Pesric. Sci. 1980, 11, 129-133

A New Synthesis of Natural Pyrethrins"

Istvan SzCkely, Marianna Lovisz-Gispar and Gibor Kovics

Chinoin Chemical and Pharmaceurical Works Lrd, H-1325 Budapest, PO Box 110, Hungary

A synthesis route, based on a by-product of a prostaglandin synthesis, provides access to rethrolones and rethrins with the same stereochemistry at the ring C-4 position as the natural compounds. For cinerin I, the overall yield is good and the product is a mixture of side-chain E and Z isomers. The Z : E ratio varies from 3: 1 to 10: 1 depending on the conditions employed.

1. Introduction

Various different approaches have been described in the last three decades for the synthesis of natural pyrethrinsl, 2 and several potentially can give optically active products. However the best route to these natural products is still from industrially available (S)-bi~allethrin.~. A new syn- thesis of natural pyrethrins is described here using an optically active prostaglandin intermediate by-product as starting material.5

The structural correlation between prostaglandins and pyrethrins, established in 1973,6, demonstrated that the chirality of pyrethin I and other pyrethrins at the ring C-4 position is opposite to that of the corresponding centre at C-11 of natural prostaglandins. The resolution by-product in the Corey prostaglandin synthesis,sp9 for example, is therefore suitable as a starting material for the preparation of natural rethrolones and rethrins.

2. Synthesis routes

2.1. Synthesis of cis-jasmone and jasmololone To work out a proper transformation sequence, cis-jasmone (IV) was prepared as outlined in Figure 1. Using a functionalised derivative (III)lo of I, the optically active 4-(tetrahydropyrany1oxy)- jasmone (V)ll could be prepared similarly and thence jasmololone with [a]E+9S0 (9.3 g in 100 ml ethanol), showing that in the critical reaction E (Figure l), the spontaneous isomerisation did not affect the ring C-4 centre.

Recently prostaglandin research at Chinoin found a very effective and direct preparation of VI and the enantiomeric lactone diol (VI) by using a regio- and stereo-specific Prins reaction.lZ The lactone diol by-product VI, the enantiomer of which has the natural prostaglandin chirality, was used as starting material to synthesise cinerin I (VII, R = Me; Figure 2), basically following the route developed for cis-jasmone. The chiroptical and spectral data were in good agreement with those in the literature.13.14 This method could also be used to synthesise jasmolin I (VII, R = Et), (S)-bioallethrin (VII, R = H) and pyrethrin I (VII, R = CH=CHz) in optically pure forms using the proper phosphorane in the Wittig step. In the case of pyrethrin I the side-chain geometry was controlled by the method of Sasaki et aL4 Examination of the side chain geometry of the cinerin I by nuclear magnetic resonance spectrometry showed no separated signal nor signal

a Presented at a symposium Recent advances in the chemistry of the pyrethroids held at St Catherine's College, Oxford, 16-19 July 1979 and organised jointly by the Pesticides Group of the Society of Chemical Industry, and the Fine Chemicals and Medicinals Group of the Industrial Division of the Chemical Society.

0031-613X/80/040&0129 $02.00 0 1980 Society of Chemical Industry

129

130 I. Szkkely et al.

0 0

(1)

OH

(11) R = H (111) R = Tetrahydropyranyloxy

c, 8 D, R~:H=CH lCH,\ CH, R l : = C H /CHz\ CH,

R

(IV) R = H (V) R = Tetrahydropyranyloxy

CI-I,-Cl R

Figure 1. Preparation of cis-jasmone. Reactions A-E are as follows: A, sulphuric acid/dichloromethane; B, methanolic sodium hydroxide; Raney nickel and hydrogen ; hydrolysis; palladium and hydrogen ; C, triphenyl- phosphineicarbon tetrachloride; di-isobutylaluminium hydride/toluene; D, propylident(triphenyl)phosphorane/ benzene or triphenyl(propyl)phosphonium bromide, sodium ethoxide, toluene, reflux; E, Jones oxidation. The overall yield of IV from 1 was 43.8 %.

0

A, $ D, R l : = C H /R

CH,-OH CH,-Br I I 0 HO HO

WI) OH 0

c, C X H , Kl:H-." /R D, K1LCH /R

\ CII, CH,

CH,

\ co 0 II co /C=CH I I CH,

/C=CH

0 (VII)

Figure 2. Synthesis of cinerin I. Reactions A-E are as follows: A, triphenylphosphine/carbon tetrabromide or bromine; di-isobutylaluminium hydride/toluene ; B, R-methylidene(triphenyl)phosphorane/benzene; C , chrysan- themoyl chloride/pyridine; D, pyridinium chlorochromate. The overall yield from VI of cinerin I ( R = Me) was 29%; forjasmolin I (R=Et) was 31.4%; for pyrethrin I (R=vinyl) was 9.57;.

group which could be used for determination of the cis: trans ratio. In the but-2-enyl side-chain, the crucial signals for the CHZ and CHa protons overlapped at 2.93 and 1.71 parts per million, respectively [Figure 3(a)].

The decoupled spectrum (irradiation at 3 parts per million) at the CHz protons [Figure 3(b)] resulted in the dq dq splitting pattern of the side-chain olefinic protons around 5.48 and 5.27 parts

New synthesis of natural pyrethrins 131

Figure 3. (a) Nuclear magnetic resonance spectrum of cinerin I showing overlapping of crucial signals for the CH2 and CH3 protons of the but-2-enyl side chain at 2.93 and 1.71 parts per million, respectively; (b) decoupled spectrum of (a) above showing dq dq splitting pattern of side chain olefinic protons around 5.48 and 5.27 parts per million (enlarged above the spectrum).

per million (enlarged above the spectrum). The additional peaks in the region can very likely be allocated to the trans isomer but these could not be used to determine the cis: trans ratio. On the other hand, when the ester bond15 was hydrolysed, the cis:trans ratio of the cinerolone obtained, with unchanged side-chain geometry, could be determined, simply by integration of the doubled methylene doublets at 2.94 and 2.9 parts per million, or of the two doubled methyl doublets at 1.72 and 1.68 parts per million, respectively (Figure 4). The olefinic proton area was uncharac- teristic and useless in this instance [Figure 4(a)l. Figure 4 shows a 3 : 1 cis: trans ratio. In this case two equivalents of the phosphorane were added to one portion; using stepwise addition (by which after one equivalent of phosphorane had been added, the precipitated phosphonium salt was filtered off, and the second equivalent phosphorane was added afterwards), an 85: 15 ratio was observed. The method of Pattenden and Storer3 was also used, in the course of the preparation of V, in the Wittig step. In this case the ratio was over 9: I .

3. Conclusions

The new synthesis of pyrethrins described here is ready for industrial preparation of cinerin I. The new method gives access to previously unavailable analogues and derivatives that could

132 I. SzCkely et al.

,-

I r -- I i i

d

Figure 4. (a) Nuclear magnetic resonance spectrum of cinerolone showing a 3: 1 cis:trons ratio; (b) the olefinic proton area of (a) above as in Figure 3(a).

contribute to the understanding of the relationship between structure and activity in this extremely important group of insecticides.

Acknowledgement The authors are grateful to Dr Pkter Dvortsak for helpful discussions of nuclear magnetic resonance spectra.

References 1. 2. 3. 4. 5.

6. 7.

Pyrethrum (Casida, J . E., Ed.), Academic Press Inc., New York, 1973, pp. 71-74. Crombie, L.; Hemesley, P.; Pattenden, G. J. Chem. SOC. (C) 1969, 1016-1024 and references therein. Pattenden, G.; Storer, R. J. Chem. SOC., Perkin Trans. Z 1974, 1603-1606 and references therein. Sasaki, M.; Okada, K.; Matsui, M. Agric. Biol. Chem. 1979, 43, 379-381. For another example of this principle, see Yamada, S.; Kitamoto, M.; Terashima, S. Tetrahedron Lett. 1976, 3 165-3 168. Miyano, M.; Dorn, C. R. J. Am. Chem. Soc. 1973, 95, 2664-2669. Begley, M. J.; Crombie, L.; Simmonds, D. J.; Whiting, D. A. J. Chem. Soc., Perkin Trans. Z 1974, 1230- 1235.

8. Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinshenker, N. M. J. Am. Chem. SOC. 1970, 92, 397-398.

New synthesis of natural pyrethrins 133

9.

10.

11. 12. 13. 14.

15.

Corey, E. J.; Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma, R. K. J . Am. Chem. Soc. 1971, 93,

Corey, E. J. ; Shirahama, H.; Yamamoto, H.; Terashima, S.; Venkateswarlu, A.; Schaaf, T. K. J. Am. Chem. Soc. 1971, 93, 1490-1491. Szekely, I . ; Lovasz-Gaspar, M.; Kovacs, G. Terrahedron Lett. 1976, 45054506. Tomoskozi, I.; Gruber, L.; Koviics, G.; Szekely, I.; Simonidesz, V. Tetrahedron Lett. 1976, 46394642. Crombie, L.; Pattenden, G.; Simmonds, D. J. J . Chem. Soc. Perkin Trans. I1975, 1500-1502. Bramwell, A. F.; Crombie, L.; Hemesley, P.; Pattenden, G.; Elliot, M.; Janes, N. F. Tetrahedron 1969, 25, 1727-1741. Horiba, M.; Kitahara, H.; Murano, A. Agrie. Bid . Chem. 1977,41, 2003-2006.

149 1-1493.