baran group meeting emily cherney agrochemistry: insecticides
TRANSCRIPT
Emily CherneyBaran Group Meeting
What does "Organic" really mean?The government created the Organic Foods Production Act in 1990 whichcontains two lists: "National list of allowed synthetic substances" and"National list of prohibited non-synthetic stubstances." If a SYNTHETIC substance is not on the first list, it cannot be used and if a NON-SYNTHETICsubstance is not on the second list, it can be used. The following is asummary of the substances for crop production only (not livestock).
Allowed synthetic substances:
(NH4)2CO3 B(OH)3 S (elemental) K2O3Si (aqueous) CuSO4
Calcium Polysulfide (CaSn) Soap (sodium lauryl sulfate)
Sucrose Octanoate Esters: Dormant, Suffocating, and Summer oils:
O O
OOHHO
OH
OR'
OH
HO
OH
OR
R= CO(CH2)7CH3R'= H or CO(CH2)7CH3
Petroleium Oil, Synthetic Sesame Oil, etc.
Prohibited non-synthetic substances:
As, CaCl2, Lead Salts, KCl, Na3AlF6, NaNO3 Styrchnine: Nicotine Sulfate:
NH+
NH+
Me
H
SO42-
N
N
H
O
O
H
H
Approved Pesticides: Natural Products
Approved Pesticides: Natural Products
O
O
Me
MeOOMe
OMe
O
O
O
Me
Me
O
O
MeN
MeMe
R
spinosyn A (R= H)spinosyn D (R= Me)
O
HOMeOH
HO
HO
HO
OOH
MeMe
Me
O
NH
ryanodine
MeOH
O
O
O O
Me
MeO2CAcO
O
OH
O
Me
Me
OOH
MeO2C
azadiractin
(See: Renata 2011 GM "Limonoids")(See: Shenvi 2004 GM "Ryanodol")
N
O
Me
OH
OHHHMe
H
HO
O
HO
OH
OH
Me
H
O
O
cevadine
OO O
Me
MeO
OMe
O
H
H
rotenone
HO
OHO
HMe CO2H
OC H
gibberellic acid(See: Cherney 2009 GM "L. N. Mander")
O
O
OAcMe
OH
H
HMe
HO
AcO
Me
OO
HO
toosendanin
O
OMeAcO
O
O
OH
MeMe
Me
O
Me
Me
HO
volkensin
H
O
O
C6H13
OH OHH
H
O
O
Me
HOH
H9
annonin I
O
O
Me
Me Me O
OH Ostrigol
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
Me OHcodelmone
Me
Me
O
O
Me
O
Me Me
Pyrethrin I
-O
O
NH2
P
O
OMe
OMeNH4
+
DL-phosphinothricin
HO
OHN P
O
OMe
OMeglyphosate
HN
O
Me
Me
HO
OMe
capsaicin
HN
N
O
OMe
Me
Me
MeMeMe
tebufenozide
O
O
O O
OO
OOO
OO
O
Me
HH
H HMe
Me
Me
Me
MeH H
H H
Me
Metetranactin
N
HN
N
NH
HO
O
HH
HO OH
CO2HOH
Me
NH2
O
OHC
H
nikkomycin X
ON
NS
NS
NS
Me
OHN
Me
Me
Me
Me
thiangazole
milbemectin(and other milbelmycins/
avermectins)
O
O
O
O
Me
O
Me
Me
HO
H
H
OH
OMe
MeO
O
MeO
O
MeH
H
Me H
Me
H
quassin
haedoxan
O
OO
OO
O
OO
O
MeO
OMe
OMe
HO
H
H
MeO
rocaglamide
O
HHO
OMe
N
O
MeMe
MeO
MeO
HO
diabroticin A
N
N
OHOH
HNMe
NH2
OOHOH
NH
O
Me
NH2
Approved Pesticides: Natural Products Cont'd
Me
OH
MeMementhol
Me Me
O
Me
citronellal
Me
OH
MeMe
MeO
HOeugenol
thymol
S
S
S
terthienyl
O
OMe
NH2methyl-
anthranilate
Me
CO2Me
OMe
strobilurin A
NH
Cl
NO2Cl
pyrrolnitrin
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
Section 1: Total Syntheses of Natural Product Pesticides1-spinosyn A
Paquette et al, JACS (1998) v. 120, pp. 2543-2562.
Br
OTBS
MeO OMe
O
tBuLi;
CeCl3;
MeO OMe
OH
OTBS
NaH, THF;MeOH, H2O
(86%)
(77%)
H
HH OTBS
H
MeO
MeO
O
13 steps
H
HH OTBS
H
O
TBDPSO
PMBO
1) DIBAL-H2) Martin sulfurane;AcOH, H2O, THF
(54%)
H
HH OH
H
TBDPSO
PMBO1) PivCl, pyr. 2) TBAF3) PCC, Al2O34) K2CO3, MeOH
H
HH OPiv
H
PMBO
O
no yieldgiven forstep 4
1) KHMDS, Comin's2) (Ph3P)4Pd, LiCl Me3SnSnMe3
H
HH OPiv
H
PMBO
Me3Sn
(48%)
O Cl
OTBDPS
Me
OTBSEt
Pd2(dba)3•CHCl3(iPr)2NEt, PhH
(83%)
H
HH OPiv
H
PMBO
O
OTBDPS
Me
OTBSEt8 steps including:
Yamaguchi lactonization2x glycosylation
spinosyn A
Roush et al: PNAS (2004) v. 101, pp. 11955-11959.
OTBDPS
SugO 1) TBAF2) Dess-Martin3) CBr4, Ph3P
(73%)
SugO
Br Br
1) O32) PPh3=CHCO2Me3) DIBAL-H4) Parikh-Doering [O]
(73%)
SugO
Br Br
CHO
P
O
Me
OPMB
O
MeO
MeO
TESO Et
1) Ba(OH)2, THF, H2O2) THF/AcOH/H2O3)
EtO POH
EtO
O O
EDCI
SugO
Br Br
O
OO
P
EtO
O
OEt
Et
Me
OPMB
(91%)
(HO)2B OH
1) Pd(PPh3)4, Tl2CO3,
2) Parikh-Doering [O]
(82%)
SugO
Br
O
OO
P
EtO
O
OEt
Et
Me
OPMB
O
(iPr)2NEt, LiCl,
CH3CN, rt, 19h
(75%)
SugO
Br
O
O
O
Me
Et
OPMB
H H
Tandem HWE-DA
(88%) Me3P (8 eq)t-amyl alcohol(0.005 M)
SugO
Br
O
O
O
Me
Et
OPMB
HH
7 stepsspinosyn A
Spinosyn A and D are the active ingredients in Spinosad (an insectisideproduced by Dow). These two natural products were isolated from soilsamples collected from an abandoned rum still by an employee vacationing in the Caribbean in 1982.
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
2-rocaglamide
Frontier et al, JACS (2009) v. 131, pp. 7560-7561
O
MeO
MeO
OOMe 1) vinylMgBr, CeCl3;
HCl (1M)2) OsO4, NMO; 3) NaIO4
O
MeO
MeO
OMeO
PhH
1) nBuLi,
2) KH, NaI, PMBCl
O
MeO
MeO
OMePMBO
Ph
45%over
5 steps
1) tBuLi, Bu3SnCl,
Et2O, !40 °C
2) mCPBA, DMF, rt
(50%)
O
OMe
OMeO
MeO
PMBO
1) DDQ2) KHMDS, PhNTf2 (59%)
O
OMe
OTfMeO
MeO
O
HO1) Pd(PPh3)4, CO,
MeOH, (iPr)2NEt,
2)PtO2, H2, EtOH
O
OMe
CO2MeMeO
MeO
O
HO
(51%)
1) NaHB(OAc)32) LiOH, THF/H2O3) Me2NH, DCC, DMAP
(28%)O
HHO
OMe
NMe2
OMeO
MeO
HO
(±)-rocaglamide
Porco et al, JACS (2006) v. 128, pp. 7754-7755
O
O
OH
OMe
MeO
OMe
PhCO2Me
PhMe/DCM, !70 °C
h" , TADDOLO
OH
O
OMe
MeO
OMe
MeO
O
Ph
O
O
HOCO2Me
OMe
MeO
MeO
1) NaOMe,MeOH;2) Me4NBH(OAc)3
O
HO
OMe
CO2MeMeO
MeO
HO
61%, 82% ee
(exo)
2 steps(!)-rocaglamide
3-thiangazole
Heathcock et al, JOC (1994) v. 59, pp. 4733-4734
CBZ
HN
NH
HN
O
O
CO2Me
Me Me
Me
SBn
BnS
SBn
4 steps
HN
NH
HN
O
OMe Me
Me
SBn
BnS
SBnO
O
NH
O
NHMe
Me OBn
Bn
1) Na, NH3, THF, !78 °C2) TiCl4, DCM
HO
NH
NS
NS
NS
Bn
Me
O
HN Me
Me
Me
Me
O
1) DMP2) TsOH,4Å sieves3) DDQ
(68%)(50%)
(38%) thia
ng
-azo
le
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
4-deguelin
Sames et al, Org. Lett. (2003) v. 5, pp. 4053-4055
MeO
MeO OH
K2CO3, DMF
Br MeO
MeO O(quant.)
OH
OHO
O
acetone, pyr.
1)
2) MeI, K2CO3
O
OMeO
Me
Me
1) nBuLi, THF, - 78 °C
2) MnO2, DCM
(36%) (87%)
MeO
MeO O
O
O
OMe
Me
Me5 mol% PtCl2,PhH, 55 °C
MeO
MeO O
O
O
OMe
Me
Me
(91%)
1) BCl3, DCM,- 78 °C2) KOAc, EtOH, !
(86%)
MeO
MeO O
O
O
O
Me
Me
(±)-deguelin
Winssinger et al, Chem. Eur. J. (2010) v. 16, pp. 9767-9771
MeO
MeO OH
OH
OHO
O
NaH, µ" 80 °C
MeO
MeO O
OH
(70%)
MeO
MeO O
OH1) NIS, TFA2) Pd(OAc)2
(49%)
Cl1)
K2CO3, KI, CuI2) µ" , m-xylene, 180 °C
(90%) O
OHO
Me
Me
Wittig
O
OH
Me
Me
(97%)
1) PPh3,DEAD, Et3N2) Grubbs II
MeO
MeO O
O
O
Me
Me
H
(49%)
1) ADmix- #2) IBX3) Zn, AcOH, µ"
MeO
MeO O
O
O
O
Me
Me
(16%)
OO O
Me
MeO
OMe
O
H
H
A story brought to you by:rotenone
Indigenous tribes in French Guiana smashedjicama roots containing rotenone to use while fishing. The rotenone poisoned the fishcausing them to rise to the surface of thewater. The fish were still edible sincerotenone is poorly absorbed by the GI tract in humans. Today it is also used in aquaticresearch to collect cryptic fish.
Section 2: From Natural Products to Synthetic Pesticides
Me Me
O
MeMe
MeO
O
pyrmethrin I
Natural Product Commericial Insectiside
Me Me
OCl
ClO CN
O
cypermethrin
1- Pyrethrin
H
H
H
H
Agrochemistry: Insecticides
($)-deguelin
Emily CherneyBaran Group Meeting
1-pyrethrin (cont'd.)
Syngenta process route to cyhalothrin: formulated in and marketed under the names "Karate" "Kung-fu" and "Matador"
Me Me
OHF3C
ClO
SOCl2, PhH
Me Me
ClF3C
ClO
OO
NaCN, Hexane, w/ or w/o H2O,w/ or w/o Et3N
Me Me
OCl
ClO CN
O
recrystallization
Me Me
OCl
ClO CN
Ar
cyhalothrin
A Synthesis of cyhalothrin: US Patent No. 7,468,453 B2
Sorry for the vague procedures here, but to quote the patent: "The reaction can be carried out in a solvent or in a mixture of a water immiscible solvent or an aqueous solution of the source of cyanide or in the absence of a solvent"
additionally... "the acid chloride and 3-phenoxybenzaldehyde can be added sequentially or simultaneously to the source of cyanide in the presence of the solvent or the solvent mixture, optionally in the presence of an organic base or an onium salt."
more vagueness continues on like this for about a dozen more paragraphs...
Analogs based on pyrethrin:ACS Symposium Series v. 504 (1992): "Synthesis and Chemistry of Agrochemicals III" pp. 258-282
R
O
OH
1) (COCl)22) H
NO
3)MgBr
RO
1) Wittig2) BH3•THF3) [O]
R
OH
NaH,
OCl
R
OO
Me Me
O
F
EtOMTI-800
simplified:
nicotine
Natural Product Commericial Insectiside
Imidacloprid
2-nicotine
N
N
MeH NCl
N
NHN
NO2
A Synthesis of Thiamethoxam: US!Patent No: 6861522 !(B2)
NC
HN
CN
1) MeNH2, NaOH,H2O, EtOH2) Aq. CH2O, 80 °C,pH 8-9
O
N
NH
N CN
Me
ClCl
1) NaSCN2) Cl2
N
S
Cl
Cl
O
N
N
N
S
NNO2
Me
Cl
A Synthesis of Thiacloprid: US Patent No:!1987-17641"A5
N-
NC CS2-
BnClK+
K+
NCN
SBnBnS
H2N
SH
- 2x BnSH N S
HNCN
N
Cl
Cl
KOH, DMF
steps
NCl
NS
NCN
thiacloprid
Other Commericial Products:
NH
NHN
S
NNO2
Me
Cl clothianidine
NCl
N NH
Me
Me
NO2
nitenpyram
N
Cl
NMe
Me
N CN
acetamiprid
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
3-organophosphates
HO
OHN P
O
OH
OHglyphosate
Natural Product Commericial Insectiside
acephate
PNH
O
Me
O
MeOMeS
Making various Phosphates:
reagents product target
- PSCl3, MeOH, NaOH, PhMe- PCl3, MeOH, NaOH, Et3N, S- P2S5, MeOH then Cl2- P(O)(OMe)2, Lawsesson's then SO2Cl2
P
S
MeO OMeCl
P
S
MeO OMeR
P
S
MeO OMeCl
P2S5, MeOH, PhHP
S
MeO OMeSH
P
S
MeO OMeSR
(R= Nu-)
(R= E+)
, NH4OH, DCMP
S
MeO OMeNH2
P
S
MeO OMeNHR
(R= E+)
P
S
MeO OMeNH2
, SO4Me2
PMeS
O
OMeNH2
PMeS
O
OMeNHR
(R= E+)
PSCl3, 2 eq RMgBr P
S
R RCl
P
S
R RR'
(R'= Nu-)
POCl3, 1 eq EtOH, Et3N P
O
EtO ClCl
P
O
EtO SnPrSnPr
ethoprop
POCl3, 1 eq EtOH, Et3Nthen 1 eq ArOH
P
O
EtO ClOAr
P
O
EtO NHROAr
fenamiphos(Tetrahedron (1995) 7981)
(Huazhong Nongye Daxue Zuebqo (2000) 339)
(Nongyao (2001) 13)
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
3-organophosphates (cont'd.)
A Synthesis of Azinophos-Methyl: Tetrahed. (1991) 8917; J. Het. Chem. (2007) 951; Bioconj. Chem. (1997) 256
O
NH2
NH2
NaNO2, HCl
O
NH
NN
CH2O, SOCl2
O
N
NN
Cl
P
S
MeO OMeSH
BaseO
N
NN
SP
S
OMeOMe
Azinophos-Methyl
A Synthesis of Methidathon: (Nongyao (2001) 13)
S C S
1) MeOH2) H2NNH2 H2N
N
SH
OMe
phosgene
HNN
S
O
OMe
P
S
MeO OMeSH
NN
S
O
OMeSP
OMeMeO
S
Methidathon
A Synthesis of Pyrimiphos-Methyl: (Huaxue Shiji (2010) 845)
H2N C NHN
Me Me H2N
NEt2
NH
Me OMe
OO
N NH
NEt2
O Me
P
S
MeO OMeCl
N N
Me
NEt2
OP
S
MeOOMe
Pyrimiphos-Methyl
CH2O
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
4- Carbamates
physostigmine
Natural Product Commericial Insectiside
xylylcarb
NMe
MeN
MeO
O
HN
Me O
O
HN
Me
Me
Me
Other Commerical Carbamates:
MeNH
ON
Me Me
SMe
O
aldicarb
MeNH
O
O
O
O
bendiocarb
MeNH
O
O
O
bendiocarbMe
NH
O
O
carbaryl
MeNH
O
O
fenobucarb
Me
Me
MeNH
ON S
O
methomylMe
Me
Section 3: Totally Synthetic Pesticides1-organochlorides*
Cl
Cl
Cl
Cl
Cl
Cl
Diels!Alder
Cl
Cl
ClCl
Cl
Cl
Aldrin
Cl
Cl
ClCl
Cl
Cl
Cl
Cl
Chlorodane
Cl
Cl
ClCl
Cl
Cl
O
OS
O
Endosulfan
Cl
Cl
ClCl
Cl
Cl
O
Endrin
Cl
Cl
Cl
Cl
Cl
Cl
hexachlorobenzene Lindane
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OH
Cl
Cl
Cl
Cl
pentachlorophenol
Cl ClCl
ClCl
dichlorodiphenyltrichloroethane (DDT)
Cl ClCl
OMe
MeO
Methoxychlor
Cl Cl
ClCldichlorodiphenyldichloroethane
Cl
chlorodecone(Kepone)
Cl Cl
OClCl
Cl
ClCl Cl
ClCl
Mirex
Cl ClCl
Cl
Cl
ClCl Cl
ClCl
Cl
DDT was discovered by a Paul Müller in 1940. It was firstbrought to market in 1944 and was used during the second half of WWII to prevent the spread of malaria and typhus.Paul Müller won the Nobel Prive in Physiology andMedicine for the discovery in 1948. It was later used as aninsecticide, however it was found to be harmful to wildlife,particularly birds including the bald eagle, and was bannedfrom use in the US in 1972.
O
H
ClCl
Cl
Cl
H2SO4 (cat.)
similarly:
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
ClO
Kepone and Mirex:
DDT etc.:
* Almost all organochlorides have been banned globally.
2-fun transformations from the agrochemistry literature!
Yamamoto et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 34-42.
RO2C
RO2C
C
S
S
1) NaOH2) ClCO2Me
SS
CO2RRO2C
RO2C CO2R
MeNHNH2
NNMe
HO CO2R
SH
Agrochemistry: Insecticides
Emily CherneyBaran Group Meeting
Meier et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 313-326.
2-fun transformations from the agrochemistry literature! (cont'd)
O
Me
RNH2(Me)2, CH2O,HCl, EtOH O
Me
R
H2NNH2
R
N
HN
Me(Me)2N
R
H2N
1) NaNO22)
MeO2C
Cl
O
MeR
HN
N
Cl
MeO2C
Ar
N
R
N
Ar
MeO2C
Guaciaro et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 56-74.
R
Cl
NOH
Et3N,
H2N CO2Me
iPrMeR
HN
ON
O
MeiPr
R
N
OH
NO
MeiPr
NaH
Theodoridis et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 134-146.
ClCl
NHNH2
CH3CHO;KNCO, AcOH;NaOCl
ClCl
N
NNH
Me
O
1) CO2H
Me
O
2) (PhO)2PON3, Et3N
OR
Wepplo et al. Synthesis and Chemistry of Agrochemicals IV (1995) p. 149-160.
O O
OH 1) NH2OH•HCl, NaOMe, MeOH2) HCl, MeOHHO HO
O
N
CO2Me
McCann et al. Synthesis and Chemistry of Agrochemicals VI (2002) p. 166-177.
R Ar
O
NH
O
, base; HClAr
O
NH3+Cl-
Ar
HN
HN
NH2
O
Ar
N
NH2
NH
NH
O
Ar
CH2(OEt)2, H+
Ar
N
NH
N
NHO
Ar
Lee et al. Synthesis and Chemistry of Agrochemicals II (1991) p. 195-208.
NH
Me
Me
CO2RRO2C
F3C CF3
DBU
N
Me
Me
CO2RRO2C
F3C CF2H
1) NaBH42) DBU
N
Me
Me
CO2RRO2C
F3C CFH2
1) NaBH42) DBU
N
Me
Me
CO2RRO2C
F3C CH3
Via:
NH
Me
Me
CO2RRO2C
F3C CF2HH
Agrochemistry: Insecticides