potent non-nucleosidal human irmnunodeficiency virus (HIV-1) specific reverse transcriptase inhibitor. Propiophenone 57 was allowed to react with acetic anhydride in the presence of sodium acetate to afford benzopyranone 58 in 56% yield subsequent deacetylation of 58 gave 59. Flavone 59 was then transformed to ( ) calanolide A (56) over several steps. 

Yet other compounds have been found to inhibit HIV-1 replication through a specific interaction with HIV-1 RT (i.e., quinoxaline S-2720 [68], 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69], dihydrothiazolo-isoindolones [70] and a number of natural substances (e.g., calanolide A and inophyllums, from the tropical rain forest trees Calophyllum lanigerum and Calophyllum inophyllum, respectively) [71,72]. All these and yet other compounds could be considered to be NNRTIs. The most potent among the NNRTIs, some of the HEPT derivatives (E-EBU-dM) [63] and a-... 

Kashman Y, Gustafson KR, Fuller RW, Cardellina JH, McMahon JB, Currens MJ, Buckheit RW Jr, Hughes SH, Cragg GM, Boyd MR. The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophylluwi lanigerum. J Med Chem 1992 35 2735-2743. 

Hydroarylation of alkynoates with phenols is applied to the synthesis of calanolides A 17 and B 18, which are active against AZT-resistant strains of HIV-1.163 The key step is the palladium-catalyzed coumarin formation reaction, as shown in Scheme 18. 

Even with the sterically demanding coumarin derivative as nucleophile, the secondary ether could be formed in excellent regio- (92 8) and enantioselectivity (98% ee) by using the bicyclic ligand 135 (Scheme 8E.36). The alkylation product has efficiently served as a key intermediate in the synthesis of (-)-calanolides A and B, which have the most potent HIV-1-specific reverse-transcriptase inhibitory activity among the chromanol family. 

Acid buffer system Benzalkonium chloride Polyacrylic acid (Carbopol 974) C2F5, C2G12, C4E10 Calanolide A Carrageenan... 

Tropical rainforest tree and Malaysian tree A number of natural products have been reported to interact with reverse transcriptase, i.e., baicalin, avarol, avarone, psycho-trine, phloroglucinol derivatives and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Numerous dipyranocoumarins have been isolated from different species of Calophyllum. According to their chemical skeleton, they have three heterocycle rings, ring B, C, and D, constructed from a phloroglucinol core A. These compounds fall into three basic structural types (1) tetracycle dipyranocoumarins in which the D rings have a gem-dimethyl group, such as (-l-)-calanolide A (1), (-l-)-calanolide B... 

Flavin et al. reported on the anti-HTV-1 activity of synthetic ( )-calanolide A and resolved (-l-)-calanolide A (1) and ( )-calanolide A [( )- ] against both strains and clinical isolates of HTV-l shown in Table 8-1. The cytotoxicity in the different ceU lines examined of the ( )-l, (+)-l, and ( )-calanolide A was approximately the same levels. However, only (+)-l exhibited HTV-l activity, which was similar to the data reported for the namral product [(+)-calanolide A, (1)], and ( )-l was inactive. Both the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17 were inhibited by ( )-l and (-T)-l. The (-T)-l was more active than ( )-I against the AZT-resistant strain G910-6 with an EC50 value of 0.027 and 0.108 pM, respectively. It was interesting that the activity of ( )-l... 

TABLE 8-2. Antiviral Activity of ( )-, (+)-, and ( )-12-Oxo-calanolide A (3) Against Varions Infected CEM-SS Cells... 

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