Total syntheses of the strobilurins G, M, and N

Article abstract of DOI:10.1016/j.tet.2004.03.092

The key reactions in the general synthesis of strobilurins are the highly (Z)-selective Wittig reaction of an (E)-cinnamaldehyde with the phosphorus ylide 8 derived from (1,1-dibromoethyl)triphenylphosphonium bromide, followed by bromine-iodine exchange and Pd-Cu co-catalyzed Stille cross-coupling of the resulting alkenyl iodide with methyl (Z)-2-tributylstannyl-3-methoxyacrylate (7). The synthetic strobilurins G, M, and N were identical with the corresponding natural compounds. In addition, the (2′ S)-configuration of strobilurin G (1) was unambiguously established by oxidative degradation of the synthetic intermediate (S)-9 to (R)-2,3-dihydroxyisovaleric acid.

Full text of DOI:10.1016/j.tet.2004.03.092

Tetrahedron 60 (2004) 4921–4929
Total syntheses of the strobilurins G, M, and N
*
Stefan Kroiß and Wolfgang Steglich
¨ ¨ ¨
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, D-81377 Munchen, Germany
Received 4 February 2004; revised 15 March 2004; accepted 19 March 2004
Dedicated to Professor Heidrun Anke on the occasion of her 60th birthday
Abstract—The key reactions in the general synthesis of strobilurins are the highly (Z)-selective Wittig reaction of an (E)-cinnamaldehyde
with the phosphorus ylide 8 derived from (1,1-dibromoethyl)triphenylphosphonium bromide, followed by bromine–iodine exchange and Pd–Cu
co-catalyzed Stille cross-coupling of the resulting alkenyl iodide with methyl (Z)-2-tributylstann0yl-3-methoxyacrylate (7). The synthetic
strobilurins G, M, and N were identical with the corresponding natural compounds. In addition, the (2 S)-configuration of strobilurin G (1) was
unambiguously established by oxidative degradation of the synthetic intermediate (S)-9 to (R)-2,3-dihydroxyisovaleric acid.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the title compounds based on a novel strategy are presented.
Retrosynthetic analysis indicated that the strobilurin side
chain could be formed by stereoselective coupling of an
appropriate (Z)-dienyl halide 5 with methyl (Z)-2-tributyl-
stannyl-3-methoxypropenoate (7) (Scheme 1). The latter
has been introduced by Hodgson et al.8 for the synthesis of
simple strobilurin analogues by Pd/Cu co-catalyzed cross-
coupling with aryl iodides. Formation of the dienyl halides 5
(X¼Br) should be realised with high (Z)-stereoselectivity
via the Wittig reaction of an appropriate cinnamaldehyde 6
with the phosphorus ylide 8 derived from (1,1-dibromo-
ethyl)triphenylphosphonium bromide.9
Strobilurins1 are important antifungal antibiotics which
have served as lead compounds for the development of a
new generation of industrial fungicides for crop protection.2
More complex compounds of this group include strobilurin
G (¼strobilurin D) (1), M (2), and N (3), which contain 1,4-
dioxepin or 1,4-dioxin moieties attached to the phenyl ring.
Strobilurin G is produced by cultures of several basidio-
mycetes3 and the ascomycete Camarops (Bolinia) lutea,4
strobilurin M by an unidentified tropical Mycena species,5
and the biologically inactive strobilurin N by fruit bodies of
Mycena crocata.6
Known methods for the synthesis of strobilurins involve
multistep procedures in which the (Z)-b-methoxyacrylate
toxophore is formed by the addition of a C-1 reagent to an
ester or keto ester in the last step.7 Herein, total syntheses of
2. Results and discussion
To apply this strategy for the synthesis of strobilurin G (1),
the optically active cinnamaldehyde 13 was needed as the
Keywords: Strobilurins; Benzodioxepins; Fungicides; Natural products; Total synthesis.
*
Corresponding author. Tel.: þ48-89-2180-77757; fax: þ49-89-2180-77756; e-mail address: wos@cup.uni-muenchen.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.092

4922
S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
Scheme 1. Retrosynthetic analysis for the strobilurin side chain.
starting material (Scheme 2). Compound 13 was obtained in
three steps from the known alcohol 9 (78% ee), a relay
substance used previously in structural investigations of
strobilurin G and related antibiotics.3a Alkylation of 9 with
3,3-dimethylallyl bromide afforded ester 11, which after
reduction with DIBAL-H and oxidation of the resulting
allylic alcohol 12 with MnO2 yielded aldehyde 13. Reaction
of the latter with the phosphorus ylide 8 generated from
(1,1-dibromoethyl)triphenylphosphonium bromide via
halogen–metal exchange9 afforded a 5:1 mixture of the
(E,Z)- and (E,E)-isomers of dienyl bromide 14. The isomers,
identified by their NMR spectra and NOE experiments, were
easily separated by column chromatography. The desired
(E,Z)-diene 14 was thereby obtained in 40% yield.
within a few days, even at 4 8C. Experiments to introduce
the methoxyacrylate residue via Rossi’s zinc reagent12 were
unsuccessful. A comparison of the spectroscopic data and
optical rotations of synthetic and natural strobilurin G4
proved their identity. The optical rotation of the synthetic
product, [a]2D0¼þ20.3, relates to 79% ee, which corre-
sponds to that of alcohol 9 used for the synthesis.
The stereochemistry of alcohol 9 had been previously
determined as (20S) by application of the high field NMR
variant of Mosher’s method.3a In order to prove this
assignment, the acetate 10 derived from 9, was subjected
to a ruthenium-mediated oxidative degradation following a
procedure of Bringmann et al.13 The optical rotation of the
resulting (R)-2,3-dihydroxyisovaleric acid, [a]2D0¼9.5 (c
0.2, 0.1 N HCl), agrees well with that of the literature,
[a]2D0¼12.1 (c 0.1, 0.1 N HCl),14 taking into account the
optical purity of the starting material. Since alcohol 9 had
been correlated to strobilurin G as well as to strobilurins I
and K before,3a the (20S)-configuration can now be safely
assigned to all three compounds.
The bromide 14 was inert to Stille coupling with stannyl
reagent 7 and therefore had to be converted into the more
reactive iodide 15 by copper(I)-mediated halogen
exchange.10,11 Treatment of 14 with n-butyl lithium and
molecular iodine in succession afforded significantly lower
yields. Pd/Cu co-catalyzed cross-coupling8 of iodide 15
with methyl (Z)-2-tributylstannyl-3-methoxypropenoate (7)
under mild conditions gave 1 in 38% yield. The low yield
reflects the instability of the iodide, which decomposes
In contrast to strobilurin G (1), the isomeric strobilurin M
(2) occurs in racemic form.5 The benzodioxin moiety
Scheme 2. Synthesis of strobilurin G (1). Reagents and conditions: (a) 3,3-dimethylallyl bromide, NaH, DMF, 0 8C, 68%. (b) DIBAL-H, THF, 278 8C, 92%.
(c) MnO2, CH2Cl2, 87%. (d) 8, THF, 250 8C, 2 h, 40%. (e) KI, CuI, HMPT, 120 8C, 2 d, 63%. (f) 7, CuI, Pd(PPh3)4, NMP, 50 8C, 24 h, 38%. Yields correspond
to chromatographically pure compounds.

S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
4923
Scheme 3. Synthesis of strobilurin M (2). Reagents and conditions: (a) SnCl4, THF, 2 h, 44%. (b) 3,3-dimethylallyl bromide, NaH, DMF, 0 8C, 32%.
(c) DIBAL-H, THF, 278 8C, 92%. (d) MnO2, CH2Cl2, 69%. (e) 8, THF, 250 8C, 2 h, 47%. (f) 1. KI, CuI, HMPT, 120 8C, 2 d; 2. 7, CuI, Pd(PPh3)4, NMP,
50 8C, 24 h, 19%. Yields relate to chromatographically pure compounds.
15
present in 2 could be prepared in 44% yield via SnCl4
catalysed cyclisation of the epoxide 16 in THF (Scheme 3).
The resulting hemiacetal 17 was alkylated with 3,3-
dimethylallyl bromide to yield acetal 18. Experiments to
obtain this compound via acid-catalyzed acetalisation were
unsuccessful. The ester 18 was converted into the dienyl
bromide 21 by the same reaction sequence as described
above. Due to the instability of the corresponding iodide, the
latter was directly used for the Stille coupling with 7 to give
strobilurin M (2) in low yield. The spectroscopic data of 2
were identical with those of the natural product,5 confirming
the proposed structure.
The synthesis of strobilurin N (3) commences from ester 24
(Scheme 4), prepared in 29% yield by condensation of ethyl
3,4-dihydroxycinnamate with the bromoketone 23.7d,16
A
similar 1.4-benzodioxin ring formation had been used in our
synthesis of strobilurin E.7d Small amounts of a disubsti-
tution product were removed by chromatography on silica
gel. Reaction of 24 with a catalytic amount of pyridinium
Scheme 4. Synthesis of strobilurin N. Reagents and conditions: (a) dihydropyran, PPTS, 20 8C, 4 h, 91%. (b) Ethyl 3,4-dihydroxycinnamate, K2CO3, acetone,
80 8C, 3 h, 29%. (c) PPTS (cat.), EtOH, 90 8C, 2 h, 48%. (d) DIBAL-H, THF, 278 8C, 20%. (e) MnO2, CH2Cl2, 28%. (f) 8, THF, 250 8C, 2 h, 38%. (g) 1. KI,
CuI, HMPT, 120 8C, 2 d; 2. 7, CuI, Pd(PPh3)4, NMP, 50 8C, 24 h, 23%. PPTS, pyridinium p-toluenesulfonate. NMP, 1-methyl-2-pyrrolidinone. Yields relate to
chromatographically pure compounds.

4924
S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
p-toluene sulfonate (PPTS)17 in ethanol cleaved the
protecting group and afforded diol 25 in 48% yield.
The latter was converted to the (Z)-vinyl bromide 28 by
the reaction sequence used in the synthesis of strobilurin G
and M. The iodine derivative corresponding to 28 was again
unstable and had to be used without further purification for
the final coupling. The resulting strobilurin N (3) was
identical with the natural product.6
121.7, 128.4, 137.7, 142.4, 144.4, 144.5, 167.3; MS (EI):
m/z (rel. int.) 360 (100) [Mþ], 293 (16), 292 (15), 248 (19),
234 (12), 233 (27), 208 (35), 163 (10), 69 (38), 40 (28);
HRMS (EI) calcd for C21H28O5 360.1937, found 360.1947;
Anal. calcd C, 69.98; H, 7.83; found C, 69.81; H, 8.12.
4.2.2. (S)-3-{4,4-Dimethyl-3-(3-methylbut-2-enyloxy)-
3,4-dihydro-2H-benzo[b][1,4]-dioxepin-7-yl}-2-propen-
1-ol (12). To a solution of 11 (0.29 g, 0.91 mmol) in THF
(20 mL) was added dropwise a solution of DIBAL-H (1.5 M
in THF, 3.50 mL, 5.25 mmol) at 278 8C. The reaction
mixture was stirred for 2 h at 278 8C, then carefully
quenched with water (1 mL) and warmed to rt. After
dilution with EtOAc (20.0 mL), the solution was washed
with 2 N HCl (3£) and water and dried over MgSO4.
Concentration and column chromatography of the residue
(hexanes–EtOAc, 1:1, v/v) furnished 12 (0.29 g, 87%, 78%
ee) as an orange oil, [a]2D0¼þ26.0 (c 1, MeOH); Rf¼0.66
(hexanes–EtOAc, 1:1); 1H NMR (300 MHz, [D6]acetone) d
1.21 (s, 3H), 1.38 (s, 3H), 1.66 (s, J¼1.4 Hz, 3H), 1.72 (s,
J¼1.4 Hz, 3H), 2.81 (br, 1H, OH), 3.56 (dd, J¼10.9, 6.2 Hz,
1H), 3.70 (dd, J¼10.9, 3.9 Hz, 1H), 3.95 (dd, J¼6.2, 3.9 Hz,
1H), 4.04 (d, J¼6.7 Hz, 2H), 4.18 (dd, J¼5.4, 1.4 Hz, 2H),
5.49 (tqq, J¼6.7, 1.4, 1.4 Hz, 1H), 6.22 (dt, J¼15.9, 5.4 Hz,
1H), 6.47 (dt, J¼15.9, 1.4 Hz, 1H), 6.79 (d, J¼8.3 Hz, 1H),
6.85 (d, J¼2.0 Hz, 1H), 6.87 (dd, J¼8.2, 2.0 Hz, 1H); 13C
NMR (75.6 MHz, [D6]acetone) d 18.0, 20.7, 25.1, 25.8,
63.3, 68.2, 69.6, 74.9, 80.3, 115.5, 117.4, 120.0, 122.3,
129.2, 129.7, 132.2, 136.9, 142.9, 143.2; MS (EI): m/z (rel.
int.) 318 (100) [Mþ], 191 (17), 166 (13), 69 (33), 41 (16);
HRMS (EI) calcd for C19H26O4 318.1831, found 318.1825;
Anal. calcd C, 71.67; H, 8.23; found C, 71.60; H, 8.63.
3. Conclusions
In conclusion, asimple procedureforassembling thestrobilurin
side chain from (E)-cinnamaldehydes has been developed, in
which a-bromoethylidene ylide 8 and (Z)-2-tributylstannyl-3-
methoxypropenoate (7) serve as building blocks. The Pd–Cu-
catalyzed coupling between the (E,Z)-dienyl iodides 5 and
stannyl reagent 7 needs further optimization. Furthermore, the
direct synthesis of iodides 5 from the corresponding
a-iodoethylidene ylide11 can be considered.
4. Experimental
4.1. General
Melting points (uncorrected): Reichert Thermovar; Optical
rotations: Perkin–Elmer 214; UV/Vis and CD: Instruments
S. A. Jobin Yvon CD-6-Dichrograph; IR: Bruker FTIR
spectrophotometer IFS 45; NMR: Bruker AMX 600 and
ARX 300 with solvent peak as internal reference (CDCl3:
dH 7.24, dC 77.0; CD3OD: dH 3.35, dC 49.0; [D6]acetone: dH
2.04, dC 29.8). Long range 1H–13C connectivities were
determined by inverse experiments using gradient pulses
optimised for a coupling constant of ,7 Hz; TLC: silica gel
Merck G plates; column chromatography: silica gel Merck
60; MS (EI) and HRMS (EI) were performed on a Finnigan
MAT 95 double focusing mass spectrometer, equipped with
an EI ion source operated at 70 eV.
4.2.3. (S)-3-{4,4-Dimethyl-3-(3-methylbut-2-enyloxy)-
3,4-dihydro-2H-benzo[b][1,4]-dioxepin-7-yl}propenal
(13). To a suspension of MnO2 (2.00 g, 23.0 mmol) in
CH2Cl2 (30 mL) was added a solution of 12 (0.73 g,
2.30 mmol) in CH2Cl2 (30 mL). After 48 h of stirring at rt,
the reaction mixture was filtered and the black solid washed
with CH2Cl2 (2£). The combined organic solutions were
evaporated, and the residue was purified by column
chromatography (hexanes–EtOAc, 3:1, v/v) giving 13
(0.58 g, 80%, 78% ee) as an orange oil, [a]2D0¼þ26.4 (c 1,
CDCl3); Rf¼0.58 (hexanes–EtOAc, 3:1, v/v); 1H NMR
(300 MHz, CDCl3) d 1.26 (s, 3H), 1.42 (s, 3H), 1.69 (s,
J¼1.4 Hz, 3H), 1.75 (s, J¼1.4 Hz, 3H), 3.58 (dd, J¼10.9,
6.6 Hz, 1H), 3.67 (dd, J¼10.9, 3.7 Hz, 1H), 4.05 (dd, J¼6.6,
3.7 Hz, 1H), 4.06 (d, J¼6.9 Hz, 2H), 5.36 (tqq, J¼6.9, 1.4,
1.4 Hz, 1H), 6.56 (dd, J¼15.8, 7.7 Hz, 1H), 6.96 (d,
J¼8.8 Hz, 1H), 7.05 (d, J¼2.0 Hz, 1H), 7.07 (dd, J¼8.8,
2.0 Hz, 1H), 7.34 (d, J¼15.8 Hz, 1H), 9.63 (d, J¼7.7 Hz,
1H); 13C NMR (75.6 MHz, CDCl3) d 18.1, 20.6, 25.0, 25.9,
68.1, 68.9, 74.3, 79.9, 117.1, 117.6, 120.6, 122.5, 127.0,
128.0, 137.8, 142.6, 145.5, 152.9, 193.7; MS (EI): m/z (rel.
int.) 316 (100) [Mþ], 248 (46), 218 (12), 217 (38), 189 (13),
175 (36), 164 (31), 163 (30), 147 (20), 136 (15), 135 (11),
107 (7), 85 (14), 69 (76), 68 (41), 67 (53), 53 (35); HRMS
(EI) calcd for C19H24O4 316.1675, found 316.1672; Anal.
calcd C, 72.13; H, 7.65; found C, 72.09; H, 7.84.
4.2. Synthesis of strobilurin G
4.2.1. Ethyl (S)-3-{4,4-dimethyl-3-(3-methylbut-2-enyl-
oxy)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl}acryl-
ate (11). To a suspension of NaH (76.0 mg, 3.15 mmol) in
DMF (10 mL) were added at 0 8C a solution of 93a (0.62 g,
2.10 mmol, 78% ee) in DMF (10 mL) and 3,3-dimethylallyl
bromide (0.38 mL, 3.15 mmol). After 16 h, 2 N HCl
(10 mL) was added and the reaction mixture extracted
with EtOAc (3£). The organic layers were washed with
water (2£) and dried (MgSO4). Evaporation and purification
of the residue by column chromatography (hexanes–
EtOAc, 3:1, v/v) yielded 11 (0.70 g, 92%) as an orange
oil, [a]2D0¼þ26.6 (c 1, CDCl3); Rf¼0.76 (hexanes–EtOAc,
3:1, v/v); 1H NMR (300 MHz, CDCl3) d¼1.25 (s, 3H), 1.32
(t, J¼7.2 Hz, 3H), 1.40 (s, 3H), 1.68 (d, J¼1.3 Hz, 3H), 1.75
(d, J¼1.3 Hz, 3H), 3.57 (dd, J¼11.0, 6.6 Hz, 1H), 3.67 (dd,
J¼11.0, 3.8 Hz, 1H), 4.03 (dd, J¼6.6, 3.8 Hz, 1H), 4.05 (d,
J¼7.0 Hz, 2H), 5.36 (tqq, J¼7.0, 1.3, 1.3 Hz, 1H), 6.26 (d,
J¼15.9 Hz, 1H), 6.91 (d, J¼8.8 Hz, 1H), 7.01 (d, J¼2.0 Hz,
1H), 7.02 (dd, J¼8.8, 2.0 Hz, 1H), 7.56 (d, J¼15.9 Hz, 1H);
13C NMR (75.6 MHz, CDCl3) d 14.4, 18.1, 20.6, 25.0, 25.9,
60.4, 68.0, 68.9, 74.2, 79.7, 116.3, 116.7, 117.4, 120.7,
4.2.4. (S)-(1E,3Z)-8-(4-Bromopenta-1,3-dienyl)-2,2-
dimethyl-3-(3-methyl-2-butenyloxy)-3,4-dihydro-
2H-benzo[b][1,4]dioxepin (14). To
a suspension of

S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
4925
(1,1-dibromoethyl)triphenylphosphonium bromide9 (1.90 g,
3.60 mmol) in THF (15 mL), maintained at 240 8C, was
added a solution of n-butyl lithium (2.5 M in hexane,
1.44 mL, 3.60 mmol). After 1 h of stirring, a solution of 13
(0.58 g, 1.83 mmol) in THF (15 mL) was added and the
reaction mixture warmed to rt. The stirring was continued
for an additional 2 h, then the mixture was quenched with
water (10 mL) and the aqueous layer extracted with EtOAc
(2£). The combined extracts were dried (MgSO4) and
concentrated in vacuo. Column chromatography (hexanes–
EtOAc, 4:1, v/v) yielded 14 (0.30 g, 40%, 78% ee) as an
orange oil, [a]2D0¼þ27.6 (c 1, CDCl3); Rf¼0.39 (hexanes–
EtOAc, 10:1, v/v); IR (KBr): 3369br, 2979m, 2952w,
1713m, 1600w, 1503m, 1438m, 1370m, 1267s, 1225m,
0.15 mmol), Pd(Ph3)4 (6.0 mg, 5 mmol), and CuI
(14.0 mg, 73 mmol). The mixture was heated at 50 8C for
24 h under argon, then cooled to rt and quenched with
saturated aqueous NH4Cl (5 mL). The aqueous layer was
extracted with EtOAc (2£), and the combined organic layers
were washed with water (2£) and dried over MgSO4.
Evaporation of the solvent and purification of the residue by
column chromatography (hexanes–EtOAc, 5:1, v/v)
furnished
1
(16.0 mg, 38%) as
a
colourless oil,
[a]2D0¼þ21.3 (c 0.75, MeOH; corresponds to 79% ee),
ref. 7b [a]2D0¼þ26.8 (c 0.75, MeOH); Rf¼0.43 (hexanes–
EtOAc, 3:1, v/v). IR (KBr) 3029w, 2990m, 1720s, 1633m,
1560m, 1551s, 1502s, 1450m, 1444w, 1430w, 1300s, 1272s,
1249s, 1220m, 1151m, 1125s, 1080s, 1010s, 985 (s),
1
1
1150s, 1121s, 1070m, 724s, 694m, 666w, 541s cm21; H
972m cm21; H NMR (300 MHz, CDCl3) d 1.21 (s, 3H),
NMR (300 MHz, CDCl3) d 1.23 (s, 3H), 1.47 (s, 3H), 1.69
(s, 3H), 1.76 (s, 3H), 2.40 (s, 3H), 3.52 (dd, J¼7.7, 3.2 Hz,
1H), 3.99 (dd, J¼12.5, 7.7 Hz, 1H), 4.14 (d, J¼6.8 Hz, 2H),
4.26 (dd, J¼12.5, 3.2 Hz, 1H), 5.35 (tqq, J¼6.8, 1.4, 1.3 Hz,
1H), 6.35 (dq, J¼10.0, 0.7 Hz, 1H), 6.50 (d, J¼15.7 Hz,
1H), 6.86 (dd, J¼15.7, 10.0 Hz, 1H), 6.86–7.07 (m, 3H);
13C NMR (75.6 MHz, CDCl3) d 18.2, 21.0, 25.9, 27.8, 29.3,
67.4, 68.8, 80.8, 82.0, 120.9, 122.0, 122.7, 123.7, 128.8,
132.1, 132.3, 132.8, 133.0, 137.6, 147.0, 151.4; MS (EI):
m/z (rel. int.) 408 (98) [Mþ, 81Br], 406 (100) [Mþ, 79Br],
340 (15), 338 (15), 328 (9), 281 (12), 279 (14), 278 (13), 277
(35), 256 (22), 254 (22), 185 (11), 175 (43), 174 (28), 173
(16), 158 (12), 157 (36), 145 (17), 129 (21), 128 (14), 115
1.47 (s, 3H), 1.69 (s, 3H), 1.76 (s, 3H), 1.96 (s, 3H), 3.50
(dd, J¼7.9, 3.2 Hz, 1H), 3.73 (s, 3H), 3.84 (s, 3H), 3.95 (dd,
J¼12.3, 7.9 Hz, 1H), 4.06 (dd, J¼11.3, 6.8 Hz, 1H), 4.15
(dd, J¼11.3, 6.8 Hz, 1H), 4.23 (dd, J¼12.3, 3.2 Hz, 1H),
5.34 (tqq, J¼6.8, 1.5, 1.5 Hz, 1H), 6.22 (d, J¼10.7 Hz, 1H),
6.37 (d, J¼15.6 Hz, 1H), 6.48 (dd, J¼15.6, 10.7 Hz, 1H),
6.85 (d, J¼7.9 Hz, 1H), 6.92 (dd, J¼7.9, 2.1 Hz, 1H), 6.93
(d, J¼2.1 Hz, 1H), 7.42 (s, 1H); 13C NMR (75.6 MHz,
CDCl3) d 18.2, 20.9, 23.8, 25.9, 27.8, 51.7, 62.0, 67.5, 68.8,
80.7, 82.1, 110.9, 120.7, 121.0, 121.7, 122.5, 125.8, 129.9,
130.5, 130.9, 133.8, 137.6, 146.9, 150.9, 159.0, 167.9; MS
(EI): m/z (rel. int.) 442 (65) [Mþ], 410 (9), 342 (11), 305
(28), 283 (10), 277 (19), 258 (22), 257 (13), 237 (11), 199
(11), 177 (16), 163 (14), 153 (20), 149 (12), 137 (12), 123
(13), 111 (15), 109 (11), 97 (22), 95 (15), 85 (25), 83 (26),
81 (14), 75 (17), 71 (28), 70 (15), 69 (100), 68 (14), 67 (25),
57 (37), 55 (32), 53 (12), 44 (21), 43 (27), 41 (62). HRMS
(EI) calcd for C26H34O6 442.2355, found 442.2373.
(14), 85 (14), 69 (100), 41 (39); HRMS (EI) calcd for
79
27
C21H BrO3 406.1144, found 406.1145.
4.2.5. (S)-(1E,3Z)-8-(4-Iodopenta-1,3-dienyl)-2,2-
dimethyl-3-(3-methyl-2-butenyloxy)-3,4-dihydro-2H-
benzo[b][1,4]dioxepin (15). To a solution of 14 (0.16 g,
0.40 mmol) in HMPT (5 mL) were added KI (0.66 g,
4.00 mmol) and CuI (0.38 g, 2.00 mmol). The mixture
was heated at 120 8C for 48 h, then cooled to rt and
quenched with water (20 mL). The aqueous layer was
extracted with EtOAc (3£), and the combined organic layers
were washed with water (2£) and dried (MgSO4).
Evaporation of the solvent and purification of the residue
by column chromatography (hexanes–EtOAc, 10:1, v/v)
yielded 15 (0.11 g, 63%, 78% ee) as a colourless oil;
Rf¼0.49 (hexanes–EtOAc, 10:1, v/v); 1H NMR (300 MHz,
CDCl3) d 1.23 (s, 3H), 1.47 (s, 3H), 1.69 (s, 3H), 1.76 (s,
3H), 2.59 (s, 3H), 3.52 (dd, J¼7.7, 3.2 Hz, 1H), 3.99 (dd,
J¼12.5, 7.7 Hz, 1H), 4.06 (dd, J¼11.6, 7.0 Hz, 1H), 4.16
(dd, J¼11.6, 7.0 Hz, 1H), 4.25 (dd, J¼12.5, 3.2 Hz, 1H),
5.35 (tqq, J¼6.8, 1.4, 1.3 Hz, 1H), 6.35 (d, J¼10.0 Hz, 1H),
6.50 (d, J¼15.7 Hz, 1H), 6.85 (dd, J¼15.7, 10.0 Hz, 1H),
6.88 (d, J¼8.4 Hz, 1H), 6.97–7.06 (m, 2H); 13C NMR
(75.6 MHz, CDCl3) d 18.5, 21.0, 25.3, 26.2, 29.6, 67.5,
68.8, 80.7, 82.1, 100.4, 115.1, 117.5, 120.4, 121.0, 125.5,
129.0, 131.5, 133.5, 138.0, 142.6, 142.8; MS (EI): m/z (rel.
int.) 454 (1) [Mþ], 412 (7), 340 (9), 338 (8), 290 (16), 274
(15), 263 (13), 238 (40), 236 (14), 222 (20), 221 (100), 220
(21), 218 (10), 207 (37), 205 (33), 203 (22), 191 (16), 190
(19), 189 (30), 179 (28), 165 (53), 163 (23), 154 (73), 149
(39), 137 (74), 85 (33), 83 (62), 69 (28); HRMS (EI) calcd
for C21H27IO3 454.1005, found 454.1011.
4.3. Oxidative degradation of acetate 10
4.3.1. Ethyl (S)-3-(3-acetoxy-4,4-dimethyl-3,4-dihydro-
2H-benzo[b][1,4]dioxepin-7-yl)acrylate (10). To
a
solution of alcohol 93a (0.29 g, 1.00 mmol, 78% ee) in
acetic anhydride (5 mL) were added pyridine (0.08 mL,
1.00 mmol) and a catalytic amount of DMAP. After 48 h at
rt, the reaction mixture was diluted with EtOAc (20 mL),
washed successively with 2 N HCl, 2 N NaOH, and water
and dried over MgSO4. Removal of solvent and column
chromatography of the residue (hexanes–EtOAc, 3:1, v/v)
yielded 10 (0.21 g, 62%, 78% ee) as a colourless oil,
[a]2D0¼þ26.5 (c 1, CDCl3); Rf¼0.53 (hexanes–EtOAc, 3:1,
v/v); IR (KBr) 2983m, 2939m, 2628w, 1743s, 1712s, 1637s,
1605m, 1573m, 1505s, 1463m, 1425m, 1371s, 1321m,
1265s, 1232s, 1178s, 1162s, 1118m, 1068m, 1038s, 983m,
953w, 900m, 861w, 830m, 754w, 701w, 674w, 645w, 629w,
1
604w, 514w, 480w cm21; H NMR (300 MHz, CDCl3) d
1.31 (t, J¼7.1 Hz, 3H), 1.37 (s, 6H), 2.15 (s, 3H), 4.18 (dd,
J¼13.0, 5.1 Hz, 1H), 4.24 (q, J¼7.1 Hz, 2H), 4.30 (dd,
J¼13.0, 2.8 Hz, 1H), 5.05 (dd, J¼5.1, 2.8 Hz, 1H), 6.30 (d,
J¼16.0 Hz, 1H), 6.94 (d, J¼8.8 Hz, 1H), 7.09–7.16 (m,
2H), 7.56 (d, J¼16.0 Hz, 1H); 13C NMR (75.6 MHz,
CDCl3) d 14.4, 21.0, 23.9, 26.4, 60.5, 69.3, 76.2, 79.9,
117.5, 121.3, 123.4, 124.5, 130.5, 143.6, 146.8, 152.9,
167.1, 170.3; MS (EI) m/z (rel. int.) 334 (100) [Mþ], 292
(12), 274 (30), 259 (11), 233 (19), 219 (13), 208 (28), 175
(7), 163 (13), 127 (32), 85 (30), 67 (11), 43 (72); HRMS (EI)
calcd for C18H22O6 334.1416, found 334.1412.
4.2.6. Strobilurin G (1). To a solution of 15 (42.0 mg,
95 mmol) in NMP (1 mL) were added 7 (61.0 mg,

4926
S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
4.3.2. Oxidative degradation of 10 to (R)-2,3-dihydroxy-
isovaleric acid. To a mixture of 10 (0.19 g, 0.57 mmol, 78%
ee), CCl4 (12 mL), acetonitrile (12 mL), and water (18 mL)
were added RuCl3 (7.00 mg, 0.03 mmol) and NaIO4 (3.65 g,
17.0 mmol). After 24 h stirring at rt, a second portion of
RuCl3 (7.00 mg, 0.03 mmol) was added and the stirring was
continued for 72 h. After addition of isopropanol (3 mL) and
BaCl2 (4.00 g), the precipitate was filtered off and washed
with CH2Cl2 (2£). The combined filtrates were acidified
with 2 N HCl, extracted with CH2Cl2 (3£) and dried over
MgSO4. Then, the solvent was evaporated and the residue
filtered through a short silica gel column (MeOH–CHCl3,
1:20, v/v) to afford a brown oil, which was dissolved in a
mixture of THF (2 mL), water (2 mL), and LiOH (15.0 mg,
0.60 mmol). After 3 h at rt, the reaction mixture was
acidified with 2 N HCl and extracted with CH2Cl2 (3£).
Evaporation of the dried (MgSO4) extracts and chromato-
graphy of the residue on a silica gel column (MeOH–
CHCl3, 1:20, v/v) yielded 11.0 mg (14%) of (R)-2,3-
dihydroxyisovaleric acid as a colourless oil, [a]2D0¼þ9.5
(c 0.2, 0.1 N HCl; corresponds to 78% ee), ref. 14a
[a]2D0¼þ12.1 (c 0.2, 0.1 N HCl). 1H NMR (300 MHz,
CD3OD) d 1.29 (s, 3H), 1.30 (s, 3H), 3.96 (s, 1H); 13C NMR
(75.6 MHz, CD3OD) d 26.0, 26.1, 73.2, 78.8, 176.3; MS
(EI): m/z (rel. int.) 135 (3) [MþþH], 117 (13), 99 (13), 85
(17), 83 (19), 73 (16), 59 (100), 43 (26), 41 (11).
chromatography of the residue (hexanes–EtOAc, 4:1, v/v)
yielded 18 (0.35 g, 32%) as a yellowish oil; Rf¼0.69
(hexanes–EtOAc, 3:1, v/v); IR (KBr): 3419 cm21 (br),
2975m, 2934m, 2875w, 1711s, 1634s, 1598m, 1584m,
1510s, 1466m, 1432m, 1384m, 1368m, 1306m, 1265s,
1175s, 1143s, 1097m, 1041m, 1009m, 982m, 845w, 808w,
736w, 640w, 604w; 1H NMR (300 MHz, CDCl3) d 1.15 (d,
J¼6.9 Hz, 6H), 1.32 (t, J¼7.2 Hz, 3H), 1.74 (d, J¼1.3 Hz,
3H), 1.78 (d, J¼1.3 Hz, 3H), 2.95 (sept, J¼6.9 Hz, 1H),
4.24 (d, J¼10.1 Hz, 1H), 4.25 (q, J¼7.2 Hz, 2H), 4.27 (d,
J¼10.1 Hz, 1H), 4.59 (d, J¼6.7 Hz, 1H), 5.50 (tsept, J¼6.7,
1.3 Hz, 1H), 6.29 (d, J¼15.9 Hz, 1H), 6.73 (d, J¼8.3 Hz,
1H), 7.04 (dd, J¼8.3, 2.0 Hz, 1H), 7.08 (d, J¼2.0 Hz, 1H),
7.59 (d, J¼15.9 Hz, 1H); 13C NMR (75.6 MHz, CDCl3) d
14.4, 18.0(2£), 18.3, 25.9, 37.1, 60.5, 66.1, 72.6, 111.5, 112.8,
114.2, 116.6, 119.5, 122.2, 128.8, 138.3, 144.4, 149.1, 150.0,
167.2; MS (EI): m/z (rel. int.) 360 (12) [Mþ], 292 (100), 247
(8), 221 (13), 208 (48), 163 (12), 85 (11), 69 (39); HRMS (EI)
calcd for C21H28O5 360.1937, found 360.1932; Anal. calcd C,
69.98; H, 7.83; found C, 69.80; H, 7.65.
4.4.3. 3-{3-Isopropyl-3-(3-methyl-2-butenyloxy)-2,3-
dihydro-2H-benzo[1,4]dioxin-6-yl}-2-propen-1-ol (19).
Following the same procedure as for 11, ester 18 (0.86 g,
2.39 mmol) was used. Column chromatography yielded
pure 19 (0.70 g, 92%) as an orange oil; Rf¼0.54 (hexanes–
1
EtOAc, 1:1, v/v); H NMR (300 MHz, CDCl3) d 0.96 (d,
4.4. Synthesis of strobilurin M
J¼6.7 Hz, 3H), 1.01 (d, J¼6.9 Hz, 3H), 1.73 (d, J¼1.3 Hz,
3H), 1.75–1.88 (m, 1H), 1.78 (s, J¼1.3 Hz, 3H), 3.09 (br,
1H, OH), 3.86 (d, J¼9.5 Hz, 1H), 4.09 (d, J¼9.5 Hz, 1H),
4.29 (dd, J¼5.9, 1.6 Hz, 2H), 4.55 (d, J¼6.7 Hz, 2H), 5.49
(tsept, J¼6.7, 1.3 Hz, 1H), 6.22 (dt, J¼15.8, 5.9 Hz, 1H),
6.47 (dt, J¼15.8, 1.6 Hz, 1H), 6.86 (d, J¼7.9 Hz, 1H), 6.89
(d, J¼1.9 Hz, 1H), 6.96 (dd, J¼7.9, 1.9 Hz, 1H); 13C NMR
(300 MHz, CDCl3) d 18.3 (2£), 18.8, 25.9, 30.8, 63.8, 66.0,
73.5, 74.6, 111.7, 115.6, 119.7, 120.0, 127.1, 131.0, 131.1,
138.2, 148.7, 149.3; MS (EI): m/z (rel. int.) 318 (9) [Mþ],
252 (100), 250 (15), 225 (56), 166 (57), 139 (38), 138 (50),
137 (20), 124 (13), 123 (41), 110 (24), 69 (81); HRMS (EI)
calcd for C19H26O4 318.1831, found 318.1827; Anal. calcd
C, 71.67; H, 8.23; found C, 71.60; H, 8.64.
4.4.1. Ethyl 3-(3-hydroxy-3-isopropyl-2,3-dihydro-2H-
benzo[1,4]dioxin-6-yl)acrylate (17). To a solution of 163a
(5.85 g, 20.0 mmol) in THF (100 mL) was added SnCl4
(1 M solution in CH2Cl2, 1.00 mL, 1.00 mmol). After
stirring for 2 h at rt, the reaction mixture was quenched
withaqueous NaHCO3 (20 mL), the precipitate filtered off and
the aqueous layer extracted with EtOAc (2£). The combined
extracts were washed with water, dried over MgSO4 and
evaporated to yield an orange oil that was purified by column
chromatography (hexanes–EtOAc, 3:1, v/v). Crystallisation
from EtOAc–hexanes afforded 2.57 g (44%) of pure 17 as a
colourless solid, mp 77 8C; Rf¼0.53 (hexanes–EtOAc, 3:1,
v/v); 1H NMR (300 MHz, CDCl3) d 1.09 (d, J¼7.0 Hz, 3H),
1.13 (d, J¼7.0 Hz, 3H), 1.32 (t, J¼7.2 Hz, 3H), 2.09 (sept,
J¼7.0 Hz, 1H), 3.16 (s, 1H, OH), 3.93 (d, J¼10.9 Hz, 1H),
4.18 (d, J¼10.9 Hz, 1H), 4.24 (q, J¼7.2 Hz, 2H), 6.28 (d,
J¼15.9 Hz, 1H), 6.92 (d, J¼8.2 Hz, 1H), 7.04 (dd, J¼8.2,
2.1 Hz, 1H), 7.07 (d, J¼2.1 Hz, 1H), 7.56 (d, J¼15.9 Hz, 1H);
13C NMR (75.6 MHz, CDCl3) d 14.4, 15.8, 16.5, 34.5, 60.5,
68.1, 96.3, 116.8, 117.2, 117.4, 122.2, 129.1, 142.0, 144.1,
144.4, 167.3; MS (EI): m/z (rel. int.) 292 (100) [Mþ], 247 (12),
221 (13), 208 (24), 207 (13), 147 (12), 71 (23); HRMS (EI)
calcd for C16H20O5 292.1311, found 292.1310; Anal. calcd C,
65.74; H, 6.90; found C, 66.00; H, 6.79.
4.4.4. 3-{3-Isopropyl-3-(3-methyl-2-butenyloxy)-2,3-
dihydro-2H-benzo[1,4]dioxin-6-yl}propenal (20). Fol-
lowing a procedure similar to that used for 12, alcohol 19
(0.67 g, 2.10 mmol) and MnO2 (1.80 g, 21.0 mmol) were
stirred in CH2Cl2 (50 mL) for 48 h at rt. Column
chromatography (hexanes–EtOAc, 2:1, v/v) yielded 20
(0.46 g, 69%) as an orange oil; Rf¼0.69 (hexanes–EtOAc,
1:1, v/v); 1H NMR (300 MHz, CDCl3) d 0.98 (d, J¼6.9 Hz,
3H), 1.02 (d, J¼6.9 Hz, 3H), 1.74 (d, J¼1.4 Hz, 3H), 1.77–
1.91 (m, 1H), 1.78 (d, J¼1.4 Hz, 3H), 3.92 (d, J¼9.5 Hz,
1H), 4.12 (d, J¼9.5 Hz, 1H), 4.55 (d, J¼6.7 Hz, 2H), 5.48
(tsept, J¼6.7, 1.4 Hz, 1H), 6.58 (dt, J¼15.8, 7.7 Hz, 1H),
6.92 (d, J¼8.2 Hz, 1H), 7.09 (d, J¼2.0 Hz, 1H), 7.12 (dd,
J¼8.2, 2.0 Hz, 1H), 7.39 (d, J¼15.8 Hz, 1H), 9.64 (d,
J¼7.7 Hz, 1H); 13C NMR (75.6 MHz, CDCl3) d 18.1, 18.4,
18.8, 25.9, 30.9, 66.1, 72.7, 74.5, 112.6, 114.4, 119.3, 123.4,
127.0, 127.8, 138.5, 149.4, 151.8, 152.9, 193.6; MS (EI):
m/z (rel. int.) 316 (4) [Mþ], 251 (22), 250 (100), 164 (60),
163 (16), 147 (23), 136 (13), 69 (49); HRMS (EI) calcd for
C19H24O4 316.1675, found 316.1680; Anal. calcd C, 72.13;
H, 7.65; found C, 72.09; H, 7.83.
4.4.2. Ethyl 3-{3-isopropyl-3-(3-methyl-2-butenyloxy)-
2,3-dihydro-2H-benzo[1,4]dioxin-6-yl}acrylate (18). To
a suspension of NaH (0.14 g, 6.00 mmol) in DMF (20 mL),
maintained at 0 8C, were added a solution of 17 (0.88 g,
3.00 mmol) in DMF (30 mL) and 3,3-dimethylallyl bromide
(0.70 mL, 6.00 mmol). The mixture was stirred for 16 h at
rt, then quenched with 2 N HCl (20 mL) and extracted with
EtOAc (3£). The organic layers were washed with water
(2£) and dried (MgSO4). Evaporation of solvent and column

S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
4927
4.4.5. (1E,3Z)-7-(4-Bromo-penta-1,3-dienyl)-2-iso-
propyl-2-(3-methyl-2-butenyloxy)-2,3-dihydro-2H-
benzo[1,4]dioxin (21). Following a procedure similar to
that used for 13, aldehyde 20 (0.40 g, 1.26 mmol) yielded 21
(0.24 g, 47%) as an orange oil (column chromatography:
hexanes–EtOAc, 7:1, v/v); Rf¼0.49 (hexanes–EtOAc, 5:1,
v/v); 1H NMR (300 MHz, CDCl3) d 0.97 (d, J¼6.8 Hz, 3H),
1.02 (d, J¼6.8 Hz, 3H), 1.78 (s, 3H), 1.79 (s, 3H), 1.81
(sept, J¼6.8 Hz, 1H), 2.41 (s, 3H), 3.90 (d, J¼9.6 Hz, 1H),
4.12 (d, J¼9.6 Hz, 1H), 4.58 (m, 2H), 5.49 (tsept, J¼6.7,
1.3 Hz, 1H), 6.37 (dq, J¼10.0, 0.7 Hz, 1H), 6.55 (d,
J¼15.7 Hz, 1H), 6.84 (dd, J¼15.7, 10.0 Hz, 1H), 6.87 (d,
J¼8.4 Hz, 1H), 6.95 (dd, J¼8.4, 2.0 Hz, 1H), 7.01 (d,
J¼2.0 Hz, 1H); 13C NMR (300 MHz, CDCl3) d 18.2, 18.4,
18.8, 25.9, 29.3, 30.8, 66.1, 73.6, 74.6, 111.6, 115.9, 119.9,
120.4, 123.5, 125.4, 128.6, 131.6, 133.5, 138.1, 149.0,
149.6; MS (EI): m/z (rel. int.) 408 (96) [Mþ, 81Br], 406 (97)
[Mþ, 79Br], 340 (12), 338 (15), 281 (10), 279 (14), 278 (15),
277 (39), 256 (25), 254 (25), 185 (11), 175 (48), 174 (24),
(25 mL) were added dihydropyran (3.12 g, 37.1 mmol) and
PPTS (0.62 g, 2.47 mmol). After 4 h stirring at rt, the
reaction mixture was diluted with anhydrous Et2O (30 mL)
and washed with brine (2£) and water (2£). Concentration
of the dried (MgSO4) solution yielded pure 23 (6.05 g, 91%)
as a colourless oil, bp 75 8C (7 mbar); 1H NMR (300 MHz,
CDCl3) d 1.36 (s, 3H), 1.40 (s, 3H), 1.65–1.93 (m, 6H),
3.30–3.39 (m, 1H), 3.44–3.53 (m, 1H), 3.83–3.89 (m, 1H),
4.49 (d, J¼16.5 Hz, 1H), 4.69 (d, J¼16.5 Hz, 1H); 13C
NMR (75.6 MHz, CDCl3) d 21.3, 21.7, 25.1, 25.8, 27.3,
31.7, 65.1, 81.3, 95.9, 205.0; MS (EI): m/z (rel. int.) 265 (1)
[Mþ, 81Br], 263 (1) [Mþ, 79Br], 251 (1), 85 (100).
4.5.2. Ethyl 3-{3-hydroxy-3-[1-methyl-1-(tetrahydro-
pyran-2-yloxy)-ethyl]-2,3-dihydro-2H-benzo[1,4]dioxin-
6-yl}acrylate (24). To a solution of 23 (5.32 g, 20.0 mmol)
in acetone (100 mL) were added ethyl 3,4-dihydroxycinna-
mate (4.16 g, 20.0 mmol) and K2CO3 (5.52 g, 40.0 mmol).
The mixture was heated at 80 8C for 1 h, then a second
portion of 23 (2.66 g, 10.0 mmol) was added and the heating
continued for another 3 h. After cooling to rt, the reaction
mixture was quenched with water (100 mL) and the aqueous
layer extracted with EtOAc (3£). The combined organic
layers were dried (MgSO4) and the solvent evaporated. The
resulting residue was purified by column chromatography
(hexanes–EtOAc, 3:1, v/v) to yield 24 (2.28 g, 29%) as a
colourless oil; Rf¼0.54 (hexanes–EtOAc, 5:1, v/v); 1H
NMR (300 MHz, CDCl3) d 1.32 (t, J¼7.2 Hz, 3H), 1.36 (s,
3H), 1.41 (s, 3H), 1.47–1.93 (m, 6H), 2.03 (s, 1H, OH),
3.45–3.59 (m, 1H), 3.82–3.91 (m, 1H), 3.94–4.05 (m, 1H),
4.03 (d, J¼11.0 Hz, 1H), 4.24 (q, J¼7.2 Hz, 2H), 4.34 (d,
J¼11.0 Hz, 1H), 6.27 (d, J¼15.9 Hz, 1H), 6.91 (d,
J¼8.1 Hz, 1H), 7.07 (d, J¼2.0 Hz, 1H), 7.08 (dd, J¼8.1,
2.0 Hz, 1H), 7.55 (d, J¼15.9 Hz, 1H); 13C NMR (300 MHz,
CDCl3) d 14.4, 19.8, 23.4, 24.3, 25.5, 30.8, 60.5, 63.0,
66.5, 73.8, 94.7, 96.5, 116.8, 117.1, 117.5, 122.5, 129.1,
141.8, 144.0, 144.4, 167.3; MS (EI): m/z (rel. int.) 392 (1)
[Mþ], 308 (94), 290 (22), 263 (32), 249 (29), 222 (77),
208 (83), 193 (66), 176 (20), 163 (41), 147 (36), 134 (23),
133 (13), 118 (8), 89 (14), 85 (100), 69 (13), 59 (64), 43
(31).
157 (42), 145 (19), 129 (23), 128 (14), 115 (14), 85 (16), 69
79
27
(100), 41 (38); HRMS (EI) calcd for C21H BrO3 406.1144,
found 406.1138.
4.4.6. Strobilurin M (2). To a solution of 21 (0.11 g,
0.27 mmol) in HMPT (4 mL) were added KI (0.45 g,
2.70 mmol) and CuI (0.26 g, 1.35 mmol). The mixture
was heated at 120 8C for 48 h, then cooled to rt, quenched
with water (20 mL) and extracted with EtOAc (3£). The
combined extracts were washed with water (2£) and dried
over MgSO4. Evaporation of the solvent yielded an orange
residue (55 mg), which, after dissolving in NMP (1 mL),
was treated with 7 (68 mg, 0.18 mmol), Pd(Ph3)4 (7 mg,
6.00 mmol), and CuI (3 mg, 12.0 mmmol). The reaction
mixture was heated at 50 8C for 24 h and then quenched
with saturated aqueous NH4Cl (5 mL). The aqueous layer
was extracted with EtOAc (2£), and the combined extracts
were washed with water (2£) and dried (MgSO4).
Concentration and purification of the residue by column
chromatography (hexanes–EtOAc, 3:1, v/v) yielded 2
(24 mg, 19%) as a yellowish oil; Rf¼0.51 (hexanes–
EtOAc, 3:1, v/v); IR (KBr): 3439(br), 2937m, 1710s,
1628m, 1507s, 1433m, 1288s, 1274s, 1237m, 1120s,
991m cm21
;
1H NMR (300 MHz, CDCl3) d 1.04 (d,
4.5.3. Ethyl 3-{3-hydroxy-3-(1-hydroxy-1-methylethyl)-
2,3-dihydro-2H-benzo[1,4]dioxin-6-yl}acrylate (25). To a
solution of 24 (8.30 g, 21.0 mmol) in EtOH (200 mL) was
added PPTS (0.53 g, 2.10 mmol). The mixture was heated at
90 8C for 2 h, then the solvent was evaporated and the
residue purified by column chromatography (hexanes–
EtOAc, 3:1, v/v) to yield 25 (3.09 g, 48%) as a colourless
J¼7.1 Hz, 3H), 1.05 (d, J¼7.1 Hz, 3H), 1.48 (s, 3H), 1.62
(s, 3H), 1.95 (d, J¼1.2 Hz, 3H), 2.43 (sept, J¼7.1 Hz, 1H),
3.73 (s, 3H), 3.84 (s, 3H), 3.93 (d, J¼11.1 Hz, 1H), 3.99 (dd,
J¼11.0, 6.9 Hz, 1H), 4.07 (dd, J¼11.0, 7.0 Hz, 1H), 4.15 (d,
J¼11.1 Hz, 1H), 5.14 (tqq, J¼7.0, 6.9, 1.3 Hz, 1H), 6.23
(dd, J¼10.6, 1.2 Hz, 1H), 6.38 (d, J¼15.6 Hz, 1H), 6.47 (dd,
J¼15.6, 10.6 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H), 6.84 (dd,
J¼8.4, 2.0 Hz, 1H), 6.92 (d, J¼2.0 Hz, 1H), 7.42 (s, 1H);
13C NMR (75.6 MHz, CDCl3) d 16.3, 17.0, 17.6, 23.5, 25.6,
31.3, 51.5, 57.6, 61.7, 64.9, 98.9, 110.8, 114.5, 116.7, 120.5,
122.2, 124.8, 129.7, 130.2, 130.7, 131.6, 136.6, 141.6,
142.6, 158.7, 167.7; MS (EI): m/z (rel. int.) 442 (100) [Mþ],
374 (39), 342 (17), 237 (65), 69 (60), 41 (62); HRMS (EI)
calcd for C26H34O6 442.2355, found 442.2334.
1
solid, mp 121 8C; Rf¼0.16 (hexanes–EtOAc, 3:1, v/v); H
NMR (300 MHz, CDCl3) d 1.32 (t, J¼7.2 Hz, 3H), 1.36 (s,
3H), 1.41 (s, 3H), 1.65 (s, 1H, OH), 2.34 (s, 1H, OH), 4.03
(d, J¼11.0 Hz, 1H), 4.24 (q, J¼7.2 Hz, 2H), 4.31 (d,
J¼11.0 Hz, 1H), 6.27 (d, J¼16.0 Hz, 1H), 6.94 (d,
J¼8.0 Hz, 1H), 7.05 (d, J¼1.7 Hz, 1H), 7.08 (dd, J¼8.0,
1.7 Hz, 1H), 7.55 (d, J¼16.0 Hz, 1H); 13C NMR (300 MHz,
CDCl3) d 14.4, 23.5, 24.3, 60.5, 66.5, 73.9, 96.5, 116.8,
117.2, 117.6, 122.6, 129.1, 141.7, 144.0, 144.5, 167.3, MS
(EI): m/z (rel. int.) 308 (100) [Mþ], 290 (6), 263 (24), 249
(24), 222 (50), 208 (76), 193 (48), 163 (29), 147 (25), 134
(12), 91 (3), 89 (6), 59 (43), 43 (20); HRMS (EI) calcd for
C16H20O6 308.1260, found 308.1257; Anal. calcd C, 62.33;
H, 6.54; found C, 62.47; H, 6.57.
4.5. Synthesis of strobilurin N
4.5.1. 1-Bromo-3-methyl-3-(tetrahydropyran-2-yloxy)-
butan-2-one (23).7d To a solution of 1-bromo-3-hydroxy-
3-methylbutan-2-one (22)16 (4.51 g, 25.8 mmol) in CH2Cl2

4928
S. Kroiß, W. Steglich / Tetrahedron 60 (2004) 4921–4929
4.5.4. 2-(1-Hydroxy-1-methylethyl)-7-(3-hydroxypro-
penyl)-2,3-dihydro-2H-benzo[1,4]-dioxin-2-ol (26). Fol-
lowing a procedure similar to that used for 11, ester 25
(0.62 g, 2.00 mmol) and a 1 M solution of DIBAL-H
(4.00 mL, 6.00 mmol) in THF were used. After 24 h, the
usual workup yielded an orange oil that was purified by
column chromatography (hexanes–EtOAc, 1:1, v/v).
Crystallisation of the product from EtOAc–hexanes
afforded pure 26 (0.11 g, 20%) as a colourless solid, mp
143 8C; Rf¼0.22 (hexanes–EtOAc, 1:1, v/v); 1H NMR
(300 MHz, [D6]acetone) d 1.34 (s, 6H), 3.78 (t, J¼5.6 Hz,
1H, OH), 3.87 (s, 1H, OH), 4.09 (dd, J¼11.1, 1.3 Hz, 1H),
4.19 (dd, J¼5.6, 5.4 Hz, 2H), 4.27 (d, J¼11.1 Hz, 1H), 5.42
(d, J¼1.3 Hz, 1H, OH), 6.22 (dt, J¼15.9, 5.4 Hz, 1H), 6.48
(dt, J¼15.9, 1.5 Hz, 1H), 6.78 (dd, J¼7.1, 1.6 Hz, 1H), 6.88
(d, J¼1.6 Hz, 1H), 6.89 (d, J¼7.1 Hz, 1H); 13C NMR
(300 MHz, [D6]acetone) d 24.2, 24.6, 63.3, 67.2, 73.8, 97.5,
115.9, 117.3, 120.3, 129.2, 129.7, 132.1, 143.2, 143.4; MS
(EI): m/z (rel. int.) 266 (100) [Mþ], 248 (5), 223 (4), 207
(22), 180 (8), 166 (28), 133 (14), 91 (10), 77 (7), 59 (50), 43
(19); HRMS (EI) calcd for C14H18O5 266.1154, found
266.1155.
(39), 174 (34), 173 (26), 161 (33), 160 (43), 159 (25), 157
(28), 145 (25), 144 (17), 143 (22), 132 (15), 131 (31), 129
(22), 128 (21), 115 (50), 103 (12), 77 (16), 59 (100), 43 (57);
79
HRMS (EI) calcd for C16H BrO4 354.0470, found
354.0467; Anal. calcd C, 54.10; H, 5.39; Br 22.49; found
C, 53.89; H, 5.33; Br 22.65.
19
4.5.7. Strobilurin N (3). To a solution of 28 (93.0 mg,
0.26 mmol) in HMPT (3 mL) were added KI (0.43 g,
2.60 mmol) and CuI (0.25 g, 1.30 mmol) The mixture was
heated at 120 8C for 48 h, then cooled and quenched with
water (20 mL). The aqueous layer was extracted with
EtOAc (3£), and the combined organic layers were washed
with water (2£) and dried (MgSO4). Concentration yielded
an orange oil (42.0 mg), which, after being dissolved in
NMP (1 mL), was treated with 7 (61.0 mg, 0.15 mmol),
Pd(Ph3)4 (6.00 mg, 5.00 mmol), and CuI (14.00 mg,
73.0 mmmol). The reaction mixture was heated for 24 h to
50 8C, cooled to rt and quenched with saturated aqueous
NH4Cl (5 mL). The aqueous layer was extracted with
EtOAc (2£), and the combined organic layers were washed
with water (2£) and dried (MgSO4). Evaporation of the
solvent and purification of the residue by column chroma-
tography (hexanes–EtOAc, 3:1, v/v) yielded 3 (23.0 mg,
23%) as a colourless oil; Rf¼0.42 (hexanes–EtOAc, 1:1,
4.5.5. 3-{3-Hydroxy-3-(1-hydroxy-1-methylethyl)-2,3-
dihydro-2H-benzo[1,4]dioxin-6-yl}propenal (27). Fol-
lowing a procedure similar to that used for 12, alcohol 26
(105 mg, 0.39 mmol) and MnO2 (0.17 g, 1.97 mmol) were
stirred in CH2Cl2 (10 mL) for 24 h at rt. Purification by
column chromatography (hexanes–EtOAc, 1:1, v/v) and
crystallisation of the product from hexanes–EtOAc
afforded pure 27 (31.0 mg, 28%) as a colourless solid, mp
158 8C; Rf¼0.45 (hexanes–EtOAc, 1:1, v/v); 1H NMR
(300 MHz, CDCl3) d 1.37 (s, 3H), 1.40 (s, 3H), 4.19 (d,
J¼11.2 Hz, 1H), 4.36 (d, J¼11.2 Hz, 1H), 6.66 (dd, J¼15.8,
7.8 Hz, 1H), 6.99 (d, J¼8.3 Hz, 1H), 7.24 (dd, J¼8.3,
2.1 Hz, 1H), 7.29 (d, J¼2.1 Hz, 1H), 7.60 (d, J¼15.8 Hz,
1H), 9.61 (d, J¼7.9 Hz, 1H); 13C NMR (75.6 MHz, CDCl3)
d 23.5, 24.3, 66.6, 73.8, 96.5, 117.5, 117.8, 123.3, 127.3,
128.5, 141.9, 145.5, 152.5, 193.7; MS (EI): m/z (rel. int.)
264 (34) [Mþ], 247 (3), 222 (27), 206 (30), 179 (29), 165
(69), 164 (100), 147 (46), 136 (40), 132 (31), 107 (19), 89
(20), 77 (22), 59 (95), 43 (58); HRMS (EI) calcd for
C14H16O5 264.0998, found 264.0991; Anal. calcd C, 63.63;
H, 6.10; found C, 63.50; H, 6.15.
1
v/v); IR, H NMR, and MS data identical with those given
for the natural product6; 13C NMR (75.6 MHz, CDCl3) d
23.2, 23.5, 24.1, 51.5, 61.8, 66.2, 73.6, 96.3, 110.7, 114.7,
117.0, 120.5, 125.4, 129.6, 130.3, 130.7, 132.6, 141.4, 141.6,
158.8, 167.8; MS (EI): m/z (rel. int.) 390 (100) [Mþ], 358 (22),
331 (9), 253 (84), 153 (47), 121 (9), 115 (15), 91 (12), 75 (36).
Acknowledgements
We thank the Bundesminister fu¨r Bildung und Forschung
(BMBF) and the Fonds der Chemischen Industrie for
financial support.
References and notes
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