Avermectin, Bla

Abalis IM, Eldefrawi AT, Eldefrawi ME (1986) Actions of avermectin Bla on the gamma-aminobutyric acid receptor and chloride channels in rat brain. J Biochem Toxicol 1 69-82... 

In the synthesis of avermectin Bla, the disaccharide fluoride 48 is prepared and coupled with avermectin aglycon 49 in the presence of SnCl2-AgC104 in dry ether to give protected avermectin Bla50 in 62% yield (Scheme 2.16) [23]. 

Several natural products and pharmaceuticals have been made in which a TRAP-catalysed oxidation of a primary alcohol to aldehyde step occnrs, and these are listed in 2.1.3 abscisic acid, altohyrtin A, (+)-arisngacin A, 14-[2H]-arteether (Fig. 2.4), astrogorgin, avermectin-Bla (Fig. 2.6), (H-)-batzelladine A (Fig. 1.13), brevetoxin B, (+)-catharanthin, ( )-epibatidine, 2-epibotcinolide, (-)-7-epicylin-drospermopsin, ( )-epimaritidine, epothilone C, irisqninone (Fig. 2.3), gambieric... 

Several syntheses of natural products and pharmaceuticals involving the conversion of secondary alcohols to ketones using TPAP/NMO/PMS/CH Clj or TPAP/NMO/ PMS/CH3CI3 have been reported. A key early example using TPAP/NMO/PMS/ CH3CI3 for conversion of a secondary alcohol to a ketone intermediate was for the anti-parasitic avermectin-Bla (Fig. 2.6 cf. 1.11) [81,167],... 

N-Bromoacetamide (NBA) is also a useful positive bromine equivalent Thus NBA in the presence of H2O or LiOAc/HOAc has resulted in the functionalization of 11,12-dihydrobenzo[e]pyrene (Scheme 69).135 NBA has also been employed in conjunction with H2O for the regio- and stereo-selective hydro-bromination of the 10,11 double bond of avermectin Bla, a complex antibiotic containing five double bonds.136... 

The catalyst (10 mg) was dissolved in toluene (25 ml) and added under argon to the solution of a mixture (1.1 g) of avermectin Bla (96%) and avermectin Bib (4%) and of m9 °f triphenylphosphine in toluene (25 ml) in a stainless steel autoclave. This starting material was then hydrogenated at 88°C under a hydrogen pressure of 20 bar with stirring of the solution. After 10 hours, HPLC analysis revealed a content of 86% dihydro-avermectin Bla and of 4 % dihydroavermectin Blb, and also of 3% tetrahydroavermectin Bla. 

The catalyst is added to a solution of 4.3 g of avermectin (Bla and Blb mixture) in 25 ml of a mixture of acetone and cyclohexane in a ratio of 2 1. After addition of 51.4 mg of tris-(mexylphenyl)phosphine, the hydrogenation is carried out in a steel autoclave at a hydrogen pressure 5 bar and at 88°C. After a hydrogenation time of 4 hours, 8.9% of starting material, 89.9% of ivermectin (Bla and Blb mixture), tetrahydroavermectin content <0.1% was obtained (according to HPLC analysis). 

In genetically altered mdrlajb (—j—) knockout mice without P-gp/ both transplacental transport of P-gp substrates and the incidence of fetal malformations increase (93). Transplacental transport of the P-gp substrates/ digoxhi/ saquinavir and paclitaxel/ was increased 2.4-/ 7-, and 16-fold/ respectively/ in the knockout mice compared to transport in the wild-type animals. In another murine study/ mdrlajh (—j—) fetuses were susceptible to cleft palate malformation induced by prenatal exposure to a photoisomer of avermectin Bla/ whereas their wild-type litter mates were protected from the teratogen (87). 

Isopropenyl carbonates 236 were introduced by Sinay [363] and were used with TMSOTf as a promoter. Reactions of imidazole carbonate derivatives 237 were assisted by ZnBr2 [522], whereas for imidazole thiocarbonate derivatives 238, AgC104 was used as the promoter [523, 524]. These methods were used in the total synthesis of avermectin Bla 245 by Ley [523,524] (Scheme 4.47). 

SCHEME 4.47 Synthesis of avermectin Bla using glycosyl carbonate donors. 

Ford, M J, Knigbt, J G, Ley, S V, Vile, S, Total synthesis of avermectin Bla. S3mtbesis of tbe carbobydrate bis-oleandrose fragment and coupling to the avermectin Bla aglycone, Synlett, 331-332, 1990. 

Hanessian, S, Ugolini, A, Therien, M, Stereocontrolled synthesis of the spiro ketal unit of avermectin Bla aglycon, J. Org. Chem., 48, 4427-4430, 1983. 

These molecules have an intermediary polarity (Fig. 2a). A two-phase solvent system, composed of n-hexane, ethyl acetate, methanol, and water, has been selected. In this case, the partition coefficients, K, are defined as the ratio of the solute concentration in the upper phase to its concentration in the lower one. A solvent mixture of n-hexane-ethyl acetate-methanol-water (19 1 10 10, v/v/v/v) yielded the best K values from 0-2.83. 25 mg of crude ivermectin separated in 4.0 h. This separation yielded 18.7 mg of 99.0% pure ivermectin Bla, 1.0 mg of 96.0 % pure ivermectin Bib, and 0.3 mg of 98.0% pure avermectin Bla. 

We have selected a two-phase solvent system composed of n-hexane, ethyl acetate, methanol, and water. As described above, this solvent system is conveniently used for the separation of components with a broad range of hydrophobicity by modifying the volume ratio between the four solvents. In the n-hexane/ethyl acetate/methanol/ water (8 2 5 5) system first examined, the K values of the components were 0, 0.46, 0.61 (avermectin Bla) oo, 1.86 (ivermectin Bib) 3.06 (ivermectin Bla) and 4.38,... 

---