The total synthesis of strobilurin B

Article abstract of DOI:10.1007/s11172-014-0458-1

A new regio- and stereocontrolled total synthesis of the antibiotic strobilurin B is performed in nine steps in 5.5% overall yield.

Full text of DOI:10.1007/s11172-014-0458-1

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 491—496, February, 2014
491
The total synthesis of strobilurin B*
V. A. Popovsky, A. V. Stepanov, and N. Ya. Grigorieva
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: ves@ioc.ac.ru
A new regioꢀ and stereocontrolled total synthesis of the antibiotic strobilurin B is performed
in nine steps in 5.5% overall yield.
Key words: biologically active compounds, strobilurins, stereocontrolled synthesis, dienols,
dienals, dienoic acids.
Strobilurins (strobilurin antibiotics) are a group of natꢀ
ural compounds discovered in the last quarter of the XX
century2,3 and exhibiting unique biological activity.4 By
disuniting the mitochondrial respiratory chain, they proꢀ
duce strong fungicidal and antimicrobial effects.5 For the
same reason, strobilurins are used in biochemical investiꢀ
gations of cell respiration.6
Fifteen members of this group of compounds are curꢀ
rently known. They are all derivatives of methyl (3Z,5E)ꢀ
6ꢀarylꢀ2ꢀmethoxymethylideneꢀ3ꢀmethylhexaꢀ3,5ꢀdienoꢀ
ate of the general formula 1 with different substituents in
the benzene ring.
the desired configuration (as in dienals 2a,c) of the arylꢀ
alkadiene system of conjugated C=C bonds is >98%. Since
the way in which esters 10a,c can be transformed into
strobilurins 1a,c is already known,10 our successful synꢀ
thesis of compounds 10a,c is equivalent to the formal synꢀ
thesis of strobilurins A (1a) and X (1c).
Here we describe the total synthesis of strobilurin B
(1b) containing two substituents in the aromatic ring that
have opposite effects on the electronic system of the conꢀ
jugated arylhexadiene fragment.
Recently,11 we have published a procedure for the synꢀ
thesis of (2E,4E)ꢀdienal 2b, the key intermediate in the
preparation of strobilurin B. The synthesis involves conꢀ
densation of ꢀEt3Si imine 3B with 4ꢀchloroꢀ3ꢀmethoxyꢀ
cinnamaldehyde (4b) (see Scheme 1). The yield of comꢀ
pound 2b was 60%, stereochemical purity >98%. Dienal
2b is quantitatively and stereospecifically reduced with
NaBH4 in ethanol to (2E,4E)ꢀdienol 5b, which was unꢀ
ambiguously identified by physicochemical methods. Speꢀ
cifically, the (2E,4E)ꢀconfiguration of the conjugated diꢀ
ene system in dienol 5b is evident from NOE data for its
1H NMR spectrum. In fact, the protons bound to the
conjugated system of the C=C bonds are manifested in the
1H NMR spectrum of dienol 5b as three signals: two douꢀ
blets at  6.29 and 6.51 and a doublet of doublets at  6.94.
However, only the signal at  6.29 shows a NOE (5.4%)
with the protons of the group CH2OH, while the doublet
of doublets at  6.94 shows a NOE (2.6%) with the proꢀ
tons of the allylic CH2 group. Therefore, the doublet at
 6.29 can be assigned to HC(3) and the C(2)=C(3) bond
can be considered to have a (E)ꢀconfiguration. Accordꢀ
ingly, the other doublet at  6.51 was assigned to HC(5).
The constant of its coupling with HC(4) (15.5 Hz) sugꢀ
gests the (E)ꢀconfiguration of the C(4)=C(5) bond. The
high stereochemical purity of dienol 5b is also evident
R1 = R2 = H (a); R1 = OMe, R2 = Cl (b); R1 = H, R2 = OMe (c)
In the last few years, our research team has accomꢀ
plished the efficient formal syntheses of strobilurins A (1a)
and X (1c) using an original sevenꢀstep procedure (Scheme
1).7 The rationale for this approach is that (2E,4E)ꢀdiꢀ
enals 2a,c are thermodynamically more favorable. Because
of this, condensations of deprotonated Nꢀ(tertꢀbutyl)ꢀ4ꢀ
benzyloxybutanimine (3A) with (E)ꢀcinnamaldehyde (4a)
and (E)ꢀ4ꢀmethoxycinnamaldehyde (4c) affords the prodꢀ
ucts with high (>98%) contents of this isomer.8 We have
found7,9 appropriate reagents and conditions for the transꢀ
formations of dienals 2a,c through such intermediates as
(2E,4E)ꢀdienols 5a,c, (1E,3Z)ꢀarylhexadienyl ethers 6a,c,
(3Z,5E)ꢀdienols 7a,c, (3Z,5E)ꢀdienals 8a,c, and (3Z,5E)ꢀ
dienoic acids 9a,c into methyl dienoates 10a,c. In each
step of this reaction sequence, the yield of the isomer with
1
from the H NMR data: the spectral region from  0 to
* On the occasion of the 80th anniversary of the N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of
Sciences. For the preliminary communication, see Ref. 1.
3.70 exhibits, apart from the signal for the OH group, only
one signal (t,  2.67) assigned to H2C(1´).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0491—0496, February, 2014.
1066ꢀ5285/14/6302ꢀ0491 © 2014 Springer Science+Business Media, Inc.

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Popovsky et al.
Scheme 1
R1 = R2 = H (a); R1 = OMe, R2 = Cl (b); R1 = H, R2 = OMe (c)
X = H (3A), SiEt3 (3B)
Y = H (8a—c), OH (9a—c), OMe (10a—c)
Reagents and conditions: i. LDA/hexane—THF (1 : 5), 0 C, 30 min; ii. 4a—c/THF, –80 C, 1 h, –80 C0 C, 4 h; iii. H3O+;
iv. NaBH4/EtOH, 3 h; v. 1) BuLi/hexane—HMPA, 0 C, 2) TsCl/HMPA, 0 C, 2.5 h; vi. LiAlH4/THF, 20 C, 4 h;
vii. AlCl3—PhNMe2 (3 : 4)/CH2Cl2, 0 C, 1 h; viii. IBX/DMF, 20 C, 1 h; ix. NaClO2/DMSO—H2O, pH 9; x. CH2N2/Et2O, 0 C.
We expected the hydroxymethyl group of dienol 5b to
be transformed into a methyl one by hydride reduction of
intermediate Hꢀsulfate or tosylate (at the C(1) atom), as it
was made with dienols 5a,c.7 However, treatment of comꢀ
pound 5b with the complex Py•SO3 followed by in situ
reduction of the reaction products with LiAlH4 gave
a complex mixture of unidentified substances. The reducꢀ
tion of a tosylate obtained from dienol 5b under the same
conditions as in the synthesis of the tosylates of dienols
5a,c (TsCl, 0 C, 2 h) afforded a 2 : 1 mixture of the target
(1E,3Z)ꢀarylhexadienyl ether 6b and its (1E,3E)ꢀisomer
(6´b) (Scheme 2).
Structures 6b and 6´b were identified by physicochemꢀ
ical methods. For instance, the HRMS of their mixture
isolated by column chromatography contains the only
ion peak ([M + Na]+). The 1H NMR spectrum of
this mixture shows signals for ester 6b at  2.64
(t, H2C(5)), 6.09 (d, HC(3)), and 6.40 (d, HC(1)) as well
as additional signals in the proximity of them: a triplet
at  2.45 and two doublets at  6.05 and  6.36. The inteꢀ
gral intensity ratio of each pair of the closely spaced sigꢀ
nals is 2 : 1. In addition, the 13C NMR spectrum of the
mixture 6b + 6´b contains not only a signal for the MeC(4)
group of the (E,Z)ꢀisomer ( 24.48) but also a less inꢀ
tense signal for the MeC(4) group of the (E,E)ꢀisomer
( 17.34).12
We attempted to increase the selectivity of tosylation
of dienol 5b by using Ts2O for this purpose. Unfortunateꢀ
ly, the mixture of products isolated by column chromaꢀ
tography after hydride reduction of the tosylates contained
not only ether 6b but also two new compounds other than
ether 6´b (see Scheme 2). Since the HRMS of this mixture
exhibits only one peak of the ion [M + H]+ and one peak
of the ion [M + Na]+, we assumed that two new products
are isomeric to ether 6b in C=C bond locations. The strucꢀ
tures of these products were determined by 1H NMR specꢀ
troscopy. Indeed, the spectrum of the mixture shows sigꢀ
nals for the major product 6b as well as two signals of the
methylidene group ( 5.02 and 4.90) with an integral inꢀ
tensity ratio of 7.5 : 1, a signal for the CH2 group between
the Ph ring and the C=C bond (d,  3.41), and a signal for
the CH2 group between two C=C bonds (d,  2.95).13 The
integral intensity ratio of the last two signals is also 7.5 : 1.
Based on the data obtained, we assigned structure 6b to
the product with the higher content in the mixture and
structure 6´´´ b, to the product with the lower content.
According to 1H NMR data, the ratio of isomers
6b : 6b : 6´´´ b is 83 : 15 : 2.

Strobilurin B
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
493
Scheme 2
 3.41
 3.41
Reagents and conditions: i. 1) BuLi/hexane—HMPA, 0 C, 2) TsCl/HMPA, 0 C, 2 h; ii. LiAlH4/THF, 20 C, 2 h; iii. 1) BuLi/hexane,
–78 C, 2) HMPA, 3) Ts2O/THF; warming to –20 C, exposure time 2.5 h; iv. 1) BuLi/hexane—HMPA, –80 C, 2) TsCl/HMPA,
–80 C, 30 min, 3) warming to –20 C, 2.5 h.
The configuration of the conjugated C=C bonds in the
transformation of dienol 5b into ether 6b through a tosyꢀ
late intermediate was largely retained by lowering the toꢀ
sylation temperature (see Scheme 2). When dienol 5b was
tosylated with TsCl at –10 C, the content of (1E,3E)ꢀ
isomer 6´b in the mixture of products obtained by subseꢀ
quent hydride reduction of the tosylates was decreased to
20% (1H NMR data). When TsCl was added at –80 C,
which was followed by slow warming of the reaction mixꢀ
ture to –20 C and reduction of the resulting tosylate with
LiAlH4 (see Scheme 2), the target ester 6b was obtained in
60% yield. Isomers 6b and 6´´´ b were not detected among
the reaction products; the content of 1E,3Eꢀisomer 6´b
was 4% (1H NMR data).
The next step in the synthesis of compound 1b along
the pathway under discussion is debenzylation of ether 6b.
Earlier, by checking several ways recommended14—19 for
deprotection of benzyl ethers, we have found9 that conjuꢀ
gated arylalkadienyl ethers are debenzylated most conveꢀ
niently with anhydrous AlCl3 in the presence of PhNMe2.16
Debenzylation of ether 6b with this reagent at –5 C gave
crystalline (3Z,5E)ꢀdienol 7b in 83% yield (Scheme 3);
the content of stereoꢀ and regioisomers in this product did
not exceed 1% (1H NMR data).
Dienol 7b was oxidized into dienoic acid 9b through
the preparation of dienal 8b, as in similar transformations
of dienols 7a,c.7 Unstable dienal 8b was obtained in good
yield by oxidation of dienol 7b with 2ꢀiodoxybenzoic acid
Scheme 3
Reagents and conditions: i. AlCl3 : PhNMe2 (3 : 4)/CH2Cl2, –5 C, 3.5 h; ii. IBX/DMF, 20 C, 2 h; iii. NaClO2/DMSO—H2O, pH 9,
0 C, 3 h; iv. CH2N2/Et2O, 0 C; v. HCOOMe, NaH, 20 C, 4 h; vi. (MeO)2SO2/DMF, 14 h.

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Popovsky et al.
(IBX)20 in DMF21 and immediately, without purification,
transformed into acid 9b under the action of NaClO2 in
aqueous DMSO at pH 9.22 Crystalline acid 9b was quantiꢀ
tatively converted into methyl ester 10b by treatment with
an ethereal solution of CH2N2. The structures of dienal
8b, acid 9b, and methyl ester 10b were proved by physicoꢀ
chemical methods, primarily by HRMS and 1H NMR
spectroscopy with NOE experiments, as described above
for dienol 5b. Their stereoꢀ and regiochemical purity is
>98% (1H NMR data).
A transformation of ester 10b into strobilurin 1b has
been only sketched earlier. We effected this transformaꢀ
tion in "one pot" using a syringe technique, by treating
ester 10b with methyl formate in the presence of NaH and
by methylating the resulting enolate with dimethyl sulfate
(see Scheme 3). Purification of the crude product by
column chromatography on SiO2 gave strobilurin B in
60% yield. Its overall yield in the nineꢀstep synthesis is
5.5%. The physicochemical characteristics of compound
1b agree with the literature data.23
(2E,4E)ꢀ2ꢀ(2ꢀBenzyloxyethyl)ꢀ5ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenꢀ
yl)pentaꢀ2,4ꢀdienꢀ1ꢀol (5b) was obtained by reduction of dienal
2b (1.07 g, 3 mmol) with NaBH4 in ethanol at room temperature
for 3 h. Yield ~100%, yellow oily substance (decomp. upon
heating). HRMS, found m/z 381.1231. C21H24O3. Calculated
[M + Na]+ = 381.1228. UV (max/nm ()): 226 (11 460), 292
(17 200), 302 (17 560), 316 (14 330). IR, /cm–1: 3607, 3427,
3066, 3018, 2960, 2942, 2866, 1589, 1572, 1491, 1463, 1455,
1411, 1363, 1295, 1253, 1223, 1177, 1092, 1064, 1030, 1008,
963, 909, 863, 805, 782, 752, 699, 668. 1H NMR, : 2.67 (t, 2 H,
H2C(1´), J = 6.2 Hz); 2.67 (w.s, 1 H, OH); 3.65 (t, 2 H, H2C(2´),
J = 6.2 Hz); 3.91 (s, 3 H, MeO); 4.15 (s, 2 H, CH2OH); 4.54
(s, 2 H, CH2Ph); 6.29 (d, 1 H, HC(3), J = 11.0 Hz); 6.51 (d, 1 H,
HC(5), J = 15.5 Hz); 6.90 (d, 1 H, Ar, J = 1.4 Hz); 6.94 (dd, 1 H,
HC(4), J1 = 11.0 Hz, J2 = 15.5 Hz); 6.96 (dd, 1 H, Ar, J1 = 8.3 Hz,
J2 = 1.4 Hz); 7.20—7.40 (m, 6 H, Ar). 13C NMR, : 29.90
(C(1´)); 56.14 (MeO); 67.90 (C(1)); 69.67 (C(2´)); 73.32 (CH2Ph);
110.05 (Ar); 119.33 (Ar); 121.66 (Ar); 124.86 (C(4)); 127.66,
127.80 (Ar); 128.47 (C(3)); 130.22 (Ar); 132.36 (C(5)); 137.46,
137.70, 140.22 (C(2), Ar)); 155.08 (COMe).
(1E,3Z)ꢀ6ꢀBenzyloxyꢀ1ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenyl)ꢀ4ꢀmeꢀ
thylhexaꢀ1,3ꢀdiene (6b). A. A 1.8 M solution of BuLi (0.8 mL,
1.44 mmol) in hexane and a solution of TsCl (0.26 g, 1.36 mmol)
in HMPA (1 mL) were successively added at –5 C to a vigorꢀ
ously stirred solution of dienol 5b (0.36 g, 1 mmol) in a mixture
of THF (8 mL) and HMPA (1 mL). The reaction mixture was
stirred at 0 to –2 C for 2.5 h and cooled to –15 C. Then
a solution of LiAlH4 (5 mmol) in THF (4.1 mL) was added dropꢀ
wise. The resulting mixture was slowly warmed to ~20 C, stirred
at this temperature for 3.5 h, and again cooled to –10 C. Water
(1 mL), 15% aqueous NaOH (1 mL), and again water (3 mL)
were successively added dropwise. The precipitate that formed
was filtered off and thoroughly washed with TBME. Standard
workup of the filtrate gave an oily mixture (0.4 g) containing
ethers 6b and 6´b in a ratio of 2 : 1 (1H NMR data).
B. A 1.8 M solution of BuLi (1.1 mL, 2 mmol) in hexane,
HMPA (2 mL), and a solution of Ts2O (0.65 g, 2 mmol) in THF
(5 mL) were successively added at –78 C to a vigorously stirred
solution of dienol 5b (0.4 g, 1.1 mmol) in THF (15 mL). The
reaction mixture was warmed to –20 C and stirred at this temꢀ
perature for 2.5 h. Then a solution of LiAlH4 (9.4 mmol) in THF
(8 mL) was added dropwise at the same temperature. The reacꢀ
tion mixture was slowly warmed to ~20 C, stirred at this temꢀ
perature for 3 h, and subjected to the workup described under A.
The resulting mixture (0.4 g) contained ethers 6b, 6b, and 6´´´ b
in a ratio of 83 : 15 : 2 (1H NMR data).
C. A solution of BuLi (7.7 mmol) in hexane (5.1 mL) and
a solution of TsCl (1.47 g, 7.7 mmol) in HMPA (6.5 mL) were
successively added at –80 C to a vigorously stirred solution of
dienol 5b (2.2 g, 6 mmol) in THF (70 mL). The reaction mixture
was warmed to –20 C and stirred at this temperature for 2.5 h.
Then a 1.2 M solution of LiAlH4 (25 mL, 30 mmol) in THF was
added at the same temperature. The reaction mixture was warmed
to room temperature, stirred for 3.5 h, again cooled to –10 C,
and subjected to the workup described under A. The ratio of
ethers 6b and 6´b in the resulting oily mixture (2.1 g) was ~96 : 4
(1H NMR data). Flash chromatography of this mixture on SiO2
with benzene as an eluent gave individual ether 6b (1.3 g, 61%)
(decomp. upon heating). HRMS: found m/z 365.1266.
C21H23O2Cl. Calculated [M + Na]+ = 365.1279. UV (max/nm
()): 226 (16 100), 294 (27 000), 302 (28 800), 314 (25 000). IR,
Experimental
UV spectra were recorded on a Uꢀ1900 spectrophotometer
in ethanol. IR spectra were recorded on a Specord Mꢀ80 specꢀ
trometer in thin films or in CHCl3 (for alcohols only). 1H and
13C NMR spectra were recorded on a Bruker ACꢀ200 spectromꢀ
eter in CDCl3 with reference to its signals ( 7.27 and 77.0,
respectively). The signals for the vinylic protons in the 1H NMR
spectra were assigned using a NOE experiment. The signals of
isomers in the 13C NMR spectra were assigned using spectral
patterns simulated with the MestReNova program (version 6.0.2)
(Mestrelab research S.I., www.mestrelab.com, 2009) and
13C NMR data for related compounds. Highꢀresolution mass
spectra (HRMS) were measured on a micrOTOF II instrument
(Bruker Daltonics). The details of the HRMS experiments: elecꢀ
trospray ionization (ESI), scan range from m/z 50 to m/z 3000,
positive ion mode (capillary voltage 4500 V); solutions of samꢀ
ples in acetonitrile were infused into the mass spectrometer
through a syringe at a rate of 3 L min–1; interface temperature
180 C, nitrogen as a nebulizing gas (4.0 L min–1). Meltꢀ
ing points were determined on a Kofler hot stage and are
given uncorrected. For column chromatography, Silica gel 60
(0.04—0.06 mm (Fluka) was used. Solvents were purified as folꢀ
lows: diethyl ether and THF were kept over KOH, distilled first
over Na and then over LiAlH4, refluxed with sodium benzopheꢀ
none ketyl until a stable blue coloration was produced, and disꢀ
tilled directly to a reaction vessel. Hexane was distilled over Na;
tertꢀbutyl methyl ether (TBME), DMF, DMSO, and HMPA
were purified by distillation. A solution of LDA was prepared
immediately in a reaction vessel from equivalent amounts of
diisopropylamine and a 1.3—1.5 M solution of BuLi in hexane.
Experiments involving NaH, BuLi, and LDA were carried out
under argon in glassware previously kept at 160 C for 12 h and
cooled in a stream of argon. "Standard workup" of organic exꢀ
tracts included neutralization, drying with Na2SO4, and conꢀ
centration in vacuo on a rotary evaporator. Dienal 2b (see Ref. 11)
and IBX (see Ref. 21) were synthesized as described earlier.

Strobilurin B
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
495
/cm–1: 3028, 2935, 2854, 1633, 1585, 1570, 1486, 1450, 1405,
1360, 1294, 1249, 1192, 1174, 1096, 1060, 1027, 961, 880, 865,
805, 739, 697. 1H NMR, : 1.90 (s, 3 H, MeC(4)); 2.64 (t, 2 H,
H2C(5), J = 7.1 Hz); 3.62 (t, 2 H, H2C(6), J = 7.1 Hz); 3.92 (s, 3 H,
MeO); 4.56 (s, 2 H, CH2Ph); 6.09 (d, 1 H, HC(3), J = 10.7 Hz);
6.40 (d, 1 H, HC(1), J = 15.4 Hz); 6.92 (s, 1 H, Ar); 6.93 (d, 1 H,
Ar, J = 7.4 Hz); 7.00 (dd, 1 H, HC(2), J1 = 10.7 Hz, J2 = 15.4 Hz);
7.29—7.40 (m, 6 H, Ar). 13C NMR, : 24.48 (MeC(4)); 33.22
(C(5)); 56.11 (MeO); 68.86 (C(6)); 70.03 (CH2Ph); 109.74 (Ar);
119.24 (Ar); 121.06 (Ar); 125.98 (C(2)); 127.25 (C(3)); 127.52,
127.56 (Ar); 128.36 (Ar); 129.54 (C(1)); 130.12 (Ar); 137.61,
138.03, 138.38 (C(4), Ar), 155.05 (COMe).
NaH2PO4•2H2O (1.09 g, 7 mmol) in water (8.8 mL) were sucꢀ
cessively added to a solution of freshly prepared dienal 8b (625 mg,
2.5 mmol) in THF (17 mL). The mixture was cooled to 0 C.
A solution of NaClO2 (413 mg, 4.56 mmol) in water (8.8 mL)
was added dropwise, and the reaction mixture was stirred in the
dark at 0 C for 3 h. Then TBME (100 mL) was added, and the
resulting immiscible layers were separated. A salt product from
the organic layer was extracted with 10% NaOH (2×50 mL).
The combined basic extracts were acidified at 0 C with dilute
(1 : 3) HCl to pH 2. Organic materials were extracted with TBME
(3×50 mL). Standard workup of the combined extracts gave
acid 9b (286 mg, 43%), m.p. 124—126 C. The content of the
(E,E)ꢀisomer in the sample is <3% (1H NMR data). HRMS:
found m/z 267.0778, 289.0605. C14H15ClO3. Calculated
[M + H]+ = 267.0782, [M + Na]+ = 289.0602. UV (max/nm
()): 228 (12 300), 294 (32 500), 305 (36 800), 320 (30 400). IR,
/cm–1: 3021, 2970, 2918, 2855, 1708, 1588, 1572, 1490, 1464,
1411, 1295, 1224, 1065, 1031, 962, 803, 726, 673, 623. 1H NMR,
: 1.98 (s, 3 H, MeC(3)); 3.34 (s, 2 H, H2C(2)); 3.94 (s, 3 H,
MeO); 6.21 (d, 1 H, HC(4), J = 11.0 Hz); 6.48 (d, 1 H, HC(6),
J = 15.2 Hz); 6.92 (dd, 1 H, HC(5), J1 = 11.0 Hz, J2 = 15.2 Hz);
6.92 (s, 1 H, Ar); 6.97 (d, 1 H, Ar, J = 8.2 Hz); 7.28 (d, 1 H, Ar,
J = 8.2 Hz). 13C NMR, : 24.67 (MeC(3)); 38.00 (C(2)); 56.19
(MeO); 109.95, 119.47, 121.65 (Ar); 124.95 (C(5)); 129.29
(C(3)); 130.28 (Ar); 131.42, 131.49 (C(4), C(6)); 137.56 (Ar);
155.14 (COMe), 177.21 (C(1)).
Methyl (3Z,5E)ꢀ6ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ
hexaꢀ3,5ꢀdienoate (10b) was obtained by treatment of acid 9b
(200 mg, 0.75 mmol) with a solution of CH2N2 in diethyl ether
at 0 C according to a standard procedure. Yield ~100%, stereoꢀ
chemical purity >98%, m.p. 78—79 C (hexane—diethyl ether
(1 : 1)). HRMS: found m/z 281.0941, 303.0754. C15H17ClO3.
Calculated [M + H]+ = 281.0939, [M + Na]+ = 303.0758. UV
(max/nm ()): 223 (16 500), 293 (29 600), 302 (30 900), 314
(26 100). IR, /cm–1: 3414, 3062, 3036, 2968, 2930, 2902, 2845,
1714, 1590, 1572, 1492, 1484, 1464, 1438, 1415, 1366, 1332,
1303, 1289, 1255, 1230, 1202, 1179, 1165, 1065, 1034, 997, 967,
880, 853, 798, 689, 622, 573. 1H NMR, : 1.94 (s, 3 H, MeC(3));
3.30 (s, 2 H, H2C(2)); 3.71, 3.93 (both s, 3 H each, MeO); 6.16
(d, 1 H, HC(4), J = 10.7 Hz); 6.45 (d, 1 H, HC(6), J = 15.4 Hz);
6.91 (dd, 1 H, HC(5), J1 = 10.7 Hz, J2 = 15.4 Hz); 6.92 (s, 1 H,
Ar); 6.97 (d, 1 H, Ar, J = 8.2 Hz); 7.28 (d, 1 H, Ar, J = 8.2 Hz).
13C NMR, : 24.57 (MeC(3)); 38.07 (C(2)); 52.02 (CO2Me);
56.11 (MeO); 109.84, 119.31, 121.42 (Ar); 125.12 (C(5)); 128.73
(Ar); 130.18 (C(4)); 131.03 (C(6)), 132.19 C(3)); 137.61 (Ar);
155.02 (COMe), 177.30 (C(1)).
(3Z,5E)ꢀ6ꢀ(4ꢀChloroꢀ3ꢀmethoxyphenyl)ꢀ3ꢀmethylhexaꢀ3,5ꢀ
dienꢀ1ꢀol (7b). N,NꢀDimethylaniline (2.2 mL, 16.8 mmol) and
anhydrous AlCl3 (1.5 g, 11.2 mmol) were successively added at
–15 C to a vigorously stirred solution of benzyl ether 6b (1.28 g,
3.7 mmol) in CH2Cl2 (35 mL). The reaction mixture was warmed
to –5 C and stirred for 3.5 h. Then dilute (1 : 10) HCl (25 mL)
was added dropwise. After 10 min, the resulting immiscible layꢀ
ers were separated. Organic material from the aqueous layer was
extracted with CH2Cl2 (3×20 mL). The combined organic exꢀ
tracts were subjected to the standard workup. The residue (1.2 g)
containing the target dienol 7b was chromatographed on SiO2
(50 g) with gradient elution from hexane to hexane—ethyl aceꢀ
tate (070%). The yield of dienol 7b was 0.77 g (83%), m.p.
79—81 C (from hexane—diethyl ether (1 : 2)); the sample is
free of the (E,E)ꢀisomer. Found (%): C, 66.39; H, 6.92; Cl, 14.12.
C14H17ClO2. Calculated (%): C, 66.53; H, 6.78; Cl, 14.03.
HRMS: found m/z 253.0984. C14H17Cl2O2. Calculated [M + H]+ =
= 253.0990. UV (max/nm, ()): 228 (12 380), 294 (23 250), 305
(30 330), 320 (22 240). IR, /cm–1: 3620, 3448, 3019, 2966, 2932,
2884, 1640, 1588, 1572, 1489, 1464, 1448, 1411, 1295, 1253,
1208, 1179, 1064, 1031, 962, 803, 789, 774, 745, 731, 669. 1H NMR,
: 1.64 (t, 1 H, OH, J = 5.8 Hz); 1.89 (s, 3 H, MeC(3)); 2.57 (t, 2 H,
H2C(2), J = 6.6 Hz); 3.77 (dt, 2 H, H2C(1), J1 = 6.6 Hz,
J2 = 5.8 Hz); 3.92 (s, 3 H, MeO); 6.16 (d, 1 H, HC(4),
J = 11.0 Hz); 6.41 (d, 1 H, HC(6), J = 15.4 Hz); 6.91 (s, 1 H,
Ar); 6.94 (d, 1 H, Ar, J = 8.0 Hz); 6.98 (dd, 1 H, HC(5),
J1 = 11.0 Hz, J2 = 15.4 Hz); 7.27 (d, 1 H, Ar, J = 8.0 Hz). 13C NMR,
: 24.06 (MeC(3)); 35.83 (C(2)); 56.14 (MeO); 60.81 (C(1));
109.73 (Ar); 119.30, 121.20 (Ar); 125.52 (C(5)); 128.40 (C(4));
130.16 (C(6), Ar); 136.68, 137.80 (C(3), Ar); 155.02 (COMe).
(3Z,5E)ꢀ6ꢀ(4ꢀChloroꢀ3ꢀmethoxyphenyl)ꢀ3ꢀmethylhexaꢀ3,5ꢀ
dienal (8b). 2ꢀIodoxybenzoic acid (1.07 g, 3.82 mmol) was added
in one portion at ~20 C (Ar) in the dark to a stirred solution of
dienol 7b (640 mg, 2.54 mmol) in DMF (20 mL). The reaction
mixture was stirred for 2 h (monitoring by TLC). Then TBME
(75 mL) was added, and the mixture was filtered through a short
column with SiO2 (12 g). The adsorbent was washed with TBME
(100 mL). The combined filtrates were subjected to the standard
workup. The residue was dried in vacuo (1 Torr) at ~20 C to
a constant weight. The yield of dienal 8b was 445 mg (70%), light
yellow thin oil, Rf 0.55 (TBME—hexane (1 : 1)). The content of
the (E,E)ꢀisomer in the sample does not exceed 2% (1H NMR
data). Dienal 8b decomposes when heated. 1H NMR, : 1.94
(s, 3 H, MeC(3)); 3.37 (d, 2 H, H2C(2), J = 2.10 Hz); 3.93 (s, 3 H,
MeO); 6.28 (d, 1 H, HC(4), J = 11.1 Hz); 6.48 (d, 1 H, HC(6),
J = 15.2 Hz); 6.84 (dd, 1 H, HC(5), J1 = 11.1 Hz, J2 = 15.2 Hz);
6.92 (s, 1 H, Ar); 6.94 (d, 1 H, Ar, J = 7.2 Hz); 7.29 (d, 1 H, Ar,
J = 7.2 Hz); 9.65 (t, 1 H, HC(1), J = 2.10 Hz).
Methyl (2E,3Z,5E)ꢀ6ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenyl)ꢀ2ꢀmethꢀ
oxymethylideneꢀ3ꢀmethylhexaꢀ3,5ꢀdienoate (1b, strobilurin B).
A 80% suspension of NaH (180 mg, 6 mmol) in mineral oil was
added (Ar) in one portion at room temperature to a stirred mixꢀ
ture of methyl dienoate 10b (156 mg, 0.56 mmol) and methyl
formate (0.5 mL, 8 mmol). The reaction mixture was stirred for
4 h, whereupon DMF (0.5 mL) and dimethyl sulfate (0.56 mL,
5.6 mmol) were added. The resulting solution was stirred for 14 h
and then diluted with water. The product was extracted with
diethyl ether (2×10 mL). The combined extracts were succesꢀ
sively washed with a saturated solution of NH4Cl, 4% aqueous
ammonia, and brine, dried with Na2SO4, and concentrated
in vacuo. The residue (0.25 g) was chromatographed on SiO2
(15 g) with gradient elution from hexane to hexane—ethyl acetꢀ
ate (030%). The yield of the target compound 1b was 108 mg
(60%), light yellow crystals, m.p. 89—90 C (cf. Ref. 23: m.p.
(3Z,5E)ꢀ6ꢀ(4ꢀChloroꢀ3ꢀmethoxyphenyl)ꢀ3ꢀmethylhexaꢀ3,5ꢀ
dienoic acid (9b). Dimethyl sulfoxide (14 mL) and a solution of

496
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Popovsky et al.
92—93 C). 1H NMR, : 1.99 (s, 3 H, MeC(3)); 3.75, 3.86, 3.91
(all s, 3 H each, MeO); 6.26 (d, 1 H, HC(4), J = 10.5 Hz); 6.43
(d, 1 H, HC(6), J = 15.5 Hz); 6.58 (dd, 1 H, HC(5), J1 = 10.5 Hz,
J2 = 15.5 Hz); 6.85 (s, 1 H, Ar); 6.92 (d, 1 H, Ar, J = 8.0 Hz);
7.26 (d, 1 H, Ar, J = 8.0 Hz); 7.44 (s, 1 H, CHOMe). The
spectrum completely agrees with the literature data.23
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Received July 16, 2013