Total synthesis of strobilurin B

Article abstract of DOI:10.1016/j.mencom.2013.07.003

A nine-stage total synthesis of strobilurin B has been carried out with an overall yield of 5.5%. The key step was the stereocontrolled condensation between N-tert-butylaldimine and a,b-enal followed by reduction of the formyl group into methyl.

Full text of DOI:10.1016/j.mencom.2013.07.003

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 190–192
Total synthesis of strobilurin B
Viktor A. Popovsky, Andrei V. Stepanov and Natalia Ya. Grigorieva*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: ves@ioc.ac.ru
DOI: 10.1016/j.mencom.2013.07.003
A nine-stage total synthesis of strobilurin B has been carried out with an overall yield of 5.5%. The key step was the stereocontrolled
condensation between N-tert-butylaldimine and a,b-enal followed by reduction of the formyl group into methyl.
Strobilurin antibiotics are a group of natural compounds1,2 with
R1
X
NBut
O
unique bioactivity3 discovered in the last quarter of the 20th cen-
i–iii
R2
tury. They can disconnect the respiratory chain in mitochondria
and thus display a high fungicide and antimicrobial activity.4 For
the same reason, strobilurins are a useful tool in studies on the
biochemistry of cellular respiration.5
To date, 15 representatives of this group of compounds are
known. All of these are derivatives of methyl (3Z,5E)-6-aryl-
3-methyl-2-methoxymethylidenehexa-3,5-dienoate with general
formula 1 differing in aromatic ring substituents.
OBn
OBn
2a–c
3a X = H
3b X = SiEt3
R1
R2
OH
iv
v, vi
OBn
R1
R2
Me
5a–c
R1
R2
Me
R1
R2
Me
OH
OMe
MeOOC
vii
1a R1 = R2 = H
1b R1 = OMe, R2 = Cl
1c R1 = H, R2 = OMe
OBn
6a–c
7a–c
R1
R2
Me
viii
O
In the past few years, our team has carried out an original
efficient formal synthesis of the simplest strobilurins A (1a) and
X (1c) (Scheme 1).6 It is based on the thermodynamic preference
for the (2E,4E)-dienals 2a,c, which ensures an over 98% content
of this isomer prepared by condensation of deprotonated 4-benzyl-
oxybutanal tert-butylimine (3a) with (E)-cinnamic (4a) and
(E)-4-methoxycinnamic (4c) aldehydes.7 Reagents and condi-
tions were found6,8 that allowed dienals 2a,c to be converted, via
the stages of (2E,4E)-dienols 5a,c, (1E,3Z)-aryldiene ethers 6a,c,
(3Z,5E)-dienols 7a,c, (3Z,5E)-dienals 8a,c and (3Z,5E)-diene
acids 9a,c, to (3Z,5E)-aryldiene esters 10a,c, with high (³98%)
retention at each stage of the aryldiene configuration of con-
jugated C=C bonds once formed in dienals 2a,c. Inasmuch as
conversion of esters 10a,c to strobilurins 1a,c, respectively, has
been reported in literature,9 the syntheses of 10a,c that we com-
pleted are equivalent to a formal synthesis of strobilurins A (1a)
and X (1c).
OH
Y
I
O
O
8a–c Y = H
ix
x
9a–c Y = OH
O
10a–c Y = OMe
IBX
R1
R2
a R1 = R2 = H
b R1 = OMe, R2 = Cl
c R1 = H, R2 = OMe
O
2, 4–10:
4a–c
Scheme 1 Reagents and conditions: i, LDA, C6H14–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, BuLi, C6H14–HMPA, 0°C, then TsCl, HMPA, 0°C, 2.5 h; vi, LiAlH4,
THF, room temperature, 4 h; vii, AlCl3–PhNMe2 (3:4), CH2Cl2, 0°C, 1 h;
viii, IBX, DMF, room temperature, 1h; ix, NaClO2, DMSO–H2O, pH 9;
x, CH2N2, Et2O, 0°C.
The purpose of this study was to find out whether Scheme 1
could be used to synthesize strobilurin B (1b) containing two
substituents at the aromatic ring that have opposite effects on the
electron system of the conjugated aryldiene moiety of the com-
pounds being studied.
Synthesis of (2E,4E)-dienal 2b, the key intermediate in the
synthesis of strobilurin B according to Scheme 1, was published
recently.10 It was carried out in 60% yield and with >98%
stereochemical purity by the Peterson condensation between
deprotonated 4-benzyloxy-2-triethylsilylbutanal tert-butylimine
3b and (E)-4-chloro-3-methoxycinnamic aldehyde 4b.
structure of 5b was confirmed unambiguously using a combina-
tion of physicochemical methods. In particular, the (2E,4E) con-
figuration of the diene bond system C=C in dienol 5b follows
from the data of 1H NMR NOE spectroscopy. In fact, the 1H NMR
spectrum of dienol 5b shows three signals in the resonance
region of protons bound to the C=C conjugated bond system:
two doublets at d 6.29 (J 11.0 Hz) and 6.51 (J 15.5 Hz) ppm and
a doublet of doublets at d 6.94 ppm (J1 11.0 Hz, J2 15.5 Hz).
In this case, only the proton with the doublet signal at d 6.29 ppm
manifests an NOE (5.4%) with the protons of the CH2OH group,
whereas the proton with a doublet-doublet signal (d 6.94 ppm)
shows an NOE (2.6%) with the protons of the allylic CH2 group.
These data allow us, first, to assign the doublet signal at d 6.29 ppm
Dienal 2b undergoes quantitative and stereospecific reduction
to (2E,4E)-dienol 5b on treatment with NaBH4 in ethanol. The
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 190–192
MeO
Cl
Me
OH
to HC(3), and second, to make a conclusion that the C(2)=C(3)
i
ii
bond has an (E)-configuration. Accordingly, the second doublet
signal at d 6.51 ppm was assigned to HC(5). Its coupling constant
with HC(4) (15.5 Hz) suggests that the C(4)=C(5) bond has an
(E)-configuration. The high stereochemical purity of dienol 5b
also follows from its 1H NMR spectral data: the spectrum region
of d 0–3.70 ppm showed the only signal [2.67 (t)], which was
assigned to =C–CH2CH2OBn.
We intended to convert the hydroxymethyl group of dienol
5b to a methyl group by hydride reduction of the corresponding
C(1)-tosylate (without isolation), as it was done for dienols 5a,c
(Scheme 1).6,8 However, reduction of the tosylation product of
dienol 5b obtained under the same conditions as those used
to synthesize individual dienol 5c tosylate (TsCl, 0°C, 2 h)8
(Scheme 2) gave a mixture of the target (1E,3Z)-aryldiene ether
6b with its (1E,3E)-isomer 11 in 2:1 ratio.
6b
83%
70%
7b
MeO
Cl
Me
O
MeO
Me
iii
43%
Cl
ROOC
8b
9b R = H
10b R = Me
iv
MeO
Cl
Me
v
60%
OMe
MeOOC
1b
Scheme 3 Reagents and conditions: i, AlCl3–PhNMe2 (3:4), CH2Cl2, –5°C,
3.5 h; ii, IBX, DMF, room temperature, 1 h; iii, NaClO2, DMSO–H2O, pH 9,
0°C, 2.5 h; iv, CH2N2, Et2O, 0°C; v, NaH, HCOOMe, room temperature,
4.5 h, then (MeO)2SO2, DMF, K2CO3, 14 h.
MeO
OH
i, ii
6b + 11
50%
Cl
2 : 1
OBn
5b
gave crystalline (3Z,5E)-dienol 7b‡ in 85% yield (Scheme 3).
The total content of stereo- and regioisomers in the product did not
exceed 1% (1H NMR data).
iii, ii 61%
OBn
MeO
Cl
Me MeO
Conversion of (3Z,5E)-dienol 7b to diene acid 9b was carried
out via the stage of unstable (3Z,5E)-dienal 8b. The latter was
obtained in a good yield by oxidation of dienol 7b with o-iodoxy-
benzoic acid (IBX)17 in DMF18 and was then converted without
additional purification to (3Z,5E)-acid 9b§ by treatment with
NaClO2 in aqueous DMSO at pH 9.19
Crystalline acid 9b containing <2% of the (3E,5E)-isomer was
quantitatively converted to its methyl ester 10b¶ on treatment with
ethereal CH2N2. The structures of dienal 8b, acid 9b and methyl
ether 10b were confirmed by HRMS and 1H NMR spectroscopy
using NOE, as described above for dienol 5b. Their stereo- and
regiochemical purity exceeds 98% (1H NMR data).
The conversion of diene ester 10b to strobilurin 1b was
reported9 without experimental details. We performed this opera-
tion (Scheme 3) in ‘one pot’ by adding NaH (6 mmol, as 80%
suspension in mineral oil) to a stirred mixture of ester 10b
(156 mg, 0.56 mmol) and methyl formate (0.5 ml, 8 mmol) at
room temperature under argon. After 4 h, the mixture was treated
with dimethyl sulfate (Scheme 3). Chromatography of the reac-
tion product on SiO2 gave strobilurin B in 60% yield. Its overall
yield in our nine-stage synthesis was 5.5%. The physicochemical
characteristics of the product†† agree with literature data.20
+
Cl
Me
OBn
6b
11
96 : 4
Scheme 2 Reagents and conditions: i: BuLi, C6H14–HMPA, 0°C, then TsCl,
HMPA, 0°C, 2 h; ii, LiAlH4, THF, 20°C, 2 h; iii, BuLi, C6H14–THF, –80°C,
then TsCl, HMPA, –80°C, 30 min, then heating to –20°C, 2.5 h.
The evidence for the structure of compounds 6b and 11 fol-
lows, first, from HMRS data: the spectrum of the mixture of these
compounds shows a single (M+Na)+ ion. Second, the 1H NMR
spectrum of this mixture contains not only signals of diene ether
6b [2.64 (t, H2C5), 6.09 (d, HC3) and 6.40 (d, HC1)] but also
additional signals close to each of them: a triplet at d 2.45 ppm and
two doublets at d 6.05 and 6.36 ppm, respectively. The integral
intensity ratio of each pair of similar signals amounts to 2:1.
Third, the 13C NMR spectrum of the mixture of compounds 6b
and 11 in question contains, along with the signal of the MeC4
group of the major (E,Z)-isomer (d 24.48 ppm), also a signal of
the MeC4 group of the (E,E)-isomer (d 17.34 ppm).11
Clean conversion 5b®6b via the preparation of its tosylate
succeeded if the temperature of the tosylation stage was decreased.
In fact, even at –10°C the content of the undesired isomer 11
decreased to 20% (1H NMR data). Further lowering the tempe-
rature of TsCl addition to –80°C followed by slow heating of the
reaction mixture to –20 °C gave a product of tosylate hydride
reduction, which was isolated in 60% yield, namely a mixture of
the target diene ether 6b† and its (2E,4E)-isomer 11 in 96:4 ratio
(1H NMR data).
‡
Individual dienol 7b, mp 79–81°C (hexane–Et2O, 1:2), yield 83%.
1H NMR (CDCl3) d: 1.64 (t, 1H, OH, J 5.8 Hz), 1.89 (s, 3H, MeC3), 2.57
(t, 2H, H2C2, J 6.6 Hz), 3.77 (dt, 2H, H2C1, J1 6.6 Hz, J2 5.8 Hz), 3.92 (s,
3H, MeO), 6.16 (d, 1H, HC4, J 11.0 Hz), 6.41 (d, 1H, HC6, J 15.4 Hz),
6.91 (s, 1H, Ar), 6.94 (d, 1H, Ar, J 8.0 Hz), 6.98 (dd, 1H, HC5, J1 11.0 Hz,
J2 15.4 Hz), 7.27 (d, 1H, Ar, J 8.0 Hz).
§
1
Acid 9b, yield 30% (with respect to 7b), mp 124–126°C. H NMR
(CDCl3) d: 1.98 (s, 3H, MeC3), 3.34 (s, 2H, H2C2), 3.94 (s, 3H, MeO),
6.21 (d, 1H, HC4, J 11.0 Hz), 6.48 (d, 1H, HC6, J 15.2 Hz), 6.92 (dd, 1H,
HC5, J1 11.0 Hz, J2 15.2 Hz), 6.92 (s, 1H, Ar), 6.97 (d, 1H, Ar, J 8.2 Hz),
7.28 (d, 1H, Ar, J 8.2 Hz).
Deprotection of diene ether 6b (Scheme 3) is the next stage
in the synthesis of 1b along the route considered. Previously,8
we checked a few methods recommended in the literature for
deprotection of benzyl ethers12–16 and found that anhydrous AlCl3
in the presence of excess PhNMe213 is the optimum reagent for
our purpose. Debenzylation of ether 6b at –5°C using this method
¶
Methyl dienoate 10b. 1H NMR (CDCl3) d: 1.94 (s, 3H, MeC3), 3.30 (s,
2H, H2C2), 3.71, 3.93 (2s, 2×3H, MeO), 6.16 (d, 1H, HC4, J 10.7 Hz),
6.45 (d, 1H, HC6, J 15.4 Hz), 6.91 (s, 1H, Ar), 6.91 (dd, 1H, HC5, J1 10.7 Hz,
J2 15.4 Hz), 6.92 (s, 1H, Ar), 6.97 (d, 1H, Ar, J 8.2 Hz), 7.28 (d, 1H, Ar,
J 8.2 Hz).
†
Ether 6b was isolated in individual state by flash chromatography.
†† Strobilurin B 1b, mp 89–91°C. 1H NMR (CDCl3) d: 1.99 (s, 3H, MeC3),
3.75, 3.86, 3.91 (3s, 3×3H, MeO), 6.26 (d, 1H, HC4, J 10.5 Hz), 6.43 (d,
1H, HC6, J 15.5 Hz), 6.58 (dd, 1H, HC5, J1 10.5 Hz, J2 15.5 Hz), 6.85 (s,
1H, Ar), 6.92 (d, 1H, Ar, J 8.0 Hz), 7.26 (d, 1H, Ar, J 8.0 Hz), 7.44 (s, 1H,
CHOMe).
1H NMR (CDCl3) d: 1.90 (s, 3H, MeC4), 2.64 (t, 2H, H2C5, J 7.1 Hz),
3.62 (t, 2H, H2C6, J 7.1 Hz), 3.92 (s, 3H, MeO), 4.56 (s, 2H, CH2Ph),
6.09 (d, 1H, HC3, J 10.7 Hz), 6.40 (d, 1H, HC1, J 15.4 Hz), 6.92 (s, 1H,
Ar), 6.93 (d, 1H, Ar, J 7.4 Hz), 7.00 (dd, 1H, HC2, J1 10.7 Hz, J2 15.4 Hz),
7.29–7.40 (m, 6H, Ar).
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Mendeleev Commun., 2013, 23, 190–192
11 A. S. Shashkov, N. Ya. Grigor’eva, I. M. Avrutov, A. V. Semenovskii,
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Received: 5th April 2013; Com. 13/4097
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