Stereochemical diversity

The three major classes of biopolymers found in eukaryotic systems are nucleic acids, proteins, and polysaccharides. The latter class is the most complex with respect to structural and stereochemical diversity. Polysaccharides indeed possess a massive information content. Furthermore, polysaccharides are commonly found in nature covalently attached (conjugated) to other biomolecules such as proteins, isoprenoids, fatty acids, and lipids.1... 

Gagne and coworkers utilized this combination to discover enantioselec-tive receptors for (-)-adenosine [12]. A racemic dipeptide hydrazone [( )-pro-aib] generated a stereochemically diverse DCL of n-mer. The dimers were composed of two chiral (DD/LL) and one achiral isomer (DL), the four trimers (DDD, LLL, DDL, and LLD), the tetramers of four chiral and two achiral isomers, etc. Two techniques were used to measure the enan-tio-imbalance that was caused by the enantioselective binding of the chiral analyte to the enantiomeric receptors (Fig. 5.11). Since the unperturbed library is optically inactive, the optical enrichment of each library component could be measured by a combined HPLC optical rotation detection scheme (laser polarimeter, LP). LP detection differentiated unselective binding (amplification but not optical enrichment) from enantioselective recognition of the analyte (amplification and optical enrichment). In this manner the LL dimer (SS) of the dipeptide was amplified and identified as the enantioselective match for (-)-adenosine. 

As fossil fuel resources dwindle, there is growing interest in developing new raw materials for future polymers [121]. As A. Gandini has stated polymers from renewable resources are indeed the macromolecular materials of the future [122]. Between the different renewable resources, carbohydrates stand out as highly convenient raw materials because they are inexpensive, readily available, and provide great stereochemical diversity. 

Triangulanes are a unique class of polycyclic hydrocarbons constructed from spiroannulated cyclopropanes. Because of a stereochemical diversity, the number of isomeric triangulanes sharply increases with increasing the number of cyclopropyl fragments. Consequently, one may speak about the land of triangulanes . 

Compounds containing the Si-N-P linkage combine the structural and stereochemical diversity of phosphorus with the reactivity of the silicon-nitrogen bond. Indeed, much of the derivative chemistry and synthetic potential of these compounds, especially the (silylamino)phosphines such as (Me3Si)2NPMe2, is based on this difunctional character. We report here a general, "one-pot" synthesis of (silylamino)phos-phines and describe their use in the preparation of several types of phosphorus-containing materials. 

There are also many examples that highlight the stereochemical diversity of lignan biosynthesis, as observed in a cell-free extract of Arctium lappa petiole [35], which afforded secoisolariciresinol with the opposite antipode (+) to that formed by Forsythia spp. 

In planning a diversity-oriented synthetic panel of constitutionally and stereochemically diverse anomeric 4a-carbafuranosylamines, our research group remained faithful to the general plan delineated in Scheme 2 (vide supra), by utilizing the pyrrole-based dienoxy silane 76 as the pivotal amine source [7b,e]. 

Su et al. [53] used allylsilanes having C-centered chirality and a distannoxane transesterification catalyst [54] in a sequence of transesterification reactions to rapidly assemble a set of stereochemically diverse macrodiolides reminiscent of polyketide-derivative natural products. Figure 15.20 summarizes the synthesis of stereochemically well defined 14- and 16-member macrodiolides 20.4 and 20.5, resembling known polyketide-derived natural products, from hydroxyl esters 20.2 and 20.3. The feasibility of cyclodimeriztion was studied using different solvents and variable concentrations. Reactions were affected by the choice of the solvent. 

High dilutions reduced the amount of oligomers formed. Preliminary experiments on enantio-enriched hydroxyl esters 20.6 and 20.7, using distannoxane transesterification catalyst, produced stereochemically diverse homo- and heterodimers 20.8-20.10. Functionalization of the macrodiolides was investigated in an effort to create additional structural diversity. Electrophilic epoxidation of macrodiolide 20.9 afforded bis-epoxide 20.11. Further diversification was achieved by treating the macrodiolide bis-epoxide with DBU, which resulted in epoxide ring opening to afford a,P-unsaturated macrolide 20.12. 

Multicomponent Reaction Design Strategies Towards Scaffold and Stereochemical Diversity... 

Molecular complexity (generally found in natural products) seems to be extremely important to obtain an optimal perturbation function and specificity of action of the chemical modulators on their protein targets [2, 9]. The goal of achieving molecular diversity can be divided in three different diversity elements (a) appendage diversity (combinatorial chemistry), (b) stereochemical diversity, and most importantly (c) scaffold diversity (Fig. 2) [2]. 

To create stereochemical diversity within MCRs there is need for stereoselective (or -specific) reactions. Since many MCRs involve flat intermediates, like imines and a,p-unsaturated ketones, they result in the formation of racemic products. Moreover, often mixtures of diastereomers are obtained if more than one stereo-genic centre is formed. However, there are several examples known of asymmetric induction, by the use of chiral building blocks (diastereoselective reactions). For example, it has been successfully applied to the Strecker, Mannich, Biginelli, Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be much harder, have been performed with organometaUic chiral catalysts and orga-nocatalysts [33, 34]. 

Scheme 3 Introduction of stereochemical diversity in the Mannich reaction applying organocatalysis...

Diversity-oriented synthesis of small molecules is a great challenge for synthetic organic chemists. DOS requires the development of new methodologies that generate scaffold diversity in addition to appendage and stereochemical diversity. 

Most examples described in paragraph 3, however, did not address the concept of stereoselectivity, since nearly all products products obtained were isolated as racemic mixtures and/or mixtures of diastereomers. The development of stereoselective MCRs (to be able to introduce stereochemical diversity) remains a major challenge for the future. 

Suzuki, S. (2002) Stereochemical diversity in lignan biosynthesis and establishment of norlignan biosynthetic pathway. Wood Res., 89, 52-60. 

Suzuki, S., Umezawa, T., Shimada, M. (2002b) Stereochemical diversity in lignan biosynthesis of Arctium lappa L. Biosci. Biotechnol. Biochem., 66,1262-9. 

RajanBabu et al. has deeply explored the chemistry of carbohydrate phosphinite complexes [84, 95]. While the carbohydrate backbone provided the necessary stereochemical diversity, substitution patterns around phosphoms were used to vary the steric and electronic properties of the ligand. 

Umarye, J. D., Lessmann, T., Garcia, A. B., Mamane, V., Sommer, S., Waldmann, H. Biology-oriented synthesis of stereochemically diverse natural-product-derived compound collections by iterative allylations on a solid support. Chem. Ear. J. 2007,13, 3305-3319. 

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