Lactones imidazole ring

Finally, mention must be made of the preparation of the perhydro-furo[2,3-c]pyridin-2-ones 71 and 72. These compounds are conformation-ally restricted analogs of pilocarpine in which the imidazole ring has been replaced by a simple alkylamine moiety fused to the lactone ring (725). 

Cyanogen bromide in alkali joins together amino and isopropylsulphonyl-amino groups as a fused 2-aminoimidazole ring without external heating [3887]. The oxazolinone (76.8) behaves as a lactone this is cleaved, and converts the diamine into an imidazole ring the remainder of the oxazolinone is attached to C-2 of the benzimidazole [3088]. 

Elegant work by W. Langenbeck (168) provided clear evidence that the two alkaloids are stereoisomers. First, he showed that the quaternary salts formed by methylating the two alkaloids are not identical, whereas the structures XVI and XVII would, like 1 4- and 1 5-dimethylimidazole (44), give identical metho salts. He then subjected each alkaloid to ozonolysis isopilocarpine yielded the methylamide XXVI of the known homoisopilopic acid, but pilocarpine gave rise to the methylamide of the hitherto unknown homopilopic acid, in 97 % yield. Thus the isomerism shown by the two alkaloids persists when the imidazole ring is destroyed under mild conditions, and it must therefore be due to a stereochemical difference in the lactonic portion of the molecule. Furthermore, the isolation of methylamides from both alkaloids confirms the 1 5 orientation of substituents in the imidazole nucleus. 

The imidazole ring can be introduced by the addition of 2-lithiol-[(dimethylamino)methyl]-lH-imidazole to 2,3,4,6-0-benzyl-glucono-l,4-lactone to give 42 [77] the reduction of which gave 43 and 44. Mesylation of the latter followed by NaH/DMF gave 45 in 38% yield. Regioselective aroylation of 43 and 44 followed by NaH/DMF gave a mixture of anomers 46 and 47 (80%) presumably via an elimination-addition mechanism (Fig. 8). 

The amino acid L-histidine is the assumed building block in the biosynthesis of pilocarpine (27) and other imidazolic alkaloids due to the presence of glyoxaline ring [8, 23]. First attempts to clarify this pathway were proposed by Boit and Leete that considered the phosphate derivative of 2-oxo-3-(5-imidazofyl)-propanol, also known as imidazole pyruvic acid, as imidazole ring precursor (Scheme 25.1-Pathway 1) [8]. This initial biosynthesis proposal was improved detailing the lactone ring formation by aldol condensation. Another biosynthetic approach suggested condensation of 2-oxobutyric acid (lactone moiety) with urocanic acid (imidazole moiety) (Scheme 25.1- Pathway 2) [8, 39]. 

A stereoselective synthesis of (+)-pilocarpine (7) starting from L-histidine (2) has been worked out by Noordam et al. (88 - 90). Use was made of the S configuration of the amino acid, which is the same as that of C-3 of the lactone ring in both (+)-pilocarpine and (+)-isopilocarpine. Furthermore, regioselective N-alkylation reactions of the imidazole nucleus of histidine had been developed by Beyerman et al. (29,91). Schemes 3 and 4 depict the different ways of the regioselective alkylations. For the synthesis of pilocarpine, the N7I-methylation has been performed via Nb-protection with the 4-nitrobenzenesulfonyl group, instead of the benzoyl group (29). 

Incorporation of a benzylic halide into the structure of the alternate-substrate lactone (12-4) led to the bifunctional lactones (13-1, Table 2.13), and (13-2), which showed rapid and irreversible inactivation of a-chymotrypsin and PPE [178]. It was postulated that the intermediate acyl-enzyme formed from attack of Ser-195 on the lactone carbonyl dehydrohalogenated to form a reactive quinone methide that coupled with His-57. If this mechanism were followed, then lactone (13-2) would be an example of a mechanism-activated inhibitor. However, lactone (13-2) is sufficiently reactive as an alkylating agent to directly couple with imidazole while the lactone ring is intact. Because of this, it is not clear, from the published data, whether acylation of Ser-195 precedes alkylation, a prerequisite for this compound to be confirmed as a mechanism-activated inhibitor. Interestingly, the corresponding coumarin (13-3) was both less potent and only provided partial inactivation of a-chymotrypsin [179, 180]. It was shown that the lactone linkage in this coumarin was stable in the presence of a-chymotrypsin and that the modified enzyme retained its intact active-site. These facts led to the postulate that, like the action of phenacyl bromides or benzyl bromides on a-chymotrypsin, the partial inactivation by (13-3) involves alkylation of Met-192 [179]. 

Triphenylsilyl ethers are typically prepared by the reaction of the alcohol with triphenylsilyl chloride (mp 92-94 °C) and imidazole in DMF at room temperature. The dehydrogenative silylation of alcohols can be accomplished with as little as 2 mol% of the commercial Lewis acid tris(pentaf1uorophenyl)borane and a silane such as triphenylsilane or triethylsilane [Scheme 4.98]. Primary, secondary, tertiary and phenolic hydroxyls participate whereas alkenes, alkynes, alkyl halides, nitro compounds, methyl and benzyl ethers, esters and lactones are inert under the conditions. The stability of ether functions depends on the substrate. Thus, tetrahydrofurans appear to be inert whereas epoxides undergo ring cleavage. 1,2- and 1,3-Diols can also be converted to their silylene counterparts as illustrated by the conversion 983 98.4. Hindered silanes such as tri-... 

Chemically, the majority of Pilocarpus alkaloids hold simultaneously an imidazole and a y-lactone ring. Epimerization at C2 and C3 carbons of the lactone moiety is commonly observed, and this change in absolute configuration gives rise to some compounds that can naturally occur in Pilocarpus species or are generated during extraction procedures [23, 25]. 

V-(Trimethylsilyl)imidazole has proven to be a good nucleophile for the ring opening of epoxides,but a moderate one for the ring opening of either optically pure iV-Cbz-L-serine- -lactone or thiiranium ion intermediates. ... 

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