Synthesis of - -PGE2 Methyl Ester

Abstracted with permission from J. Org. Chem., 1992,57, 441 1992 American Chemical Society 

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Scheme 49 Synthesis of PGE2-methyl ester using cross-metathesis of aikyne.

Overview The utility of combinatorial chemistry within drug discovery is ultimately linked to the ability to rapidly construct complex molecules on polymer supports. With this in mind, a polymer-supported approach to the prostaglandin core was seen as an important benchmark in the progress of this chemistry. First a two-step liquid-phase version of Noyori s (5) three-component coupling strategy was realized. It allowed the successful synthesis of PGE2 methyl ester la (6) and PGF2 (7) lb (Fig. 1). 

SCHEME 24.84. Synthesis of PGE2 methyl ester by aUtyne CM/Lindlar reduction. 

The selected example by Chen and Janda [175] reported the validation of a method for the synthesis of prostanoid libraries on a soluble polymeric support made by non-crosslinked chloromethylated polystyrene (NCPS). The synthesis of supported PGE2 methyl ester is shown in Figure 7.23. 

FIGURE 7.23 Synthesis of supported PGE2 methyl ester. 

The 2-hydroxyethylthio observation was pursued with the synthesis of many related compounds, a few of which are included in Table VII (69). However, the effect of this substituent proved to be quite structure specific. Thus, homologation of the chain (see entry 14), replacement of sulfur with oxygen (U), and replacement of hydroxy with sulfhydryl (1 ) or with methyl were ineffective. On clinical investigation, 1-11-deoxy-lla-(2-hydroxyethylthio)-PGE2 methyl ester (I) at aerosol doses as high as 800 ijg in asthmatic patients failed to produce a consistent bronchodilation (69). 

The discovery by Upjohn researchers that natural [l.e. 15(S)] PGA2, PGE2 and esterified derivatives are found in the gorgonian coral, Plexaura homomalla (from various locations in the Caribbean area) has led to a short, efficient partial synthesis of PGE2 and PGF20 15(S)-PGA2, acetate, methyl ester ( 1.5 of the frozen wet weight of coral) was con-... 

R H) involving reduction of (R = THP) to the lactol which gave when treated with Fe2(CO)j 2 Addition of the carboxyl sidechain and Collins oxidation, which also disrupted the iron carbonyl complex, gave the desired product. 8-Methyl-PGC2 (R = H, R = CH ), synthesized from 6, had about 3% of the activity of PGE2 in "the smooth muscle test". The eplmeric methyl esters had about 60% of the potency of PGA2 as inhibitors of gastric secretion in the rat. CrabbI has also reported O the synthesis of 5 (R THP, R = H) via ] and A synthesis of optically pure 1 was published, which... 

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