Syntheses of Allelochemicals for Insect Control Isoprenoid Synthesis Olof Smitt Doctoral Thesis Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av filosofie doktorsexamen i organisk kemi, fredagen den 27:e september 2002, kl. 10:00 i Fälldin- salen (N 109), Mälthuset, Åkroken, Mitthögskolan, Sundsvall. Fakultetsopponent: professor Torbjörn Frejd, Organisk kemi 1, Lunds Universitet. Avhandlingen försvaras på svenska. ii “The synthetic chemist is more than a logician and strategist; he is an explorer strongly influenced to speculate, imagine, and even to create. These added elements provide the touch of artistry which can hardly be included in a cataloguing of the basic principles of synthesis, but they are very real and extremely important.” E. J. Corey, Nobel Prize for chemistry, 1990 © Olof Smitt Chemistry, Department of Natural and Environmental Sciences Mid Sweden University, SE-851 70 Sundsvall, SWEDEN Organic Chemistry, Department of Chemistry Royal Institute of Technology (KTH), SE-100 44, Stockholm, SWEDEN ISSN 1100-7974 ISBN 91-7283-277-0 ISRN KTH/IOK/FR--02/70--SE TRITA-IOK Forskningsrapport 2002:70 iii Smitt, O.; Syntheses of Allelochemicals for Insect Control: Isoprenoid Synthesis. Royal Institute of Technology: Stockholm, 2002. ABSTRACT This thesis describes the synthetic preparation of some compounds, which can serve as chemical signals for use in the development of control methods for pest insects. The compounds synthesised are of the isoprenoid type and of two kinds: carvone derivatives and germacranes. The derivatives of carvone are based on modifications of this compound, by reactions of either its endocyclic or its exocyclic double bond. One type of modifications was accomplished by chemoselective additions of thiophenol. The latter ones imply additions to the exocyclic double bond and seem to constitute general, previously rarely studied reactions. In other modifications of its exocyclic side chain, carvone afforded some sesqui- and diterpeniod natural products. The following compounds were synthesised in an enantioselective way: (-)-epi-delobanone, (-)-delobanone, (-)-7-hydroxy-3,10-prenyl- bisaboladien-2-one (an insecticidal constituent of Croton linearis) as well as its diastereomer and some other compounds with similar structures. All of these compounds were tested for their antifeedant/feeding deterrent capability against gnawing of the pine weevil, Hylobius abietis. The germacranes prepared by means of enantioselective total syntheses are: (–)- 1(10),5-germacradien-4-ol and (–)-germacrene D. The former is a constituent of the defence secretion (an allomone) from the larvae of the pine sawfly, and the needles of Scots pine. (–)-Germacrene D is a ubiquitous compound in nature. For example, it occurs in the peels of apples and acts as one component of a lure (a kairomone) to the apples, which attracts the codling moth, Cydia pomonella. The main problem in the total syntheses of the germacranes was the formation of the unsaturated monocyclic 10-membered ring. This was achieved by intramolecular alkylation with a suitably functionalised/protected cyanohydrin derivative, which, after further elaboration, afforded a monocyclic 10-membered enone, that was used in the syntheses of the two germacranes mentioned above. In the initial steps in the synthetic sequence the stereochemistry was established by alkylation of an amide enolate attached to a chiral auxiliary. This approach could most likely also readily furnish the (+)-enantiomers of these germacrenes (of the germacrane terpenoid class) using the opposite enantiomer of the chiral auxiliary in the initial steps. Keywords: isoprenoids, natural product synthesis, allelochemicals, kairomones, allomones, bisabolane terpenoids, Hylobius abietis, germacrane terpenoids, Neodiprion sertifer, stereoselective synthesis. iv This thesis is mainly based on the following papers and supplements, referred to in the chapters by their Roman numerals. I Chemoselective Additions of Thiophenol to Carvone and Perill- aldehyde. Smitt, O.; Högberg, H.-E. J. Chem. Res., Synop. 2002 and J. Chem. Res. Miniprint 2002, in press. II Syntheses of a prenylbisabolane diterpene, a natural insecticide from Croton linearis, and of the bisabolane sesquiterpenes (–)-delobanone and (–)-epi-delobanone. Smitt, O.; Högberg, H.-E. Tetrahedron 2002, 58, 7691. III Carvone and less volatile analogues as repellent and deterrent antifeedants against the pine weevil, Hylobius abietis (L.). Schlyter, F.; Löfqvist, J.; Smitt, O.; Sjödin, K.; Högberg, H.-E. Manuscript for J. Chem. Ecol. IV First Total Synthesis of (–)-1(10),5-Germacradien-4-ol. Smitt, O.; Högberg, H.-E. Synlett 2002, 1273. V Appendix: Total Syntheses of (–)-1(10),5-Germacradien-4-ol and (–)-Germacrene D - Experimental Part. Smitt, O. The papers were reprinted with kind permission from: Science Reviews Ltd., U.K. (paper I); Elsevier Science Ltd., U.K. (paper II) and Georg Thieme Verlag, Germany (paper IV). v CONTENTS Abstract iii List of papers iv Abbreviations vi 1. INTRODUCTION 1 1.1 Semiochemicals 1 1.2 Antifeedants/feeding deterrents 3 1.3 Isoprenoids 3 1.4 Natural product synthesis 8 1.5 This thesis 9 2. THIOPHENOL-BASED CARVONE ANALOGUES 11 2.1 Biological background 11 2.2 Hypothetical slow release system based on carvone 12 2.3 1,4-addition of thiophenol to carvone 13 2.4 Radical addition of thiophenol to carvone and perillaldehyde 15 3. LOW VOLATILITY CARVONE ANALOGUES 17 3.1 Background of the aim at decreasing the volatility 17 3.2 Terpenoids of the bisabolane type, and a synthetic strategy for their preparation 17 3.3 Syntheses of carvone analogues with an exocyclic alkyl side chain 20 3.4 Syntheses of carvone analogues with an exocyclic alkenyl side chain 22 3.5 Biological activity of the carvone analogues 28 4. TOTAL SYNTHESES OF 1(10),5-GERMACRADIEN-4-OL AND GERMA- 31 CRENE D 4.1 Biological background 31 4.2 A literature survey of methods considered suitable for the syntheses of 1(10),5- 33 germacradien-4-ol (9) and germacrene D (10) 4.3 Retrosynthetic analysis and approach towards the synthesis of 1(10),5-germa- 40 cradien-4-ol (9) and germacrene D (10) 4.4 Synthesis of i-Pr substituted key fragment; (3E,7S)-7-[(tert-butyldimethylsilyl)- 42 oxymethyl]-4,8-dimethylnon-3-en-1-ol (70) 4.5 Synthesis of the monocyclic ten-membered ring compound; (2E,4S,7E)-4-iso- 44 propyl-7-methylcyclodeca-2,7-dien-1-one (82) 4.6 Properties of the 10-membered monocyclic enone 82 and completion of the 47 synthesis of 1(10),5-germacradien-4-ol (9) and Germacrene D (10) 5. CONCLUSIONS AND OUTLOOK 51 vi ABBREVIATIONS Ac acetyl Ms methanesulfonyl ADP adenosine 5´-diphosphate MTPA 2-methoxy-2-(trifluoro- AIBN 2,2´-azobisisobutyronitrile methyl)phenylacetic acid ATP adenosine 5´-triphosphate NADPH reduced nicotinamide 9-BBN 9-borabicyclo[3.3.1]nonane adenine dinucleotide Bn benzyl phosphate bp boiling point NOE nuclear Overhauser effect Bu butyl NMO 4-methylmorpholine N- CoA coenzyme A oxide Cp cyclopentadienyl NMP N-methylpyrrolidinone Cy cyclohexyl Ph phenyl d chemical shift in ppm PPTS pyridinium 4-toluene- relative to TMS [(CH3)4Si] sulfonate DX heat at reflux R generalised structure unit d doublet rt room temperature dba dibenzylideneacetone TBAF tetrabutylammonium DIBALH diisobutylaluminium hydride fluoride DMAP 4-(dimethyl)aminopyridine TBDMS tert-butyldimethylsilyl DMF dimethylformamide TBDPS tert-butyldiphenylsilyl DMSO dimethyl sulfoxide Tf trifluoromethanesulfonyl ED50 dose that is effective in 50% THF tetrahydrofuran of test subjects TLC thin layer chromatography ee enantiomeric excess TMS trimethylsilyl or tetramethyl- EE 1-ethoxyethyl silane (in NMR) equiv equivalent TPAP tetrapropylammonium Et ethyl perruthenate hn indicates radiation (in photo- Ts 4-toluenesulfonyl chemical reactions) X halogen i-Pr isopropyl Xc chiral auxiliary J coupling constant (in NMR) LDA lithium diisopropylamide Lg leaving group LHMDS lithium hexamethyl- disilazane m-CPBA 3-chloroperoxybenzoic acid Me methyl mp melting point 1 1. INTRODUCTION Organic chemistry is the science dealing with the compounds containing carbon. Although called organic, such compounds do not have their own mind and consciousness, that is, they are dead materia, but despite this fact they are the building blocks of organisms. All living organisms consist of molecules containing carbon in some way. These can be linked together in a sophisticated way to form larger carbon molecules (e.g. carbohydrates, lipids, proteins), which in turn form organelles and cellular compartments, the main components of living cells. Organic molecules perform other tasks than just to serve as construction material. They are, for example, responsible for communication both at the intra- and intercellular level, and between fully developed organisms (working in parallel with the acoustic and optical stimuli, that humans normally consider as communication). The organic chemist studies carbon-containing compounds, normally as homo- geneous samples of one individual compound. This science, which is full of nuances, involves: isolation of new compounds from natural sources, investigation of their structures, studies on how they are formed, their preparation (i.e. organic synthesis) from natural and artificial starting materials, determination of their properties and so forth. There are ubiquitous examples of the use of synthetic organic compounds, which play an essential role in normal everyday life. Such useful chemicals are found