Synthetic Studies of the Novel Herbicidal Natural Product, Resormycin

Abstract

This research poster was presented at the 10th IUPAC International Congress on the Chemistry of Crop Protection, Basel, Switzerland in August, 2002

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Synthetic Studies of the Novel Herbicidal
Natural Product, Resormycin
Chris R.A. Godfreya, Margaret Huggetta, Alan Russella, Peter Ivankoc, Marian Valentinyd,
William Lutzb, Traugott Schüzb, Ngo Le-Vanb, G. Wayne Craigb*
Lead Finding
a. Syngenta, Jealotts Hill; b. Syngenta, Basel; c. Pavol Josef, Safarik University, Kosice, Slovakia d. Synkola AG, Bratislava, Slovakia
2. Derivatization of Primary
Nitrogen Groupsc
4. De-Aza and -Amino Cinnamates b,c,d 5. Results & Conclusions
Acknowledgements: We thank our co-workers for their expert assistance S. Burnsidea, E. Siegerb, P. Kollerb, R.
Dahindenb,T. Winklerb, O. Jacobb, P. Renoldb, Syngenta Crop Protection; W. Lottenbache, Solvias AG; and the first
isolation team, J-J. Sanglier, C.T.V. Le-Van and R. Chollet, Sandoz AG.
Sect.1) Synthetic fragments were inactive but the deprotected B-C
fragment was weakly herbicidal. Sect. 2-3) Natural product derivatives
of the carboxyl or amino groups were inactive which implicate possible
uptake or metabolic differences compared to the natural product. The
reduced isomers, recently reported to retain herbicidal activity3, have
not yet been screened due to limited quantities. Sect. 4) Library
microscreen show hints of activity for the cinnamate analog, 3while all
other simple acyl or benzoyl analogs were inactive. The de-aza analog
3replaces the dipeptide with a lipophilic carbon chain indicating the
dipeptide may not be essential for herbicidal activity. Although opposite
in geometric configuration to Resormycin, this suggests 3might be
more herbicidal where the carbon chain is cis to the aromatic ring.
Overall, these results show that clear simplification of the Resormycin
structure while maintaining herbicide activity is not readily achievable.
1. Fragment and Total SynthesisaThe strategy was to prepare samples of homochiral Resormycin, A-B-C, to confirm its
published herbicidal activity, its 2 constituent dipeptides, A-B &B-C and its 3 constituent amino acids, A,B, and C.
3. Derivatization of Carbon
Functionalityc,e
Reagents: (i) BzOCOCl, 2N NaOH, (64%); (ii) EtOCOCl, N-
methylmorpholine, NaBH4, H2O, (100%); (iii) TsCl, pyr., (83%); (iv) NaCN,
DMF, (100%); (v) c.HCl,(77%).
Reagents: (i) n-BuLi, Glyme, -70oC, acetone, AcOH, ( 85%);
(ii) d.HCl; (iii) (BOC)2O, Et3N, MeOH, H2O; Separation (62%);
(iv) 5N HCl; heat; (v) Propyleneoxide, EtOH, reflux, (70%).
Reagents: (i) LiCl, DMA, reflux, (90%); (ii) c.H2SO4(cat), MeOH, (100%);
(iii) t-BDMSCl, imidazole, DMF, (100%); (iv) LiAlH4, THF, -20oC, (60%); (v)
MnO2, THF, heat, (30%); (vi) AcNHCH2CO2H, Et3N, EtOCOCl, toluene, 100oC,
(30%); (vii) d.HCl, dioxane, reflux, (50%).
Reagents: (i) (BOC)2O, Et3N, THF, H2O, (44%); (ii) EDC, DMAP
(cat.), CH2Cl2, (S)-hydroxyvaline m ethyl ester, (75%); (iii) NaOH,
dioxane, (100%); (iv) d.HCl, dioxane, (100%); (v) EDC, DMAP(cat),
CH2Cl2, H-Gly-OMe, (78%); (vi) EDC, DMAP, 2, sieves,
ClCH2CH2Cl, (21%).
Reagents: (vii) (BOC)2O, NaHCO3, THF, H2O, (80%); (viii) N-
hydroxysuccinimide, DCC, THF, H-Gly-OH, K2CO3, H2O; (ix) d.HCl
(55%); (x) EtOCOCl, Et3N, DME, 2, 70oC, (30%); (xi) d.HCl, dioxane,
reflux, (95%); (xii) TFA, CH2Cl2, (90%); (xiii) A(BOC protected see (i)),
EDC, THF, DMAP(cat), (10%).
Fragment A
Fragment AFragment BN-Ac Fragment C
Fragment BDeprotection (iii)-(iv)
Fragment A-B
Deprotection (xi) Fragment B-C
1, A-B-C Synthetic sample 1:1 diastereomeric mixture
Reagents: (i) NaOMe, Wittig reagent; (ii) NaH, Gly-phosphonate (36%, Z); (iii) NaH, hydantoin
phosphonate (1:2 E/Z 58%); (iv) NaH, azido acetate (65%, Z) (v) Ph3P, PhCO2H (55%) (vi) H2, Lindlar
catalyst, (90%) (vii) Et 3N, RCOCl.
De-Aza -Amino
References: 1. M. Igarashi et. al. J. Antibio tics 1997, 50 (12) 1020-25. 2. Ibid. 50 (12) 1026 -31.
3. Ibid. 2001, 54 (12) 1072-9. 4. N. Le-Van, IUPAC, Basel, August 4-9, 2002: Poster 2b.04.
Resormycin, 1is a novel chlorinated tripeptide found in nature. It was isolated from Streptomyces platensis MJ953-SF5 and first reported by
Japanese researchers in 1997.1-2 It controls > 80% several important biannual weeds at relatively low foliar application rates, < 500 ppm in our
biological screen.4The total synthesis and a strategy for the derivatization of 1is described. Total synthesis methodology for fragment C allowed
preparation of substituted benzaldehydes for cinnamate building blocks. Subsequent library N-acylation of these cinnamates gave 55 analog
combinations while single analog syntheses resulted in 31 variations for screening. The related isolation of Resormycin is described elsewhere.4
N.B. epimersation
O
O
Cl
OH
R
O
O
Ar
Ar
R
O
O
O
Ar
R
O
O
ON
O
O
O
Rx
O
Ar
Ar
N
O
N
O
N
Ar
OO
N+
N
NH2
Ar
OO
N
HAr
OO
R1
O
Z3
E/Z6
7Z
Wittig
Horner-Emmons-
Wadsworth (Rx = Bn or tBu)
R = n-C7H16
(ii)
(iii)
(i)
(iv)
(vi)
(vii)
(v)
R1 = 55 Various
2
Ar = 3,5-diMeO-4-ClPh
Library
1
4
5
E/Z
. TFA salt
N-Protection2(BOC)2O, dioxane-H2O, RT, 3 hr, 92%
Deprotection 2N HCl / THF, RT, 2 days, 50%
ReductioneH2 (g), [Rh(cod) DiPFe]]BF4
, MeOH,10 bar,
69 hr, RT, 43%,18/25 mix of 2 diastereoisomers
Carboxyl (MeO)2SO2, K2CO3, 1 eq
AlkylationcTHF, RT, 2 days, 34% yield
NH2
NH2
N
H
O
OH
O
N
H
OH OH
Cl
CO2H
NH2OH
ONH2
NH2
OH
O
OH
Cl
t-BuMe2SiO OSiMe2t-Bu
CHO
BOCNH N
H
O
OH
O
BOCHN
OMe
BOCNH N
H
O
OH
O
BOCHN
N
HCO2H
NH2OH
ONH2
BOCNH
OH
O
N
H
CO2H
BOCNH
OH
O
N
t-BuMe2SiO OSiMe2t-Bu
Cl
O
BOCNH
BOCHN
N
H
O
OH
O
N
t-BuMe2SiO OSiMe2t-Bu
Cl
O
NH2
OH
O
OH
NH2
NH2
O
OH
N
N
OMe
MeO
HO OH
Br
CO2H
Cl
OH OH
N
H
O CO2H
(i)-(v) (i)-(v) (i)-(v) (vi)-(vii)
(i)-(ii)
(iii)(v)(iii)
(vi)
(iii)
(vii)-(ix)
(x)
(xii)-(xiii)
. HCl salt
2