The use of chiral synthons in the preparation of enantiomerically pure pesticides is described in this chapter. The major part of this chapter deals with synthons derived from the "natural chiral carbon pool" Applications of carbohydrates, amino acids, hydroxyacids and terpenes in the syntheses of several classes of pesticides are illustrated.
The use of chiral synthons in the preparation of enantiomerically pure pesticides is described in this chapter. The major part of this chapter deals with synthons derived from the "natural chiral carbon pool" Applications of carbohydrates, amino acids, hydroxyacids and terpenes in the syntheses of several classes of pesticides are illustrated.
The use of chiral synthons in the preparation of enantiomerically pure pesticides is described in this chapter. The major part of this chapter deals with synthons derived from the "natural chiral carbon pool" Applications of carbohydrates, amino acids, hydroxyacids and terpenes in the syntheses of several classes of pesticides are illustrated.
WoIIIng (IdIfors), S/ereoeelec/iti/, of Pee/iciJee, Biologicol onJ
Clenicol ProIlene. l988 IIsovIor ScIonco IubIIshors I.V., Amsfordnm IrInfod In Tho ofhorInnds 453 Chapter 15 CHIRAL SYNTHONS IN PESTICIDE SYNTHESES Ben L. Feringa I 1.1 Introduction 1.2 Asymmetric synthesis II 2.1 Chiral synthons 2.2 Sources of chiral building blocks 2.3 Use of chiral synthons III 3.1 Carbohydrates 3.2 Aminoacids 3.3 Hydroxyacids 3.4 Terpenes IV Miscellaneous syntheses of chiral pesticides 4.1 Herbicides and plant growth hormones 4.2 Insecticides and fungicides V References Abstract: The use of chiral synthons in the preparation of enantiomerically pure pesticides is described in this chapter. Several routes to chiral synthons based on asymmetric synthesis or on natural products are illustrated. Important sources of chiral building blocks are reviewed. Furthermore the implications of the use of a chiral synthon in the design of a synthetic route to a new pesticide will be discussed. The major part of this chapter deals with chiral synthons derived from the "natural chiral carbon pool". Applications of carbohydrates, amino acids, hydroxyacids and terpenes in the syntheses of several classes of pesticides are illustrated. Finally some miscellaneous syntheses of chiral pesticides are described with a focus on organophosphor compounds and plant hormones. 454 1.1 INTRODUCTION The total synthesis of biologically active compounds has advanced to a stage of design of molecular architecture in which complete regio- and stereo- chemical control can be exerted in every stage of the process allowing the obtainment of enantiomerically pure* target molecules. The necessity for optically pure* compound syntheses is evident from structure-activity studies and practical routes to high activity, low toxicity pesticides. 1 Thus the R(-)- enantiomer of Flamprop-Isopropyl 1 controls wild oats and blackgrass grown in barley and wheat whereas the racemic form only controls wild oats in barley. 2
This is an example of competitive inhibition by the antipodal compound. S- Warfarin 2 has a sevenfold larger rodenticidal activity than R-2; 3 the (+) and (-) enantiomers of phenoxy propionic acids 3 exhibit auxin and anti-auxin activity respectively 4 and the 2S,4R isomer of etaconazole 4 (active ingredient of the fungicide Sonax R ) is roughly 100 times more active than the 2R,4R isomer against Cercospora and Puccinia. 5
* Optically pure and enantiomerically pure are used throughout this chapter although they are not equivalent: optical purity (o.p.) is defined as % o.p. = [] D T
[ o ] D T
R-S (e.e.) % e.e. = .100 R+S .100; enantiomeric purity is defined as enantiomeric excess 455 The absolute configuration dependency of pyrethroid insecticides 6
(pyrethrin I) 5, planthormones (Gibberellin acid GA3) 6 7 and pheromones 8 is well established. Furthermore it has been found that some enzymes can only dehalogenate the l-isomer of chloroalkanoic acids that are used as herbicides. 9
The compounds shown here illustrate the diversity of enantiomerically pure structural targets that is encountered. A key aspect of the design of a synthesis of an optically active pesticide is therefore a decision at which stage it is most economical to work with enantiomerically pure compounds. Resolution 10 of racemic mixtures at a final stage of the synthesis of a complex target molecule might be advantageous even though one half of the compound is sacrificed. This can be the case when no suitable chiral starting material is available or when the synthesis starting from chiral synthons is too complicated compared to the racemic route. Racemization or recycling of the "wrong" enantiomer during resolution, generally useful at an earlier stage of the synthesis, allows in theory 100% use of chiral building blocks. In general one wishes to use enantiomerically pure intermediates as early as possible in the synthesis; introduced either via stereodifferentiating (asymmetric) synthesis or via the use of chiral synthons. This necessitates stereochemical control at every subsequent step, especially when new elements of chirality are introduced. It is also necessary to aim for racemization free chemical conversions. 1.2 ASYMMETRIC SYNTHESIS Asymmetric syntheses 11 can be performed in an enantioselective (a) or diastereoselective (b) way (scheme 1). In the first case enantiotopic faces or groups of achiral compounds are differentiated using optically pure reagents. Examples of enantioselective alkylation using an alkyne-lithium reagent, 12
with a l-proline derived chiral ligand and an enantioselective reduction using Baker's yeast 13 are outlined in eqs. 1 and 2. Especially advantageous in enantioselective synthesis are the use of optically pure catalysts 11,14 or 456 enzymes. 11,13,15 A single enantiomer of a racemic starting material can also be converted to a desired component by these methods 11,15 (see also this volume, chapter 14).
In a diastereoselective process a prochiral group in an enantiomerically pure compound, generally obtained from an achiral compound and a chiral auxiliary, is selectively converted with formation of a new chiral center. Thus the prochiral CH 2 of the S-(-)-1-amino-2-(methoxymethyl)-pyrrolidine derivative 14 of 3-pentanone is diastereoselectively propylated. This route provides enantiomerically pure (S)-4-methyl-3-heptanone (16), the principal alarm pheromone of the leaf-cutting ant Alta texana, after removal of the chiral auxiliary (eq. 3). 16
45? 2.1 CHIRAL SYNTHONS Ultimately the methods described above start with enantiomerically pure natural products that are used as such or via chemical conversions, e.g. the proline derived chiral auxiliary 8. Facile resolution procedures or asymmetric syntheses yield a variety of chiral starting materials. On the other hand natural products themselves can be used as chiral building blocks in synthesis. Nature provides us with a rich source of enantiomerically pure materials that are converted via suitable modifications into chiral precursors and form the major part of the so called "chiral pool". 17 Chiral synthons 18 or chiral building blocks will be used in the same context throughout this chapter. The chiral synthon approach requires relative low molecular weight, enantiomerically pure and synthetically versatile compounds. Either of the above mentioned methods for the formation of chiral synthons can be applied in routes to physiological active target molecules, as is illustrated for crysanthemic acid (scheme 2).
scheme 2. Crysanthemic acid synthesis, chiral synthons from: a. natural product (-)--pinene; 19 b. asymmetric synthesis using 8-phenylmenthol as a chiral auxiliary; 20 c. resolution; 21 d. enzymatic hydrolysis. 22
458 2.2 SOURCES OF CHIRAL BUILDING BLOCKS Relatively cheap terpenes, carbohydrates, hydroxyacids and aminoacids can be selected as chiral starting material depending on the required carbon framework, functionalities, the number of asymmetric centers and the sense of chirality. Many chiral building blocks derived from these classes of natural products can be purchased, others can be easily obtained by chemical modifications. Scott 17 has recently provided a list of commercially or synthetically available chiral building blocks together with an indication of costs. Selected examples of chiral building blocks that have been applied in pesticide synthesis are given in table 1. table 1
459
In all examples summarized in table 1, the natural product itself serves as the cyclic- or acyclic chiral building block with upto five asymmetric centers or the synthon can easily be recognized as derived from a natural product. Other valuable chiral synthons have also become available through asymmetric synthesis 11 in recent years. An indepth treatment of chiral synthons derivable through asymmetric synthesis lies outside the scope of this chapter. A few examples can be found in the preceding section. Important classes of chiral synthons that fall in this category are: epoxides: A large variety of chiral epoxides in high enantiomeric excess can be obtained via Sharpless epoxidation of allylic alcohols and have mainly been applied in pheromone synthesis. 23
460 alcohols: Allylic-, propargylic- and benzylic alcohols are produced in high e.e.'s using S-(-)- or R-(+)-binaphthol modified lithiumaluminiumhydride reagents (eq. 5); 24 various other ligands might be used. 11
Asymmetric hydroboration using for instance dipinanylborane 11,25 and asymmetric hydrogenations using chiral transition metal catalysts 26 (eq. 6) give access to optically active alcohols. The asymmetric synthesis of amino acids using chiral Wilkinson catalysts is probably the most extensively studied catalytic asymmetric synthesis. 14 Only a very limited number of aminoacid synthesis using this procedure has reached the stage of commercialization. acids: A number of procedures have been developed for optically active - and - substituted acids, 27 for instance using chiral sulfoxides or oxazolines as chiral auxiliaries. An example of the latter procedure is given in eq. 7. 28
An increasing number of chiral synthons is available through enzymatic techniques; see chapter 14. The remaining part of this chapter will concentrate on chiral synthons derived from natural products i.e. the "chiral carbon pool". 46l 2.3 USE OF CHIRAL SYNTHONS Several points have to be considered during the planning of a synthetic route to enantiomerically pure pesticides wherein chiral synthons are to be used. - Recognition of a chiral synthon derived unit in a target molecule. In the use of carbohydrates as chiral templates in synthesis Hanessian 29 distinguishes apparent-, partially hidden-, or hidden carbohydrate symmetry in optically active molecules and has devised a computer aided discovery program for analysis of carbohydrate symmetry. - Availability/costs. Carbohydrates and several amino acids are a relatively cheap and almost unlimited source of chiral carbon atoms; for other chiral starting materials catalytic or enzymatic asymmetric processes might have to be devised for large scale industrial preparation. The term "chiral economy" has been introduced; 30 the use of one enantiomer might however strictly depend on the application. Thus (+)-disparlur (about $ 300/g) is preferred for traps (mg quantities needed), whereas ()-disparlur ($ 0.30/g) is effective for mating disruption of the gypsy moth. The number of chemical steps required from the natural product has to be considered especially with carbohydrates. Several additional steps may be required when a chiral synthon related to an unnatural amino acid or sugar has to be used and a resolution procedure might become more advantageous in such a case. - Availability of both enantiomers. - Synthetic versatility; the usefulness of a chiral synthon in a particular route will strictly depend on functional groups, chain length, (a)cyclic structure, oxidation state etc. - Enantiomeric purity of the chiral building block. The e.e. (of natural product derived synthons) should be chequed in all cases especially when terpenes are used as chiral starting material (for an excellent discussion, see J.W. Scott in ref. 11). - Stereochemical versatility. Important aspects are the number of asymmetric centers required in the synthon, and the stereochemical integrity during the synthesis (precludes often racemization prone synthons or synthetic methods). Especially in routes wherein various asymmetric building blocks are to be connected in a convergent synthesis and/or when the product must be obtained with an unambiguous absolute configuration, the use of chiral synthons is virtually mandatory. Successful syntheses shown here do not imply that they are all suitable for industrial use. It is obvious that safety, economical and environmental reasons are involved while upscaling these syntheses. 462 The crucial steps in the route to optically pure pesticides with chiral synthons involve conversions at the existing asymmetric center or the creation of new asymmetric centers. Methods for chirality transfer and for complete stereochemical control of the relative configurations are essential. A few important conversions are given in eqs. 8-10. - Diastereoselective reduction or addition, 1,2-transfer of asymmetry.
- Nucleophilic subsitution at one chiral center: retention inversion
- or at two vicinal chiral centers via epoxides
The synthesis of 7R,8S-Disparlur from L-glutamic acid illustrates these principles: 31,32
463
1) HNO 2 ; 2) ClCOCOCl; 3) (nC 10 H 21 ) 2 Cd; 4) NaBH 4 ; 5) KOH. Retention of configuration in the intramolecular nucleophilic substitution (step a), diastereoselective reduction (step b), and inversion in the nucleophilic substitution (step c) occurs. - 1,3-C-O to C-C transfer of chirality via Claisen rearrangements. Clean transfer of stereochemical information from existing to new chiral centers is exerted in the formation of the cigarette beetle pheromone serricornin from hydroxyester 63 (eq. 12). 33 The key step in the preparation of the male dried bean beetle pheromone 70 is a ortho-ester Claisen rearrangement in which the chirality of the asymmetric carbon atom in propargyl alcohol 67 is transferred into axial chirality of the allenic structural unit. 34
1) (H 5 C 2 O) 3 CCH 3 , H 5 C 2 CO 2 H; 2) . 464 Furthermore the correlation between the E/Z configuration of an olefine and the R/S configuration via the Claisen rearrangement or RR,SS/RS configuration via the cis elimination from 1,2-diols (eq. 14) has found important applications in pheromone synthesis. 8,31
3.1 CARBOHYDRATES A large variety of chiral synthons with several asymmetric centers that are not easily racemized can be obtained from carbohydrates. 11,29,35,36 Excellent stereochemical control can be exerted in chemical conversions of for instance methyl--D-glycopyranoside 75 in which the methoxygroup adopts an axial position due to the anomeric effect 37 and in which a conformationally restricted hexapyranose ring is present.
The versatility of D-glucose as starting material is further exemplified by the fact that it may also be used in the acyclic, furanose or pyranose forms, which can be converted by selective functional group transformation and (de)protections into chiral building blocks with 1,4-, 1,5-, etc. dioxygen relationships. Derivatives of L-sugars, not readily available, might be obtained by selective reduction followed by oxidation at "the other end" of the sugar chain, 29 whereas an oxidation-reduction sequence at one hydroxyl center provides inverted sugars (e.g. 79-81). The Emoto route 38 to S(-)-frontalin illustrates some of these basic conversions (scheme 4). 465
1) DMSO, Ac 2 O; 2) NaBH 4 , MeOH; 3) MsCl; 4) MeOH, H 2 SO 4 ; 5) 6 equiv. MeMgI; 6) cyclohexanone, H 2 SO 4 ; 7) 70% AcOH aq.; 8) NaIO 4 ; 9) NaBH 4 ; 10) BnCl, KOH; 11) 66% AcOH; 12) NaBH 4 , EtOH; 13) acetone, CuSO 4 ; 14) H 2 , 10% Pd/C, EtOH; 15) NaIO 4 ; 16) Ph 3 PCHCOMe; 17) H 2 , 10% Pd/C, MeOH; 18) TsOH, Et 2 O. Note the repeated diol cleavage to tetrosederivative 86 and the fact that only the C 2 -asymmetric center is preserved. Conversion of 80 to enolacetate 88 gives access to D-gulose derivatives 35,39 (position 3 and 4 inverted).
Similarly the tosylate of 81 can be converted to 90, a precursor for D-galactose derivatives 35,40 (C 4 -inverted).
466 Several methods have been developed for dideoxygenation of the C 5 and C 6
hydroxyl groups e.q. conversion of 75 to 92. 29,35,41
1) SO 2 Cl 2 , pyridine; 2) NaI; 3) Bu 3 SnH, AIBN. Useful procedures are LiAlH 4 reduction of tosylates 35 and nickel reductions of thiophenolates. 43 In the synthesis of (+)-exo-brevicomin, 45 the western pine beetle attractant, the problem of removing three hydroxyl groups had to be faced. 1) BnBr, Na; 2) AcOH; 3) (EtO) 3 CH, AcOH; 4) Ph 3 CCO 2 H, 170 (or 93 to 94 i TsCl, py, ii NaI, iii LiAlH 4 ); 5) HCl, MeOH; 6) NaCS 2 , MeI; 7) Bu 3 SnH; 8) H 3 O + ; 9) Ph 3 PCHCOCH 3 ; 10) Pd/H 2 . Barton's deoxygenation procedure 44 via the xanthate 95 provided the ultimate solution. The syntheses described above illustrate selective conversions at various positions in furanose derivatives. The synthesis of both enantiomers of frontalin by Hicks and Fraser Reid 46
demonstrate the importance of 75 and 77 as pyranose chiral building blocks in which the primary hydroxyl group, the 4,6-hydroxyl-groups or the 2,3-hydroxyl- groups can be converted selectively (scheme 6). 29,35
46? 1) TsCl; 2) NaH, DMF, Ts-triazole; 3) LiAlH 4 ; 4) pyridiniumchlorochromate; 5) MeMgI, Et 2 O, -65C (101:102 = 9:1); 6) Ph 3 PCH 2 ; 7) Hg(OAc) 2 , NaBH 4 ; 8) BnCl, NaH; 9) H 2 SO 4 , dioxan aq.; 10) Ac 2 O, BF 3 .OEt 2 ; 11) NaBH 4 ; 12) NaIO 4 ; 13) see scheme 4. Reductive removal of the 3-hydroxy group via ringopening of epoxide 99 followed by oxidation gives key intermediate 100 with a conformationally restricted trans decaline structure. Due to the anomeric asymmetric center 37
diastereoselective conversions both in the chelation controlled Grignard reaction to 101 and in the oxymercuration to 102 take place. The two isomeric hexosederivatives were cleaved to tetrose derivatives, which were the precursors for (+)- and (-)-frontalin. High stereochemical control is also exerted in the nucleophilic ringopening of epoxides 104 and 105 to diaxial substituted derivatives. 29,47 Whereas 105 adds organometallic reagents to provide C 3 alkylated products with a
cis-C 1 -methoxy-, C 3 -alkyl-relationship, a similar reaction of 104 yields the C 2 - alkylated product with a trans relationship between C 1 -methoxy- and C 2 -alkyl- substituents. These concepts are illustrated in the synthesis of (-)--multistriatine from D-glucose. 48 The epoxide 104 is readily obtained from chiral synthon 77. 468
1) Me 2 CuLi, Et 2 O; 2) NaH, CS 2 , MeI, Et 2 O; 3) Bu 3 SnH, PhCH 3 ; 4) TsOH, CH 3 OH; 5) TrCl, pyridine; 6) CrO 3 -2 pyridine; 7) Ph 3 PCH 2 , Et 2 O; 8) H 2 , (Ph 3 P) 3 RhCl; 9) HS(CH 2 ) 3 SH, BF 3 .OEt 2 , CH 2 Cl 2 ; 10) (MeO) 2 CMe 2 , TsOH; 11) t-BuLi then EtI, HMPA; 12) TsOH, MeOH; 13) HgO, HgCl 2 , MeCN. There are three carbohydrate alkylation procedures involved in this synthesis. First the methyl-substituent at C 2 was introduced via epoxide ringopening. A Wittig methylenation followed by catalytic hydrogenation introduced the C 4 -methyl-substituent and the 1,3-diaxial relationship of the methylgroups. Finally the ethylsubstituent was obtained via alkylation of the dithiane anion of 109. In the synthesis 49 of the aggregation pheromone 3S,4S-4-methyl-3-heptanol 115 the required threo-configuration of the methyl- and hydroxyl-substituents was obtained in a similar manner via epoxide ringopening of 105. A complication was the fact that the sense of chirality at the C 2 and C 3 asymmetric centers in 112 is opposite to that found in 115. An oxidation-epimerization-reduction sequence of 112 to 113 secured the necessary stereochemistry.
1) MeMgCl; 2) DMSO, TFAA, CH 2 Cl 2 ; 3) Et 3 N, DMF; 4) LiAlH 4 , Et 2 O; 5) H 2 SO 4 ; 6) HS(CH 2 ) 3 SH, H + ; 7) Pb(OAc) 4 , MeCN; 8) Ph 3 P=CHMe; 9) BnBr, Ba(OH) 2 , DMF; 10) MeI, aq. acetone; 11) Ph 3 PCH 2 ; 12) Pd/C, H 2 , Et 2 O. 469 Another class of useful chiral building blocks consists of glucalesters 117 (commercially available) and 119 which are obtained from acetobromoglucose 116 50
either by base catalyzed- or reductive elimination. 50,53
1) Zn/CuSO 4 , NaOAc, HOAc; 2) BF 3 .OEt 2 , EtOH; 3) Et 2 NH, Bu 4 NBr. The 2,3-unsaturated pyranose 118 is obtained by the Ferrier rearrangement 52,53
and 116 and 118 serve as substrates for a large range of C 1 -alkylated derivatives. Hydrolysis of 118 (with Ba(OH) 2 ) and subsequent oxidation yields enone synthon 120 with one glucose chiral center left (except for the anomeric center). Selective cuprate addition to the enone moiety followed by Wittig olefination are essential steps in the Fraser-Reid route 54,55 to - multistriatin.
1) Me 2 CuLi; 2) Ph 3 PCH 2 ; 3) H 2 /Pd/C. Carbocyclic ring annelation to pyranose synthons 53,57 has been succesfully applied in the preparation of crysanthemum dicarboxylic acid 110 via a cyclopropanation at the C 2 ,C 3 positions of 104. Reduction and hydrolysis yields cis-aldehyde 124 which was converted to (+)-128 by oxidation and olefination followed by epimerization. The (-)-isomer of 128 was obtained from the same chiral synthon by a reverse sequence starting with an epimerization of 124 to 126. Useful synthons were derived from -glucosan, 58 D-mannitol, 59 L-ascorbic acid and D- and L-arabinose (both of which are commercially available). 29 D- glyceraldehyde as its isopropylidene derivative 130 is presumably the most widely used sugar derived chiral synthon. 35,60,61 D- and L-glyceraldehyde are obtained from lead tetraacetate oxidation of D-fructose and L-sorbose 62 whereas 130 is obtained from di-O-isopropylidenemannose 63 (129). 4?0 1) (EtO) 2 P(O)CH(CH 3 )CO 2 Et, NaH, 160C; 2) LiAlH 4 , Et 2 O; 3) MsCl, DMF; 4) LiAlH 4 , THF; 5) H 2 O, dioxane, reflux 6) NaOMe, MeOH; 7) Ph 3 PC(CH 3 )CO 2 Me, CH 2 Cl 2 ; 8) TsOH, MeOH; 9) NaIO 4 ; 10) Ag 2 O, NaOH, dioxane.
D-glyceraldehyde can also be converted into the L-enantiomer by an oxidation- reduction sequence that interchanges the aldehyde and primary alcohol functionalities provided proper protection is taken care of. Using analogous methods both R- and S-epichlorohydrin 45 can be obtained from D- glyceraldehyde. 64 Several electrophilic three carbon chiral synthons such as 131 are based on glyceraldehyde. 11,29,65 When using glyceraldehyde synthon 130 care has to be taken to prevent racemization during the chemical conversions. An application of D(+)-glyceraldehyde in the synthesis of the Ips bark beetle pheromone component ipsdienol 135 is shown in scheme 10. 66
In the first step the Wittig reaction on glyceraldehydeacetonide occurred with partial racemization. Conversion into epoxyalcohol 133, condensation with malonester and subsequent transformations yielded optically impure ipsdienol. 4?l 1) Ph 3 P + CHMeI - , NaH, DMSO; 2) Hg(OAc) 2 ; 3) NaBH 4 ; 4) HCl; 5) TsCl; 6) KOH; 7) CH 2 (CO 2 Et) 2 , NaOEt; 8) H 3 O + ; 9) CH 2 O, Et 2 NH; 10) (PhSe) 2 , NaBH 4 ; 11) Dibal-H; 12) Ph 3 P + CH 3 I - , NaH, DMSO. Examples of optically active pheromones obtained from 130 include - multistriatin, 67 (+)- and (-)--multistriatin, 68 the mosquito oviposition attractant pheromones erythro- and threo-6-acetoxy-5-hexadecanolide 69 and pheromone components of Andrena wilkella. 70
3.2 Aminoacids Many important chiral synthons are now derived from amino acids. 11,61
Various L-amino acids are relatively inexpensive, and more recently some D-amino acids have become available. These are prepared by resolution procedures, see chapter 15, via asymmetric syntheses, 11,14,71 or via ingenious procedures from L-amino acids. 72
A recent synthesis starting from L-serine 73 is shown in eq. 19.
1) R 1 Li or nBuLi, R'MgBr; 2) HS(CH 2 ) 2 SH, BF 3 .OEt 2 ; 3) RaNi; 4) O 2 , Pt; 5) HBr, EtOH. The most important transformation of amino acids to obtain chiral synthons is the diazotation to the corresponding diazoniumsalts. 71,74
Subsequent decomposition with participation of the carboxylate group via an -lactone 140, results in -hydroxyacids or -haloacids with retention of configuration 71,75 (scheme 11). 4?2
1) HNO 2 ; 2) EtOH, HCl; 3) dihydropyran, pTsOH, Et 2 O; 4) LiAlH 4 , Et 2 O; 5) TsCl, pyridine; 6) AcOH, THF, H 2 O; 7) KOH; 8) CH 2 (CO 2 Et) 2 , NaOEt; 9) KOH aq.; 10) CH 2 O aq., Et 2 NH; 11) PhSeH; 12) iBu 2 AlH; 13) Ph 3 PCH 2 ; 14) 2-(1,3- butadienyl)magnesiumchloride. The stereochemical result of the nitrous acid diazotation depends on reaction conditions, solvent, substituents etc. 71,74-76 For instance the Comstock mealybug pheromone R-(+)-3-acetoxy-2,6-dimethyl-1,5-heptadiene was obtained with low optical purity (19% e.e.) from L-phenylalanine. 77 Mori's synthesis 78 of S-(-)-ipsenol 145 illustrates the use of hydroxyacid 141 obtained via diazotation from S-(+)-leucine (139) (scheme 11). The ethylester of 141 was converted into the monotosylate. Subsequent treatment with base to afford epoxide 143 followed by malonic ester condensation yielded the ipsenol-precursor 144. The bark beetle (Ips paraconfusus) pheromone is composed of enantiomers of 145 and (+)-cis-verbenol whereas the spined engraver beetle (Ips grandicolis) responds only to S-(-)-ipsenol. In a similar conversion R-(+)-2-hydroxybutanoate was obtained from D-(-)--aminobutyric acid and was converted into S-epoxybutane (scheme 12). Condensation with dianion 149 provided the 2R,5R and 2R,5S diastereoisomers of chalcogran (150), the principle pheromone of Pityogenes Chalcographus which infects Norway spruce. 79
1) NaNO 2 , aq. H 2 SO 4 ; 2) CH 2 N 2 ; 3) dihydropyran, pTsOH; 4) LiAlH 4 ; 5) MeOH, pTsOH; 6) HBr, AcOH, mixture of bromoacetates; 7) KOH; 8) 149; 9) KOH. It is obvious that complementary routes from amino acids, -hydroxyacids and sugars exist for many chiral synthons described here. Especially when chiral epoxides, diols etc. have to be used in the synthesis of a pesticide, costs of 4?3 starting material and chemical conversions will dictate the route to be chosen. Glutamic acid 34 is extensively used as a building block in the synthesis of chiral pheromones. Both enantiomers are commercially available although D-34 is approximately 40 times more expensive than L-34. On diazotation -butyrolactone- -carboxylic acid 58 is formed with complete retention of configuration presumably via nucleophilic opening of the -lactone intermediate by the second carboxyl group (eq. 20). 80,81
The -lactone 58 is also readily obtained from R-(+)-glyceraldehyde. 82 The enantiomer of 58 can be obtained from R-(-)-glutamic acid 80-82 or S-(-)-glyceraldehyde or via an three step epimerization of S-58. 83
Transformations of 58 lead to admirable chiral synthons e.g. acid chloride 152, aldehyde 153 or tosylate 154. Scheme 13 shows their use in some of thenumerous applications in the synthesis of biologically active compounds. Tosylate 154 is a precursor for diol 163 that was transformed via the monotosylate (157) and reduction to 164 followed by esterification into the grain borer beetle pheromones 165 and 166. -Lactones 159, 160, components of attractants of several beetles were obtained by cuprate additions 85 whereas a reduction and Wittig sequence led to sulcatol 162, pheromone of the ambrosia beetle. 86 The aldehyde 153 was used as chiral synthon for the pheromone of the Japanese beetle. 87 Other applications shown are short routes to the gypsy moth pheromone disparlur 62 (obtained in 88% e.e.) 86,88 and an alternative route to chalgogran 149 (as a mixture of epimers due to the additional presence of a ketal chiral center over which no stereochemical control can be exerted. 85,89
Furthermore a synthesis of (+)-exobrevicomin 98 with a diastereoselective reduction of acylderivative 155 using L-selectride as a key step has been reported. 90 It is clear from the foregoing discussion that a variety of chemical transformations is possible using lactone 58 and it will very likely serve as a valuable chiral synthon in future applications in pesticide chemistry. It should be kept in mind that lactones 152 and 153 are sensitive to racemization. Finally it is noted that unsaturated -lactone 168 is also easily obtained from D- ribonolactone and the material from both source has been used in pheromone synthesis e.g. rice weevil pheromone 170. 91
4?4
Another interesting starting material is aspartic acid. Both R- and S- aspartic acids are commercial products 17 and have been applied to prepare several enantiomerically pure -hydroxyesters that are precursors for
4?5 pheromones, herbicides etc. (see also 3.3). Nitrous acid treatment of 171 gave S-malic acid in 94% optical purity, further purified by crystallization (eq. 22). Hunsdiecker degradation to bromo ester 172 followed by cuprate addition completed the scheme. 92
Important use of amino acids as chiral building blocks lies certainly in peptide synthesis and in incorporation of the amino acid as such in a chiral pesticide. 93 For example phosphinothricin (174) and its tripeptide 175, which was isolated from Streptomyces, are suitable as herbicides. 94
An asymmetric synthesis of phosphinothricin and analogs was achieved by Michael addition of chiral glycine Schiff bases to vinyl phosphorus compounds using a pinene derivative as a chiral auxiliary. 95
1) KOtBu, -78C; 2) 6N HCl. Herbicidal acitivity and plant growth regulation has also been shown with condensation products of -aminoalkylphosphinic acids attached to alanyl residues. 95 Enantiomeric amino acids have been incorporated in peptides such as the enantio-[5-valine]malformin isomer of the growth stimulator malformin. 96 The L-(-)enantiomers of six N-(purin-6-yl) amino acid methyl esters, 179, obtained from L-amino acid methylesters and 6-chloropurine, showed higher cytokinin activity in tobaccocallus and seed germination tests than their antipodes. 97
The new approaches for insect control 93 will surely result in a greater use of amino acids for synthesis of peptide inhibitors selective for insects. Other uses may lie in recent developments such as peptide prodrug systems i.e.
4?6 antifungal L-alanyl-2-(5-fluorouracil-1-yl)-glycine (180) 98 and the conjugates of L- and D-glutamic ester and related amino acids with 2,4- dichlorophenoxypropionic acid that showed different auxin activity 99 depending upon the configuration. Many amino acid derivatives, although not strictly considered as chiral synthons because they are not incorporated into the chiral target molecule, have shown tremendous success in applications as chiral auxiliaries in asymmetric syntheses of a variety of other chiral synthons. 11
Thus 1-amino-2-(methoxymethyl)pyrrolidine and 2-amino-1-phenyl-1,3-propanediol have been employed in asymmetric alkylations, amino acid and pheromone synthesis and in the synthesis of secondary-alcohols, hydroxyacids and lactones with high enantiomeric excess (see section 1.2). 11,100 Chiral pyrrolidine-diamines and norephedrin have been applied in asymmetric alkylations, reductions, aldol reactions and Diels Alder reactions. 11,14,100 Various other aminoalcohols derived from amino acids were used in controlling acyclic stereochemistry, in asymmetric reductions and in the preparation of chiral ligands for transition metal catalysts. 11,14,100 For instance asymmetric synthesis of 5S,6R- and 5R,6S- 6-acetoxy-5-hexadecanolides 185, major components of mosquito oviposition attractant pheromone, was achieved via reduction of cyclohexenone using a S- aspartic-acid derived chiral lithiumaluminiumhydride complex (182) (eq. 24). 101
Dihydrochrysanthemolactone 188 (34% optical yield) was prepared by decomposition of diazoacetic ester 186 using the chiral copper (II) complex 187 containing a R-phenylalaniol derived ligand. 102 Several improvements on the optical yield (up to 90%) have been reported. 14,103
Optically active intermediates for the preparation of chiral pyrethroids (phenvalerate-) and arylethanolamines were obtained by catalytic HCN addition to aldehydes using cyclic dipeptides e.g. (R)-3-benzyl-(R)-6-(4-imidazolyl
4?? methyl)-2,5-piperazinedione (190) 104 or cyclo(D-phenylalanine-D-histidine) 105 as catalysts. Finally the diastereoselective photocycloaddition of ethylene to bicyclic lactam 192, derived from (S)-valinol, gave 193 (12:1 ratio of diastereoisomers), a precursor for the synthesis of (-)-grandisol 194. 106
3.3 HYDROXYACIDS A number of chiral agrochemicals can easily be seen as derivable from optically active hydroxyacids, an example being the phenoxy-propionic acid 3 based on lactic acid. The limited number of asymmetric centers and the opportunity for selective modification of the carboxylic acid functionality have added to the success of this class of chiral starting materials. 11,16,107,128 S- (-)-malic acid and S-(-)-lactic acid are prepared by fermentation. The enantiomers are available by resolution, R-(+)-malic acid was also prepared from R,R-tartaric acid. 107,128 A method for the conversion of ethyl-(S)-lactate, via its mesylate, into ethyl-(R)-lactate without racemization using cesiumpropionate was developed. 108 An efficient asymmetric synthesis of (S)- and (R)-malic acid from ketene and chloral in 98% enantiomeric excess was achieved using quinidine as a catalyst. 109 Analogous procedures gave (S)-methyl-3-hydroxyalkanoates and (R)- and (S)-citramalic acid. 110 Both R,R- (natural) and S,S-(unnatural) tartaric acid and hydroxyaminoacids such as D-threonine containing two asymmetric centers are commercially available. Hydroxyacids and lactones with multiple chiral centers include D-gluconic-, D-galactonic- and D-saccharic acid and L-ascorbic acid. Optically pure S-(-)-ethyl-2-mesylpropionate is readily formed by mesylation of S-(-)-ethyllactate in the presence of triethylamine with complete retention of configuration 108,111 (eq. 28).
4?8 This is an excellent chiral synthon for nucleophilic substitutions that occur with complete inversion of configuration. Using phenolates, 112 substituted phenoxy-phenolates 113,115 or N-arylbenzoylamides 114 as nucleophile optically active members of various classes of herbicides have been prepared (scheme 14).
However it should be reminded that partial racemization might occur depending upon nucleophile and reaction conditions. Phenoxy-phenoxypropionic acid (PPP) herbicides 203 form a large class of commercially important herbicides 115 two examples of which are the wild oat herbicide diclofop-methyl 205 and the systemic grass herbicide pyrifenop 206.
The D-(R)-enantiomers are the active herbicides in post-emergence applications; presumably racemization takes place in pre-emergence application resulting in equal activity of D- and D,L-enantiomers. 116 The enantiomeric forms are generally prepared as illustrated above or via resolutions using alkaloids. R- (+)-Diclofop-methyl was prepared via resolution of the acid with cinchonine (optical purity, o.p 58%), from L-(-)-2-bromopropionic acid methylester (o.p. 70%) and from tosylate analogue of 196 (o.p. 80%). 117 Chlorfenprop-methyl, active ingredient of Bidisin R was resolved via the acid with brucine 118 whereas other examples derived from lactic acid include N,N-diethyl-2-(1-
4?9 naphthyloxy)propionamide, a pre-emergence herbicide, 119 and 2-[4-(6-chloro-2- quinoxalinyloxy)phenoxy]propanoate. 120 -Halosubstituted esters, derived from d- or l-mandelic acid, have been applied in the synthesis of enantiomers of Papthion and Papoxon, acetylcholinesterase inhibiting insecticides 121 (eq. 29).
S-(-)-1,2-Epoxypropane, an important chiral synthon, is readily obtained from S- (-)-ethyllactate via tosylate 211 (eq. 30). 122 A few examples of its extensive use in chiral pheromone syntheses are shown in scheme 15. The preparation of wasp pheromone 213, 123 a queen honeybee pheromone ((R)-9-hydroxy- (E)-2-decenoic acid 215), 124 the flat grain beetle aggregation pheromone 125 and the carpenter bee pheromone 217 126 and 2,7-dimethyl-1,6- dioxaspiro[4,6]undecane 127 are illustrated.
R,R-(+)-Tartaric acid is a unique synthon in that the C 2 symmetry present ensures that the pairs of functional groups, hydroxy and carboxyl, are identical. Monofunctionalization, for instance 39 to 221, leads to threo- and erythro- (after epimerization at one chiral center) building blocks with two distinct chiral centers. 128 Note that this sequence gives access to chiral synthons formally derived from meso-tartaric acid. A large variety of C 4 - chiral synthons is now available mainly due to the development of methods for extensive modification of "natural" and "unnatural" tartaric acid by Seebach and coworkers. 128 Some are shown in scheme 16; in the formation of 222 an inversion
480
of configuration at one hydroxyl-center was achieved using Mitsunobu's method. 129 Further examples of the chiral epoxide pool, important chiral alkylating agents that are readily obtained from tartaric acid, include both enantiomers of propylene oxide, bis-epoxides and bromoepoxides. 128
exo-Brevicomin, the western pine beetle aggregation pheromone was obtained from tartaric acid by Mori and Meyer. 130 The synthesis of (1S,5R,7S)-(-)-98 of 81% optical purity started with diethylester of tartaric acid acetonide 227, which was converted into bromide 228 via several steps. Alkylation with dithiane salt 229 followed by reduction and hydrolysis yielded 98 (scheme 17).
A synthesis of (-)--Multistriatin 235 was achieved from D-(-)-tartaric acid through epoxydiester 231 with stereoselective ring opening with dimethylcuprate as the key step. 131
48l
1) HBr, HOAc; 2) EtOH, HBr; 3) NaOEt, EtOH; 4) Me 2 CuLi, Et 2 O, -55 to -20C; 5) dihydropyran, pTsOH; 6) LiAlH 4 ; 7) MeOH, pTsOH; 8) Me 2 CO, pTsOH; 9) TsCl, py, KI; 10) LDA, Et 2 CO, THF 11) 10% HCl, MeCH. The (7R,8S)-chiral oxirane unit in (-)-dispalure 162, the sexual attractant of the gypsy moth, was derived from the vicinal diol chiral centers in (2R,3R)- tartaric acid (scheme 19). 132
1) ref. 132 b ; 2) iAm 2 CuLi, Et 2 O; 3) BCl 3 , CH 2 Cl 2 ; 4) dihydropyran, pTsOH; 5) iBu 2 AlH; 6) nC 8 H 17 PPh 3 Br, nBuLi, THF; 7) H 2 , Pd/C; 8) TsCl, C 5 H 5 N; 9) TsOH, MeOH; 10) KOH, MeOH. Other examples of pheromones derived from tartaric acid include all four stereoisomers of erythro-3,7-dimethylpentadec-2-yl acetate (pine sawflies) via chiral epoxides 133 ; (+)-erythro-(5S,6R)-6-acetoxy-5-hexadecanolide (mosquito oviposition pheromone); 134 (+)-disparlur via an alternative route as described above; 135 3S,4S-4-methyl-3-heptanol (Scolytus multistriatus) 136 and erythro- serricornin. 137
S-(-)-malic acid has served as starting material for a number of chiral synthons, for example, 239 (homologue of glyceraldehyde derivative 130), 224 and
482 diol 240. 138 The latter can also be obtained from -hydroxybutyrates 41 which are readily prepared via enzymatic reduction of -ketoesters. 15,139
The synthesis of the stereoisomers of 2,8-dimethyl-1,7-dioxaspiro[5,5]undecane (245), the pheromone of Andrena wilkella illustrates the combined use of chiral synthons from both these important hydroxyacids (scheme 20). 140
1) see ref. 140 b ; 2) NaI, NaHCO 3 , Me 2 CO; 3) H 3 CCOCH 2 CO 2 CH 3 , NaH, nBuLi, THF; 4) see ref. 140 c ; 5) K 2 CO 3 , Me 2 CO, 242; 6) KOH; 7) pTsOH, MeOH; 8) TsCl, pyridine; 9) LiAlH 4 . Alkylation of ethylacetoacetate first with the tosylate 241 derived from S- malic acid and subsequently with iodide 242 derived from R--hydroxybutyrate 41 gave after decarboxylation and removal of the terminal hydroxyl group the spiroketal 245. Along similar lines components of the pheromone of the olive fruit fly, 141
the pheromone of the western corn rootworm 142 and S-(+)-ipsdienol 143 were prepared. Several derivatives of hydroxy acids have been employed as chiral auxiliaries in asymmetric synthesis. 11 The most important with respect to chiral pesticides are the enantiomers of di-isopropyltartrate as ligands in the Sharpless asymmetric epoxidation procedure (see also 1.2). 23 Thus 2R,3S-epoxide
483 247 was prepared in 96% enantiomeric excess by asymmetric epoxidation of 1- penten-3-ol and was subsequently converted into 1R,2S,7S-endo-brevicomin (248). 144
Other pheromones recently prepared using this method are (3S,4S)-4-methyl- 3-heptanol, 145 (2S,3S)-2,3-octanediol and (S)-2-hydroxy-3-octanone, 146 the four optical isomers of the pheromone of the mosquito Culex pipens fatigans 147 and S- frontalin. 148
Extensive use has been made of chiral hydroxyacids to prepare chiral phosphines such as DIOP from tartaric acid. 149 These phosphines are used as ligands in asymmetric hydrogenations with Wilkinson catalysts to furnish amino acid derivatives (see also 2.1). 14,150
3.4 TERPENES The main application of terpenes has been in chiral pheromone synthesis. (+)-Camphor however, available in bulk quantities finds even wider use for it is the precursor for important resolving agents such as (+)-3-bromocamphor-8- sulfonic acid (250) and (+)-camphor-10-sulfonic acid 10 (251). For instance triadimefon 252 (Bayer AG) has been resolved in optical isomers using 250. 151
The latter is a typical example of a large class of N-imidazole and triazole- fungicides. 151 Analogous methods yielded the enantiomers of acylaniline fungicides such as metalaxyl 253 (Ridomil R , Ciba Geigy) and other pesticides. 152
484 Both (+)- and (-)-- and -pinene are turpentine constituents and have served as starting material for three membered ring - e.g. methyl-(+)-trans- crysanthemate 153 and four membered ring - e.g. (+)-grandisol 194 - compounds. 1 54 Hobbs and Magnus 154 synthesized (+)-1R,2S-194 from (-)--pinene (254) starting with an ozonolysis of the olefinic bond and oxidation of the endo- methyl substituent to afford 255 without affecting the four membered ring.
Subsequent steps included Wittig olefination and hydroboration to 256 and Norrish type II cleavage of ketone 257 to aldehyde 258. Rhodium catalyzed decarbonylation and hydrolysis afforded enantiomerically pure grandisol. Ohlhoff 155 devised a procedure to convert -pinene into S-(-)- or R-(+)-- citronellol widely used chiral building blocks for acyclic pheromones.
Pheromone syntheses based on the use of citronellol and citronellic acid include those of the red- and yellow scale, 156 female dermestid beetle pheromones, 157
3S,4S-4-methyl-3-heptanol 158 and multistriatin (European elm bark beetle pheromones), 159 trogodermal, 160 eldanolide, 161 analogs of the aggregation
485 pheromone of the red flour beetle, 162 sex attractants of pine sawflies, 163 the aggregation pheromone of tribolium castaneum 164 and 14-methyl-1-octadiene (lyonetia clerkella L). 165 Mori prepared R-citronellic acid (259) of 100% optical purity from R-pulegone (260) and used it as a single chiral source for both enantiomers of the pheromone of the German cockroach 267 166 (scheme 22).
By means of selective modifications at either end of chiral synthon 261 the enantiomeric tosylates 264 and 266 were obtained which were coupled with bromides (S)- and (R)-265 obtained via similar strategies. Limonenes 11 are also relatively inexpensive chiral starting materials. Both R-(+)- and S-(-)-24 occur naturally in a number of ethereal oils. They have been applied in the synthesis of juvenile type hormones. 167,168 (+)-Juvabione 271 167
for instance, was prepared via selective hydroboration of the disubstituted olefinic bond of limonene (mixture of diastereoisomers) followed by conversion into the nitrile 268 and alkylation to ketone 269. Subsequent conversion of the ringmethyl substituent into an aldehyde functionality yielded the precursor for natural Juvabione.
486 Several syntheses of cis- and trans-chrysanthemate, starting from -pinene and -carene have been reported 6,19,169 (see also 1.2). The latter terpene is especially attractive as the dimethylcyclopropyl-structural entity is already present. A typical synthesis of both enantiomers of 21 started with ozonolysis followed by conversion of 273 into ketoester 274 and anhydride 275. Monoalkylation of 274 followed by hydrolysis gave (-)-21 whereas bis-methylation of 275 provided (+)-trans-chrysanthemic acid after epimerization with base. 170
Several terpenes, especially pinene, menthol and camphor have served as chiral auxiliaries in the synthesis of pesticides (see also scheme 2, eqs. 23, 32). 11
Of the many examples that may be cited, only a recent application in the synthesis of frontalin, component of pine beetle pheromones, is given. 171 8- Phenylmenthol 278, derived from natural pulegone, is readily converted into pyruvate ester 279. Addition of Grignard reagent 280 proceeds diastereoselectively and subsequent reduction with lithiumaluminum hydride (removal of the chiral auxiliary 278) and ozonolysis gives optically pure S- frontalin in a very efficient process.
48? IV Miscellaneous syntheses of chiral pesticides 4.1 HERBICIDES AND PLANT GROWTH HORMONES The optical isomers of triazolylpentenols e.g. 284, which can be applied as herbicides against crabgrass but also show plant growth and fungicidal properties were prepared by asymmetric reduction using a lithium aluminiumhydride reducing agent made chiral by incorporation of the alkoxide derived from (+)-menthol (eq. 33). 172
Four stereoisomers, the result of a chiral center and atropisomerism, of the grass herbicide Metolachlor (288) (active ingredient of Dual R ) exist. They were prepared via resolution using l--phenylethylamine and by the use of the p- nitrophenylsulfonatederivative of lactic ester 286 as a chiral building block (see also 3.3). 173
Analogous methods can be applied for the syntheses of structurally similar herbicides like benzoyl propethyl (Suffix R ) 174 and acylanilide fungicides like furalaxyl and metalaxyl. 152,175 Alkaloids such as quinine, brucine and cinchonine have been applied extensively in classical resolution procedures of many pesticides. 10 A representive example is the resolution of thiophosphate 289 with brucine followed by conversion to phosphoramidothioate 290. 176 The (+)- isomer of 290 shows higher activity against barnyard grass than (-)-290.
488 Abscisins, for instance (+)-abscisic acid 7 291, constitute important plant hormones and have been subject to the synthesis of various chiral analogues. 177
Thus R-(-)-carvone served as chiral starting material for didemethylabscisate 293. 178
The Sharpless procedure for asymmetric epoxidation 23 of allylalcohols, which has been the key to the syntheses of many optically active pesticides (see also 1.2), was used with -cyclogeraniol as the substrate to prepare (+)- and (-)-295. These were converted into 296; the (+)-enantiomer of which showed 10 3
times higher plant growth inhibitory activity (eq. 37). 179
A large number of compounds of the gibberellic acid class of hormones have been isolated. 7 In the first total synthesis of gibberellic acid ((-)-GA-3, 299) Corey and coworkers 180 applied a resolution of 297 via the urethane derivative with (-)--methylbenzylamine to prepare the natural (-)-enantiomer.
4.2 INSECTICIDES AND FUNGICIDES Optical isomers of novel fungicidal compounds 175,181 obtained through resolution include -benzylidene--valerolactones 182 and diaryltriazolylethanol derivatives. 183
489 The isomers of etaconazole (303), the active ingredient of the fungicide Sonax R , were prepared using the enantiomers of 1,2-butanediol as a chiral synthon. 184 This compound is readily prepared from either malic-, tartaric-, or -aminobutyric acid or from D-mannitol. 11,128,185
The diastereoisomers of 303 were separated and it was found that the 2S and 4R configuration additively contribute to the activity. 184
An important class of cholinesterase inhibiting insecticides are phosphor derivatives e.g. parathion, malathion, and demeton. It is well known that the sense of chirality at the phosphorus atom of an organophosphorus derivative often has a significant effect on the biological activity. 186 Many phosphorus insecticides were resolved by classical methods, for instance S p -(-)-leptophos 306 was obtained through resolution of thiophosphate 304 with (-)-- methylbenzylamine followed by a transformation into 306 with a double inversion at phosphor. 187
1) (-)-C 6 H 5 CH(CH 3 )NH 2 , crystallization; 2) PCl 3 ; 3) KOC 6 H 2 Cl 2 Br. (+)- and (-)-Debromoleptophos oxon, a metabolic product of debromoleptophos was prepared via separation of the diastereoisomeric l-proline ester derivatives 307 followed by methanolysis. 188
Similar approaches were used to prepare a series of phenylphosphonothiolates 189
and might be used also to obtain enantiomers of chiral Phosdrin R analogous such as the recently prepared enol phosphonates 308 which show promising insecticidal
490 and fungicidal properties. 190 Wustner and Fukuto 191 prepared the four stereoisomers of the demeton analog 313 via the combined use of s-butanol as a chiral synthon and -methylbenzylamine as a resolving agent. An excellent review of the syntheses of important chiral phosphorous-derivatives has recently appeared. 189a
Optically active DDT analogues 315 were obtained via resolution of aniline derivatives 314 using tartaric acid. 192
Similary chlordane insecticides like 2-chloro-heptachlor were prepared through diastereomeric 3-acetoxyetienylderivatives of alcohol 316. 193
Juvenile hormone 322 has been shown to have the 10R,11S configuration by a synthetic route in which resolution of the phthalate halfester of 3-methylpent- 1-yn-3-ol 318 provides the chiral synthon 319. 194
49l Subsequent reaction with hydroxy ester 320 involving a Claisen rearrangement gave the precursor 321 for juvenile hormone and its trans-epoxide analog (eq. 41). Major synthetic effort has been devoted to insect antifeedants such as drimanes and clerodanes, which are potentially new insecticides. 195 Typical examples of natural compounds are warburganal 323 and clerodin 324.
Syntheses of optically active antifeedants have only recently begun to appear. 13,196 (-)-Abietic acid (325) was used as a chiral starting material for the first synthesis of (-)-warburganal. 196
Conversion of the carboxyl group into a methylsubstituent, ringcleavage and degradation of the side chain were the key steps in this synthesis. The avermectins 197 are another class of potent insecticidal compounds with numerous asymmetric centers and high structural complexity as compared to the compounds described above. Hanessian and coworkers 198 recently described the first synthesis of (+)-Avermectin B1a 331 and their route illustrates the use of several chiral starting materials. The chiral synthons 327, 330 and 328 were derived from S-diethylmalate (or S-tartaric acid), S-malic acid (or D-glucose) and L-isoleucine respectively. The upper half of the macrocyclic lactone was prepared from 327, 330 and the synthon 329 prepared via an asymmetric Sharpless epoxidation (see 1.2). The bottom half of the molecule and the disaccharide subunit were obtained via degradation of natural avermectin B1a. In addition a synthetic route for the disaccharide moiety from d-glucose was developed. 199
Other insecticidal macrolides include compounds such as leucanicidin. 200
492 The examples shown here illustrate the importance of chiral "synthons" for preparation of new, structurally diverse, optically pure pesticides.
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