A short total synthesis of aureothin and N-acetylaureothamine

Article abstract of DOI:10.1021/ol047594l

(Chemical Equation Presented) The total synthesis of the nitrophenyl pyrones, (±)-aureothin and (±)-N-acetylaureothamine, starting from known 2-ethyl-6-methoxy-3,5-dimethyl-4H-pyran-4-one are described. The key steps involved in the synthesis are the cons

Full text of DOI:10.1021/ol047594l

ORGANIC
LETTERS
2005
Vol. 7, No. 4
641-644
A Short Total Synthesis of Aureothin
and N-Acetylaureothamine
Mikkel F. Jacobsen, John E. Moses, Robert M. Adlington, and Jack E. Baldwin*
Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford, OX1 3TA, United Kingdom
jack.baldwin@chem.ox.ac.uk
Received November 23, 2004
ABSTRACT
The total synthesis of the nitrophenyl pyrones, (±)-aureothin and (±)-N-acetylaureothamine, starting from known 2-ethyl-6-methoxy-3,5-dimethyl-
4H-pyran-4-one are described. The key steps involved in the synthesis are the construction of the tetrahydrofuran motif using a palladium-
catalyzed cycloaddition and the ruthenium-catalyzed cross-metathesis reaction of an alkenyl boronic ester.
Aureothin 1 and N-acetylaureothamine 2 are two unusual
natural products, both featuring a rare nitroaryl group and a
highly substituted conjugate diene system. N-Acetyl-
aureothamine 2, isolated from Streptomyces netropsis, has
been shown to be a highly selective and potent agent against
Helicobacter pylori, a common cause of chronic gastritis.1
Aureothin 1 has been found in the mycelia of several
actinomycetes, and possesses antitumor, antifungal, and
pesticidal activities.2 Recently, studies on the biosynthesis
of 1 have revealed that an unprecedented type of N-oxy-
genase, AurF, is responsible for the oxidation of p-ami-
nobenzoate to the corresponding nitro compound, which
serves as a starter unit for the polyketide synthase resulting
in the formation of 1.3 Furthermore, a multifunctional
cytochrome P450 monooxygenase, AurH, catalyzes the
formation of the exomethylene tetrahydrofuran ring of 1.4
Both compounds are members of a small family of nitro-
phenyl pyrones featuring a tetrahydrofuran-derived motif
(Figure 1).5
Our continued interest in polypropionate metabolites, and
in particular their biomimetic synthesis, has driven us to
search for new and efficient methods for polyene-pyrone
synthesis.6 Herein we report short total syntheses of
(()-aureothin 1 and (()-N-acetylaureothamine 2.7,8
Our retrosynthetic analysis of 1 and 2 is outlined in
Scheme 1. We envisaged that the congested diene system
could be constructed via a sequence of trans-selective Suzuki
(3) He, J.; Hertweck, C. J. Am. Chem. Soc. 2004, 126, 3694.
(4) He, J.; Mu¨ller, M.; Hertweck, C. J. Am. Chem. Soc. 2004, 126, 16742.
(5) Isoaureothin: Ishibashi, Y.; Nishiyama, S.; Shizuri, Y.; Yamamura,
S. Tetrahedron Lett. 1992, 33, 521 and references therein. 3: Kakinuma,
K.; Hanson, C. A.; Rinehart, K. L. Tetrahedron 1976, 32, 217. Luteothin:
Washizo, F.; Umezawa, H.; Sugiyama, N. J. Antibiot. 1954, 7, 60. 4 and 5:
(a) Kurosawa, K.; Takahashi, K.; Tsuda, E. J. Antibiot. 2001, 54, 541. (b)
Takahashi, K.; Tsuda, E.; Kurosawa, K. J. Antibiot. 2001, 54, 548. (c)
Kurosawa, K.; Takahashi, K.; Fujise, N.; Yamashita, Y.; Washida, N.;
Tsuda, E. J. Antibiot. 2002, 55, 71. (d) Lim, Y.-H.; Parker, K. A. J. Am.
Chem. Soc. 2004, 126, 15968.
(6) (a) Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.;
Cowley, A. R. Org. Lett. 2002, 21, 3731. (b) Moses, J. E.; Baldwin, J. E.;
Bru¨ckner, S.; Eade, S. J.; Adlington, R. M. Org. Biomol. Chem. 2003, 1,
3670. (c) Moses, J. E.; Baldwin, J. E.; Adlington, R. M. Tetrahedron Lett.
2004, 45, 6447.
(1) Taniguchi, M.; Watanabe, M.; Nagai, K.; Suzumura, K.-I.; Suzuki,
K.-I.; Tanaka, A. J. Antibiot. 2000, 53, 844.
(2) (a) Hirata, Y.; Nakata, H.; Yamada, K.; Okuhara, K.; Naito, T.
Tetrahedron 1961, 14, 252-274. (b) Oishi, H.; Hosogawa, T.; Okutomi,
T.; Suzuki, K.; Ando, K. Agric. Biol. Chem. 1969, 33, 1790. (c) Schwartz,
J. L.; Tishler, M.; Arison, B. H.; Shafer, H. M.; Omura, S. J. Antibiot.
1976, 29, 236. (d) Maeda, K. J. Antibiot. 1953, 6, 137.
(7) Although 1 and 2 exist as single enantiomers in Nature, it has been
reported that 1 is very prone to racemization. Thus, racemization of 1 occurs
within 24 h in CDCl3 at room temperature, see: Nair, M. G.; Chandra, A.;
Thorogod, D. L. Pestic. Sci. 1995, 43, 361.
(8) A previous total synthesis provided (-)-1 with low ee in only 0.01%
yield from 9 in 13 steps, see: Ishibashi, Y.; Ohba, S.; Nishiyama, S.;
Yamamura, S. Bull. Chem. Soc. Jpn. 1995, 68, 3643.
10.1021/ol047594l CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/21/2005

Scheme 2. Synthesis of Tetrahydrofuran Fragment 18a
Figure 1. Family of nitroaryl-substituted γ-pyrone metabolites.
Scheme 1. Retrosynthesis of (()-1 and (()-2
yielded the rather unstable olefin 12.10 Further oxidation of
12 furnished aldehyde 9 in excellent overall yield using the
Lemieux-Johnson protocol.11 This short route to 9 consti-
tutes a considerable improvement compared to the previously
published route,12 thus allowing easy access to this important
building block.13
Next, we turned our attention to the construction of the
tetrahydrofuran framework of 1 and 2. We found to our
delight that the palladium-bound TMM complex generated
from 13 and Pd(PPh3)4 underwent a facile reaction with 9
in the presence of In(acac)2 as cocatalyst affording an
excellent yield (93%) of 8.14,15 The recent reports of the cross
metathesis of alkenyl boronic esters with 1,1-disubstituted
coupling of dibromide 6 with boronic ester 7 and subsequent
stereospecific methylation. We believed that cross metathesis
(CM) could be used for the construction of boronic ester 7
from alkene 8, while the tetrahydrofuran ring in 8 could
conceivably be obtained by subjecting 9 to [3+2] cycload-
dition with a palladium trimethylenemethane complex. This
led back to the known aldehyde 9, which we prepared from
readily accessible ethyl pyrone 10.9
(10) Oxidation with H2O2/NaHCO3 instead afforded a lower yield (55%)
of 12.
(11) Rappo, R.; Allen, D. S., Jr.; Lemieux, U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(12) (a) Suzuki, E.; Sekizaki, H.; Inoue, S. J. Chem. Res. 1977, 200,
2273. (b) Suzuki, E.; Hamajima, R.; Inoue, S. Synth. Commun. 1975, 192.
(13) Moses, J. E. D. Phil Thesis, University of Oxford, Oxford, UK,
2004.
(14) (a) Trost, B. M.; Sharma, S.; Schmidt, T. J. Am. Chem. Soc. 1992,
114, 7903. (b) Trost, B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985, 107,
1778.
Preparation of aldehyde 9 from 10 began by converting
10 to the corresponding phenylselenyl compound 11 via its
potassium enolate. Subsequent oxidation of 11 using NaIO4
(9) Hatakeyama, S.; Ochi, N.; Takano, S. Chem. Pharm. Bull. 1993, 41,
1358.
(15) The use of the 2-[(tributylstannyl)methyl]-2-propen-1-yl acetate/
Pd(OAc)2 + PPh3 system instead provided a comparable yield (88%) of 8.
642
Org. Lett., Vol. 7, No. 4, 2005

unexpected alkyne 20, due to dehydrobromination of 19
and/or 21. The use of Tl2CO3 was not successful either, as
it gave further rise to the formation of the dialkylated product
22 in addition to 20 and 21. Gratifyingly, the use of TlOEt
afforded exclusively the desired intermediate 21 in a satisfy-
ing 72% yield (42% isolated yield of (Z)-21).20,21 The
configuration of the Z-isomer was confirmed by an NOESY
experiment.
Scheme 3. Influence of Base on the Suzuki-Coupling of Boronic
Ester 18 with Dibromide 19a-c
The palladium-catalyzed methylation of alkenyl halides
with Grignard or zinc reagents can be problematic due to
configurational instability of the intermediate palladium
species leading to products of stereoinversion.22,23 To ac-
complish the stereospecific conversion of (Z)-21 to (()-1,
we first attempted the recently reported palladium-catalyzed
Suzuki-Miyaura coupling of trimethylboroxine (Me3B3O3,
Cs2CO3, Pd(PPh3)4, aq DMF, 80 °C).24 Disappointingly, this
led to extensive decomposition of the starting material.
Instead, we were pleased to find that the exposure of (Z)-21
to the Negishi-type coupling with Me2Zn and catalytic
amounts of Pd(tBu3P)2 gave the light-sensitive (()-aureothin
1 with complete retention of the required E-stereochemistry
and in excellent yield (Scheme 4).23 The (()-aureothin 1
Scheme 4. Stereospecific Methylation of (Z)-21 and
Conversion to (()-1 and (()-2
a The ratio of 20, 21, and 22 was determined by 1H NMR of the
b
crude product. 20 and 21 were obtained as 1:1.2 E/Z mixtures of
c
isomers. 22 was obtained as a mixture of isomers.
olefins seemed an attractive approach to the otherwise not
easily accessible boronic ester 18.16
Initially, the CM reaction of 8 with commercially available
2-vinyl-1,3-dioxolane 14 and catalyst 15 was attempted,
which gave a good yield of the CM product 16. Having
established the viability of 8 in CM reactions, we exposed 8
to the reaction with 15 and alkenyl pinacol boronate 1716 to
furnish 18 in almost quantitative yield, albeit with low E/Z-
selectivity.
With the key cross-coupling partner 18 at hand, we set
out to examine the Suzuki coupling with the known dibro-
mide 1917 that was prepared in high yield (87%) from
p-nitrobenzaldehyde (Scheme 3). Suzuki couplings of alkenyl
dibromides are known to occur with high trans-selectivity;18
however, the choice of base is sometimes crucial in order to
obtain only the monoalkylated product.19 We found that the
use of NaOH as base was plagued by the formation of the
obtained had identical spectral data (1H NMR, 13C NMR,
and IR) to those previously reported for (+)-aureothin.8
A suitable reduction/acetylation sequence of 1 was all that
remained for the synthesis of 2. We found that neither a
(16) (a) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031. (b)
Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.;
Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58.
(17) Shastin, A. V.; Korotchenko, V. N.; Nenajdenko, V. G.; Balenkova,
E. S. Synthesis 2001, 14, 2081.
(18) (a) Rousch, W. R.; Riva, R. J. Org. Chem. 1988, 53, 710. (b) Rousch,
W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B. J. Org. Chem. 1997, 62,
8708.
(20) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush,
W. R. Org. Lett. 2000, 2, 2691.
(21) The E- and Z-isomers of 21 were easily separated by column
chromatography.
(22) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E.-I. J. Am. Chem. Soc. 2003,
125, 13636.
(23) Shi, J.-C.; Zeng, X.; Negishi, E.-I. Org. Lett. 2003, 11, 1825.
(24) Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle, M.
Tetrahedron Lett. 2000, 41, 6237.
(19) Starr, J. T.; Evans, D. A. J. Am. Chem. Soc. 2003, 125, 1351.
Org. Lett., Vol. 7, No. 4, 2005
643

SnCl2-mediated reduction nor the ultrasound-assisted reduc-
tion of (()-1 with Sm/NH4Cl25 was compatible with our
substrate. On the other hand, by employing Zn/NH4Cl
instead, a very clean transformation followed yielding 23 in
a 98% yield. Acetylation with AcCl afforded pure (()-N-
acetylaureothamine 2, identical by spectral analysis (1H
NMR, 13C NMR, and IR) with that previously reported for
(+)-2.1
developed synthetic methodology for the synthesis of spec-
tinabilin 3, and its subsequent biomimetic conversion to 4
and 5.
Acknowledgment. We thank Roche for funding to M.F.J.
and EPSRC for funding to J.E.M. We thank Dr. B. Odell
for NMR assistance.
In conclusion, we have developed short total syntheses of
(()-aureothin 1 and (()-N-acetylaureothamine 2 affording
the natural products in 23% and 18% overall yield from
known 10, respectively. Further efforts in our laboratories
are now being directed toward the implementation of our
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1, 2, 8-9,
1
11-12, 18-19, 21, and 23 and H NMR and 13C NMR
spectra of (()-1 and (()-2. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) Basu, M. K.; Becker, F. F.; Banik, B. K. Tetrahedron Lett. 2000,
41, 5603.
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