Enantioselective Synthesis of ( + )-Polyzonimine , Defensive Monoterpene Alkaloid Produced by a Milliped Polyzonium rosalbum , and Determination of Its S Absolute Configuration by Its Conversion to ( 4 S , 5 R , 6 S )-( + )-Nitropolyzonamine

A adição de Michael da enamina derivada do 2,2-dimetilciclopentanocarboxaldeído e do éter metílico do ( S)-prolinol com o nitroetileno, forneceu o aduto correspondente em 75-76% ee, o qual foi convertido na (+)-polizonimina enantiomericamente pura, um espiro composto nitrogenado isolado das glândulas que contêm os compostos de defesa do “milliped” Polyzonium rosalbum. Através da conversão da (+)-polizonimina na (4 S, 5R, 6S)-(+)-nitropolizonamina, foi possível estabelecer a configuração absoluta desta como sendo S.


Introduction
Chemical defense against predation by other organisms is an important research subject in chemical ecology as pioneered by Eisner 1 .In 1975, in the course of their studies on compounds from the defensive glands of a milliped Polyzonium rosalbum, Meinwald, Eisner and their respective co-workers isolated and identified the following two nitrogen-containing spirocyclic compounds 2,3 .(+)-Polyzonimine {6,6-dimethyl-2-azaspiro [4.4]non-1-ene (1)} was isolated as a volatile insect repellent, which acts as a topical irritant to predating insects such as ants and cockroaches 2 (Figure 1).

Results and Discussion
Our synthesis of polyzonimine (1) and nitropolyzonamine (2) are summarized in Scheme 1.We envisaged that asymmetric Michael addition of enamine 8 or its analogues to nitroethylene must be successful, if a proper chiral auxiliary is chosen.Nevertheless, we were not too optimistic to expect 100% asymmetric yield in that step, and therefore the enantiomeric purity of the product must be enriched later via an appropriate crystalline derivative.
2,2-Dimethylcyclopentanecarboxaldehyde (7), the known starting material, was synthesized by a route different from the previous ones. 2,5Commercially available 2-methylcyclohexanone (3) was converted to 4 according to Kawanobe et al. 8 .Oxidation of 4 with hydrogen peroxide afforded 5 9 , which was reduced with lithium aluminum hydride to give alcohol 6. Swern oxidation of 6 furnished the desired aldehyde 7.
For the preparation of chiral enamine such as 8, three chiral amines derived from (S)-proline were examined: (i) (S)-proline tert-butyl ester as employed by Yamada's group 10 , (ii) (S)-prolinol methyl ether as used by Seebach's group 11 , and (iii) (S)-1-amino-2-(1-methoxy-1ethylpropyl)pyrrolidine as developed by Enders's group 12 .The aldehyde 7 could be converted to the corresponding enamines, when it was treated with the former two amines in the presence of MS 4A 13 .The third one which was prepared according to Enders et al. 14 , however, did not afford the corresponding enamine, presumably due to the presence of the two bulky ethyl groups on the side-chain.
The next step was the crucial asymmetric Michael addition of the enamine 8 as well as its analogue prepared from (S)-proline tert-butyl ester to nitroethylene generated from 2-nitroethyl acetate 15 and N-ethylmorpholine in acetonitrile 16 .Chromatographic purification of the product over silica gel gave crude 9 with concomitant removal of the chiral auxiliary.Because neither determination of its absolute configuration nor estimation of its enantiomeric purity was possible, the crude product 9 was further processed to give 1 eventually.The absolute configuration of 9 as depicted in the formula became clear only after its conversion to (4S,5R,6S)-(+)-2.
Prior to the reduction of the nitro groups of 9, its formyl group was protected as ethyleneacetal to give 10.Reduction of the nitro compound 10 to amine 11 was best accomplished with lithium aluminum hydride.Catalytic hydrogenation of 10 with various catalysts was very sluggish in our hands.Treatment of 11 with hydrochloric acid gave (+)-polyzonimine (1), whose enantiomeric purity could be estimated by GC analysis on Chirasil-DEX-CB ® .The enamine (S)-8 turned out to be the superior one in the asymmetric Michael reaction to give (+)-1 of 75-76% ee, while the enamine derived from 7 and (S)-proline tert-butyl ester furnished (+)-1 of only 4% ee.It thus became clear that the use of (S)-8 gave predominantly the product 9 leading to the naturally occurring (+)-enantiomer of polyzonimine (1).The overall yield of (+)-1 via (S)-8 was 42% based on 7 (5 steps).
In a similar manner, the opposite enantiomer (-)-1' of polyzonimine, [α] D 23 = -3.3(CHCl 3 ), was synthesized via enamine 8' derived from 7 and (R)-prolinol methyl ether.Conversion of (-)-1' to (-)-2' was also achieved.The enantiomers of polyzonimine (1 and 1') were bioassayed to compare their insect repellent activity.The test was executed under the standard conditions employed in Sumitomo Chemical Co. and was not designed to estimate their activity as a topical irritant.Neither of them showed insect repellent activity when tested on the German cockroach (Blattella germanica).Both of them, however, showed oviposition deterrant activity against the webbing clothes moth (Tineola bisselliella).