Pyrazole Alkaloids

Scheme 11.30. Synthesis of the pyrazole alkaloid withasomnine 117, with cyclopropanation of ethyl 4-chloro-butyrate (113) as an initial step [66],...

Syntheses of pyrrolo[l,2-Z>]pyrazole alkaloid vitasomnin and its structural analogs 03MI21. 

The unique pyrazole alkaloid, withasomnine (33), has been independently synthesised by two groups in not less than four routes. One of these uses... 

In incorporation studies80 with intact Withania somnifera plants, the pyrazole alkaloid withasomnine (124) incorporated activity from DL-[3-14C]phenylalanine (0.002%) and DL-[2-14C]ornithine (0.004%). No degradations were carried out so the significance of these very low incorporations is not clear. 

Fig. 3.6 Pyrrolidine and piperidine alkaloids from Withania somnifera stereochemistry not given due to isomerizations (see Fig. 3.5). In the structure of the pyrazol alkaloid withasomnine, a masked pyrrolidine, the second biogenetic element, phenethylamine (derived from L-phenyla-...

Adesanya SA, Nia R, Fontaine C, Pais M (1994) Pyrazole alkaloids from Newbouldia laevis. Phytochemistry 35 1053-1055... 

Ravikanth V, Ramesh P, Diwan PV, Venkateswarlu Y (2001) Pyrazole alkaloids from Elytraria acaulis. Biochem Syst Ecol 29 753-754... 

Schroter HB, Neumann D, Katritzky AR, Swinboume FJ (1966) Withasomnine. A pyrazole alkaloid from Withania somnifera Dun. Tetrahedron 22 2895-2897 Schulte KE, Rucker G, El-Kersch M (1972) Nicotin und 3-Formyl-4-hydroxy-2H-pyran aus... 

The alkaloid whitasomnine 44 was prepared according two different routes. The first approach (route A) was based on the cyclization of the l-(3-chloropropyl)cyclopropanol 41 (Scheme 3). The final cyclization involved the reaction of 3-(3-chloropropyl)pyrazole 42 to form the final pyrazole 43 in 40% yield, which is then transformed to the natural product <1996TL1095>. The second approach (route B) is based on the radical cyclization of the substituted pyrazole 45 in the presence of Bu3SnH in acetonitrile under refluxing toluene. Whitasomnine 44 was isolated in 38% yield <2002TL4191>. 

Aromatic azapentalenes have not been found naturally, though an imidazo[4,5-d]imidazole derivative has been implicated in the prebiotic synthesis of purines130 74 (see also Section III,A,l,d). Saturated derivatives occur fairly widely the Senecio alkaloids contain the reduced pyrrolol l,2-a]pyrrole (pyrrolizidine) skeleton,487 and the alkaloid withasomnine is a derivative of pyrrolo[ l,2-6]pyrazole.374,488 The mitomycin antibiotics mentioned earlier in this review (Sections III,B,l,f and III,B,5) contain the pyrrolol l,2-a]indole ring,166,331 and the recently reported fungal metabolite sporidesmin is a saturated derivative of pyrrolo[2,3-6]indole.489... 

It was possible also to incorporate unnatural precursors into the alkaloids of Dolichothele sphaerica (164,165,168,169). On feeding of 3-aminoethyl-pyrazole, the alkaloid 3-(Ar-isovalerylaminoethyl)pyrazole (112) was produced, and A -isocaproylhistamine was obtained by the simultaneous feeding of 4-methylpentanoic acid (isocaproic acid) and of 4(5)-aminoethy-... 

Kulinkovich, O., N. Masalov, et al. (1996). New synthetic route to the alkaloid whithasomnine by ring transformation of a functionalized cyclopropanol via the parent pyrrolo (1,2-b) pyrazole. Tetrahedron Letters 37(7) 1095-1096. a Dep. Organic Chem., Belarussian State Univ., Fr. Scorina Av. 4, Minsk 220050, Belarus. 

Proton NMR data of a series of 5,6-dihydro-4 f-pyrrolo[l,2-b]pyrazoles (25) have been described in a paper related to synthesis of the alkaloid withasomnine (R = Ph, R = H) <83TL1067>, and are collected in Table 2. 

Similarly, for the construction of a central imidazolinone core skeleton of rhopaladin D, a marine alkaloid, the PS-BEMP promoted aza-Wittig reaction followed by intramolecular cyclization was used [64], and a tetrasubstituted pyrazole ring of sildenafil... 

Legentil L, Benel L, Bertrand V, Lesur B, Delfoume E (2006) Synthesis and antitumor characterization of pyrazolic analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines. J Med Chem 49 2979-2988... 

Amidations of vinyl iodides have also been used to advantage in synthesis. Enamides such as 50-52 are representative of the procedures available (Scheme 1-3). By proper choice of nucleophile, annulations to either pyrroles 54 (15 examples) or pyrazoles 55 (10 examples) can be induced with Cul-catalysis after an initial amidation of enyne 53. " Subsequent 5-endo-dig cyclization produces the heteroaromatic products (Scheme 1-4). Several total syntheses have successfully applied this approach, as examples, to construction of key enamide antibiotic CJ-15,801 (56), and the naturally occurring cyclopeptide alkaloid paliurine F (57), where this methodology served as a tool for macrocyclization. " ... 

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