PGE2 methyl ester

On the other hand, treatment of 11-nor PGE2 methyl ester (216) with an excess of o-mesitylenesulfonylhydroxylamine in CH2C12 at 0 °C, followed by passage of the reaction mixture through a bed of basic alumina yielded regioselectively the y-lactam prostaglandin (217)12). 

Alkyne metathesis is employed for constructing the a-chain of PGE2.methyl ester. Reaction of alkyne 144 and symmetrical alkyne 145 in a slight excess in the presence of the I4O/CH2CI2 catalyst produces the desired CM product 146 in 51% yield, which is then converted to PGE2.methyl ester by partial reduction with a Lindlar catalyst leading to (Z)-olefin 147 and subsequent deprotection (Scheme 49). 

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

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. 

PGE2 methyl ester PGE2 methyl ester PGE2 methyl ester ester... 

Particularly high sclcctivities are obtained with diisobutylaluminum 2,6-di-/m-buty 1-4-methyl phenoxide (16, see Table 1, p4101). Thus, the prostaglandin PGE2 methyl ester is reduced to the 8,9-cis-prostaglandin PGF2a methyl ester in 95% yield and 100% ee132. 

Enprostil (Gardin) (+)-4,5-Dide hydro-16-phenoxy-a-tetranor-PGE2 methyl ester... 

None of the above noted 11-substituted analogs was more than minimally effective in our bronchodilator assays. However, lla-(2-hydroxyethylthio)PGE2 methyl ester (235) did prove to be a potent bronchodilator of sufficient interest to warrant clinical investigation (see Section VB). This compound was prepared as a separable mixture with its llp-epimer 236 by the addition of 2-mercaptoethanol to I-PGA2 methyl ester (2W) (69,107). 

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). 

Figure 9.39 Methane chemical ionization spectra at 2.0Torr reactor 225 °C. (A) PGEi methyl ester. (B) PGE2 methyl ester. (C) PGFi methyl ester. Samples were applied to the belt continuously (Privett and Erdahl, 1978).

Patterson and Fried [139] inserted the a-side chain by alkylation of a cyclo-pentatone enol ether. Intermediate (127) was first obtained by reaction of cyclopent-2-enone with an organocopper reagent followed by formation of the silyl enol ether and the a-chain then added by alkylation of 127 with c/s-7-bromooct-5-enoate, thus leading to ( )-l l-deoxy-PGE2 methyl ester. 

The biological activity [229,230], pulmonary effects [231] and cardiovascular actions [232] of the 15(/ )-15-methyl analogue of PGE2 have been reported. In addition, both 15(5)-15-methyl-PGE2 methyl ester and 16,16-di-methyl-PGE2 have been reported to be potent inhibitors of hormone-stimulated lipolysis [233], and the potency and selectivity of these analogues on rat gastro-... 

There have been no reports to date demonstrating an anti-ulcer effect in similar patients. One of the significant factors in the activity of this analogue is that the unnatural configuration at the 15-position undergoes epimerisation in gastric juices or in dilute HO solution to a 1 1 mixture of both the 15(/ ) and 15(5) compounds [315]. Comparable efforts to epimerise 15(/J)-15-methyl-PGE2 methyl ester resulted in only a trace formation of the 15(5) compound. 

Another Upjohn analogue, 16,16-dimethyl-PGE2 methyl ester has also been shown to be anti-secretory after oral administration to healthy volunteers [316,317]. Similar studies in patients with duodenal ulcers indicated that much... 

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). 

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