Potent reaction conditions

These modified Rosenmund von Braun reaction conditions were also used by Gopalsamy et al. for the rapid cyanation of the 1,3,4,9-tetrahydropyrano-[3,4-fc]indole skeleton while searching for potent and selective Hepatitis C virus polymerase inhibitors (Scheme 74) [84]. 

Kataoka, M., Shimizu, K., Sakamoto, K., Yamada, H., and Shimizu, S. 1995b. Lactonohydrolase-catalyzed optical resolution of pantoyl lactone selection of a potent enzyme producer and optimization of culture and reaction conditions for practical resolution. Appl. Microbiol. Biotechnol, 44, 333-338. 

N-Arylation of phenylpyrrolylmethanone 199 to afford A -aryl derivative 200 was performed in Suzuki reaction conditions using phenylboronic acid, Cu(ii) acetate, and pyridine (Scheme 43) <2005JME5140>. The best yields were obtained in the presence of A -methylpyrrolidone (NMP) by microwave-assisted heating (60 W, 120 °C, 3 x 50 s). Reduction of methanone 200 with LiAlH4 gave methanols 201, which were then treated with GDI to afford imidazoles 202, potent anti-Candida agents. 

The second example illustrates a problem with SES protection of a serine resi-due during a total synthesis of the potent antitumour decadepsipeptide (-)-San-dramycin 316 Removal of the two SES protecting groups from the symmetrical intermediate 139.1 [Scheme 8.139] was accomplished with TBAF (10 equiv) in the presence of rer/-butyl dicarbonate (30 equiv) at room temperature so that the liberated amine could be trapped as its Boc derivative before it could react with the proximate ester function — a reaction which occurred under the more basic conditions associated with TBAF alone. The mildness of the reaction conditions were welcome and fortuitous since deprotection of SES-protected amines usually requires higher reaction temperatures (50-100 °C). Probably Boc acylation precedes and activates the subsequent SES deprotection. Under the acidic conditions of the Boc deprotection, the liberated amine is protonated and therefore cannot react with ester function. 

Addition of Acetylide to an Aromatic Ketone. The synthesis of efavirenz, a potent HIV transcriptase inhibitor, required tbe enantioselective addition of lithium cyclopropylacetylide to the carbonyl carbon of a trifluoroacetophenone (eq 3). Careful control of reaction conditions and the use of the lithium salt of the title ligand affords the desired alcohol in 91% yield and >99.5% ee. ... 

In the laboratory of B.M. Trost, the second generation asymmetric synthesis of the potent glycosidase inhibitor (-)-cyclophellitol was completed using a Tsuji-Trost allylation as the key step. The synthetic plan called for the conversion of the a-nitrosulfone allylation product to the corresponding carboxylic acid or ester. Numerous oxidative Nef reaction conditions were tested, but most of them caused extensive decomposition of the starting material or no reaction at all. Luckily, the nitrosulfone could be efficiently oxidized with dimethyidioxirane under basic conditions (TMG) to afford the desired carboxylic acid in high yield. 

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

This methodology was applied to synthesis of 2/,3/-didehydro-2/,3/-dideoxy-nucleosides, potent anti-HIY agents. The bis-xanthate of the V3-methyluridine derivative was subjected to radical reaction conditions in water, giving the corresponding alkene in 82% yield. Similar results were also achieved in the case of the adenosine derivative (76% yield). However, Kita et al. found that the combination of a water-soluble radical initiator, 2,2 -azobis[2-(2-imid-azolin-2-yl)propane] (VA-061), a water soluble chain carrier, 1-ethylpiperidine hypophosphite (EPHP), and a surfactant, cetyltrimethylammonium bromide (CTAB), resulted in a radical cyclisation that occurred in water with a variety of hydrophobic substrates16 (Table 5.2). 

Unsymmetrical ir-allyl-Pd complexes usually suffer attack of the hydride nucleophile at the less substituted position in an SN2-type reaction. However, the site selectivity of the process is controlled by steric and/or electronic effects. The reaction is strongly dependent on the structural features of the substrate and the reaction conditions. Opposite site selectivity is observed when the reduction occurs at the sterically more hindered position via a cationic intermediate (SN1-type). Very potent nucleophilic hydride sources, such as LiBHEt3 or LiAlH4, may rapidly attack intermediate it-ally 1 complexes at the less hindered terminal position to give the more substituted alkene, while less effective hydride-transfer reagents (NaBH3CN, NaBH4) attack the it-allyl systems at the site best able... 

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