First Highly Stereoselective Synthesis of Fungicide Systhane

Article abstract of DOI:10.1021/ol0168723

Highly enantiopure (R)-2-p-chlorophenyl-2-(1H-1,2,4-triazol-1-ylmethyl)hexanenitrile 1 (myclobutanil or systhane) was obtained in six synthetic steps from commercially available 1-hexyne (35% yield, 92% ee). The sulfinyl group controls the two key steps o

Full text of DOI:10.1021/ol0168723

ORGANIC
LETTERS
2002
Vol. 4, No. 1
55-57
First Highly Stereoselective Synthesis of
Fungicide Systhane
Jose´ L. Garc´ıa Ruano,* Marta Cifuentes Garc´ıa, Ana M. Mart´ın Castro, and
Jesu´s H. Rodr´ıguez Ramos*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received October 8, 2001
ABSTRACT
Highly enantiopure (R)-2-p-chlorophenyl-2-(1H-1,2,4-triazol-1-ylmethyl)hexanenitrile 1 (myclobutanil or systhane) was obtained in six synthetic
steps from commercially available 1-hexyne (35% yield, 92% ee). The sulfinyl group controls the two key steps of the synthetic sequence, the
highly stereoselective hydrocyanation of vinyl sulfoxides with Et2AlCN and the further introduction of the proper functionality into the molecule.
2-p-Chlorophenyl-2-(1H-1,2,4-triazol-1-ylmethyl)hexaneni-
trile 1 (myclobutanil, also known as systhane) (Figure 1) is
Commercially available systhane (from Rohm ad Haas Co,
U.S.A.) is racemic, and there is no reported evidence on the
biological activity of each enantiomer. Additionally, although
its racemic synthesis is well documented via butylation and
condensation with paraformaldehyde and 4-chlorobenzyl
cyanide, followed by alkylation of a triazole salt,4 to our
knowledge no preparation of enantiopure systhane has been
so far reported either by enzymatic resolution or by asym-
metric synthesis. To date, the closest approach to the
obtention of both enantiomers of systhane in their optically
pure form has been reported by the enzymatic resolution of
a racemic analogue, (()-2-cyano-2-phenyl-hexanol 2,5 which
was performed using Pseudomonas fluorescens lipase (S-
enantiomer, 99% ee) and Candida rugosa lipase (R-enanti-
omer, 98% ee), although with moderate yields.6 Quite
Figure 1. Structure of systhane.
a polyfunctionalized non-natural compound which is used
as a fungicide due to its ability as inhibitor in the biosynthesis
of the ergosterol.1 Its fungicide effectiveness has proved to
be superior to the conventional pesticides for controlling
powdery mildews in different plant species, either by itself2
or in synergistic fungicidal compositions.3 From a stereo-
chemical point of view, its main structural feature is the
presence of a quaternary chiral center at the R-position of a
cyano group.
(2) McGrath, M. T.; Shishkoff, N. Plant Dis. 2001, 85, 147. Berrie, A.
M.; Burgess, C. M. Acta Hortic. 1997, 439, 791. Warkentin, T. D.; Rashid,
K. Y.; Xue, A. G. Can. J. Plant Sci. 1996, 76, 933.
(3) Wachendorff-Neumann, U.; Gayer, H.; Heinemann, U.; Seitz, T.;
Krueger, B.-W.; Kraemer, W.; Assmann, L. Ger. Offen. 2001, 58 pp (Patent
No. DE 10021412). Reuveni, M.; Harpaz, M.; Reuveni, R. Eur. J. Plant
Pathol. 1998, 104, 853. Reuveni, M.; Oppenheim, D.; Reuveni, R. Crop
Prot. 1998, 17, 563. Reuveni, M.; Reuveni, R. Indian J. Pharm. Sci. 1995,
57, 311.
(4) Graves, D. D. U.S. Patent 1996, 5 pp (Patent No. US 5510493). Li,
X.; Liu, L. Hu, X.; Hong, L. Nongyao 2001, 40, 11.
(5) Miller, G. A.; Carley, H. E.; Chan, H. F. DOS 2 604 047, 1976,
Rohm ad Haas Company.
(1) Haug, G.; Hoffmann. Chemistry of Plant Protection - Sterol
Biosynthesis, Inhibitors and Antifeeding Compounds; Springer: Berlin, 1986;
p 25.
10.1021/ol0168723 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/11/2001

recently a high-performance chiral separation of systhane by
sulfated â-cyclodextrin-mediated capillary electrophoresis has
been reported,7 although no characterization of the enantio-
merically pure title compound was provided.
Recently we reported a straightforward highly stereo-
selective method to achieve the hydrocyanation of double
bonds of vinyl sulfoxides with Et2AlCN, which was claimed
as a potentially useful procedure for the synthesis of any
kind of enantiomerically enriched compounds bearing tertiary
or quaternary chiral carbons, after chemical modification of
the sulfinyl and cyano group (Scheme 1).8
to start from (E)-vinyl sulfoxide 3 and therefore to control
the configuration of the quaternary chiral center with that
of the sulfinyl sulfur. To complete the synthesis of (R)-
systhane, in full agreement with the stereochemical pathway
of the hydrocyanation,8 it was necessary to start from the
(S)-sulfoxide.
The synthesis of optically pure (S)-3 was performed as
indicated in Scheme 3. The sulfinylation of the commercially
Scheme 3
Scheme 1
available 1-hexyne with (S)-menthyl sulfinate, following the
previously reported method,9 yielded (+)-(S)-hexynyl p-tolyl
sulfoxide (4), which reacted with a mixture of 4-chlorophen-
ylmagnesium bromide and CuI-dimethyl sulfide in THF,10
affording optically pure (1E,SS)-(-)-2-p-chlorophenyl-1-
hexenyl p-tolyl sulfoxide (3)11 in 90% yield (Scheme 3).
Hydrocyanation of vinyl sulfoxide 3 with Et2AlCN at room
temperature proceeded in 1 h in a highly stereoselective
manner to give a 96:4 diastereomeric mixture of â-sulfinyl
nitriles 511 (55% isolated yield) along with unaltered starting
material (40%) which could be reused.12 The configuration
of the major isomer was established as (2S,SR) on the basis
of the stereochemical pathway of these reactions, which
presumably involves the association of the aluminum of the
reagent with the sulfinyl oxygen, as a step previous to the
intramolecular cyanide transfer through the most stable
chairlike TS (Scheme 4).8
In the herein reported synthesis of systhane, we take
advantage of the usefulness of this reaction as well as the
chemical versatility of the sulfinyl group to be transformed
into other functional groups.
In Scheme 2 is depicted a plausible retrosynthetic sequence
Scheme 2
The reported method to prepare the racemic fungicide
describes the transformation of the alcohol 5 in systhane by
to prepare optically pure systhane (1). This compound is a
nitrile derivative bearing a quaternary chiral carbon at C-R,
which could be obtained by hydrocyanation of the proper
vinyl sulfoxide. The configuration at this carbon can be
controlled by choosing either that of the sulfinyl sulfur or
the Z or E stereochemistry of the starting olefin. The triazol
moiety would be obtained by appropriate modification of
the sulfinyl function. The synthesis of the vinyl sulfoxide 3
could be easily performed from commercially available
1-hexyne by making use of well-known reactions in sulfoxide
chemistry.
(9) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org.
Chem. 1987, 52, 1078. Garc´ıa Ruano, J. L.; Esteban Gamboa, A.; Mart´ın
Castro, A. M.; Rodr´ıguez, J. H.; Lo´pez-Solera, M. I. J. Org. Chem. 1998,
63, 3324.
(10) Marfat, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem. 1979, 44,
3888.
(11) 1H NMR (CDCl3) and specific rotations. Compound 3: [R]20D -27.1
(c 0.5, CHCl3); δ 7.56 and 7.28 (AA′BB′ system, 4H), 7.31 (m, 4H), 6.39
(s, 1H), 3.01 (t, 2H, J 7.0), 2.37 (s, 3H), 1.49-1.38 (m, 4H), 0.89 (t, 3H,
J 7.0). Compound 5 (de assigned by integration of well-separated signals
(CH2S) in the 1H NMR spectrum of the crude mixture): [R]20 +59.5 (c
D
1
0.7, CHCl3); H NMR (for major diastereomer) δ 7.47 and 7.24 (m, 8H),
3.42 and 3.19 (AB system, 2H, J 13.6), 2.39 (s, 3H), 2.12 (m, 2H), 1.52-
1.09 (m, 4H), 0.84 (t, 3H, J 7.0). Compound 2: [R]20 ) -6.1 (c 0.2,
D
Taking into account that reactivity of vinyl sulfoxides with
Et2AlCN decreases with the size of the substituents in cis-
arrangement with respect to the sulfinyl group, we decided
1
CHCl3); H NMR δ 7.44-7.31 (s, 4H), 3.89 and 3.84 (AB system, 2H, J
13.6), 2.13-2.03 (m, 1H), 1.89-1.79 (m, 1H) 1.49-1.09 (m, 4H), 0.84 (t,
3H, J 7.0). Compound 1: [R]20D ) -43.1 (c 0.1, CHCl3); 1H NMR δ 7.88
(s, 1H), 7.87 (s, 1H), 7.37 and 7.25 (AA′BB′ system, 4H), 4.61 and 4.49
(AB system, 2H, J 14.5 Hz), 2.16-2.04 (m, 2H), 1.47-1.11 (m, 4H), 0.86
(t, 3H, J 7.0).
(12) When the reaction was conducted at 0 °C the reaction rate
substantially decreased, 7 days being needed to get a 20% yield, along with
a 72% of recoverable starting material. However, the diastereomeric excess
increased up to >98%; [R]20D ) +59.5 (c 0.7, CHCl3). These new conditions
allow for preparation of enantiomerically pure systhane, although in
moderate overall yield. The low yield of the hydrocyanating stage at low
temperature prompted us to follow the sequence with the enantiomerically
enriched (92% de) mixture obtained at room temperature.
(6) Im, D. S.; Cheong, C. S.; Lee, S. H.; Youn, B. H.; Kim, S. C.
Tetrahedron 2000, 56, 1309.
(7) Wu, Y. S.; Lee, H. K.; Li, S. F. K. J. Chromatogr. 2001, 912, 171.
(8) Garc´ıa Ruano, J. L.; Cifuentes Garc´ıa, M.; Laso N. M.; Mart´ın Castro,
A. M.; Rodr´ıguez Ramos, J. H. Angew. Chem., Int Ed. 2001, 40, 2507.
The general procedure for the hydrocyanation reaction consists of the
treatment of the corresponding alkenyl sulfoxide with Et2AlCN (1 equiv)
in refluxing THF and further quenching with aqueous potassium sodium
tartrate.
56
Org. Lett., Vol. 4, No. 1, 2002

by X-ray diffraction, its absolute configuration could not be
unequivocally established. On the other hand, the specific
Scheme 4
rotation of the synthesized systhane {[R]20 -43.1 (c 0.1,
D
CHCl3) for the sample of 92% ee} could not be correlated
because enantiomerically pure systhane has not been reported
so far (see above). Therefore, to unequivocally establish the
configuration of the quaternary chiral carbon created in the
hydrocyanation step, we prepared (-)-2-phenyl-2-hydroxym-
ethylhexanenitrile (8) from compound 4, following the same
sequence used in the synthesis of the alcohol 2 precursor of
systhane (Scheme 6). The comparison of the specific rotation
mesylation into the corresponding methanesulfonate deriva-
tive, followed by treatment with triazole sodium salt.4
Therefore, we decided to determine the experimental condi-
tions to transform the sulfinyl moiety into a hydroxyl group.
This reaction was accomplished by a one-pot two-step
sequence involving Pummerer conditions13 and subsequent
reduction of the resulting hemithioacetal with NaBH4 (see
Scheme 5).
Scheme 6
Scheme 5
of the so obtained compound 8 with those of both enanti-
omers of this compound, obtained by enzymatic resolution
of the racemic mixture,6 allowed us to conclude that its
absolute configuration was S, as can be deduced from
Scheme 6. Its high optical purity (>98% ee) was determined
The choice of the Pummerer conditions are of utmost
importance in the resulting yield. Thus, when the base
employed was 2,4,6-trimethylpyridine,14 2 was obtained in
52% yield,11,15 which was improved up to 70% by using sym-
collidine under the same reaction conditions. The optical
purity of (S)-2 was established as 92% ee by 1H NMR using
R-methoxy-R-trifluoromethylphenylacetic acid (Mosher’s
reagent) as the chiral derivatizating agent (CH2O AB systems
as diagnostic signals).
Compound (S)-2 was transformed into (R)-systhane (1)11
under the conditions depicted in Scheme 5, according to the
procedure reported in the ref 6. The ee of the systhane was
determined as 92% by 1H NMR (C4H6 as diagnostic signals)
using Yb(hfc)3 as the LSR. This value was identical to that
found for the alcohol 2, and both were consistent with the
diastereomeric ratio resulting from the hydrocyanation reac-
tion. These results prove that the optical purity of systhane
was defined in the hydrocyanation step and was not modified
in further steps.
1
by H NMR using Mosher’s reagent as the chiral derivati-
zating agent. This result strongly supports the fact that
configuration S must also be assigned to the alcohol 2, which
agrees with that predicted from the stereochemical course
of the hydrocyanation.8
In conclusion, in this paper we describe the first highly
stereoselective synthesis of the (2-p-chlorophenyl-2-(1H-
1,2,4-triazol-1-ylmethyl)hexanenitrile), a fungicide known as
myclobutanil or systhane, in high optical purity (92% ee) in
just six steps starting from commercially available 1-hexyne,
involving the highly stereoselective hydrocyanation of vinyl
sulfoxides as the key step of the reaction.
Acknowledgment. We thank CAICYT (Grants BQU2000-
0246 and PB98-0102) for financial support.
Supporting Information Available: Experimental sec-
tion containing characterization of compounds 1-3 and 5,
and the intermediate 2-(4-chlorophenyl)-2-cyanohexyl meth-
anesulfonate. This material is available free of charge via
the Internet at http://pubs.acs.org.
As none of the compounds involved in the synthetic
sequence of systhane afforded crystals suitable to be studied
(13) De Lucci, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157.
(14) Bravo, P.; Frigerio, M.; Resnati, G. J. Org. Chem. 1990, 55, 4216.
(15) Although some stable derivatives of 2 were prepared, none of them
showed suitable crystals to be studied by X-ray analysis.
OL0168723
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