Total synthesis of mevashuntin

Article abstract of DOI:10.1021/ol300221e

The total synthesis of (±)-mevashuntin, a structurally unique naturally occurring pyrano-naphthoquinone-thiazolone, is described. The route is centered upon a late stage regioselective Diels-Alder reaction between two highly functionalized components, as

Full text of DOI:10.1021/ol300221e

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1484–1487
Total Synthesis of Mevashuntin
Christopher C. Nawrat and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7
2RD, United Kingdom
c.j.moody@nottingham.ac.uk
Received January 27, 2012
ABSTRACT
The total synthesis of (()-mevashuntin, a structurally unique naturally occurring pyrano-naphthoquinone-thiazolone, is described. The route is
centered upon a late stage regioselective DielsÀAlder reaction between two highly functionalized components, as well as an improved protocol
for the one pot synthesis of benzothiazolones from ortho-bromoaryl isothiocyanates. The strategy results in a highly convergent route, providing
access to the natural product in 11 steps from 3-(4-methoxyphenoxy)propanol and confirming its relative stereochemistry.
The DielsÀAlder reaction employing quinones as die-
nophiles has been an important tactic in the total synthesis
of natural products for some 60 years, since Woodward’s
early work on cholesterol,1 and has subsequently been
applied in the construction of an impressive range of
alkaloids, steroids and polyketides. Well known examples
include reserpine,2,3 ibogamine,4 tetrodotoxin,5,6 giberellic
acid,7,8 and myrocin C.9 In particular, the reaction is
uniquely suited to the construction of naphthoquinone
containing natural products, of which many commercially
and biologically important examples exist.10 Surprisingly,
the majority of naphthoquinone syntheses based around
this DielsÀAlder strategy have employed relatively simple
dienes and benzoquinones. However, for more complex
targets, this typically necessitates a large number of steps
after the cycloaddition reaction, and often reduction and
protection of the sensitive quinone, making the routes to
these compounds linear and lengthy. For this reason, a much
more appealing strategy for polycyclic naphthoquinone con-
taining natural products would be a convergent, late-stage
DielsÀAlder reaction involving diene and quinone compo-
nents containing as much functionality as possible.11À13
(1) Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.;
McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223–4251.
(2) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead,
R. W. J. Am. Chem. Soc. 1956, 78, 2023–2025.
(3) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead,
R. W. Tetrahedron 1958, 2, 1–57.
(11) Pearlman, B. A.; McNamara, J. M.; Hasan, I.; Hatakeyama, S.;
Sekizaki, H.; Kishi, Y. J. Am. Chem. Soc. 1981, 103, 4248–4251.
(12) Smith, A. B.; Sestelo, J. P.; Dormer, P. G. J. Am. Chem. Soc.
1995, 117, 10755–10756.
(13) Choshi, T.; Kumemura, T.; Nobuhiro, J.; Hibino, S. Tetrahe-
dron Lett. 2008, 49, 3725–3728.
(14) McErlean, C. S. P.; Moody, C. J. J. Org. Chem. 2007, 72, 10298–
10301.
(4) Sallay, S. I. J. Am. Chem. Soc. 1967, 89, 6762–6763.
(5) Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.;
Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94,
9217–9219.
(15) McErlean, C. S. P.; Sperry, J.; Blake, A. J.; Moody, C. J.
Tetrahedron 2007, 63, 10963–10970.
(16) Coombes, C. L.; Moody, C. J. J. Org. Chem. 2008, 73, 6758–
6762.
(17) Guillonneau, L.; Taddei, D.; Moody, C. J. Org. Lett. 2008, 10,
4505–4508.
(6) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.;
Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94,
9219–9221.
(7) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.;
Gopalan, B.; Larsen, S. D.; Siret, P.; Gras, J. L. J. Am. Chem. Soc. 1978,
100, 8034–8036.
(8) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.;
Keck, G. E.; Gras, J. L. J. Am. Chem. Soc. 1978, 100, 8031–8034.
(9) Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am.
Chem. Soc. 1994, 116, 11213–11228.
(18) Padwal, J.; Lewis, W.; Moody, C. J. Org. Biomol. Chem. 2011, 9,
3484–3493.
(19) Smith, M. J.; Nawrat, C. C.; Moody, C. J. Org. Lett. 2011, 13,
3396–3398.
(10) Thomson, R. H. Naturally Occurring Quinones IV. Recent
advances, 4th ed.; Blackie: London, 1997.
(20) Padwal, J.; Lewis, W.; Moody, C. J. J. Org. Chem. 2011, 76,
8082–8087.
r
10.1021/ol300221e
Published on Web 02/27/2012
2012 American Chemical Society

Recently, as part of our ongoing studies on the synthe-
sis of naturally occurring quinones,14À20 we became
interested in the structurally unique pyranonaphthoquinone
mevashuntin, reported in 2005 by Shin-ya and co-workers
(Figure 1).21 The highly unusual benzothiazolonequinone
motif of 1 was appealing both as an unsolved problem in
heterocyclic chemistry and as a novel synthetic target.
The pyran 3 was chosen as a suitable diene, containing a
protected alcohol in place of the acid found in the natural
product. It was anticipated, in accordance with pioneering
work by Brassard,23À26 as well as related literature pre-
cedent,27,28 that the bromine atom present in 4 would
confer high levels of regioselectivity in the DielsÀAlder
reaction, as well as aid in aromatization of the initial
cycloadduct. Although we have recently reported the use
of protected aminobenzoquinones in DielsÀAlder reac-
tions toward aminonaphthoquinone natural products,29
model studies on the construction of thiazolones from such
precursors were unpromising, and the use of this tactic
would result in a more linear sequence.
For the preparation of the benzothiazolonequinone, a
modified form of the copper catalyzed cyclization of ortho-
bromoaryl thiocarbamates, generated in situ from the
corresponding isothiocyanates, reported by Patel was
used.30 The substrate for this reaction was prepared by
bromination of 2,5-dimethoxyaniline, followed by conver-
sion into the isothiocyanate 6 by heating with thiocarbo-
nyldiimidazole (TCDI) (Scheme 2). In the original
procedure, after initial cyclization to the 2-ethoxyben-
zothiazole had occurred, trifluoroacetic acid was added
to the reaction mixture to effect hydrolysis to the desired
benzothiazolone 7 in 56À68% yield. During optimization
of this step it was found that once the starting isothiocya-
nate had been consumed, concentration of the reaction
mixture, followed by addition of 6 M hydrochloric acid to
the residue and heating gave the desired product 7 in
almost quantitative yield. Furthermore, under these con-
ditions the product could be isolated by simple filtration
and did not require additional purification. N-Methylation
and oxidation to the quinone were then carried out to
give the required dienophile 4 in excellent yield. Although
the overall yield from dimethoxyaniline is depressed by
the poor yield obtained in the initial bromination step, the
inexpensive nature of the starting material meant that
batches of more than 10 g of the benzoquinonethiazolone
could be routinely obtained, requiring only two purifica-
tion steps over the entire sequence.
Figure 1. Mevashuntin 1 and the structurally related cdc25
inhibitor 2.
However, the unknown relative and absolute stereo-
chemistry of the pyran substituents in mevashuntin, and
uncertainty in the relative position of the sulfur and
nitrogen atoms, as the structure was assigned predomi-
nantly by NMR methods, demanded the use of a flexible
approach in which both halves of the molecule could be
easily varied. This, in addition to the benefits outlined
above, suggested the use of a late-stage DielsÀAlder stra-
tegy. Comparison of the NMR data reported for 1with those
available for the structurally related cdc25 inhibitor 2,22
the cis-arrangement of pyran substituents being con-
firmed by NOE experiments (such experiments were
not carried out on the natural product 1), led us to target
the cis-diastereomer of the natural product. Thus, applica-
tion of the DielsÀAlder disconnection to cis-1 gave the
pyran-containing silyl ketene acetal 3 and the bromoben-
zoquinone thiazolone 4 as the diene and dienophile com-
ponents respectively (Scheme 1).
For the preparation of the diene component, the route
began from the known 3-(4-methoxyphenoxy)propanol
9.31 This was converted directly into the R,β-unsaturated
(21) Shin-ya, K.; Umeda, K.; Chijiwa, S.; Furihata, K.; Hayakawa,
Y.; Seto, H. Tetrahedron Lett. 2005, 46, 1273–1276.
(22) Kulanthaievel, P.; Perun, T. J.; Belvo, M. D.; Strobel, R. J.; Paul,
D. C.; Williams, D. C. J. Antibiot. 1999, 52, 256–262.
(23) Banville, J.; Grandmai, Jl; Lang, G.; Brassard, P. Can. J. Chem.
1974, 52, 80–87.
Scheme 1. Late Stage DielsÀAlder Disconnection
(24) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 4911–4914.
(25) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455–3464.
(26) Boisvert, L.; Brassard, P. J. Org. Chem. 1988, 53, 4052–4059.
(27) Botha, M. E.; Giles, R. G. F.; Yorke, S. C. J. Chem. Soc., Perkin
Trans. 1 1991, 85–88.
(28) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.;
Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens,
J. E. J. Org. Chem. 1991, 56, 91–95.
(29) Nawrat, C. C.; Lewis, W.; Moody, C. J. J. Org. Chem. 2011, 76,
7872–7881.
(30) Murru, S.; Mondal, P.; Yella, R.; Patel, B. K. Eur. J. Org. Chem.
2009, 2009, 5406–5413.
(31) Murphy, J. A.; Schoenebeck, F.; Findlay, N. J.; Thomson,
D. W.; Zhou, S.-z.; Garnier, J. J. Am. Chem. Soc. 2009, 131, 6475–6479.
Org. Lett., Vol. 14, No. 6, 2012
1485

Scheme 2. Preparation of the Dienophile Component 4
Scheme 3. Preparation of the Diene 3
ester using the one pot tandem oxidative process reported
by Taylor.32,33 Hydrolysis of the ethyl ester gave the
corresponding acid in good yield, which was subsequently
converted into the acid chloride 10 and used directly
for pyranone formation with the β-ketoester 11, readily
prepared by alkylation of the dianion of methyl aceto-
acetate.34 Pyranone 12 was then subjected to hydrogena-
tion at 200 psi over palladium-on-carbon to give the
expected saturated compound. Conversion of the β-ketoe-
ster into the required acrylate was then carried out accord-
ing to a literature procedure.35 Thus, the ketone was first
converted into the enol phosphate 13 using diethyl chlor-
ophosphate and sodium hydride, and this was then dis-
placed by treatment with excess lithium dimethylcuprate in
ether to give 14 in good yield. At this point, the syn
stereochemistry of the two pyran substituents, a conse-
quence of the hydrogenation, was confirmed by NOESY
experiments. Finally, acrylate 14 was treated with TMSCl
and LDA to give the required diene component 3(Scheme 3).
With both diene and dienophile now in hand it was time
to explore the crucial DielsÀAlder reaction to unite them.
It was found that simply stirring quinone 4 (1 equiv) with a
slight excess of diene 3 and triethylamine (1 equiv) in
dichloromethane at 0 °C gave a good yield of the desired
tetracycle 15 as a single regioisomer. Deprotection of the
PMP ether using standard conditions (CAN in various
solvents) gave only traces of the desired product, despite
the fact that deprotection of the diene precursor 14 could
be carried out in excellent yield. Eventually, it was found
that treatment of 15 with excess AgO and HNO3 in
dioxane effected rapid deprotection in excellent yield.36
Although these conditions have been extensively used in
the preparation of quinones from hydroquinone ethers, we
believe this is the first report of their application to the
removal of oxidatively labile protecting groups. Finally,
oxidation directly to the acid using Jones’ reagent in ace-
tone gave 1 in good yield (Scheme 4).
Interestingly, during characterization of the synthetic
material it was found that the NMR spectroscopic data
(both 1H and 13C) was highly concentration dependent and
this made comparison with the reported data for the
natural product difficult. This effect is believed to originate
from the two different modes of hydrogen bonding avail-
able to 1 as well as the intermolecular dimeric hydrogen
bonding typically displayed by carboxylic acids, intramo-
lecular hydrogen bonding between the acid and pyran oxygen
is also possible. Presumably, the former predominates in
more concentrated solutions where as the latter mode is more
(32) Blackburn, L.; Wei, X. D.; Taylor, R. J. K. Chem. Commun.
1999, 1337–1338.
(33) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res.
2005, 38, 851–869.
(34) Gelin, S.; Gelin, R. Bull. Soc. Chim. Fr. 1968, 288–298.
(35) Blouin, M.; Beland, M. C.; Brassard, P. J. Org. Chem. 1990, 55,
1466–1471.
(36) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227–
231.
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Org. Lett., Vol. 14, No. 6, 2012

out. Thus, treatment with excess trimethylsilyldiazomethane
gave the methyl ester 16 in excellent yield, and the data
obtained were found to match very closely those reported
(see Supporting Information). The syn nature of the pyran
substituents in 16 was confirmed though the use of NOESY
NMR experiments that showed a strong interaction between
the two methine signals confirming, for the first time, the
relative stereochemistry of the natural product.
Scheme 4. DielsÀAlder Reaction and Completion of the
Synthesis of (()-Mevashuntin 1
In conclusion, we have developed a convergent and
scalable route to mevashuntin. Key steps include the
copper-catalyzed formation of a benzothiazolone and the
successful implementation of a late-stage regioselective
DielsÀAlder strategy to unite two highly functionalized
fragments. This allowed construction of the natural pro-
duct with minimal use of protecting group chemistry
and without recourse to reduction and protection of the
quinone moiety. The synthesis confirms both the highly
unusual structure of the natural product and its relative
stereochemistry.
Acknowledgment. We thank the EPSRC for funding
(DTA studentship to C.C.N.).
Supporting Information Available. Full experimental
1
details and copies of H and 13C NMR spectra for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
favorable in very dilute solutions. Fortunately, during the
structural elucidation of 1the corresponding methyl ester was
also prepared and characterized, and in order to facilitate
comparison, methylation of the synthetic acid was carried
The authors declare no competing financial interest.
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