Total synthesis of spirobacillene A

Article abstract of DOI:10.1021/ol4013958

The first total synthesis of spirobacillene A, an indole alkaloid isolated from Lysinibacillus fusiformis, is reported. A Lewis acid mediated spirocyclization of an anisole derivative onto a tethered ynone was used as a key step, drawing inspiration from

Full text of DOI:10.1021/ol4013958

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of Spirobacillene A
William P. Unsworth,* James D. Cuthbertson, and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U.K.
william.unsworth@york.ac.uk; richard.taylor@york.ac.uk
Received May 17, 2013
ABSTRACT
The first total synthesis of spirobacillene A, an indole alkaloid isolated from Lysinibacillus fusiformis, is reported. A Lewis acid mediated spirocyclization
of an anisole derivative onto a tethered ynone was used as a key step, drawing inspiration from a potential biosynthesis of the natural product.
Microorganisms that exist in extreme environments
are an abundant source of novel heterocyclic scaffolds.1
Unique secondary metabolites with useful biological prop-
erties are commonly isolated from such organisms (known
as extremeophiles), and it is thought that the production
of these compounds is often done in response to the harsh
ecological conditions in which they live. Kwon et al.
recently reported the discovery of a number of natural prod-
ucts derived from a bacterial strain found in such extreme
conditions.2 Four new compounds (1À4, Figure 1) were
isolated from a 24 h broth culture of Lysinibacillus fusi-
formis obtained from coal-mine drainage, contaminated
with sulfuric acid (pH 3.0) and iron-rich heavy metals. In
addition, two known indole alkaloids soraphinol A (5) and
kurasoin B (6) were also isolated, which are closely related
to the diolmycins (for example, 7).3
Figure 1. Spirobacillenes and related natural products.
Of these products, spirobacillenes A and B (1 and 2)
possess by far the most interesting structures. Both possess
was found to display inhibitory activity against the pro-
completely novel carbon frameworks within the field of
duction of nitric oxide and reactive oxygen species.2 In
natural products, and to date, neither of their total syn-
view of all this, and of a longstanding interest in the
theses have been reported. Furthermore, spirobacillene A
synthesis of quinone4 and spirocyclic-based5 natural prod-
ucts in our research group, we decided to investigate their
(1) (a) Rothschild, L. J.; Mancinelli, R. L. Nature 2001, 409, 1092. (b)
total synthesis.
Stierle, D. B.; Stierle, A. A.; Patacini, B.; McIntyre, K.; Girtsman, T.;
Bolstad, E. J. Nat. Prod. 2011, 74, 2273 and references therein.
(2) Park, H. B.; Kim, Y.; Lee, J. K.; Lee, K. R.; Kwon, H. C. Org.
Lett. 2012, 14, 5002.
(3) Tabata, N.; Sunazuka, T.; Tomoda, H.; Nagamitsu, T.; Iwai, Y.;
Omura, S. J. Antibiot. 1993, 46, 762.
(4) (a) Taylor, R. J. K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.;
Wei, X. D.; Lewis, N. Synthesis 1998, 775. (b) Hookins, D. R.; Burns, A. R.;
Taylor, R. J. K. Eur. J. Org. Chem. 2011, 451 and references therein.
r
10.1021/ol4013958
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Our original retrosynthetic strategy centered on 1,2-
dicarbonyl tautomer 3, which was isolated along with the
spirobacillenes and has been proposed as a potential bio-
synthetic precursor.2 We considered that the site-selective
oxidation of 3 would allow access to either natural prod-
uct following spirocyclization (Scheme 1). This approach
is appealing, as both targets could be accessed from a
single, relatively simple precursor. Similar spirocycliza-
tions are known to take place under acidic conditions,6
adding support to the idea that this approach may be
biomimetic and, furthermore, the high levels of iron-rich
heavy metals that contaminate the environment that the
Lysinibacillus fusiformis was obtained from may help to
promote the requisite oxidation.7
during its isolation.2 An alternative synthetic strategy was
therefore proposed, focusing solely on the synthesis of
spirobacillene A. It was hoped that ynone 11, which is at
the same oxidation state as the initially required 1,2-
diketone, could be used as a synthetic equivalent. Such
ynones are usually stable and are far easier to synthesize
than the analogous 1,2-diketones. Furthermore, the ynone
moeity should provide a greater degree of regiocontrol
in the spirocyclization, compared with the corresponding
diketone.
Scheme 2. Attempted Formation of 10 and Ynone 11 as a
Synthetic Equivalent
Scheme 1. Proposed Biomimetic Route to the Spirobacillenes
Electrophilic cyclization reactions of alkynes have at-
tracted increasing attention in recent years.9 One such
transformation, the iodonium/bromonium-induced intra-
molecular ipso-cyclization of electron-rich aromatics onto
ynone derivatives, first reported by Larock and co-
workers10 and subsequently modified by others,11 ap-
peared particularly well suited to the synthesis of the
spirobacillene A framework. We envisioned that a simple
ynone 14 would undergo cyclization (via iodonium ion 15)
to generate spirocycle 16 which, following conversion of
the iodide into a hydroxyl, would provide a rapid, high
yielding synthesis of the target molecule 1 (Figure 2).
The synthesis began with iodination and Boc-protection
of indole to form iodide 1812 in excellent yield over the two-
step telescoped sequence (Scheme 3). Sonogashira cou-
pling with trimethylsilyl acetylene followed by TMS clea-
vage then afforded alkyne 19,13 again in excellent yield
over the two-step sequence. Next, the treatment of 19 with
n-butyllithium followed by Weinreb amide 20 afforded
In order to test this approach, alkene 8 and 1,2-diol 9
were synthesized using a previously reported route, de-
scribed during the synthesis of the related natural product
diolmycin A1 (7, Figure 1).3 It was then hoped to convert
one of these compounds into diketone 10, a protected
analogue of diketone tautomer 3. However, all attempts to
generate diketone 10 failed; a number of methods were
examined,8 but all resulted in the formation of complex
mixtures of unidentified products (Scheme 2). This result
was disappointing, although not entirelyunexpected, given
that the related compound 3 was reported to be unstable
(5) (a) Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org.
Lett. 2010, 12, 3446. (b) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org.
Chem. 2011, 6821. (c) Bastin, R.; Dale, J. W.; Edwards, M. G.; Papillon,
J. P. N.; Webb, M. R.; Taylor, R. J. K. Tetrahedron 2011, 51, 10026.
(6) (a) Iwata, C.; Fusaka, T.; Fujiwara, T.; Tomita, K.; Yamada, M.
J. Chem. Soc., Chem. Commun. 1981, 463. (b) Nagao, Y.; Lee, W. S.;
Jeong, I.-Y.; Shiro, M. Tetrahedron Lett. 1995, 36, 2799. (c) Hashmi,
A. S. K.; Schwartz, L.; Bolte, M. Tetrahedron Lett. 1998, 39, 8969. (d)
Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Dohi, T.; Kita, Y. Org. Lett.
2008, 10, 3559. (e) Snyder, S. A.; Sherwood, T. C.; Ross, A. G. Angew.
Chem., Int. Ed. 2010, 49, 5146.
(7) Gregg, D. J.; Ollagnier, C. M. A.; Fitchett, C. M.; Draper, S. M.
Chem.;Eur. J. 2006, 12, 3043.
(8) DessÀMartin periodinane and Swern oxidation methods were
trialled, in addition to the procedures found in the following: (a) Amon,
C. M.; Banwell, M. G.; Gravattpp, G. L. J. Org. Chem. 1987, 52, 4851.
(b) Khurana, J. M.; Kandpal, B. M. Tetrahedron Lett. 2003, 44, 4909. (c)
Plietker, B. Org. Lett. 2004, 6, 289.
(9) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111,
2937 and references therein.
(10) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230.
(11) (a) Tang, B.-X.; Tang, D.-J.; Tang, S.; Yu, Q.-F.; Zhang, Y.-H.;
Liang, Y.; Zhong, P.; Li, J.-H. Org. Lett. 2008, 10, 1063. (b) Yu, Q.-F.;
Zhang, Y.-H.; Yin, Q.; Tang, B.-X.; Tang, R.-Y.; Zhong, P.; Li, J.-H.
J. Org. Chem. 2008, 73, 3658. (c) Tang, B.-X.; Yin, Q.; Tang, R.-Y.; Li,
J.-H. J. Org. Chem. 2008, 73, 9008. (d) Dohi, T.; Kato, D.; Hyodo, R.;
Yamashita, D.; Shiro, M.; Kita, Y. Angew. Chem., Int. Ed. 2011, 50,
3784. (e) Low-Beinart, L.; Sun, X.; Sidman, E.; Kesharwani, T. Tetra-
hedron Lett. 2013, 54, 1344.
(12) Mothers, C.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2008, 73,
6706.
(13) Trost, B. M.; Dyker, G.; Kulawiec, R. J. J. Am. Chem. Soc. 1990,
112, 7809.
B
Org. Lett., Vol. XX, No. XX, XXXX

This forced us to consider an alternative strategy. It
was hoped that ynone 21 would undergo spirocyclization
promoted by a Lewis or Brønsted acid, rather than iodine,
to afford an unsubstituted cyclopentenone which, follow-
ing oxidation,16 would allow access to the enolized 1,2-
diketone moiety of spirobacillene A. While there is no direct
precedent for this type of cyclization, Haack introduced a
conceptually similar reaction. In this work, terminal al-
kynes were reacted with acid chlorides and aluminum
trichloride to form spirocyclic cyclohexadienones, via
ynones, in one pot,17 but this reaction has received remark-
ably little attention. This may be because the majority of
the reported examples are low-yielding,17,18 possibly due to
the formation of naphthalene-based side products (related
spirocyclic compounds are known to rearrange under simi-
larly harsh acidic reaction conditions).17,19 Previous work in
our group has demonstrated the efficacy of SnCl2 2H2O as
3
a promoter of a diverse array of cyclization reactions, and it
was hoped that this reagent would be sufficiently mild to
promote spirocyclization without subsequent rearrange-
ment and degradation.20 SnCl2 2H2O is a versatile, cheap,
3
Figure 2. Retrosynthesis of spirobacillene A (1).
nontoxic reagent that can be used without any special care
or precautions, and it was anticipated that the water present
in the reagent would be beneficial, as it could facilitate the
loss of methanol via hydrolysis following cyclization.
ynone 21. We were then pleased to find that the treatment
of 21 with iodine and NaHCO3 afforded spirocycle 22 in
good yield after stirring at room temperature for 10 min.
Protecting group cleavage was also achieved smoothly,
following treatment with TFA, affording indole 23, the
structure of which was confirmed by X-ray crystallo-
graphy14 (Figure 3). Unfortunately, all attempts to convert
either vinyl iodide 22 or 23 into the requisite enol were
unsuccessful; a range of copper- and palladium-catalyzed
CÀO bond forming methods were screened, but all led to
substrate decomposition.15
Thus, ynone 21 was stirred with 5 equiv of SnCl2 2H2O
3
in DCM for 18 h at room temperature, and we were
pleased to observe remarkably clean conversion into the
desired spirocyclic cyclohexadienone 24, which was iso-
lated in 89% yield after chromatography (Scheme 4).
Furthermore, the treatment of the same ynone with TFA
also led to spirocyclization, but with concomitant Boc-
cleavage, affording spirocycle 25 in 92% isolated yield. To
the best of our knowledge, these reactions are the first
reported examples in which an acid has been used to promote
the direct conversion of an ynone into a spirocyclic cyclohexa-
dienone. An X-ray crystal structure of spirocycle 25 was
obtained, supporting its assigned structure (Figure 3).14
Unfortunately all attempts to oxidize either enone 24 (to
obtain28) or25(toobtain1) failed; a rangeofoxidantsand
conditions were trialled but resulted in either no reaction21
or substrate decomposition.22 It appears that the enone is
Scheme 3. Synthesis of Spirocycle 23
ꢀ
(16) Fernandez-Mateos, A.; Martın de la Nava, E. M.; Coca, G. P.;
Gonzalez, R. R.; Ramos Silvo, A. I.; Simmonds, M. S. J.; Blaney, W. M.
ꢀ
J. Org. Chem. 1998, 63, 9440.
(17) Haack, R. A.; Beck, K. R. Tetrahedron Lett. 1989, 30, 1605.
(18) (a) Boyle, F. T.; Matusiak, Z. S.; Hares, O.; Whiting, D. A.
J. Chem. Soc., Chem. Commun. 1990, 518. (b) Boyle, F. T.; Hares, O.;
Matusiak, Z. S.; Li, W.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1
1997, 2707. (d) Appel, T. R.; Yehia, N. A. M.; Baumeister, U.; Hartung,
€
€
H.; Kluge, R.; Strohl, D.; Fanghanel, E. Eur. J. Org. Chem. 2003, 47.
(19) (a)Juteau, H.;Gareau, Y.;Lachance, H. Tetrahedron Lett. 2005, 46,
4547. (b) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236.
(c) Qiu, W.-W.; Surendra, K.; Yin, L.; Corey, E. J. Org. Lett. 2011, 13, 5893.
ꢀ
(20) (a) Cayley, A. N.; Gallagher, K. A.; Menard-Moyon, C.;
Schmidt, J. P.; Diorazio, L. J.; Taylor, R. J. K. Synthesis 2008, 3846.
(b) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2013, 15,
258. (c) Unsworth, W. P.; Gallagher, K. A.; Jean, M.; Schmidt, J. P.;
Diorazio, L. J.; Taylor, R. J. K. Org. Lett. 2013, 15, 262.
(21) m-CPBA, with and without NaHCO3, DCM, 0 °C and rt; PIFA,
CF3CH3OH, 0 °C and rt; PIDA, DCM, rt; Davies oxaziridine, NaHCO3,
CH3CN, rt and 70 °C.
(14) CCDC 934317 (23) and CCDC 934316 (25) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(15) (a) Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan, J.; You, J.
Angew. Chem., Int. Ed. 2009, 48, 8729. (b) Xu, H.-J.; Liang, Y.-F.; Cai,
Z.-Y.; Qi, H.-X.; Yang, C.-Y.; Feng, Y. S. J. Org. Chem. 2011, 76, 2296.
(c) Thakur, K. G.; Sekar, G. Chem. Commun. 2011, 47, 6692.
(22) H2O2, NaOH, MeOH at 0 °C; m-CPBA, with and without
NaHCO3, 50 °C; DMDO, acetone, rt.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Total Synthesis of Spirobacillene A (1)
Figure 3. X-ray structures of cyclohexadienones 23 and 25.
not reactive enough to be oxidized in the presence of the
sensitive cyclohexadienone moiety. In order to negate this
problem, the carbonyl of enone 24 was reduced under
Luche conditions, thus rendering the alkene more electron
rich and generating allylic alcohol 26 in 62% yield, or 82%
based on recovered starting material.23 Epoxidation of
allylic alcohol 26 with m-CPBA gave an unstable epoxy-
alcohol (27), which was directly oxidized with buffered
DessÀMartin periodinane (DMP), affording epoxy ke-
tone 28 in 42% yield over the two steps, as well as 20%
of enone 24, which presumably is formed by a known
rearrangement16 of 27. The reaction of 28 with p-TsOH
effected epoxide opening, completing the hydroxyl instal-
lation, affording enol 29. Finally, treatment with TFA in
DCM resulted in Boc-cleavage to give spirobacillene A
(1).24 The spectroscopic data accrued closely matched
those reported for the natural product, but it should be
noted that in our hands compound 1 is only sparingly
soluble in CD3CN, the NMR solvent used during the
natural product isolation.2 This meant that some of its
13C NMR signals were not observed, and therefore addi-
tional NMR data were recorded in DMSO-d6 (see Support-
ing Information for a fuller discussion and comparison of
these data).
In summary, we have completed the first total synthesis
ofthe recently isolated natural product spirobacillene A (1)
in 11 steps and 14% overall yield from indole. The most
pleasing aspects of this work were the extremely efficient
six-step syntheses of spirobacillene A analogues 24 and 25
(61% and 63% overall yields, respectively). These routes,
which were inspired by a potential biosynthesis of the
natural products, were performed on a large scale and
culminated in high yielding acid-mediated spirocyclic cy-
clohexadienone formations. Future work will focus on the
synthesis of spirobacillene B and will be reported in due
course.
Acknowledgment. The authors wish to thank the
EPSRC (EP/G068313/1, W.P.U.) and The University of
York (J.D.C.) for funding and Dr. A. C. Whitwood
(University of York) for X-ray crystallography studies.
Supporting Information Available. Synthetic proce-
dures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(23) A small amount of unreacted starting material 24 and over-
reduced side products were isolated as a mixture, which was reoxidized
with buffered DMP regenerating 24 (see Supporting Information).
(24) The treatment of epoxide 28 with TFA to produce 1 directly was
unsuccessful.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX