N-sulfonyl amino acid amides, a novel class of compounds with fungicidal activity [1]

Article abstract of DOI:10.2533/000942903777678542

Novel types of oomycete fungicides have been designed and prepared. The synthetic approach to these N-sulfonyl amino acid amides is outlined. Bioassays demonstrate their high efficacy against important plant diseases like Phytophthora infestans (tomato and potato late blight) and Plasmopara viticola (grape downy mildew). Structure-activity relationship studies are discussed.

Full text of DOI:10.2533/000942903777678542

CROP PROTECTION RESEARCH
680
CHIMIA 2003, 57, No.11
Chimia 57 (2003) 680–684
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
N-Sulfonyl Amino Acid Amides,
a Novel Class of Compounds with
Fungicidal Activity [1]
Fredrik Cederbauma, Alain De Mesmaekera, André Jeanguenata, Hans-Joachim Kempfb,
Clemens Lambertha*, Anita Schnyderd, Martin Zellerc, and Ronald Zeunb
Abstract: Novel types of oomycete fungicides have been designed and prepared. The synthetic approach to
these N-sulfonyl amino acid amides is outlined. Bioassays demonstrate their high efficacy against important
plant diseases like Phytophthora infestans (tomato and potato late blight) and Plasmopara viticola (grape
downy mildew). Structure–activity relationship studies are discussed.
Keywords: Amino acid derivative · Fungicide · Phytophthora infestans · Plasmopara viticola ·
Ugi reaction · Valinamide
Introduction
compounds, the amino acid valine is linked the biological profile by replacing the car-
to a 1-phenylethylamine or 1-benzothia- bamate moiety in 1–3 by different func-
Oomycetes have always been a threat to zolyl-ethylamine. Also amides like 3, in tional groups. Soon sulfonamides of type
mankind; for instance Phytophthora infes- which a N-carbamoyl valine is linked to a 6 were identified as compounds with
tans, one representative of this group of 2-phenylethylamine, have been described distinct fungicidal activity especially
phytopathogenic fungi, was responsible for as agrochemical fungicides [5]. Very simi- against oomycetes. Interestingly, the sul-
the dramatic Irish potato famines of the lar alkoxy-substituted 2-phenethylamines fonyl function linked to valine is not only
nineteenth century [2]. The continuous have also been reported to be part of fungi- an even better substitute for the carbamate
search for new oomycete fungicides, driven cidally active arylalkoximino acetic acid of valinamide 3, but in connection with
by resistance problems and the need for en- amides e.g. 4 [6] and mandelamides like 5 phenylglycine also mimics perfectly the
vironmentally safe pesticides, has focused [7].Afew years ago we decided to start a re- oxime and hydroxy functions in com-
recently on amino acid derivatives. With search program with the goal to improve pounds 4 and 5.
Bayer’s iprovalicarb (1) [3] the first mem-
ber of the class of N-carbamoyl vali-
O
O
O
O
H
N
H
N
namides recently reached the market, ben-
thiavalicarb (2) is currently under devel-
opment at Kumiai (Fig.) [4]. In these
O
F
O
S
N
H
N
H
O
N
O
2
1
*Correspondence: Dr. C. Lambertha
Tel.: + 41 61 3232373
Fax: + 41 61 3238529
E-Mail: clemens.lamberth@syngenta.com
aSyngenta Crop Protection AG
Research Chemistry
Optimisation
O
O
O
O
O
H
N
N
O
O
N
H
N
H
O
Schwarzwaldallee 215
CH–4002 Basel
4
3
bSyngenta Crop Protection AG
Research Biology
O
O
O
Disease Control
O
R
H
N
Schaffhauserstr. 101
CH–4332 Stein
O
HO
N
H
S
N
H
O
cSyngenta Crop Protection AG
Process Development
Breitenloh 5
R
O
R
CH–4333 Münchwilen
6
5
Cl
dSolvias AG
Catalysis Development
Klybeckstr. 191
Cl
CH–4002 Basel
Fig. Fungicidally active amino acid amides, alkoximino acetic acid amides and mandelamides

CROP PROTECTION RESEARCH
681
CHIMIA 2003, 57, No.11
In this paper, we present the synthesis of
novel N-sulfonyl amino acid amides and an
analysis of their structure-activity relation-
ships.
OH
O
O
H
7
Chemistry
NaCN, HCl
MeNO2
72%
Synthesis of 2-(4-hydroxy-3-
methoxyphenethyl)amine (11)
56%
An important building block for the
amine moiety is 2-(4-hydroxy-3-methoxy-
phenethyl)amine (11), also known as 3-O-
methyldopamine or 3-methoxytyramine
(Scheme 1). It is applied as a versatile pre-
cursor in the synthesis of tetrahydroiso-
quinoline [8] and morphine alkaloids [9],
serotonin receptor antagonists [10], cap-
saicin-like agonists [11] and 5-lipoxy-
genase inhibitors [12]. In principle, 11 can
be prepared by many different methods;
three of which are highlighted in Scheme 1.
A first possibility is the reduction, using ei-
ther catalytic hydrogenation [13] or lithium
aluminium hydride [14], of the nitrostyrene
8 which may be obtained by the Henry
reaction of vanillin (7) and nitromethane.
Another strategy is the catalytic hydrogena-
tion of vanillin cyanohydrin (9) [15]. The
third approach is the catalytic hydrogena-
tion of the benzylcyanide (13), which can
be obtained directly from vanillinol (12)
through a quinoid transition state [16].
During the course of our work on
N-sulfonyl amino acid amides, we required
a reliable approach to relatively large quan-
tities of 11. The nitrostyrene route to 11 is
OH
O
OH
O
N
O
2 N
OH
8
9
H2, Pd/C
NaBH4
H2, Pd/C
77%
81%
OH
O
OH
O
H2, Pd/C
95%
(from 8)
O2 N
H2N
11
10
H2, Pd/C
OH
91%
OH
O
NaCN, ∆
N
79%
HO
O
12
13
probably the most widely applied, but in Scheme 1. Different synthetic approaches to 2-(4-hydroxy-3-methoxyphenethyl)amine (11)
scale-up studies we found that both
currently known reduction methods suffer
from major disadvantages. Lithium alu-
minium hydride is impractical for bulk
O
O
O
O
preparative work because of the hazards in-
herent in the use of this relatively expensive
metal hydride and the difficult work-up
procedures. Up-scaling the one-step cat-
alytic hydrogenation of both the alkene and
the nitro functions of 8 resulted in very vari-
able and unsatisfactory results, accom-
panied by completely undesirable high
exothermic reaction profiles. By splitting
the hydrogenation of the alkene and nitro
functions into two different steps, we could
avoid the capricious results of the direct
transformation of 8 to 11. Thus, the sodium
borohydride reduction of the nitrostyrene 8
to the phenylnitroethane 10 and its subse-
quent catalytic hydrogenation provided a
high-yielding access to the phenethylamine
11, which is well suited for its further trans-
formation into N-sulfonyl amino acid
amides.
H
O
H2N
N
11, BOP, EtN(iPr)2
MeSO2Cl, NaOH
79%
OH
S
OH
O
71%
14
16
17
15
OH
O
H
N
O
EtC CCH2Cl, NaOMe
76%
S
N
H
O
O
O
H
O
N
S
N
H
O
The field of amino acid chemistry is
already well documented [17]. In the syn-
Scheme 2. Synthesis of N-sulfonylvalinamides

CROP PROTECTION RESEARCH
682
CHIMIA 2003, 57, No.11
thesis of amino acid amides, the connection
between the acid part and the amine moiety
(the so-called peptide-coupling) generally
seems to be the key step [18]. It turned out
that two completely different peptide-
coupling procedures were the optimum
approaches to our envisioned N-sulfonyl-
valinamides and -phenylglycinamides.
HCO2Et or
OH
O
OH
HCO2H, Ac2O
O
54%
H2N
H
N
H
O
11
18
HC CCH2Br,
NaOMe
O
O
POCl3, NEt3
81%
O
98%
H
N
H
19
Synthesis of N-Sulfonylvalinamides
1. 4-MePhCHO,
+
The N-sulfonylation of L-valine (14)
under Schotten-Baumann conditions [19]
led to the acid 15, which could be reacted
with 11 using Castro’s reagent (BOP) [20]
(Scheme 2). Alternatively, it was also pos-
sible to transform 15 into the corresponding
acid chloride and to link it with 11. In both
cases the valinamide 16 was obtained in
good yields and could be alkylated to the
desired target compound 17. Although
rather strong bases were applied in this re-
action sequence, no racemization was ob-
served at the chiral centre of the amino acid.
The epimerisation is probably prevented by
the fact that because of the acidity of the
sulfonamide hydrogen deprotonation took
place rather at this position than at the
α-carbon atom of valine.
-
HCO2 NH4
O
O
O
O
2. HCl, EtOH
O
+
H2N
83%
_
N
N
H
C
20
21
O
O
O
Me2NSO2Cl, NEt3
85%
H
O
N
S
N
H
N
O
22
Scheme 3. Synthesis of N-sulfonylphenylglycinamides
Table 1. Structure–activity relationship study of the amino acid chain
Synthesis of
N-Sulfonylphenylglycinamides
O
O
H
O
S
N
N
H
O
In contrast to the above described
route to N-sulfonylvalinamides, we decid-
ed to approach our envisioned N-sulfonyl-
phenylglycinamides via an Ugi four-com-
ponent condensation to obtain more flexi-
bility in the introduction of substituents in
the phenyl ring of the acid moiety. The Ugi
reaction is a classical multi-component
condensation, in which an amine, a car-
bonyl compound, a carboxylic acid, and an
isocyanide are assembled in one step to an
α-acylaminocarboxamide, and a new chiral
centre is formed at the C-atom derived from
the carbonyl group [21]. Recently multi-
component reactions received much atten-
tion as a powerful tool for the generation of
molecular diversity in combinatorial li-
braries and for the easy assembly of com-
plex chemical structures [22]. The phen-
ethylamine 11 was converted into the iso-
cyanide 20 by standard N-formylation,
O-propargylation and dehydration (Scheme
3). Hereby, the formyl group serves as pro-
tecting group of the amine function during
the O-alkylation and as precursor for the
formation of the isocyanide function. The
Ugi reaction of the isocyanide 20 with
p-tolualdehyde and ammonium formate,
which is the amine as well as the acid com-
O
R
I
Entry
R
Conf.
EC80 values [ppm]a
Phytophthora infestans
(tomato late blight)
42
Plasmopara viticola
(grape downy mildew)
2
Iprovalicarb (for comparison)
1
2
H
Me
-
148
> 200
9
> 200
> 200
49
L
3
CH2CH=CH2
n-Pr
D,L
L
4
60
20
5
i-Pr (17)
c-Pr
L
8
2
6
L
20
19
7
s-Bu
L
3
2
8
i-Bu
L
12
18
9
CHEt2
D,L
L
16
16
10
11
12
13
14
CH(OH)CH3
CH2CH2CO2H
CH2CH2SCH3
c-Hex
148
> 200
> 200
55
109
> 200
> 200
> 200
15
L
L
D,L
D,L
4-Cl-Ph
20
a EC80 value: calculated concentration in ppm obtained from greenhouse trials where
the tested compound shows 80% activity.

CROP PROTECTION RESEARCH
683
CHIMIA 2003, 57, No.11
Table 2. Structure–activity relationship study of the sulfonyl group
However, the positive biological result of a
racemic 4-chlorophenylglycine derivative
(entry 14) encouraged us to venture also
into this direction.
O
O
H
O
N
S
N
O
R
H
Influence of the Sulfonyl Group
O
The fungicidal activity of phenylglycin-
amides of the general formula II (Table 2)
could be further increased by application of
a n-propylsulfonyl function at the amino
group (entry 5). The efficacy dropped with
increasing or decreasing chain length of
other linear sulfonyl substituents. However,
best results were obtained with a dimethyl-
sulfamoyl cap at the amino function (entry
9), delivering a compound acting effective-
ly against the two major oomycete phy-
topathogens Phytophthora infestans and
Plasmopara viticola. The incorporation of
the amino group into a sulfinylamino-,
alkylamino-, amide- or carbamate function
– instead of protecting it with a sulfonyl
group – led to totally inactive compounds.
II
Entry
R
EC80 values [ppm]a
Phytophthora infestans
(tomato late blight)
42
Plasmopara viticola
(grape downy mildew)
2
Iprovalicarb (for comparison)
1
2
Me
F3C
32
-
42
104
> 200
76
3
Et
50
49
6
4
H2C=CH
n-Pr
5
5
6
i-Pr
> 200
45
10
2
60
7
n-Bu
17
8
MeNH
Me2N (22)
4-MePh
10
Influence of the p-Phenol
Substituent
9
3
10
109
16
One of the earlier findings during our
expedition through the chemistry and biol-
ogy of N-sulfonyl amino acid amides was
the favourable activity of N-2-phenethyl-
valinamides of the general formula III
(Table 3) with a 2-pentynyloxy substituent
in the para position of the phenyl ring in the
amine moiety (entry 6). Decreasing (entries
4 and 5) or increasing the chain length
(entry 7) as well as introducing alkyl side
branches on both sides of the C–C triple
bond (entries 8 and 9) reduced the fungi-
cidal efficacy. Surprisingly, the replace-
ment of the 2-pentynyl group in entry 6 by
a 4-halophenyl-propenyl moiety resulted in
a further enhancement of biological activi-
ty (entry 10). Reducing the degree of unsat-
uration in the 4-chlorophenyl-propargyl
sidechain of entry 10 led to decreased bio-
logical potency (entries 11–13).
a EC80 value: calculated concentration in ppm obtained from greenhouse trials where
the tested compound shows 80% activity.
Conclusion
ponent, led to a N-formylphenylglycin- (entry 10) and glutamic acid (entry 11) did
amide, which could be transformed into the not lead to good fungicidal activity. But
The connection of N-sulfonyl amino
free phenylglycinamide 21 by acidic hy- several naturally occurring amino acids acids with selected 4-alkynyloxy substitut-
drolysis. Finally, N-sulfonylation of 21 without polar groups like glycine (entry 1), ed 2-phenethylamines leads to novel
yielded the desired N-sulfonylphenylgly- alanine (entry 2) and methionine (entry 12) amides with high fungicidal activity. Espe-
cinamide 22.
did not achieve fungicidal efficacy either. cially derivatives with valine and phenyl-
Examples for suitable amino acids are glycine as amino acid moieties are distin-
valine (entry 5) and isoleucine (entry 7), but guished by broad efficacy against the two
also structurally related non-proteogenic major oomycete phytopathogens Phytoph-
amino acids like cyclopropylglycine (entry thora infestans (tomato and potato late
6) and allylglycine (entry 3) were tolerated. blight) and Plasmopara viticola (grape
Biology
Influence of the Amino Acid Chain
The amino acid of general formula I The configuration of the chiral α-carbon downy mildew).
(Table 1) needs a lipophilic backbone for atom is also important. The naturally
fungicidal activity. The application of polar occurring L-form shows in most of the cases
proteogenic amino acids like threonine higher activities than their D-enantiomers.
Received: September 15, 2003

CROP PROTECTION RESEARCH
684
CHIMIA 2003, 57, No.11
Table 3. Structure–activity relationship study of the p-phenol substituent
O
O
R
H
O
N
S
N
O
H
O
III
Entry
R
EC80 values [ppm]a
Phytophthora infestans
(tomato late blight)
42
Plasmopara viticola
(grape downy mildew)
2
Iprovalicarb (for comparison)
1
2
H
> 200
> 200
109
55
> 200
89
53
18
8
Me
3
Et
4
CH2C CH
5
CH2C CCH3
35
6
CH2C CCH2CH3 (17)
CH2C CCH2CH2CH3
CH(CH3)C CCH2CH3
CH2C CCH(CH3)2
CH2C C(4-Cl-Ph)
CH2CH=CH(4-Cl-Ph)
CH2CH2CH2(4-Cl-Ph)
CH2CH2O(4-Cl-Ph)
8
2
7
60
32
109
17
2
8
45
9
26
10
11
12
13
0.02
6
2
10
60
26
43
a EC80 value: calculated concentration in ppm obtained from greenhouse trials where
the tested compound shows 80% activity.
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