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The common silk moth (bombyx mori)

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(10E,12Z)-hexadeca-10,12-dien-1-ol

(10E,12Z)-hexadeca10,12-dien-1-ol

Bombykol The sex pheromone (10E,12Z)-hexadeca10,12-dien-1-ol

765-17-3

The bombyx mori silk moth

Well, it was the first insect pheromone to be identified nearly 50 years ago, in 1959, by Adolf Friedrich Johann Butenandt (1903-1995), photo,.
He won a Nobel Prize for Chemistry in 1939 at the age of 36, for his work on sex hormones; after that, he turned his attention to insect attractants, successively at theKaiser-Wilhelm Institute of Biochemistry at Berlin-Dahlem; the University of Tbingen(1945-56), and the University of Munich (1956-71).

The saturated acid first undergoes oxidation catalysed by a Z11 desaturase enzyme, to generate the first double bond. The second step is more unusual, involving 1,4-elimination of two hydrogens to afford a conjugated diene, catalysed by a 10,12desaturase enzyme. Finally a reductase enzyme converts the carboxylic acid group into a primary alcohol (fatty acyl reduction).

Bombykol, 10(E),12(Z)-hexadienol, has been identified as a sex pheromone of the silkworm Bombyx mori and can be used in pest control. It has been synthesized on a gram scale according to the route indicated in Fig. 1. Starting from vernolic acid (1), first the epoxy group was ringopened, resulting in a diol product (2). This diol could be selectively cleaved to the aldehyde (3) without affecting the carbon-carbon double bond and leaving hexenal (4) as a side-product, that in itself may find useful applications in the flavor industry. Protecting the carboxylic acid group and isomerization of the double bond yielded a reactive intermediary product [12-oxo-10(E)-dodecenoic acid (5)] which contained a carboxylic ester and also an aldehyde functionality in conjugation with the carbon-carbon double bond. Subsequent Wittig olefination of (5) leads to the 10(E), 12(Z)-product (6), which is selectively reduced to bombykol (7).

He did this by bioassays. Unlike the wild silk moth (Bombyx mandarina), the domesticated silk moth cannot fly, but responds to the female's pheromone by getting excited and flapping his wings in what is known as a "flutter dance". The scientists tested each fraction by diluting it and finding out the minimum concentration needed to make 50% of the males in a sample respond. The purer the material, the less needed to produce the flutter dance. Eventually material was obtained that contained just one component, and was pure bombykol. The team were lucky in that the pheromone only comprised one substance; multi-component pheromones are common (although the female Bombyx mori emits a mixture comprising bombykol with a small amount of the corresponding aldehyde, bombykal, the male receptor only bonds bombykol).

Male silk moth, right, gets excited by the female. The female is bigger, because of the eggs she is carrying. She is extending her pheromone gland and releasing bombykol. Reproduced with the permission of Professor Walter S. Leal.

Overall structure of the B. mori PBP. Disulfide bridges are shown in yellow, and the loop covering the binding pocket (see text) is in orange. Bombykol is shown in a ball-and-stick representation with double bonds in green. Reproduced with permission of Professors Jon Clardy and Walter S. Leal from: B.H.Sandler, L.Nikonova, W.S.Leal and J.Clardy, Chem. Biol., 7, (2000) 143.

Bombykol is at the centre of the figure in ball-and-stick representation. The hydroxyl group is red, and the double bonds are green. Residues surrounding bombykol are shown in stick representation. The hydroxyl group of bombykol forms a hydrogen bond with the sidechain of Ser56 with an O-O distance of 2.8 . Reproduced with permission of Professors Jon Clardy and Walter S. Leal from: B.H.Sandler, L.Nikonova, W.S.Leal and J.Clardy, Chem. Biol., 7 (2000) 143.

1.Bombykol, the sex pheromone of the silkworm moth, has been prepared in the following way: 1-pentyne + n-C4H9MgBr CH3CH2CH2CCMgBr

A + HCHO; then H+ CH3CH2CH2C CCH2OH


B + PBr3 CH3CH2CH2CCCH2Br C + Ph3P, base CH3CH2CH2CCCH=PPh3 D + OHCCH2(CH2)7CO2C2H5 CH3CH2CH2CCCH=CHCH2(CH2)7CO2C2H5 E + H2/Pd CH3CH2CH2CH=CHCH=CHCH2(CH2)7CO2C2H5 (cis)

F + LiAlH4 CH3CH2CH2CH=CHCH=CHCH2(CH2)7CH2OH (cis)

Extraction and purification It was the German chemist Adolf Butenandt who worked out what was really going on. He started by taking the pheromone glands from the female silk moth and extracting the chemicals they produced. Since bombykol is only ever produced in tiny quantities by the moths, he needed lots of glands to get even the tiniest amounts of material to work with

Spectroscopy and identification After many cycles of purification, Butenandt started to work out the chemical structure of the molecule. He used infrared spectroscopy to reveal that there is an alcohol group and two carbon-carbon double bonds present. He used a variety of chemical degradation methods to work out the length of the carbon chain and the position of the double bonds. Butenandt managed to confirm the structure by synthesising bombykol from scratch. He prepared all four of the possible geometric isomers of the double bonds, and found that one of them was at least a billion times more effective at exciting the male moths!

1HNMR

C13 NMR

INTERMEDIATES

C13 NMR

C13 NMR

C13 NMR

Bibliography

Dictionary of Organic Compounds, J. Buckingham and F. McDonald, eds., Chapman and Hall, London, 6th

edition, 1995, Compound H-0-00578 http://en.wikipedia.org/wiki/Bombykol J.H. Fabre, The Life of the Caterpillar, trans. A. Texeira de Matos, Hodder and Stoughton, London, 1912, p.246 ff;http://www.ibiblio.org/eldritch/jhf/c11.html W. C. Agosta, Chemical Communication. The Language of Pheromones, Scientific American Library, 1992, esp. pp 63 ff. D. Schneider, Science, 1969, 163, 1031. (insect olfaction: deciphering system for chemical messages) P. Witzgall and A. El-Sayed (eds), Insect Semiochemicals - IOBC wprs Bulletin 22(9), 2000 (Proceedings of IOBC wprs Symposium, Dachau 1998) http://www.phero.net/iobc/dachau/bulletin99/schneider.pdf (Schneider's research on detecting pheromones) A. Butenandt, R. Beckmann, D. Stamm and E. Hecker, Z. Naturforsch, Teil B, 1959, 14, 283 (characterisation of bombykol) T. Ando, T. Hase, A. Funayoshi. R. Arima and M. Uchiyama, Agric. Biol. Chem., 1988, 52, 141 (biosynthesis of bombykol) B.H. Sandler, L. Nikonova, W.S. Leal and J. Clardy, Chem. Biol., 2000, 7, 143 (structure of the bombykol-PBP complex) V. Klusk, Z. Havlas, L. Rulek, J. Vondrek and A. Svato, Chem. Biol., 2003, 10, 331 (ab initio study of the bombykol-PBP complex) W.S. Leal, A.M. Chen, Y. Ichida, V.P. Chiang, M.L. Erikson, T.I. Morgan and J.M. Tsuruda, Proc. Nat. Acad. Sci. USA, 2005, 102, 5386 (pheromone binding) R. Rybczynski, R.G. Vogt and M.R. Lerner, J. Biol. Chem., 1990, 265, 19712 (deactivating pheromones) Y. Ichida and W.S. Leal, Proc. Nat. Acad. Sci. USA, 2005, 102, 14075 (deactivating pheromones) F. Grter, B.L. de Groot, H. Jiang and H. Grubmller, Structure, 2006, 14, 1567 (pheromone release from the bombykol-pheromone binding protein complex) C. Lautenschlager, W.S. Leal and J. Clardy, Structure, 2007, 15, 1148. (flexibility of the PBP binding site)

Biosynthesis of sex pheromone Bombykol

Silkmoth Sex Pheromones We have identified a fatty acid desaturase gene (bmpgdesat1) and a pheromone gland-specific fatty-acyl reductase gene (pgFAR) involved in species-specific sex pheromone biosynthesis in the Bombyx mori silkmoth. A transformed yeast,Saccharomyces cerevisiae, expressed the B. mori pgFAR evoked typical mating behavior in male moths when cultured with the pheromone precursor. We hope to establish a novel method for pest control using similar insect genes. For example, if we plant transgenic weeds that express these insect genes around grains, the species-specific sex pheromone released from the weeds may interrupt the chemical communication among the harmful target insects, and thus may decrease our dependency on agricultural chemicals in the future. t

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