Stannylation and Stille Coupling of Base-Sensitive Tetrahydroxanthones to Heteromeric Biaryls

Article abstract of DOI:10.1002/adsc.201500524

Herein, the synthesis of heteromeric tetrahydroxanthone biaryls is described, a widespread core structure of many natural products. The development of both stannylation and Stille coupling procedures of base-sensitive tetrahydroxanthones enabled their cou

Full text of DOI:10.1002/adsc.201500524

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DOI: 10.1002/adsc.201500524
Stannylation and Stille Coupling of Base-Sensitive
Tetrahydroxanthones to Heteromeric Biaryls
Stephanie Lindner,a Martin Nieger,b and Stefan Bräsea,c,*
a
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: (+49)-721-6084-8581; phone: (+49)-721-6084-2903; e-mail: braese@kit.edu
Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, P. O. Box 55, 00014 University of
b
Helsinki, Finland
c
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344
Eggenstein-Leopoldshafen, Germany
Received: May 30, 2015; Revised: July 18, 2015; Published online: October 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500542.
Abstract: Herein, the synthesis of heteromeric tetra- structures that are analogous to parnafungins as well
hydroxanthone biaryls is described, a widespread as to dimeric compounds similar to secalonic acids or
core structure of many natural products. The devel- phomoxanthones.
opment of both stannylation and Stille coupling pro-
cedures of base-sensitive tetrahydroxanthones ena-
bled their coupling with benzene derivatives as well Keywords: heteromeric biaryls; stannylation; Stille
as with xanthenes. These methods provide access to coupling; tetrahydroxanthones
Introduction
complex structures. Among them the tetrahydroxan-
thone biaryls play an important role. A recently iso-
The tetrahydroxanthone moiety is a common scaffold lated fascinating subgroup, the parnafungins (such as
of many mycotoxins that display a broad range of 1a and 1b, Figure 1), comprises a tetrahydroxanthone
pharmacological and agrochemical activities.[1] Beside unit linked to a benzoxazolidinone by a biaryl bond.[2]
monomeric tetrahydroxanthone natural products like Moreover, a variety of homo- and heterodimeric tet-
blennolides A–C, this unit is often connected to more rahydroxanthone biaryls have been identified, with
Figure 1. Selected natural products containing a heteromeric tetrahydroxanthone biaryl moiety.
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2,2-linked secalonic acids[3] (such as 2) being the most Results and Discussion
famous representatives.
While various syntheses of monomeric tetrahydro- Since the tetrahydroxanthone core is sensitive to
xanthones have been described by our group[4] as well bases and oxidation, previous trials to apply Suzuki[13]
as by Nicolaou,[5] Porco[6] and Tietze,[7] the prepara- or oxidative[14] couplings turned out to be problematic
tion of tetrahydroxanthone biaryls remains underex- (Scheme 1).
plored. Snider and co-workers reported on the synthe-
Thus, we decided to investigate the stannylation
sis of parnafungin A and C models via a Suzuki cou- and Stille cross-coupling of easily accessible tetrahy-
pling reaction using a far less sensitive xanthone droxanthones. We developed a method for the palla-
system.[8] Recently, Porco et al. accomplished the first dium-catalyzed stannylation of tetrahydroxanthones,
total syntheses of three homodimeric natural prod- using bromide 6a[13] as model substrate (Table 1).
ucts, the secalonic acids A and D, using a copper-cata- While similar results were obtained by replacing
lyzed oxidative coupling of aryl stannane monomers[9] PdCl2(PPh3)2 with Pd(PPh3)4 (entries 2 and 3), a re-
as well as the atropselective synthesis of rugulotrosin markable optimization (up to 60% yield, entry 4)
A.[10] Although this displays a milestone in the synthe- could be achieved by adding the Buchwald[15] ligands
sis of tetrahydroxanthone biaryls,[11] heterodimers are SPhos (8a) and XPhos (8b), respectively (entries 4
not accessible by this method. Herein we report a flex- and 5). It has already been shown, that such electron-
ible method for the synthesis of heteromeric tetrahy- rich and bulky ligands have a positive effect on every
droxanthone biaryls via the Stille coupling reaction.[12] step of the catalytic cycle.[12c] Furthermore, neither
Scheme 1. Sensitivity of the tetrahydroxanthone scaffold.
Table 1. Optimization of the synthesis of tetrahydroxanthone stannane 7.
Entry
X
Catalyst
Additive/ligand
Equiv. [mol%] (cat./ligand)
Solvent
Isolated yield [%]
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
DIPEA
–
–
2/–
2/–
2/–
2/5
2/5
2/5
2/5
1/2.5
4/10
2/5
2/5
toluene
toluene
toluene
toluene
toluene
dioxane
NMP
toluene
toluene
toluene
toluene
19
24
25
60
49
56
traces
49
SPhos
XPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos, Bu4NI
9
10
11
52
53[a]
31[b]
Br
[a]
Reaction time: 2 d.
Reaction time: 20 h.
[b]
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Stannylation and Stille Coupling of Base-Sensitive Tetrahydroxanthones
the exchange of toluene as solvent (entries 6 and 7)
nor varying the amount of the catalyst/ligand system
(entries 8 and 9) led to enhanced yields. After com-
pletion of these studies, Porco et al.[9] reported on an
alternative stannylation procedure of tetrahydroxan-
thones. Here, the formation of tin organyls was ach-
ieved using Pd2(dba)3 in combination with air sensi-
tive P(t-Bu)3 as ligand, whereby Bu4NI was necessary
to obtain full conversion. Therefore, we also tested
the addition of Bu4NI. However these attempts only
led to decreased yield due to side reactions (entry 11).
Thus, in our case the best conditions for the Pd-cata-
lyzed stannylation of tetrahydroxanthone halides
turned out to be the use of Pd(PPh3)4 as catalyst in
combination with SPhos as ligand in toluene
(entry 4).
The optimized stannylation conditions were applied
to further xanthene halides, yielding the correspond-
ing stannanes 9–12 (Figure 2).
Figure 2. Successfully synthesized stannanes starting from
the corresponding bromides or iodides.
Although this linkage does not exist in nature, the
stannylation in the 6-position was performed. Inter- nane 16a together with the tetrahydroxanthone halide
estingly, in contrast to the other positions, for the first 6a (entry 1) while the other combination only led to
time dimerization was observed leading to dimer 15 30% of the coupling product 18 (entries 2 and 3).
as a side product (Scheme 2). This might be explained However, starting from electron poor ester 17, the
À
by the increased nucleophilicity of the C Sn bond biaryl only could be obtained using tetrahydroxan-
due to the electron donor in the meta position, which thone stannane 7 (entries 4–8). In doing so, the best
facilitate transmetallation. The yield of the dimer, results were reached with triflate as coupling partner
based on bromide 13, could be increased by using in dioxane (entry 7). These conditions were also
lesser amounts of (SnBu3)2.
adapted to other benzene triflates, whereby the par-
With tetrahydroxanthone stannanes in hand we nafungin B analogous linkage 20a as well as other
proceeded with the synthesis of biaryls analogous to electron poor biaryls 20b and 20c could be obtained
the parnafungin core (Table 2). Hereby, both building (Figure 3).
blocks were implemented as stannanes and as halides
The formation of dimeric compounds was first ex-
or triflates either way. In the case of the toluene de- plored on the synthesis of the homodimer of tetrahy-
rivative 18 the best result was obtained using stan- droxanthone 6, starting from stannane 7 and bromide
Scheme 2. Stannylation of bromide 13. Yields are based on tetrahydroxanthone bromide 13.
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Table 2. Synthesis of tetrahydroxanthone biaryls similar to parnafungins and molecular structure of 19 (CCDC 1020439; dis-
placement parameters are drawn at 50% probability level).
Entry
R
X
Y
Additive
Solvent/temperature
Time
Yield [%]
1
2
3
4
5
6
7
8
Me
Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Sn(Bu)3
Br
Br
Sn(Bu)3
Sn(Bu)3
Br
Br
CuBr
LiCl
THF/reflux
toluene/808C
toluene/808C
THF/reflux
dioxane
dioxane/808C
dioxane/808C
toluene/808C
5 h
3 d
40 h
5 h
2 d
3 d
3 d
3 d
40
19
30
–
traces
18
52
Sn(Bu)3
Sn(Bu)3
Br
LiCl, CuI
CuBr
LiCl, CuBr
LiCl, CuI
LiCl, CuI
LiCl, CuI
Br
Sn(Bu)3
Sn(Bu)3
Sn(Bu)3
OTf
OTf
30
plied to the coupling of the other synthesized xan-
thenes and the corresponding stannanes leading to
a variety of heterodimers (Figure 4, for further exam-
ples see Figure 1 in the Supporting Information).
Thus, dimeric xanthone biaryls with different linkages
could be synthesized successfully in up to 61% yield.
The 2,2- and 2,4-linkages (as in 21a, 21b and 21d) cor-
respond to the core structure of natural products like
secalonic acid C (2) and phomoxanthone B (3), whilst
the 2,3- and 3,4-linkage (as in 21c and 21e) represent
new kinds of connections. The reason for the absence
of these linkages in nature is based on the biaryl bio-
synthesis via oxidative coupling of phenols.
Conclusions
We have developed an approach to base-sensitive het-
eromeric tetrahydroxanthone biaryls, a widespread
core structure of many natural products. The elaborat-
ed stannylation and Stille cross-coupling procedures
Figure 3. Synthesized tetrahydroxanthone biaryls.
6a or the corresponding triflate 6c (21k, see Table 1 in that are reported herein provide access to versatile
the Supporting Information). Therefore, we tested and complex tetrahydroxanthone biaryl structures.
various catalysts, (Pd(PPh3)4, Pd2(dba)3, Pd(dba)2,
Pd(PPh3)2Cl2, Ni(dppe)Cl2), in combination with spe-
cial ligands such as AsPh3 or bulky phosphines
(SPhos, TFP) and additives like copper halides[16] or
LiCl[17] in different solvents (toluene, DMF, dioxane,
NMP, THF).[12c] The only successful coupling reaction
was achieved using bromide 6a as coupling partner
catalyzed by Pd(PPh3)4 in combination with CuBr in
Experimental Section
General Procedure for the Pd-Catalyzed Stannylation
of Xanthenes (GP 1)
A vial equipped with a crimp top and a stirring bar was
THF at 608C. These conditions were subsequently ap- charged with the haloxanthenone (1.00 equiv.), Pd(PPh3)4
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Stannylation and Stille Coupling of Base-Sensitive Tetrahydroxanthones
Figure 4. Selected synthesized dimeric tetrahydroxanthone biaryls. The part that was implemented as stannane is displayed
in grey. Numbers of starting material are shown in brackets. Reaction conditions: Pd(PPh3)4 (10 mol%), CuBr (30 mol%),
THF, 608C, 1–4 d.
(2 mol%) and SPhos (5 mol%, 8a). The vial was closed and
absolute and degassed toluene [c(haloxanthene)ꢀ200 mM)
was added under an argon atmosphere. Hexabutyldistan-
nane (1.50 equiv.) was added and the reaction mixture was
heated to 808C for 3 d. After cooling to room temperature,
the solvent was removed under reduced pressure and the
residue was diluted with dichloromethane. The mixture was
displaced with an aqueous solution of KF (7M,
cꢀ0.7 mLmmolÀ1) and stirred for 30–60 min. After filtra-
tion over Celiteꢁ, the solution was dried over Na2SO4 and
the solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography.
a Bruker-Nonius Kappa CCD diffractometer at 123(2) K
(5Br-4) using Mo-Ka radiation (l=0.71073 Š). Direct meth-
ods (SHELXS-97)[18] were used for structure solution. Re-
finement was carried out using SHELXL-2013 or SHELXL-
97[18] (full-matrix least-squares on F2), and hydrogen atoms
were localized by difference Fourier synthesis and refined
using a riding model. Semi-empirical absorption correction
were applied.
19: yellow crystals, C21H17NO6, Mr =379.36, crystal size
0.15”0.10”0.06 mm, monoclinic, space group P21/c (No.
14), a=11.7991(6) Š, b=12.8236(10) Š, c=11.7731(8) Š,
b=100.555(5)8, V=1751.3(2) Š3, Z=4, 1=1.439 Mg/mÀ3
,
m(Mo-Ka)=0.107 mmÀ1, F(000)=792, 2qmax =508, 7475 re-
flections, of which 3082 were independent (Rint =0.037), 254
parameters, R1 =0.055 [for 2138 I>2s(I)], wR2 =0.133 (all
data), S=1.05, largest diff. peak/hole=0.323/À0.199 eŠÀ3.
5Br-4: yellow crystals, C13H11BrO2, Mr =279.13, crystal
size 0.50”0.40”0.30 mm, monoclinic, space group P21/
c (No. 14), a=8.822(1) Š, b=6.017(1) Š, c=20.660(2) Š,
b=94.91(1)8, V=1092.6(2) Š3, Z=4, 1=1.697 Mg/mÀ3,
m(Mo-Ka)=3.742 mmÀ1, F(000)=560, 2qmax =558, 12650 re-
flections, of which 2500 were independent (Rint =0.021), 145
parameters, R1 =0.023 [for 2196 I>2s(I)], wR2 =0.054 (all
data), S=1.07, largest diff. peak/hole=0.388/À0.422 eŠÀ3.
Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publications no. CCDC 1020439
(19) and CCDC 1061611 (5Br-4). These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for the Stille Coupling Reactions
of Haloxanthenes with Xanthene Stannanes (GP 2)
A vial equipped with a crimp top and a stirring bar was
charged with the stannane (1.00 equiv.), the halide
(1.00 equiv.), Pd(PPh3)4 (10 mol%) and CuBr (0.300 equiv.).
The vial was closed and absolute tetrahydrofuran [c(halo-
xanthene)ꢀ100 mM) was added under an argon atmos-
phere. The reaction mixture was heated to 608C for the ap-
propriate time. After cooling, the reaction mixture was dis-
placed with an aqueous solution of KF (7M,
c
ꢀ0.7 mLmmolÀ1) and stirred for 60 min. After filtration
over Celiteꢁ, the solution was dried over Na2SO4 and the
solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography.
Crystal Structure Determination
The crystal structures were determined on an Agilent Super-
Nova Diffractometer with EOS detector at 173(2) K (19) or
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Stephanie Lindner et al.
19, 4876–4882; b) L. F. Tietze, L. Ma, J. R. Reiner, S.
Jackenkroll, S. Heidemann, Chem. Eur. J. 2013, 19,
8610–8614; c) L. F. Tietze, S. Jackenkroll, J. Hierold, L.
Ma, B. Waldecker, Chem. Eur. J. 2014, 20, 8628–8635.
[8] Q. Zhou, B. B. Snider, J. Org. Chem. 2010, 75, 8224–
8233.
Acknowledgements
We thank the Landesgraduiertenfçrderung Baden-Württem-
berg for financial support and V. Kappings for the synthesis
of 5Br-4.
[9] T. Qin, J. A. Porco, Angew. Chem. 2014, 126, 3171–
3174; Angew. Chem. Int. Ed. 2014, 53, 3107–3110.
[10] T. Qin, S. L. Skraba-Joiner, Z. G. Khalil, R. P. Johnson,
R. J. Capon, J. A. Porco Jr, Nat. Chem. 2015, 7, 234–
240.
[11] T. Wezeman, K.-S. Masters, S. Bräse, Angew. Chem.
2014, 126, 4612–4614; Angew. Chem. Int. Ed. 2014, 53,
4524–4526.
References
[1] a) K.-S. Masters, S. Bräse, Chem. Rev. 2012, 112, 3717–
3776; b) S. Bräse, F. Gläser, C. Kramer, S. Lindner,
A. M. Linsenmeier, K. S. Masters, A. C. Meister, B. M.
Ruff, S. Zhong, The Chemistry of Mycotoxins, Springer,
Berlin, Heidelberg, 2013.
[12] a) V. Farina, V. Krishnamurthy, W. J. Scott, W. J. Scott,
The Stille Reaction, Wiley, New York, 1998; b) J. K.
Stille, Angew. Chem. 1986, 98, 504–519; Angew. Chem.
Int. Ed. Engl. 1986, 25, 508–524; c) C. Cordovilla, C.
BartolomØ, J. M. Martínez-Ilarduya, P. Espinet, ACS
Catal. 2015, 5, 3040–3053.
[2] a) C. A. Parish, S. K. Smith, K. Calati, D. Zink, K.
Wilson, T. Roemer, B. Jiang, D. Xu, G. Bills, G. Platas,
F. Pelµez, M. T. Díez, N. Tsou, A. E. McKeown, R. G.
Ball, M. A. Powles, L. Yeung, P. Liberator, G. Harris, J.
Am. Chem. Soc. 2008, 130, 7060–7066; b) D. Overy, K.
Calati, J. N. Kahn, M.-J. Hsu, J. Martín, J. Collado, T.
Roemer, G. Harris, C. A. Parish, Bioorg. Med. Chem.
Lett. 2009, 19, 1224–1227.
[3] a) F. Kraft, Arch. Pharm. (Weinheim). 1906, 244, 336–
359; b) B. Franck, E. M. Gottschalk, Angew. Chem.
1964, 76, 438–438; c) B. Franck, E.-M. Gottschalk, U.
Ohnsorge, F. Hüper, Chem. Ber. 1966, 99, 3842–3862.
[4] a) C. F. Nising, U. K. Ohnemüller, S. Bräse, Angew.
Chem. 2006, 118, 313–315; Angew. Chem. Int. Ed. 2006,
45, 307–309; b) E. M. C. GØrard, S. Bräse, Chem. Eur.
J. 2008, 14, 8086–8089; c) M. C. Brçhmer, E. Bourcet,
M. Nieger, S. Bräse, Chem. Eur. J. 2011, 17, 13706–
13711; d) A. C. Meister, A. Encinas, H. Sahin, E. M. C.
Singer, C. F. Nising, M. Nieger, S. Bräse, Eur. J. Org.
Chem. 2014, 2014, 4861–4875.
[13] C. F. Nising, U. K. Schmid, M. Nieger, S. Bräse, J. Org.
Chem. 2004, 69, 6830–6833.
[14] H. Sahin, M. Nieger, S. Bräse, Eur. J. Org. Chem. 2009,
2009, 5576–5586.
[15] a) E. R. Strieter, D. G. Blackmond, S. L. Buchwald, J.
Am. Chem. Soc. 2003, 125, 13978–13980; b) S. D.
Walker, T. E. Barder, J. R. Martinelli, S. L. Buchwald,
Angew. Chem. 2004, 116, 1907–1912; Angew. Chem.
Int. Ed. 2004, 43, 1871–1876; c) T. E. Barder, S. D.
Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem.
Soc. 2005, 127, 4685–4696; d) R. A. Altman, S. L. Buch-
wald, Nat. Protocols 2007, 2, 3115–3121.
[16] V. Farina, S. Kapadia, B. Krishnan, C. Wang, L. S. Lie-
beskind, J. Org. Chem. 1994, 59, 5905–5911.
[17] a) S. Verbeeck, C. Meyers, P. Franck, A. Jutand,
B. U. W. Maes, Chem. Eur. J. 2010, 16, 12831–12837;
b) I. J. S. Fairlamb, R. J. K. Taylor, J. L. Serrano, G.
Sanchez, New J. Chem. 2006, 30, 1695–1704.
[5] K. C. Nicolaou, A. Li, Angew. Chem. 2008, 120, 6681–
6684; Angew. Chem. Int. Ed. 2008, 47, 6579–6582.
[6] T. Qin, R. P. Johnson, J. A. Porco, J. Am. Chem. Soc.
2011, 133, 1714–1717.
[7] a) L. F. Tietze, S. Jackenkroll, C. Raith, D. A. Spiegl,
[18] G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64,
112–122.
J. R. Reiner, M. C. Ochoa Campos, Chem. Eur. J. 2013,
3308
asc.wiley-vch.de
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