Racemic compounds, fragments

As shown in Figure 11.19, tetrahydrofolate can carry one-carbon fragments attached to N-5 (formyl, formimino or methyl groups), N-10 (formyl) or bridging N-5—N-10 (methylene or methenyl groups). 5-Formyl-tetrahydrofolate is more stable to atmospheric oxidation than folate itself, and is therefore commonly used in pharmaceutical preparations it is also known as folinic acid, and the synthetic (racemic) compound as leucovorin. 

Furthermore, Sato and Ikekawa (238) have obtained by chromic acid oxidation of (257 )-22,26-acetylepimino-3/3,16(8-diacetoxycholesta-5,22-diene (LX), prepared from solasodine (I) by acetylation (238, 239), 16 -hydroxy-3(8-acetoxy-22,23-bisnorchol-5-enic lactone (acetyldios-genin lactone, LXI). The side chain fragment of this degradation, which involves the carbon atoms 23-27 including the center of chirality C-26, has been identified as (R)-( — )-4-amino-3-methylbutyric acid (LXII) (240), the constitution of which was confirmed by comparison with the synthesized racemic compound. Its absolute configuration was confirmed by conversion into (R)-( +)-methylsuccinic acid (LXIII) (225, 226). 

Camptothecin.— The alkaloid camptothecin (3), which exhibits antileukemic and cytostatic activity, has been a vogue target for a number of years, and several syntheses are known. Biichi has now devised a short synthesis of the racemic compound (3) in which the fragment (5) was coupled with the amine (4) to give an intermediate (6). This substance (6) was then cyclized as indicated, and two further steps gave the target, (3). Crouse, under Corey s direction, has described the first... 

A closer analogy to dehydrosecodine (228) has been developed using A2-piperideines (e.g. 236). These compounds are not isolated but are produced by the fragmentation of salt (235). This elegant method is illustrated in Scheme 42 by the synthesis of racemic pandoline (237) and its C2o epimer. This reaction has provided an efficient route to a number of aspidosperma alkaloids (80JOC3259). 

The gross structural features, presence of a tetramic acid and E-decenoyl side chain, could be inferred from NMR studies. Methanolysis (HCl/MeOH) of 47 and pentane extraction of the quenched reaction mixture gave two compounds that were determined to be the methyl esters of decenoic acid and N-(2-decenoyl)leucine. The nature of the 3-acyl tetramic acid was deduced from the identification of 48 and 49 in the aqueous portion of the methanolysis reaction mixture following treatment with trifluoroacetic acid anhydride. The unusual C-C bond fragmentation under acidic conditions, and the structure of the antibiotic was confirmed by synthesis of racemic 47 [86]. The configuration at the lone chiral centre was established as R by chiral GC. The carbon NMR spectrum of 47 indicated an equilibrium between three tautomers in which the A2-pyrrolin-4-one form is preferred (60%) and the two internal tautomers (50, 51) make equal contributions (20% each). 

The oxazol-5(4//)-one coupling method (Scheme 4) is uniquely appropriate for C -tetra-substituted a-amino acids, since racemization or epimerization is unlikely to occur with these compounds. It represents the main methodology exploitable for fragment condensation of peptides based on C -tetrasubstituted a-amino acids. Due to the gem-dialkyl effect on the C°... 

The use of click chemistry has also been applied to the synthesis of benzophe-none-modified y-secretase probes. The group of Yao reported the preparation of a compound library built up from Bpa-containing alkyne 77 and azide 78 (Fig. 7) [81]. The azide part contains a racemic hydroxyethylene moiety, and variations were made in its aryl sulfonamide domain. The compound library was screened for its potency against y-secretase inhibition and the most potent compounds were used to label active PS1 in a cell lysate. In addition, Fuwa and coworkers reported a divergent synthesis of y-secretase A/BPs by means of click chemistry with alkyne 79 and azide 80 [82]. Variations were made in the aryl part of the alkyne (dibenzoazepine or benzodiazepine) and in the type of spacer between the benzo-phenone moiety and biotin in the azide. PAL using these probes provided the authors with evidence that the molecular target of this type of probe is the N-terminal fragment of PS1. 

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