Polyzonimine

Last but not least, a very intriguing terpenoid pyrrolidine alkaloid, poly-zonimine was milked from the millipede Polyzonium rosalbum (148). The structural formula of polyzonimine (118) is based on an X-ray crystallographic analysis of its perchlorate and by a total synthesis. 

Perhaps the most interesting arthropodan defensive compounds from the point of view of structural diversity are the alkaloids. While alkaloids had long been believed to arise only as a consequence of plant secondary metabolism, it has become apparent over the last few decades that arthropods are both prolific and innovative alkaloid chemists. The millipede Polyzonium rosalbum, once thought to secrete camphor (20), in fact gives off a camphoraceous/earthy aroma produced by the spirocyclic isoprenoid imine polyzonimine (21). 

Another millipede, Polyzonium rosalbum, contains two alkaloids, poly-zonimine (19) and nitropolyzonamine (49), in its defensive secretion (Tables II and IV). Polyzonimine (19) is repellent to such natural enemies as ants and might effect the deterrence of various insects by acting as a topical irritant 113). 

Polyzonimine (19), isolated from a millipede secretion by preparative gas-liquid chromatography (Table II), has been assigned the molecular formula... 

The racemic polyzonimine (19) is prepared as shown in Scheme 33. The expoxide (314) is rearranged to the aldehyde (315) by refluxing with LiBr-HMPA in benzene. Morpholine enamine (316) derived from 315 is condensed with nitroethylene, generated in situ from 2-acetoxynitroethane, to afford the nitroaldehyde (317). Ethylene acetalization, reduction over Raney nickel, and subsequent deacetalization give ( )-polyzonimine (19) in 22% overall yield from the epoxide (314) 113). 

Natural (-l-)-polyzonimine (19) has been synthesized by a reaction sequence using the asymmetric [2,3]sigmatropic rearrangement of the ammonium ylide to generate the chiral intermediate. The Homer-Emmons reaction of the ketone... 

Nitropolyzonamine (49) (Table IV) can be isolated as colorless crystals from the secretion of the millipede, P. rosalbum, by preparative gas chromatography or as its crystalline perchlorate from an ethereal solution of the crude defensive secretion. The structure and stereochemistry have been determined by an X-ray analysis of the base perchlorate 153). Racemic nitropolyzonamine (49) can be synthesized from polyzonimine (19). Treatment of polyzonimine (19) with 3-nitropropyl iodide gives a crystalline salt (344) which is readily cyclized to racemic nitropolyzonamine (49) in boiling pyridine (Scheme 37) 153). 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

The defence secretion of the milliped Polyzonium rosalbum contains the spiro-monoterpenoid polyzonimine (35) 97 the isolation of the spirocyclic nitro-compound (36)98 might suggest a non-geranyl pyrophosphate biogenetic route from a pyr-rolizidine alkaloid. The production of verbenone in the bark beetle Dendroctonus sp. may be associated with chemical communication.99... 

Nothing is known of the biological activity of these spiropentano-pyrrol-izidine oximes. A bicyclic spiropentano-pyrroline, polyzonimine from a millipede is a potent topical irritant to insects 154). 

The pyrrolizidine oximes are unknown in Nature except in amphibians. There are, however, two closely related natural products, nitropoly-zonamine (the oxime of236 is replaced by a j3-nitro substituent in nitropo-lyzonamine) and its proposed bicyclic precursor polyzonimine, both of which were isolated from defensive secretions of the millipede Polyzonium rosalbum 154,155). Nitropolyzonamine, like the amphibian pyrrolizidine oximes, is dextrorotatory 155). Neither nitropolyzonamine nor polyzonimine has been detected in amphibians. 

The second gave the trisubstituted alkene -98 (together with 9% of the Z-isomer) and this was used to make the interesting millipede compound polyzonimine.18... 

Our synthesis of (5,)-(+)-polyzonimine (69) is summarized in Figure 3.18.52,53 Commercially available 2-methylcyclohexanone A was converted to aldehyde B. This was treated with (S)-prolinol methyl ether... 

The first synthesis of polyzonimine (119) was a synthesis of the racemate carried out by Smolanoff and co-workers in 1975 at the time of its isolation and structure elucidation (111). Oxidation of 3,3-dimethylcyclohexene (368) with meto-perchlorobenzoic acid followed by treatment of the epoxide with lithium bromide and HMPA in refluxing benzene gave the carboxal-dehyde 369. The morpholino enamine 370 was then subjected to Michael addition with nitro-ethylene, generated from 2-acetoxy-nitroethane, to afford a nitro aldehyde 37L Ketalization and reduction with Raney nickel then afforded ( )-119 in overall yield for the five steps of 22% (Scheme 45) (111). 

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