I.J. ArIons, J.J.S. vnn !onson, W.

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.

1) O
3
; 2) MeMgBr; 3) Br
2
, HgO, CCl
4
; 4) h; 5) RuO
2
, KIO
4
; 6) LiAlH(OEt)
3
,
-20C; 7) Ph
3
PCH
2
; 8) thexylborane; 9) H
2
O
2
, NaOH; 10) Ac
2
O, pyridine; 11)
POCl
3
, pyridine; 12) CrO
3
, 2 pyridine; 13) H
2
, Pd; 14) h, NaHCO
3
, MeOH; 15)
(Ph
3
P)
3
RhCl; 16) LiAlH
4

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.

Acknowledgement
I am grateful to Profs. H. Wynberg and R.M. Kellogg for helpful suggestions
and critical reading of the manuscript. I thank Karin de Jager and W. Kuil for
their contributions in preparing this chapter.
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49?
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