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Baran Group Meeting Agrochemistry: Emily Cherney

What does "Organic" really mean? Approved Pesticides: Natural Products Me Me The government created the Organic Foods Production Act in 1990 which N Me Me contains two lists: "National list of allowed synthetic substances" and Me H "National list of prohibited non-synthetic stubstances." If a SYNTHETIC O OMe substance is not on the first list, it cannot be used and if a NON-SYNTHETIC Me O O substance is not on the second list, it can be used. The following is a N OH summary of the substances for crop production only (not livestock). Me OMe HO MeO OH Allowed synthetic substances: O O H Me H OH (NH ) CO B(OH) S (elemental) K O Si (aqueous) CuSO 4 2 3 3 2 3 4 O O OH R H Calcium Polysulfide (CaS ) Soap (sodium lauryl sulfate) n O O cevadine O Sucrose Octanoate Esters: Dormant, Suffocating, and Summer oils: O HO Me Petroleium Oil, Synthetic Sesame Oil, etc. O OR spinosyn A (R= H) OH OR' Prohibited non-synthetic substances: spinosyn D (R= Me) O O OC H HO As, CaCl , Lead Salts, KCl, Na AlF , NaNO Me 2 3 6 3 HO O OH Styrchnine: Sulfate: H HO OH N Me CO2H H OH OH H O O gibberellic acid H O NH+ (See: Cherney 2009 GM "L. N. Mander") R= CO(CH ) CH Me HO 2 7 3 N H O O R'= H or CO(CH ) CH N H 2 7 3 H H+ SO 2- O Me O 4 MeO O O Me Me OMe rotenone Approved Pesticides: Natural Products O Me H Me O toosendanin OAc AcO OH Me HO OHMe O Me O HO O HO HO HO MeO2C OH Me volkensin Me O Me O O Me O Me O O H Me Me O O O Me Me Me O O AcO OH OH OH H O AcO OH Me MeO C HO NH 2 O HO O O H OH strigol O O H azadiractin C6H13 O 9 O Me (See: Shenvi 2004 GM "Ryanodol") (See: Renata 2011 GM "Limonoids") H H OH OH Me annonin I Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

Approved Pesticides: Natural Products Cont'd Me Me O OH OH N HO Me N Me MeO H HO NH NH2 O O NH Me 2 HN Me N Me O H O H O H H O OH OH O O Me MeO tetranactin O O S diabroticin A Me N O O rocaglamide Cl Me Me OMe O O O Me S H H H H Me Me Me NO2 Me N Cl OHC Me S N OH NH2 N H H CO2H NH OH O OH N pyrrolnitrin N Me O Me Me Me Me Me Me N Me O H O HO H H N menthol citronellal thymol thiangazole nikkomycin X HO OH Me O Me O O MeO H HN N Me OMe N Me Me Me HO O O eugenol NH2 Me Me OMe S O methyl- Me O Me HO anthranilate Me O Me Me Me H H MeO S Me N O O O Me HO H H Me capsaicin Me Me O Me O S H H O Me O O Me O O quassin terthienyl P OMe H NH + -O O OH 4 OMe Me milbemectin NH2 (and other milbelmycins/ MeO DL-phosphinothricin O O I O H avermectins) O N P OMe OMe HO O H HO O OMe O O H glyphosate CO2Me O O O OMe Me OH Me O MeO Me haedoxan codelmone strobilurin A Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

Section 1: Total Syntheses of Natural Product Pesticides Roush et al: PNAS (2004) v. 101, pp. 11955-11959. 1-spinosyn A 1) O3 1) TBAF SugO SugO 2) PPh3=CHCO2Me Spinosyn A and D are the active ingredients in (an insectiside 2) Dess-Martin 3) DIBAL-H SugO produced by Dow). These two natural products were isolated from soil 3) CBr4, Ph3P 4) Parikh-Doering [O] CHO samples collected from an abandoned rum still by an employee vacationing in the Caribbean in 1982. (73%) (73%) Paquette et al, JACS (1998) v. 120, pp. 2543-2562. OTBDPS Br Br t Br Br Br BuLi; MeO OMe NaH, THF; H H OTBS 1) Ba(OH)2, THF, H2O CeCl3; MeOH, H2O OH 2) THF/AcOH/H2O O OPMB Me 3) O O MeO OMe (77%) MeO SugO OPMB P MeO H H EtO OH OTBS O EtO EDCI MeO OTBS O O P Me (91%) MeO O (86%) 13 steps O O 1) DIBAL-H Br Br TESO Et 2) Martin TBDPSO sulfurane; O Et H H OH TBDPSO H H P AcOH, H2O, THF OTBS OEt EtO (54%) 1) Pd(PPh3)4, Tl2CO3, H H H H (HO)2B OH O 2) Parikh-Doering [O] PMBO 1) PivCl, pyr. PMBO OPMB (82%) no yield 2) TBAF Me Me given for 3) PCC, Al2O3 SugO OPMB SugO step 4 4) K2CO3, MeOH O i ( Pr)2NEt, LiCl, O 1) KHMDS, Comin's H H O O H H OPiv Me3Sn OPiv CH3CN, rt, 19h 2) (Ph3P)4Pd, LiCl H H O Et Me3SnSnMe3 O O (75%) Br Tandem HWE-DA Br (48%) H H H H O Et Me3P (8 eq) O P (88%) OEt t-amyl alcohol PMBO PMBO EtO (0.005 M) OTBDPS OTBDPS OPMB Me Me Pd (dba) •CHCl Me H H 2 3 3 OPiv (iPr)2NEt, PhH O O (83%) O Cl 7 steps SugO O Et OTBS spinosyn A H H 8 steps including: Et OTBS O Et H Yamaguchi lactonization H PMBO 2x glycosylation spinosyn A Br Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

2-rocaglamide O Frontier et al, JACS (2009) v. 131, pp. 7560-7561 Porco et al, JACS (2006) v. 128, pp. 7754-7755 O OMe MeO OMe 1) vinylMgBr, CeCl3; OMe O Ph OMe OH O HCl (1M) CO2Me MeO OH O Ph MeO 2) OsO4, NMO; PhMe/DCM, !70 °C 3) NaIO4 O h" , TADDOL O MeO O MeO O (exo) MeO MeO OMe OMe 45% 1) nBuLi, over H Ph 5 steps 2) KH, NaI, PMBCl HO O PMBO Ph MeO CO Me MeO O HO 2 1) NaOMe, MeO HO CO Me t OMe MeOH; 2 1) BuLi, Bu3SnCl, PMBO 2) Me NBH(OAc) Et O, !40 °C 4 3 2 MeO O O 2) mCPBA, DMF, rt MeO MeO MeO O (50%) O 61%, 82% ee 2 steps OMe (!)-rocaglamide 1) DDQ OMe MeO 2) KHMDS, OMe PhNTf2 (59%) 3-thiangazole O O MeO CO Me Heathcock et al, JOC (1994) v. 59, pp. 4733-4734 MeO 1) Pd(PPh3)4, CO, HO 2 HO OTf i BnS Bn MeOH, ( Pr)2NEt, O Me 2)PtO2, H2, EtOH H H N N CO2Me (51%) MeO O CBZ N S N MeO O Me H Me O Me 1) DMP SBn SBn 2) TsOH, 1) Na, NH3, S N OMe THF, !78 °C 4Å sieves - OMe g 2) TiCl , DCM 3) DDQ e n 4 Me l

a

o 4 steps (50%) i

z NMe (68%) h

t (38%) a HO H 2 S N MeO HO O 1) NaHB(OAc)3 Me 2) LiOH, THF/H2O BnS Me OBn 3) Me2NH, DCC, DMAP O Me O NH H H O O MeO O (28%) N N NHMe HO Bn N N H H O Me O Me O HN Me (±)-rocaglamide Me SBn SBn OMe Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

4-deguelin Winssinger et al, Chem. Eur. J. (2010) v. 16, pp. 9767-9771 Sames et al, Org. Lett. (2003) v. 5, pp. 4053-4055 O 1) NIS, TFA K CO , DMF MeO NaH, µ" MeO OH MeO OH 2 3 80 °C 2) Pd(OAc)2 MeO Br MeO (70%) (49%) MeO OH MeO O (quant.) MeO O MeO OH MeO O 1) nBuLi, THF, - 78 °C 2) MnO2, DCM 1) O 1) Cl O OH O OH O OH acetone, pyr. O OMe K2CO3, KI, CuI OH 2) µ" , m-xylene, 2) MeI, K2CO3 180 °C Wittig (36%) Me Me (87%) OH (90%) O (97%) Me OH O Me O Me Me

1) PPh3, Me (49%) DEAD, Et3N 2) Grubbs II Me O O 5 mol% PtCl2, Me Me PhH, 55 °C Me 1) ADmix- # O O Me O Me 2) IBX O (91%) 3) Zn, AcOH, µ" Me OMe O MeO OMe MeO H (16%) MeO O MeO O MeO O MeO O H H MeO O ($)-deguelin 1) BCl3, DCM, A story brought to you by: Me MeO O - 78 °C (86%) rotenone 2) KOAc, EtOH, ! H O O Me O Section 2: From Natural Products to Synthetic Pesticides O Me 1- Pyrethrin H O O Natural Product Commericial Insectiside MeO H Me Me Me Me MeO O OMe Indigenous tribes in French Guiana smashed Me Cl H Me jicama roots containing rotenone to use while O O O MeO O fishing. The rotenone poisoned the fish Me Cl causing them to rise to the surface of the O O CN (±)-deguelin water. The fish were still edible since rotenone is poorly absorbed by the GI tract in O humans. Today it is also used in aquatic pyrmethrin I research to collect cryptic fish. Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

1-pyrethrin (cont'd.) 2-nicotine A Synthesis of : US Patent No. 7,468,453 B2 Natural Product Commericial Insectiside Syngenta process route to cyhalothrin: formulated in and marketed under the names "Karate" "Kung-fu" and "Matador" N N Me Me Me Me H Cl N N SOCl2, Me N H F3C PhH F3C O N OH Cl O NO2 Cl Cl nicotine O O NaCN, Hexane, w/ or w/o H2O, w/ or w/o Et3N A Synthesis of : US!Patent No: 6861522 !(B2)

Me Me Me Me 1) MeNH2, NaOH, cyhalothrin H O, EtOH Cl 2 Cl recrystallization Cl 2) Aq. CH O, 80 C, O Ar 2 ° O NH N O H pH 8-9 O N Cl Cl S O CN O CN NC CN N N CN Sorry for the vague procedures here, but to quote the patent: "The reaction can be Me steps carried out in a solvent or in a mixture of a water immiscible solvent or an aqueous O N solution of the source of or in the absence of a solvent" 1) NaSCN Cl 2) Cl2 S additionally... "the acid chloride and 3-phenoxybenzaldehyde can be added sequentially N NNO2 or simultaneously to the source of cyanide in the presence of the solvent or the solvent N Cl Cl Me mixture, optionally in the presence of an organic base or an onium salt." Cl more vagueness continues on like this for about a dozen more paragraphs... A Synthesis of : US Patent No:!1987-17641"A5 Analogs based on pyrethrin: ACS Symposium Series v. 504 (1992): "Synthesis and Chemistry of Agrochemicals III" H2N CN + CN pp. 258-282 K N HN - BnCl SH N Cl O 1) (COCl)2 1) Wittig NC CS - + 2 K - 2x BnSH N S 2) H 2) BH3•THF BnS SBn N 3) [O] OH Cl N OH O O R R R 3) MgBr Other Commericial Products: KOH, DMF NaH, CN NNO2 N Me Cl Cl N N N O O N N S O H H Me R S N NO2 Cl N F clothianidine Me Cl N CN thiacloprid Me Me Me N N simplified: O H MTI-800 Cl N Me EtO Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

3- 3-organophosphates (cont'd.) Natural Product Commericial Insectiside A Synthesis of Azinophos-Methyl: Tetrahed. (1991) 8917; J. Het. Chem. O O (2007) 951; Bioconj. Chem. (1997) 256 O O O O O H MeO P N P OH N Me CH2O, HO MeS H NaNO , HCl OH NH2 2 NH SOCl2 N Cl glyphosate N N NH2 N N Making various Phosphates: reagents product target O S S - PSCl3, MeOH, NaOH, PhMe S S Base - PCl , MeOH, NaOH, Et N, S P P 3 3 P P N S OMe MeO OMe - P2S5, MeOH then Cl2 OMe MeO OMe MeO OMe N SH - P(O)(OMe)2, Lawsesson's then SO2Cl2 Cl R - N (Phosphorous, Sulfur, Silicon and Related Elements (2010) 347) (R= Nu ) Azinophos-Methyl S S A Synthesis of Methidathon: (Nongyao (2001) 13) P P P S , MeOH, PhH MeO OMe MeO OMe O 2 5 1) MeOH SH SH SR phosgene S (R= E+) 2) H2NNH2 (Nongyao (2001) 13) S C S H2N N OMe HN OMe S S S N P P P O MeO OMe, NH OH, DCM MeO OMe MeO OMe 4 NH NHR S S Cl 2 + S (Phosphorous, Sulfur, Silicon and Related Elements (2010) 347) (R= E ) S CH2O P N OMe P S O O MeO N MeO OMe OMe SH P P P Methidathon MeO OMe, SO Me MeS OMe MeS OMe 4 2 NH NHR NH2 2 + A Synthesis of Pyrimiphos-Methyl: (Huaxue Shiji (2010) 845) (Phosphorous, Sulfur, Silicon and Related Elements (2010) 347) (R= E ) O O NEt2 S S H NEt N H2N C N 2 N NH P P Me OMe PSCl3, 2 eq RMgBr R R R R Me Me H N NH Cl R' 2 O Me (Phosphorous, Sulfur, Silicon and Related Elements (2010) 347) (R'= Nu-)

O O NEt2 POCl3, 1 eq EtOH, Et3N P P S EtO Cl EtO SnPr S N N Cl SnPr P MeO OMe (Huazhong Nongye Daxue Zuebqo (2000) 339) ethoprop P MeO O Me Cl O O OMe POCl , 1 eq EtOH, Et N 3 3 P P Pyrimiphos-Methyl then 1 eq ArOH EtO Cl EtO NHR OAr OAr (Tetrahedron (1995) 7981) Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

4- Kepone and : Cl Cl Cl Cl Cl Cl Natural Product Commericial Insectiside Cl Cl Cl Cl Cl Cl O Cl Cl Me H O Cl Cl Cl O N H Cl Cl Cl Cl O N Cl Cl Cl MeN Me Me Cl Cl Cl Cl Cl Cl Cl Cl N O O Me chlorodecone Mirex Me (Kepone) physostigmine Me xylylcarb DDT etc.: Cl Cl Cl Cl O H2SO4 Cl Cl Other Commerical Carbamates: (cat.) Cl O O O H Me Me Cl Me Me Cl Me N Me N O N O MeO OM N O S Cl Cl e H H H Cl O O dichlorodiphenyl trichloroethane (DDT) O DDT was discovered by a Paul Müller in 1940. It was first O Cl Cl O bendiocarb brought to market in 1944 and was used during the second Me Me half of WWII to prevent the spread of malaria and typhus. N O N O Me Paul Müller won the Nobel Prive in Physiology and H H O Medicine for the discovery in 1948. It was later used as an Me N S , however it was found to be harmful to wildlife, Cl Cl N O Me particularly birds including the bald eagle, and was banned dichlorodiphenyl H from use in the US in 1972. dichloroethane Me Me Cl Cl OH Section 3: Totally Synthetic Pesticides Cl Cl Cl Cl Cl Cl 1-* Cl Cl Cl Cl Cl Cl Cl Cl Diels Cl Cl Cl Cl Cl Cl Cl !Alder Cl hexachlorobenzene pentachlorophenol Cl * Almost all organochlorides have been banned globally. Cl Cl Cl Cl 2-fun transformations from the agrochemistry literature! similarly: Yamamoto et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 34-42. Cl Cl Cl Cl Cl Cl Cl RO2C CO2R Cl O Cl O Cl 1) NaOH HO CO R Cl Cl S Cl RO C S 2 2 2) ClCO Me MeNHNH C 2 2 Cl O S S N Cl Cl Cl Cl Cl Cl RO2C S N SH O Me Chlorodane RO2C CO2R Baran Group Meeting Agrochemistry: Insecticides Emily Cherney

2-fun transformations from the agrochemistry literature! (cont'd) McCann et al. Synthesis and Chemistry of Agrochemicals VI (2002) p. 166-177. Meier et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 313-326. O H H N N R R R NH Ar Ar NH2 NH2(Me)2, CH2O, R Ar HCl, EtOH H NNH , base; HCl + - O O O 2 2 N NH3 Cl HN O O (Me)2N Me Me Me 1) NaNO2 O Ar 2) Ar R MeO C R R NH + 2 Me CH2(OEt)2, H NH2 Cl Ar N N N H2N HN N Ar N NH Ar MeO2C MeO C N NH NH 2 O Ar O Cl Lee et al. Synthesis and Chemistry of Agrochemicals II (1991) p. 195-208. Guaciaro et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 56-74. Me Me Me Et3N, R R R Me iPr OH Me Me Me N N 1) NaBH4 H2N CO2Me NaH RO C CO R RO C CO R RO C CO R NOH O O 2 2 DBU 2 2 2) DBU 2 2 HN N Cl O i Me F3C N CF3 F C N CF H F C N CFH iPr Me Pr H 3 2 3 2 Theodoridis et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 134-146. 1) NaBH4 CH3CHO; Cl Cl 2) DBU Cl Cl KNCO, AcOH; O Via: NaOCl Me Me N OR NH NHNH2 Me Me 1) O CO H N 2 RO C CO R RO C CO R Me 2 2 2 2 Me 2) (PhO)2PON3, Et3N F3C N CF2H F3C N CH3 H H Wepplo et al. Synthesis and Chemistry of Agrochemicals IV (1995) p. 149-160. 1) NH OH HCl, OH 2 • CO2Me NaOMe, MeOH HO 2) HCl, MeOH HO N O O O