Total synthesis of strobilurin B using a hetero-bis-metallated pentadiene linchpin

Article abstract of DOI:10.1039/b514233d

An efficient, six-step stereocontrolled total synthesis of the antifungal agent strobilurin B is reported and was based on a convergent bi-directional coupling featuring a hetero-bis-1,4-metallated pentadiene system as the linchpin. The Royal Society of C

Full text of DOI:10.1039/b514233d

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Total synthesis of strobilurin B using a hetero-bis-metallated pentadiene
linchpin{
Robert S. Coleman* and Xiaoling Lu
Received (in Bloomington, IN, USA) 6th October 2005, Accepted 2nd November 2005
First published as an Advance Article on the web 6th December 2005
DOI: 10.1039/b514233d
An efficient, six-step stereocontrolled total synthesis of the
antifungal agent strobilurin B is reported and was based on a
convergent bi-directional coupling featuring a hetero-bis-1,4-
metallated pentadiene system as the linchpin.
The strobilurins are a widely occurring family of natural products
produced by higher fungi that possess potent and effective
antifungal activity. These compounds possess a b-methoxyacrylate
group as a common and critical structural element, and there has
been extensive industrial development of these compounds and
their analogs for use as agricultural chemicals.1 This family of
compounds inhibits the mitochondrial respiratory chain by
binding to the ubihydroquinone oxidation center in the bc1
complex, arresting ATP formation.2 In producing organisms such
Fig. 1 Retrosynthetic analysis of strobilurin B, illustrating use of the
hetero-bis-metallated pentadiene reagent 2.
as Srobilurus tenacellus, specific mutations in the cytochrome b
protein reduce the binding affinity of the strobilurins in the host
organism.3
using MnO2 afforded known enal 7 (74% for two steps).11 Takai
olefination12 of aldehyde 7 with dichloromethylborinate 813
proceeded smoothly, but afforded pentadiene 2 (94%) as a 1 : 1
mixture of stereoisomers about the vinylstannane olefin, presum-
ably as a result of the intermediacy of delocalized radical or
cationic species.14
Syntheses of members of this family of natural products have
been reported,4 including a 1989 account by Sutter5 of the total
synthesis of strobilurin B. This synthesis was accomplished in a
non-stereocontrolled manner in 11 linear steps, wherein the final
product was isolated as a 1 : 1 mixture of olefin stereoisomers in
52% combined yield.
An alternative route to pentadiene 2 relied on hydroboration to
introduce the trans-vinylborinate (Scheme 2). Monolithiation of
1,4-bis-trimethylsilyl-1,3-butadiyne (9, THF, 25 uC) and alkylation
of the lithium acetylide with iodomethane (THF, 280 uC) afforded
pentadiyne 10 (56%). Regio- and stereoselective stannylcupration15
afforded the known vinylstannane 1116 (quantitative); removal
of the trimethylsilyl group (KF, MeOH, 25 uC) afforded enyne
12 (quantitative). Hydroboration of the triple bond of 12
using the reagent system developed by Snieckus and co-
workers17 cleanly introduced the trans-vinylboronate and afforded
2 (75%).
Our goal in undertaking this work was to employ modern
palladium-catalyzed coupling protocols for the convergent and
efficient syntheses of these natural products. This goal was
achieved and the total synthesis of strobilurin B (1) was
accomplished in 6 steps. The synthetic plan we implemented
(Fig. 1) was based on a bi-directional coupling of novel hetero-bis-
metallated pentadiene 2 with known iodoacrylate 3,6,7 via a Stille
coupling,8 and with aryl iodide 4, via a Suzuki/Miyaura coupling.9
This linchpin strategy has proven useful in other natural product
contexts.10 The synthesis as proposed is convergent and occurs
with control of olefin geometry, a problem that has plagued other
syntheses.4,5 Because of the modular nature of the synthetic plan,
introduction of structural diversity becomes straightforward by
simple variation in the three coupling partners.
Stille coupling of vinylstannane 2 and vinyl iodide 3 occurred
extremely slowly under a variety of conditions,18 and the coupled
Our initial attempt towards the synthesis of hetero-bis-
metallated pentadiene 2 started with hydroalumination/transme-
tallation of 2-butyn-1-ol (5), which afforded vinyl stannane 6 as a
single isomer (Scheme 1). Oxidation to the corresponding aldehyde
Department of Chemistry, The Ohio State University, 100 West 18th
Ave., Columbus, OH, 43210, USA.
E-mail: coleman@chemistry.ohio-state.edu; Fax: +1 614-292-1685;
Tel: +1 614-292-4548
{ Electronic supplementary information (ESI) available: full experimental
procedures and spectral characterization of intermediates and products.
See DOI: 10.1039/b514233d
Scheme 1
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Chem. Commun., 2006, 423–425 | 423

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Scheme 2
Scheme 4
product 13 could be isolated in poor yield (Scheme 3). Under
more forcing reaction conditions, diene 2 and the coupling
product 13 were not stable, and no increases in yield
were observed. Apparently, the combination of steric crowding
of the vinylic stannane 2, the unreactivity of the vinylic iodide
3, and the instability of the boronate of product 13
combined to effectively shut-down this normally facile reaction
manifold.
In developmental work on hetero-bis-metallated diene systems,10
we successfully demonstrated that Stille coupling occurred cleanly
and in high yield in the presence of a vinyl boronate. Furthermore,
we showed that simple addition of fluoride to such Stille reaction
mixtures permitted a subsequent Suzuki–Miyaura coupling to be
performed in a sequential and one-pot fashion. We assumed that
the opposite ordering of coupling reactions—Suzuki–Miyaura
followed by Stille—would not be possible because Stille coupling
would occur competitively with the desired Suzuki–Miyaura
reaction. However, this assumption was never tested.
The total synthesis of strobilurin B was short and efficient
(longest linear sequence, six steps from butadiyne 9; eight total
steps from commercially available methyl b-methoxyacrylate,
4-chloro-3-methoxyaniline, and 1,4-bis-trimethylsilyl-1,3-buta-
diyne). Essentially complete control of geometry about the three
stereogenic double bonds of 1 was obtained.
This work was supported by a grant from the National Cancer
Institute (NIH R01 CA91904). We thank Mr Matthew C.
Walczak for helpful discussions.
Notes and references
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G. Bertram, A. Scherer, W. Steglich and W. Weber, Tetrahedron Lett.,
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5 M. Sutter, Tetrahedron Lett., 1989, 30, 5417.
6 Prepared in 77% yield from methyl 3-methoxyacrylate by iodination
(NIS, AcOH, CH2Cl2) and elimination (Et3N): D. M. Hodgson,
J. Witherington, B. A. Moloney, L. C. Richards and J. L. Brayer,
Synlett, 1995, 32.
7 R. Rossi, F. Bellina and A. Carpita, Synlett, 1996, 356.
8 D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1978, 100, 3636;
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In the present case, the attenuated reactivity of the vinyl
stannane of pentadienyl system 2 permitted chemoselective
Suzuki–Miyaura coupling of the terminal vinyl boronate in this
system (Scheme 4). Under aqueous coupling conditions using
(t-Bu)3P as the ligand19 on palladium and aryl iodide 420 as the
coupling partner, chemoselective arylation of the vinyl boronate
terminus of pentadiene 2 occurred,21 and 14 could be isolated from
the reaction as the only coupling product observed (74%).
Subsequent Stille coupling of the vinyl stannane of 14 with vinyl
iodide 3 now occurred using t-Bu3P as the palladium ligand and
in the presence of CuI, and strobilurin B (1) was produced as a
single stereoisomer in 45% yield. Further optimization of this
coupling reaction was unsuccessful. Proton and carbon NMR
spectral data for synthetic strobilurin B were identical with
published data.22
10 R. S. Coleman, M. C. Walczak and E. L. Campbell, J. Am. Chem. Soc.,
2005, 127, 16038; R. S. Coleman and M. C. Walczak, Org. Lett., 2005,
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17 A. V. Kalinin, S. Scherer and V. Snieckus, Angew. Chem., Int. Ed., 2003,
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18 For example: (Ph3P)4Pd, CuI, CsF, DMF; PdCl2(CH3CN)2, DMF;
Pd2dba3, P(furyl)3, NMP; (Ph3P)4Pd, CuTC, DMF.
Scheme 3
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20 Iodide 4 was prepared in 84% yield from commercially available
4-chloro-3-methoxyaniline by diazotization (NaNO2, HCl(aq), 0 uC) and
reaction of the aryl diazonium intermediate with KI.
21 Other reaction conditions were unsuccessful in providing useful yields of
coupled product 14: (Ph3P)4Pd, K3PO4, dioxane; Pd2dba3, t-Bu3P, KF,
THF; (Ph3P)4Pd, K2CO3, toluene/EtOH.
22 T. Anke, F. Oberwinkler, W. Steglich and G. Schramm, J. Antibiot.,
1977, 30, 806; G. Schramm, W. Steglich, T. Anke and F. Oberwinkler,
Chem. Ber., 1978, 111, 2779; T. Anke, G. Schramm, B. Schwalge,
B. Steffan and W. Steglich, Liebigs Ann. Chem., 1984, 1616.
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