Calanolide synthesis

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. 

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. 

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... 

Chenara et al." was the first research group to establish the racemic calanolide A ( 1) in 1993 (Scheme 8-1) and the related (zb)-calanolide C and D via a five-step synthesis with 15% overall yield starting from phlorglucinol and then constructed the coumarin (A, B rings) followed by the chromanone ring (C) using a Lewis... 

Synthesis of Optically Active Calanolide A (1) and Calanolide B (2) (-l-)-Calanolide A (1) and (—)-calanolide B (15) have been shown to be potent inhibitors of HIV-1 RT. Synthesis of both optically active calanolide A and calanolide B have been accomplished by Deshpande et al. (Scheme 8-7)." ° They reported on the first enantioselective total synthesis of (-l-)-calanolide A (1) and (-l-)-calanolide B (2) and their (—)enantiomers, (—)-calanolide A (a new compound) and (—)-cala-nolide B (15), using a process that generated all three contiguous chiral centers (the (—)-calanolide B is also known as costatolide), respectively. 

Ishikawa et al. reported that ( )-quinine-catalyzed asymmetric intramolecular oxo-Michael addition (IMA) of 7-hydroxy-8-tigloylcoumarin gave cis-2,3-dimethyl-4-chromanone systems with high enantioselectivity and moderate diaster-eoselectivity, especially when chlorobenzene was used as a solvent. " Therefore, total synthesis of (+)-calanolide A (1) was achieved by application of the (—)-quinine-catalyzed asymmetric IMA. However, the synthetic route starting from 1,3,5- trimethoxybenzene was too long (13 steps with 3.5% overall yield) to practice. Finally, the authors improved and shortened the original synthetic route by application of Mgl2-assisted demethylation. 

The total synthesis of (+)-calanolide A (1) was carried out by application of the synthetic method for (+)-inophyllum B (3) using the same strategy. 

The (—)-quinine-catalyzed IMA of 40 gave cw-(- -)-methoxy chromanone cou-marin (cA-41) in 67% yield with 98% ee and its trans-41 in 21% yield with lower eantioselectivity (39% ee). The Mgl2-assisted isomerization of cis-(+)-41 accompanied by demethylation followed by the reaction of the formed diastereomeric mixture of chromanone 42 (without separation) with senecioyl aldehyde in the presence of phenyl boronic acid under the same condition to construct the 2,2-dimethyl chromanone ring reported in the synthesis of (+)-inophyllum B (3). The yield of trans-(+)-43 in 61% with 91% ee and its cw-isomer (+)-43 corresponded to the (+)-calanolide D as a minor product in 23% yield with 84% ee. At last, the synthesis of (+)-calanolide A (1) was accomplished by hydride reduction of (+)-43 with... 

I.4 Synthesis of (-)-Calanolide A and (—)-Calanolide B Using a Catalytic Enantioselective Approach... 

S Synthesis of (+)-Calanolide A From Enzyme-Catalyzed Optical Resolution of Compound (+)-53... 

Synthesis of (-I-) calanolide A (Scheme 8-11) was achieved by enzyme catalyzed resolution of the aldol products ( )-53. Compound 7 with acetaldehyde by aldol reaction in the presence of LDA/TiCU stereoselectively produced a mixmre of ( )-53 and ( )-54 (94% yield), the ratio of which was 96 4. ( )-53 was then resolved by lipase AK-catalyzed acylation reaction in the presence of tert-butyl methyl ether and vinyl acetate at 40 °C to obtain 41% yield of (+)-55 and 54% yield of the acetate (—)-56. Mitsunobu cyclization of (+)-55 in the presence of tri-phenylphosphine and dielthyl azodicarboxylate afforded 63% yield of (-l-)-43 with 94% ee as determined by chiral HPLC. Luche reaction on (+)-43 with CeCla 7H2O and triphenyl phosphine oxide and NaBH4 in the presence of ethanol at 30 °C gave the crude product. It was purified by column chromatography on silica gel to give 78% yield of a mixture containing 90% of (+)-calanolide A and 10% (+)-calanohde B, which were further separated by HPLC. 

The synthetic ( )-calanolide A was resolved into its enantiomers, (+)-calanolide A (1) and ( )-calanolide A, by using a semipreparative chiral HPLC column packed with amylose carbamate eluting with hexane/ethnol (95 5). The ultraviolet detection was set at a wavelength of 254 nm. (+)-calanolide A and its enantiomer (—)-calanohde A were collected, and their chemical structures were identified based on their optical rotations and spectroscopic data, as compared with the corresponding natural and synthesis compounds. 

Sekino, E. Kumamoto, T. Tanaka, T. Ikeda, T. Ishikawa, T. Concise synthesis of anti-HIV-1 active (-l-)-inophyllum B and (-l-)-calanolide A by application of (—)-quinine-catalyzed intramolecular oxo-Michael addition. J. Org. Chem., 2004, 69 2760-2769. 

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (—)-calanolide A and B. In the latter example, the anthracenyldiamine -based ligand was required for optimum selectivity. The synthesis of (—)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5//)-furanone to provide a single product in 89% yield. One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts." ... 

The total synthesis of the calophylium coumarin (-)-calanolide A was accomplished by D.C. Baker and co-workers. This compound attracted considerable attention because it is a potent inhibitor of HIV-1 reverse transcriptase. In order to introduce a formyl group at C8, a regioselective Vilsmeier reaction was employed on a coumarin lactone substrate. 

Quite recently, the use of natural cinchona alkaloids as catalysts for the intramolecular oxo-Michael addition of o-tigloylphenol (3), furnishing chiral ris-2,3-dimethyl-4-chromanone 4, which is a valuable intermediate for the synthesis of the anti-HIV-1 active coumarins, (+ )-calanolide A (5a), and (+ )-inophyllum B (5b), was reexamined by Ishikawa and coworkers (Scheme 9.2) [2], The parent cinchona alkaloids,... 

Several reviews have been published dealing with natural products-derived antiviral compounds [11,12,16-23]. Presently, there are only two plant-derived compounds under clinical development [2]. (+)-Calanolide A (12) is a C22 coumarin isolated from the Malaysian rainforest tree, Calophyllum langigerum by the U.S. National Cancer Institute [2]. It shows a potent HIV-RT inhibitory activity [2]. In vitro studies of 12 demonstrated activity against HIV-1 including AZT and other nonnucleoside RT inhibitors-resistant strains. It also shows synergistic anti-HIV activity in combination with nucleoside RT inhibitors 7, 8 and 9 [2]. To overcome the difficulty of supply of 12, its total chemical synthesis was accomplished [2]. In June 1997, clinical development of 12 was started as a potential drug for treatment of AIDS. A single -center 7-month U.S. phase la clinical trial of 12 was started to assess its safety and... 

Flavin, M., et ah. Synthesis, chromatographic resolution and anti-human immunodeficiency virus activity of (+/—)-calanolide A and its enantiomers, J. Med. Chem. (1996) 39(6), 1303—1313. 

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