Substituted diversity-oriented synthesis

The term diversity-oriented synthesis (DOS) is relatively new and, as mentioned above, is usually defined as the synthesis of complex, natural product-like molecules using a combinatorial approach and employing the full palette of modern organic reactions. It may be a subject of discussion what exactly qualifies a molecule as being natural product-like [4], and in most cases the similarity to an actual natural product seems reciprocal to the number of synthesized compounds. However, even in less complex cases, the products may be highly substituted polycyclic structures with defined stereochemistry, reminiscent of natural products [19, 20]. In these cases, a moderately complex backbone structure is subsequently modified with a well-established set of selective reactions to introduce diversity. 

When compounds such as pyrazoles are being made to develop new drugs, a number of related compounds can be prepared at once by diversity-oriented synthesis, that is, methods designed to be general for a wide range of compounds. An example where both components are aliphatic 13 and a tri-substituted example 15 make the point. In this work, the synthesis of 25 different di-or tri-substituted pyrazoles was attempted by the same method only one example failed. 

Practical and diversity-oriented synthesis of multi-substituted benzo[lr] furans was accomplished from simple phenols through a Pummerer annula-tion/cross-coupling sequence. Operationally simple and rapid reactions of phenols with ketene dithioacetal monoxides with the aid of trifluoroacetic anhydride provided the corresponding 2-methylsulfanylbenzo[ ]furans (14BCJ1349). 

Georges and co-workers used the Dimroth rearrangement in their synthesis of substituted verdazyl compounds as templates for the diversity-oriented synthesis of heterocyclic compounds. Verdazyl derivative 71 did not undergo rearrangement to form 72 when refluxed in ethyl acetate (not shown). However, treatment of 71 with either two equivalents of sodium hydride at room temperature or lithium diisopropyl amine in THF at 0 °C gave the corresponding Dimroth product 72 in 82% yield. 

Before this total synthesis project began, we had just completed a diversity-oriented synthesis project that made use of the allylboration reaction to access simple substituted a-methylene y-lactones, which were further functionalized using a variety of transition metal-catalyzed reactions. We were now interested in applying this allylboration methodology to pursue a target-oriented synthetic problem that would demonstrate its suitability toward a complex natural product. Chinensiolide B presented this sort of challenge. 

Scheme 12.5 Schreiber and coworkers application of substituted [3]dendralenes in diversity-oriented synthesis.

Fujita, T. et al.. Synthesis of the new mannosidase inhibitors, diversity-oriented 5-substituted swain-sonine analogues, via a stereoselective Mannich reaction, Org. Lett, 6, 827, 2004. 

The advantages of this method are the ease of modification of each unit and their combination with other pharmacophores as potential pharmacological agents. This transformation could be of immense importance to medicinal chemists using appropriate templates to generate a hbrary of substituted xanthenes. It is proved to be a diversity-oriented protocol for the synthesis of pharmaceutically important molecules like coumarins, chalcones, Schiff base, aiylcoumarins, and dioxocine analogs. 

In 2003, the Uemura group reported a diversity-oriented approach to highly substituted furans based on ruthenium- and platinum-catalyzed intramolecular annulation of propargylic alcohols 59 and ketones 60 (Scheme 19.28) [22]. This reaction is related to the aforementioned pyrrole synthesis (Scheme 19.13). Based on the time profile of the reaction, in which rapid formation/consumption of the alk-4-yn-l-one 63 was seen but only gradual formation/consumption of the diketone 122 was observed, they proposed a mechanism including alkyne hydration and subsequent cyclization of the resulting diketones. However, this reaction can be considered as a furan synthesis by formal reaction between the C=0 and alkyne groups. 

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