Total synthesis of hydroxystrobilurin A via Stille coupling

Article abstract of DOI:10.1016/j.tetlet.2008.02.056

A six-step total synthesis of the fungicidal natural product hydroxystrobilurin A is described, utilising Stille chemistry for efficient access to the strobilurin (E,Z,E)-triene system.

Full text of DOI:10.1016/j.tetlet.2008.02.056

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2414–2417
Total synthesis of hydroxystrobilurin A via Stille coupling
Darby G. Brooke a,b, Jonathan C. Morris a,c,
*
a Department of Chemistry, University of Canterbury, Christchurch, New Zealand
b Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland,
Private Bag 92019, Auckland 1000, New Zealand
c School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia
Received 8 January 2008; revised 7 February 2008; accepted 11 February 2008
Available online 14 February 2008
This work is dedicated to the memory of the late Andrew J. Rea
Abstract
A six-step total synthesis of the fungicidal natural product hydroxystrobilurin A is described, utilising Stille chemistry for efficient
access to the strobilurin (E,Z,E)-triene system.
Ó 2008 Elsevier Ltd. All rights reserved.
SnBu3
The strobilurins are a family of 17 natural products
produced by a variety of fungi in climate zones the world
over, and the potent fungicidal activity they exhibit has
been exploited in the development of several synthetic
analogues as agrochemical fungicides.1 This bioactivity is
due to their (E)-b-methoxyacrylate subunit,2 which enables
binding to the ubiquinol oxidation centre of the cyto-
chrome b–c1 complex in the mitochondrial membrane, thus
halting ATP generation.3 Crucially, Strobiluris sp. are pro-
tected from the effects of their own products by a mutation
in their ubiquinol binding sites, which prevents the binding
of strobilurins.4 Several total syntheses of natural strobilu-
rins have been reported,5 together with synthetic studies
which led to the structural revision of several strobilurins.6
Coleman and Lu’s recent total synthesis of strobilurin B
utilises palladium catalysis to assemble the triene system
Ph
OH
MeO2C
Ph
OH
OMe
Br
OMe
MeO2C
4
5
hydroxystrobilurin A (1)
CO2Me
SnBu3
Br
+
Ph
Br
2
3
Fig. 1.
retrosynthesis in Figure 1; thus, a Stille coupling9 of phenyl-
ethyne stannane 210 and dibromoester 3,11 followed by
reduction, should afford diene alcohol 4, followed by a sec-
ond Stille coupling of 4 with known stannyl acrylate 512 to
form 1. This proposed strategy is both convergent and
incorporates the required stereoselectivity in the formation
of the strobilurin triene system. Investigation of this first
approach to 1 began with the radical hydrostannylation
of phenylethyne (6) to give phenylethenyl stannane 2
[94%, 12.4:1.0 (E):(Z) ratio] (Scheme 1).10a However, sub-
sequent Stille coupling of 2 with dibromoester 313 afforded
a poor yield of diene ester 7 (<20%).14
in a stereocontrolled manner,7 the absence of which having
5
ˆ
been the bete noire of previous total synthetic efforts.
We have also been investigating palladium-catalysed
protocols for stereoselective strobilurin construction, and
herein describe the first total synthesis of hydroxystro-
bilurin A (1).8 Our approach to 1 was based upon the
Thankfully, iodoester 8 (obtained by subjecting 3 to the
Finkelstein conditions of Caddick et al.15) reacted effi-
ciently16 with 2 under Stille conditions17 to give 7 (66%)
*
Corresponding author. Tel.: +61 8 8303 5770; fax: +61 8 8303 4358.
E-mail address: jonathan.morris@adelaide.edu.au (J. C. Morris).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.056

D. G. Brooke, J. C. Morris / Tetrahedron Letters 49 (2008) 2414–2417
2415
CO2Me
X
a
SnBu3
Br
Ph
Ph
OMe
Ph
Ph
OH
Br
MeO2C
6
2
3
Br
5 (X=SnBu3)
14 (X=Br)
15 (X=I)
4
b
a
CO2Me
CO2Me
I
Ph
c
OMOM
c
Ph
OMOM
OMOM
Br
8
Br
Br
11
7
4
SnBu3
13
d
e
5
d
f
b
e
Stille conditions
Ph
Ph
OH
1
X
Ph
Ph
OMOM
OMe
Ph
Br
Br
I
MeO2C
Ph
16
12
f
g
h
OAc
OMe
OAc
5, Stille
condXitions
MeO2C
OH
Ph
OH
9
10
OMe
I
MeO2C
17
1
Scheme 1. Reagents and conditions: (a) Bu3SnH, AIBN, 50 °C, 94%; (b)
NaI, acetone, reflux, 67%; (c) Pd(dppf)Cl2, DMF, 80 °C, 66%; (d) DIBAL-
H, Et2O, ꢀ78 to 0 °C, 89%; (e) Ac2O, NEt3, DMAP, CH2Cl2, 0 °C?rt,
92%; (f) 5, Pd2dba3, AsPh3, CuI, NMP, 50 °C, 51%.
Scheme 2. Reagents and conditions: (a) MOM–Cl, (i-Pr)2NEt, CH2Cl2,
0 °C?rt, 57%; (b) 5, Pd2dba3, AsPh3, CuI, NMP, 50 °C, dark, 18%; (c)
(Bu3Sn)2, Pd(PPh3)2Cl2, PhMe, reflux, dark, 40%; (d) Pd(dppf)Cl2, DMF,
rt?50?100 °C, dark, <10%; (e) I2, Et2O, 0 °C, 66%; (f) 5, Pd2dba3,
˚
AsPh3, CuI, NMP, 50 °C, dark, 57%; (g) TMSBr, 4 A molecular sieves,
as a single stereoisomer. Subsequent DIBAL-H reduction
of 7 to diene alcohol 4 proceeded without an incident
(89%). Unfortunately, ensuing attempts to couple 4 and
stannyl acrylate 5 under a variety of Stille conditions18
were unsuccessful, with only unreacted or degraded start-
ing materials isolated from reaction mixtures (Scheme 1).
Given that Hodgson et al. had successfully used 5 in
several Stille couplings,12b and despite the fact that one
of the usual strengths of the Stille coupling is its tolerance
of a wide variety of functionalities, it seemed that the
hydroxyl group of 4 was inhibiting the reaction. This
hypothesis was confirmed when we examined the Stille cou-
pling of acetate 9 (obtained by the reaction of 4 with acetic
anhydride) with acrylate 5 and obtained triene 10 in 51%
˚
ꢀ30?0 °C, 11%; (h) TMSBr, 4 A molecular sieves, ꢀ30 to 0 °C, 45%.
did afford a very low yield (11%) of 1 (Scheme 2). However,
efforts to improve the efficiency of this process by scaling
up the reaction resulted in even lower yields, with apparent
triene isomerisation occurring subsequent to deprotection.
Moreover, although MOM iodide 16 could also be hydro-
lysed to free-hydroxyl iodide 17, it proved as unreactive as
its bromo-analogue 4 as a Stille coupling partner for 5 en
route 1.
We now turned to exploring the potential of a functional
group interconversion approach, whereby it was proposed
that 1 might be accessible via selective reduction of an ester
or aldehyde precursor. Reaction of bromide 7 and stann-
ane 5 under Stille conditions furnished an excellent yield
(86%) of triene ester 18. Unfortunately, subsequent
attempts to selectively reduce the non-vinylogous ester of
18 afforded a complex mixture of reduced products, from
which only very low quantities of 1 could be recovered
(Scheme 3).
1
yield (Scheme 1). However, H NMR spectroscopic analy-
sis indicated that isomerisation had occurred19 to give a
triene acetate with (Z,E,E)-stereochemistry, presumably
via a p-allyl palladium-catalysed process.
In a bid to prevent this isomerisation from occurring,
the protecting group was changed to a MOM group
(Scheme 2). Reaction of 4 with MOM–Cl gave the MOM
ether 11, which was reacted with stannane 5, in the pre-
sence of Pd2dba3, AsPh3 and CuI, in NMP, to afford the
desired triene 12, albeit in 18% yield. In an effort to
improve the yield of this key step, the MOM ether 11
was converted to stannane 13 via a Pd-catalysed process.
Unfortunately, 13 proved to be unreactive with both
bromoacrylate 1411 (no reaction) and iodoacrylate 1511,12
(<10%) under Stille conditions.
CO2Me
Ph
OH
Ph
b
a
7
5
OMe
OMe
MeO2C
MeO2C
18
hydroxystrobilurin A (1)
e
d
CHO
CHO
c
Ph
Ph
4
OMe
Br
19
MeO2C
20
However, iodide 16, obtained via iododestannylation of
13, proved to be an efficient20 coupling partner with 5
under Stille conditions, furnishing a 57% yield of 12 (91%
Scheme 3. Reagents and conditions: (a) Pd2dba3, AsPh3, CuI, NMP,
dark, 50 °C, 86%; (b) DIBAl-H, CH2Cl2, ꢀ78 to 0 °C, 12%; (c) TPAP/
1
pure by H NMR analysis). The MOM ether of 12 proved
˚
NMO, 4 A molecular sieves, CH2Cl2, rt, 67% (79% based on recovered
to be immune to hydrolysis with catalytic acid,21 but treat-
ment with trimethylsilyl bromide as per Hanessian et al.22
starting material); (d) 5, Pd2dba3, AsPh3, CuI, NMP, 50 °C, 74%; (e)
NaBH4, MeOH, 0 °C?rt, 9% (14% based on recovered starting material).

2416
D. G. Brooke, J. C. Morris / Tetrahedron Letters 49 (2008) 2414–2417
and Ref. 1b], some of the corynanthe alkaloids [Lounasmaa, M.;
Reasoning that an aldehyde might prove more amenable
to hydride reduction than an ester, alcohol 4 was oxidised23
to diene aldehyde 19 (67%, 79% based on recovered start-
ing material) with TPAP/NMO24 (Scheme 3). Stille cou-
pling of 19 and 5 furnished a pleasing 74% yield of triene
aldehyde 20. It was hoped that the aldehyde moiety of 20
might be more reactive to reduction by a hydride agent
than the vinylogous ester group of 18, however DIBAL-
H treatment of 20 produced a complex mixture from which
only a trace of 1 (<5%) was isolated.
Tolvanen, A. The Corynantheine–Heteroyohimbine Group. In Chem-
istry of Heterocyclic Compounds; Chichester, United Kingdom, 1994;
Vol. 25, pp 57–159], and the cyrmenins [Leibold, T.; Sasse, F.;
Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem. 2004, 431–435], whilst
b-linked (E)-b-methoxyacrylate, -acrylamide or -ester subunits are
present in the myxothiazoles [Trowitzsch, W.; Reifenstahl, G.; Wray,
V.; Gerth, K. J. Antibiot. 1980, 33, 1480–1490 and Bedorf, N.; Kunze,
B.; Reichenbach, H.; Ho¨fle, H. In Scientific Annual Report of the
Gesellschaft fu¨r Biotechnologische Forschung mbH; Braunschweig,
Germany, 1986; p 14], the melithioazoles/cystothiazoles [Bo¨hlendorf,
B.; Herrmann, M.; Hecht, H.-J.; Sasse, F.; Forche, E.; Kunze, B.;
Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem. 1999, 2601–2608;
Ojika, M.; Suzuki, Y.; Tsukamoto, A.; Sakagami, Y.; Fudou, R.;
Yoshimura, T.; Yamanaka, S. J. Antibiot. 1998, 51, 275–281] and
haliangicin [Fudou, R.; Iizuka, T.; Sato, S.; Ando, T.; Shimba, N.;
Reduction of 20 with NaBH4 was more successful,
affording a low but improved yield of 1 (9%, 14% based
on recovered starting material). Spectroscopic data for syn-
thetic hydroxystrobilurin A (1) were in good agreement
with those published.8,25 However, further optimisation
of this reaction was unsuccessful. Greater amounts of
NaBH4 drove the reaction to completion (2.0 equiv. led
to the complete consumption of 20), but this was concom-
itant with a proportional increase in the number of allylic
Yamanaka, S. J. Antibiot. 2001, 54, 153–156].
ˇ
´
´ ˇ
´
3. (a) Subık, J.; Behun, M.; Musılek, V. Biochim. Biophys. Res. Commun.
ˇ
ˇ
1974, 57; (b) Sub´ık, J.; Behu´nˇ, M.; Smiga´nˇ, P.; Mus´ılek, V. Biochim.
Biophys. Acta 1974, 343, 363; (c) Anke, T.; Steglich, W. b-Methoxy-
acrylate Antibiotics: From Biological Activity to Synthetic
Analogues. In Biologically Active Molecules; Schlunegger, U. P.,
Ed.; Springer: Berlin, 1989; pp 9–25.
1
proton signals in the H NMR spectrum, presumably a
4. Kraiczy, P.; Haase, U.; Gencic, S.; Flindt, S.; Anke, T.; Brandt, U.;
von Jagow, G. Eur. J. Biochem. 1996, 235, 54–63.
result of 1,4-addition of hydride. The use of Luche’s selec-
tive 1,2-hydride addition conditions26 did seem to prevent
this, but unfortunately also afforded only trace amounts
of 1 and several new unidentified products.
This first total synthesis of hydroxystrobilurin A (1)
comprises the longest linear sequence of six steps from phe-
nyl ethyne (6). The use of Stille chemistry enabled efficient,
stereocontrolled formation of the strobilurin triene system
under relatively undemanding conditions.
5. (a) Anke, T.; Schramm, G.; Schwalge, B.; Steffan, B. A. M.; Steglich,
W. Liebigs Ann. Chem. 1984, 1616–1625; (b) Beautement, K.; Clough,
J. M. Tetrahedron Lett. 1987, 28, 475–478; (c) Sutter, M. Tetrahedron
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Weber, W.; Anke, T. Tetrahedron Lett. 1996, 37, 7955–7958; (e)
Uchiro, U.; Nagasawa, K.; Aiba, Y.; Kobayashi, S. Tetrahedron Lett.
2000, 41, 4165–4168; (f) Uchiro, U.; Nagasawa, K.; Aiba, Y.;
Kotoake, T.; Hasegawa, D.; Kobayashi, S. Tetrahedron Lett. 2001,
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Acknowledgement
7. Coleman, R. S.; Lu, X. Chem. Commun. 2006, 423–425.
8. Engler, M.; Anke, T.; Klostermeyer, D.; Steglich, W. J. Antibiot.
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We thank the University of Canterbury for financial
assistance (Ph.D. teaching assistantship to D.G.B.).
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Supplementary data
Supplementary data (experimental procedures, charac-
terisation data and copies of the NMR spectra of hydroxy-
strobilurin A) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.02.056.
References and notes
1. (a) Sauter, H.; Ammermann, E.; Ro¨hl, F. Strobilurins—From
Natural Products to a New Class of Fungicides. In Crop Protection
Agents from Nature: Natural Products and Analogues, Copping, L. G.,
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Discovery from Nature, Grabley, S., Thiericke, R., Eds.; Springer:
Heidelberg, 1999; (c) Daferner, M.; Anke, T.; Hellwig, V.; Steglich,
W.; Sterner, O. J. Antibiot. 1998, 51, 816–822; (d) Buchanan, M. S.;
Steglich, W.; Anke, T. Z. Naturforsch 1999, 54c, 463–468; (e) Sauter,
H.; Steglich, W.; Anke, T. Angew. Chem., Int. Ed. 1999, 38, 1328–
1349; (f) Bartlett, D. W.; Clough, J. W.; Godfrey, C. R. A.; Godwin,
J. R.; Hall, A. A.; Heaney, S. P.; Maund, S. J. Pestic. Outlook 2001,
12, 143–148.
13. Prepared in 83% yield by radical dibromination (Br2, CCl4) of methyl
propynoate (see Ref. 11).
14. (a) Von Auwers, K.; Muller, W. Justus Liebigs Ann. Chem. 1923, 434,
¨
165; (b) Rousseau, G.; Marie, J.-X. Synth. Commun. 1999, 29, 3705–
3710.
15. Caddick, S.; Delisser, V. M.; Doyle, V. E.; Khan, S.; Avent, A. G.;
Vile, S. Tetrahedron 1999, 55, 2737–2754.
16. Such differences between reactivities of alkenyl bromides and iodides
in oxidative addition processes are well-known (e.g.: Angara, G. J.;
Bovonsombat, P.; McNelis, E. Tetrahedron Lett. 1992, 33, 2285–
2288).
17. Several palladium/ligand catalyst and solvent combinations were
tried, affording yields of 7 ranging from 48% to 66%.
18. Including: Pd(PPh3)2Cl2, DMF; Pd2dba3, AsPh3, CuI, NMP;
Pd2dba3, P(t-Bu)3, CsF, NMP.
2. Other natural products containing a-linked (E)-b-methoxyacrylate
subunits include the oudemansins, also from Strobiluris sp. [Weber,
W.; Anke, T.; Steffen, B.; Steglich, W. J. Antibiot. 1990, 43, 207–212

D. G. Brooke, J. C. Morris / Tetrahedron Letters 49 (2008) 2414–2417
2417
´
19. Although strobilurins are known to undergo double-bond isomeriza-
tion if subject to prolonged UV-irradiation [vide Refs. 1e and 4] it
seems more likely that this is a palladium-mediated process: (a)
Nakamura, H.; Iwama, H.; Ito, M.; Yamamoto, Y. J. Am. Chem. Soc.
1999, 121, 10850; (b) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org.
Chem. 2002, 67, 4627–4629.
20. This further illustrates the greater reactivity of alkenyl iodides versus
bromides in oxidative additions (vide Ref. 16).
21. Auerbach, J.; Weinreb, S. M. J. Chem. Soc., Chem. Commun. 1974,
298–299.
22. Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984, 25,
2515–2518.
23. Attempts were made to access aldehyde 19 directly, by reduction
of ester 7, however these literature-based procedures: (a) Zakharkin,
L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 14, 619–620; (b)
Szantay, C.; To¨ke, L.; Kolonits, P. J. Org. Chem. 1996, 31, 1447–1451
afforded trace amounts of 19, small amounts of 4, and mostly
unreacted 7.
24. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639–666.
25. Data for hydroxystrobilurin A: 1H (500 MHz, CDCl3) d 2.22 [br s,
1H, OH], 3.75 [s, 3H, 1-OMe] 3.85 [s, 3H, 20-OMe], 4.25 [s, 2H, H-30],
6.51 [d, 1H, J = 9.3 Hz, H-4], 6.62 [d, 1H, J = 15.4 Hz, H-6], 6.66 [dd,
1H, J = 15.3, 9.3 Hz, H-5], 7.22 [dd, 1H, J = 7.3 Hz, H-10], 7.30 [dd,
2H, J = 7.3 Hz, H-9], 7.35 [d, 2H, J = 7.3 Hz, H-8], 7.54 [s, 1H, H-20];
13C (126 MHz, CDCl3) d 51.8 [1-OMe], 62.0 [20-OMe], 66.6 [C-30],
107.8 [C-2], 125.6 [C-5], 126.5 [C-8], 127.6 [C-10], 128.5 [C-9], 130.8
[C-4], 133.6 [C-7], 134.0 [C-6], 137.3 [C-3], 160.4 [C-20], 168.1 [C-1]; IR
(film, cmꢀ1) 3445, 1699, 1622; MS (EI) 274.1205 (M+).
26. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.