Muscone library

Nicolaou, K. C. Pastor, J. Winssinger, N. Murphy, F. Solid Phase Synthesis of Macrocycles by an Intramolecular Ketophosphonate Reaction. Synthesis of a (7//)-Muscone Library, J. Am. Chem. Soc. 1998,120, 5132. 

Solid-Phase Synthesis of Macrocyclic Lactones and a Combinatorial Synthesis of a Muscone Library. 187... 

The same authors demonstrated a solid-phase combinatorial synthesis of a muscone library starting from the monomethyl methanephosphonate 96 bovmd to the Merrifield resin. The key steps were the synthesis of the /1-ketophospho-nates 97, introduction of the aldehyde group, which was necessary for the cyclorelease, and final reduction of double bonds in 98 to the modified mus-cones 99 (Scheme 27). 

FIGURE 11.17 Muscone library. (From Nicolaou, K.C. et al., Solid phase synthesis of macrocycles by an intramolecular ketophosphonate reaction synthesis of a (rfZ)-muscone library, J. Am. Chem. Soc., 120, 10814, 1998.)... 

One of the earliest researchers in the area of natural product-like libraries is K.C. Nicolaou. Inspired by the total synthetic efforts of his group on many important natural product targets and coupled with his interest in synthetic methodology and chemical biology, Nicolaou reported a number of elegant examples (see Chapter 11) that include natural product-like libraries based upon Taxol, " sarcodictyins, epothiolones, vancomycin, muscone, and psammaplin a. ... 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

Another cyclo-release strategy is the HWE reaction, which is attractive because troublesome phosphorus byproducts remain bound to the solid support. Nicolaou et al. demonstrated its potential in the solid-phase synthesis of (J/)-muscone 308 and, using SMART microreactors, a library of analogs.(t//)-Muscone is a natural product... 

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