Small Chiral Building Blocks

Scheme 4.18 Biocatalytic racemic resolution of small chiral building blocks.

Contrary to azithromycin, 12-aza-epothilones 1 and 2 are not available from their natural congeners. Therefore, these target molecules must be approached by total synthesis, starting from small chiral building blocks. The key issue in their synthesis. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

There also is some interest in QA as a chiral building block and a food acidu-lant. The compound is not naturally produced by E. coli but, as noted above, an E. coli engineered for the production of SA fortuitously produced modest amounts of QA [78, 79]. A very similar mutant, which lacked DHQ dehydratase (see Fig. 8.13), produced QA in copious amounts (49 g L 1), along with a small amount (3.3 g L 1) of DHQ [80]. 

In 1982 we have first become aware of the existence of the biopolymer PHB, consisting of (J )-3-hydroxybutanoates (HB), which we used as a source of readily available chiral building block for syntheses of natural products, such as elaiophylidin [1], We flien learned that short-chain PHB (ca. 150 HB units) is found in small amounts in all living cells and tissues, where it has been looked for (Figure I), including plants, for instance... 

Asymmetric hydrogenation of bromo-substituted aromatic a-enamides 14 affords the corresponding bromo-amino acid derivatives 15, which subsequently is subjected to Pd-catalyzed cross-coupling with aryl and vinyl boronic acids. In addition to diverse phenylalanine derivatives 16, a broad array of other novel aromatic and heterocyclic amino acids have been produced rapidly from a small number of bromo-functionalized intermediates [24], This same two-step process may be applied to the production of many other classes of aromatic and heterocyclic chiral building blocks, such as arylalkylamines, amino alcohols, diamines, and directly on peptides as well. 

PD is currently produced commercially in small quantities by chemical synthesis using the toxic feedstock acrolein. Although 1,3-PD has not been produced on a large scale, there are dozens of potential uses in polymer synthesis and as a chemical intermediate (26), Cameron has also been involved in studies on strains of Clostridium thermosaccharolyticum that produce R(-)-1,2-propanediol, a useful chiral building block in organic synthesis (27),... 

Chirality is an essential property of life, which can be found throughout all biological self-assembled and self-organized architectures. Over many millennia nature has, through trial and error, learned how to utilize the chiral properties of the small building blocks, for example, amino acids and nucleic acids and how to express this structural property in a hierarchical process at the quaternary level. This expression of chirality at the quaternary level in turn... 

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

The formation of two-dimensional nanocrystals, by peptide amphiphiles is also influenced by the chirality of the peptide building block.125 Three types of two-dimensional crystals were observed after the assembly of the functionalized peptide amphiphiles 17-19 shown in Figure 7.11 (above) at the air-water interface, which was followed by polymerization. These two dimensional crystals include (/) a racemic compound, in which each enantiomer is packed with its mirror image in a crystalline order, (it) enantiomorphous conglomerates, in which each enantiomer is segregated into small domains, and (iii) a solid solution, in which all molecules are randomly distributed without crystalline order. Interestingly, in the case of the two-dimensional system arising from the racemic compound,... 

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