Synthesis and Chemistry of Agrochemicals III - American Chemical

Chapter 21

New Series of Milbemycin Macrolides (LL-F28249) with Endectocidal, Insecticidal, and Acaricidal Activity Downloaded by OHIO STATE UNIV LIBRARIES on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch021

Synthetic Modification and Biological Activity T. C. Barden, G. Asato, Ζ. H. Ahmed, D. J. France, V. Kameswaran, E. Parker-Jackson, S. Y. Tamura, S-S. Tseng, and B. L. Buckwalter Agricultural Research Division, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400

LL-F28249 is a new series of 16-membered macrolides recently isolatedfromS. cyanogriseus by the Medical Research Division of American Cyanamid. Several features of this series distinguish it from the related milbemycins and avermectins. The chemical modification of F28249α, the major component of fermentation broths, is described. The chemistry focuses on the unique characteristics of LL-F28249. The endectocidal, acaricidal and insecticidal activity of representative F28249αderivatives also is presented.

Since the discovery of the milbemycins from Streptomyces hygroscopicus by Sankyo researchers in 1974 many other members of this class of macrolides have been reported from a variety of Streptomyces species (7). All milbemycins contain a 16-membered macrolide ring and a spiroketal moiety although considerable diversity is seen around the periphery of the ring. It is not possible in the space available to comprehensively review all the isolation, characterization and synthetic research in this area. Rather, this introduction attempts briefly to place the current work into proper context and to provide key references and reviews for those interested in further information ( 2-4). Milbemycin D 1 is typical of the materials produced by S. hygroscopicus. Others arc further oxidized at C(22), C(23), C(4cc), or C(5). In a few cases the tetrahydrofuranyl ring is incomplete or C(2-7) may be aromatized. A variety of pendant alkyl groups are found at C(12), C(24) and C(25) (5,6). S. avermitilis, first characterized by chemists at Merck in 1978, produces a group of glycosylated milbemycins (2). Avermectin B 2 typifies this group of milbemycins which is further oxidized at C(13) and contains an cc-L-oleandrosyl-ccL-oleandrosyl disaccharide at this position. The major series, A and B ^ are l a

x

0097-6156/92/0504-0226$06.00A) © 1992 American Chemical Society

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

21.

BARDENETAL.

New Series of Milbemycin Macrolides

227

unsaturated at C(22, 23) although hydroxylation at C(23) is seen in the A and B series. Other structural variations found in this series parallel those in the rest of the milbemycins. The entire family of milbemycin natural products recently has been reviewed (3,4). In 1984 Carter et al. in the Medical Research Division of American Cyanamid isolated a new series of milbemycins from S. cyanogriseus (7). The distinguishing feature of these compounds, designated F28249, is a C(25) alkenyl substituent. The series is exemplified by F28249cc 3, the main component in fermentation broths. The C(23) position of all components is hydroxylated; no 22,23 C(23)-dehydroxy variants are present. Various alkyl substitution is present at the C(25) olefin terminus or at C(12). Still other structural modifications are similar to those produced by S. hygroscopicus and S. avermitilus (3). Shortly after the Cyanamid discovery, Glaxo researchers isolated the same series, in their nomenclature S541,from5. thermoarchaensis (8). Factor A of this series is identical to F2824910). The analog completely unsubstituted at C(23) is obtained by tributyltin hydride/AIBNreductionof 8 (8-»ll) or the C(23) β-bromo analog. The C(23) ketone of F28249a (12) is a versatile intermediate. It can be prepared from the C(5) protected material by various standard procedures (Swern Oxidation, Mofatt Oxidation, RUO4/IPAP, etc.) (26). Alkyl and aryl Grignard reagents add to 12 to generate the corresponding C(23) tertiary alcohols. The yields are high even though a large excess of reagent is required (26). The base sensitive macrolide carbonyl in unaffected by the presence of these metal alkyl bases although basic conditions can produce lactone opening, epimerization at C(2), isomerization of Δ · double bond to the Δ » position and aromatization (27). Presumably initial formation of the C(7) magnesium alkoxide suppressesreactionat these proximate sites. The C(23) ketone also readily forms O-alkyl oximino and hydrazone derivatives (26). One of these, moxidectin 17, has been developed by American Cyanamid and has emerged as a promising new anthelmintic product. The surpris ing range of biological activity shown by these alkoximes and hydrazones will be presented later. 2 2

2 3

2 3

2 4

2 2 ,

2 3

3

2 4

4

2

3


Downloaded by OHIO STATE UNIV LIBRARIES on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch021

SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

-10°C, 5 min R = H 0°C, 30 min R = Ac HO" 7 x

H 0

OR

2

2

C(0)C0 CH , R = Ac 2

3

2

6 Figure 2. Selective deprotection of 6.

2 2

2 3

A, 180° C ^

Δ ' R=H 9

BusSnH^ AffiN

R=Η u

r

OH

R = OC(S)OTol 8 DAST DME, -78° C

ν 23,24 R = H, 5-OAc 10

Figure 3. Dehydration/reduction of the C(23)-OH


R =H 2 = 3 x

R

H

21.

BARDEN E T

Al»


231

C(25) Sidechain Modification The olefinic sidechain distinguishes the F28249 series from other milbemycins and avermectins. Functionalization of the Δ · olefin affords a unique set of analogs. Halogenation of F28249a with N-chlorosuccinimide (NCS) or N-bromoacetamide (NBA) occurs with rearrangement of the allylic olefin (Figure 4) (18). Carefully controlled conditions are required to limit the reaction to the sidechain olefin. The second most reactive olefin is the Δ position. Upon treatment with silver salts, the transient allylic carbonium ion is trapped with various nucleophiles, regenerating the starting double bond. Mixtures of Ε and Ζ olefin isomers are usually obtained. The reaction works well for a wide range of nucleophiles. Reduction of the allylic halide with tributyltin hydride/AIBN gives back the Δ · olefin. m-CPBA Epoxidation also is selective for the sidechain olefin. The selectivity between the sidechain and the Δ · position is sensitive to the reaction conditions and the nature and orientation of the C(23) substituent. The sidechain olefin is generally the favored reaction site but this can be completely reversed by certain C(23) groups (Figure 5). Litde insight into the reasons for this substituent dependence is gained from semi-emperical AMI calculations. The substituent at C(23) has a negligible effect on the conformation of the ring and sidechain (Figure 6). While there is some variation in the calculated electron density of the sidechain carbons with the different groups at C(23), it is small and does not correlate at all with the experimentally determined product ratios. More sophisticated calculations will be needed to fully understand this effect. 2 6

2 7


1 4 , 1 5

2 6

2 7

1 4

1 5

C(13) Modification Oxidation of a doubly protected F28249cc derivative with Se0 in aqueous formic acid selectively gives the 13-p-formate though oxidation of the C(25) sidechain olefin is competitive (Figure 7) (20). By careful monitoring the reaction can be stopped before sidechain oxidation products accumulate although unreacted starting material sometimes still remains. The 13-β alcohol can be obtained by hydrolysis of the formate or, alternatively it is produced directly by oxidation with Se0 in aqueous trifluoroethanol (TFE). The alcohol gives access to 13-p-halo analogs and 13-p-ethers. The reactivity of the allylic sidechain is again dependent on the C(23) substituent, suggesting that the same effect which influences epoxidation ratios is operating here as well. With most C(23) substituents oxidation occurs preferentially at the C(13) position before doubly oxidized products appear. The C(23)-dehydroxy derivative gives only slightly selective oxidation at C(13) and monooxidation products at C(13) and C(26cc) can be isolated. The C(23) methyl oxalate is the most convenient substrate; the reaction can be allowed to run to completion with minimal overoxidation. 2

2

Biological Activity The naturally occurring F28249 macrolides already have potent endo- and ectoparasiticidal and insecticidal activity. A semisynthetic program was initiated to optimize the biological activity. Many synthetic derivatives retained the high biological


SYNTHESIS AND CHEMISTRY O F AGROCHEMICALS III


OH

Figure 4. C(25) Sidechain modification of F28249oc.

ure 5. Influence of C(23) substituent on epoxidation regioselectivity




BARDEN E T A L .


233


234

SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

activity found in the parent or had improved activity. However, the effect of subtle structural changes on the potency of similar analogs is striking. In the tables winch follow the endectocidal and insecticidal profile of analogs is modeled by their activity against representative pest species. The sheep parasite Trichostrongylus colubriformis provides a measure of endoparasitic activity while the ectoparasite activity is assessed with the rabbit ear mite Psoroptes cuniculi. Representative crop pests are the two-spotted mite Tetranychus urticae and southern armyworm Spodoptera eridania. Activity against a number of other destructive insect species often is seen as well. The activity in all tables is reported as % kill/control at the indicated dose. The structural differences between the C(23)-dehydroxy 11 and dehydrated (9 and 13) F28249oc derivatives is small yet they have a very different endectocidal activity spectrum (Table I). Compared to F28249a, both 9 and 13 have better Γ. colubriformis activity but are less active against P. cuniculi whereas 11 has about the reversed activity spectrum. All three derivatives in Table I have improved acaricidal and insecticidal activity over F28249a, but simply changing the position of the double bond substantially changes the potency of 9 and 13 against the last two species. Although the C(25) sidechain derivatives substituted at C(26cc) have poor biological activity overall, epoxidation of the side chain 26,27 double bond considerably improves the activity in certain screens (Table Π). Epoxide 14 is much more potent against T. colubriformis than 3 but is a less effective ectoparasiticide. Epoxidation at the 14, 15 olefin or double epoxidation causes no such dramatic im provement (15,16). The novel 23-imino derivatives were the most promising compounds to be identified. This group included O-alkyl oximes, acyUiydrazones, carbazides and semicarbazones. Within the O-alkyl oximes some interesting selectivities were noted. As the size of the alkyl moiety increased the endoparasiticidal activity dropped sharply while the acaricidal, insecticidal and ectoparasiticidal activity remained high (17 - 20) (Table ΙΠ). In contrast, the formyl (21) and acetyl (22) hydrazones are much more active against T. colubriformis and weaker against P. cuniculi than the O-alkyl oximes. Moxidectin 17 has the optimal activity spectrum with substantially improved activity than F28249cc in all four areas. The precursor to the above derivatives, ketone 12, retains most of the activity shown by 3 but is a much weaker ectoparasiticide. Several other classes of derivatives also have improved biological activity over F28249oc in one screen or another. These include C(5) esters, C(23) dehydroxy analogs, Grignard adducts from C(23) ketones and C(13) β-ether and β-halides. The C(13) substituted compounds, in particular, are potent broad spectrum endectocides, acaricides and insecticides. Recent field trials indicate that F28249 has commercial potential as an acaricide. On cotton F28249cc gives good control of the two-spotted mite T. urticae and broad mite Polyphagotarsonemus latus at 30 grams per hectare (Table IV). Addition of a small amount of oil reduces the amount needed to 11 grams per hectare. The oil here may serve several roles (20). It might provide some protection from UV degradation and air oxidation, give better plant coverage of the miticide and also aid in penetration of the cuticule. LL-F28249 is a new series of milbemycins active against many animal parasites and crop pests. The characteristic unsaturated sidechain and uniform hydroxylation of C(23) affords practical access to many novel derivatives.


21.

BARDENETAL.


235

Table I. Testing of C(23) dehydroxy and dehydrated derivatives


R

OH %

Control

T. colubriformis P. cuniculi (μg/cm ) (mg/kg) 1,0 0Λ 0,0625 0,0313 100 93 = OH (F28249a) 88 68 44 100 100 =H 89 82 81 = Η,Δ · 100 95 = Η,Δ · 96 85 34 71 2

3: 11: 9: 13:

R R R R

2 2

2 3

2 3

2 4

T. urticae (ppm) 1.0 0.1 90 30 100 100 100 100 100 30

S. eridania (ppm) 100 10 80 0 100 100 100 10 100 100

Table Π. Testing of epoxide derivatives OH

% Control T. colubriformis P. cuniculi ^g/cm ) (mg/kg) Q.Q625 0,0313 .1,0 0,1 R = OH(F28249a) 88 100 93 68 26,27 epoxide 100

Synthesis and Chemistry of Agrochemicals III - American Chemical

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