The total synthesis of (-)-aurafuron A

Article abstract of DOI:10.1021/ol3011387

The first total synthesis of (-)-aurafuron A is presented. It features a Suzuki cross-coupling reaction and a high yielding anionic aldol addition as central carbon skeleton building reactions. The synthesis confirms the proposed structure including its configuration and allows for detailed SAR studies.

Full text of DOI:10.1021/ol3011387

ORGANIC
LETTERS
2
012
Vol. 14, No. 12
064–3067
The Total Synthesis of (À)-Aurafuron A
3
Olaf Hartmann and Markus Kalesse*
Institut f u€ r Organische Chemie and Centre of Biomolecular Drug Research (BMWZ),
Leibniz Universit a€ t Hannover, Schneiderberg 1B, 30167 Hannover, Germany
markus.kalesse@oci.uni-hannover.de
Received April 27, 2012
ABSTRACT
The first total synthesis of (À)-aurafuron A is presented. It features a Suzuki cross-coupling reaction and a high yielding anionic aldol addition as
central carbon skeleton building reactions. The synthesis confirms the proposed structure including its configuration and allows for detailed SAR
studies.
Myxobacteria are a rich source of biologically active
natural products exhibiting a variety of variations in their
shown to have moderate antifungal and antibiotic (MIC
À1
for 1: 6.3 μg mL , mucor hiemalis DSM 6566), as well as
1
2
À1
backbone. In particular the spirangiens and aurafurons
1 and 2, Figure 1) are of special interest since they address
novel yet unidentified cellular targets.
cytotoxic properties (IC50 for 1: 4 μg mL , mouse
(
fibroblast cell line L929). Aurafuron A (1) contains three
defined stereocenters, one racemic hemiacetalic carbon
incorporated in the unusual furanone core and two
E- and one Z-configured double bonds. The characteristic
4
(2H)-furanone core as 2-hemiacetal can be found in
3
other natural products such as AS-183 from the fungus
5
6
Scedosporium, polypropionates from the marine mollusc
,7
8
Siphonaria or the actinofuranones isolated from actino-
mycetes MAR4, none of which have been made by total
synthesis so far. While AS-183 was shown to inhibit the
acyl-CoA cholesterol acyltransferase (ACAT) of rabbit
liver microsomes, the aurafurons’ mode of action still
remains unknown.
The biosynthesis consists of several unusual features
such as an iterative use of one PKS module and a post-
PKS BaeyerÀVilliger-type oxidation to build up the fur-
Figure 1. Structures of the aurafurons. Aurafuron B exists as
8
,9-E and 8,9-Z isomers.
9
anone core. Additionally, it remains undetermined
whether aurafuron B is a self-contained natural product
or an artifact derived through elimination of aurafuron A
The aurafurones were isolated by H o€ fle and co-workers
from the myxobacterium Stigmatella aurantiaca DW4/3-1,
and their structure was elucidated by a combination of
3
mass spectrometry and NMR spectroscopy. They were
(
4) Haug, T. T.; Kirsch, S. F. Targets in Heterocyclic Systems:
Chemistry and Properties 2009, 13, 57.
5) Kuroda, K.; Yoshida, M.; Uosaki, Y.; Ando, K.; Kawamoto, I.;
(
Oishi, E.; Onuma, H.; Yamada, K.; Matsuda, Y. J. Antibiot. 1993, 46,
1196.
(6) Paul, M. C.; Zubia, E.; Ortega, M. J.; Salv ꢀa , J. Tetrahedron 1997,
53, 2303.
(7) Bromley, C. L.; Popplewell, W. L.; Pinchuck, S. C.; Hodgson,
A. N.; Davies-Coleman, M. T. J. Nat. Prod. 2012, 75, 497.
(8) Cho, J. Y.; Kwon, H. C.; Williams, P. G.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. J. Nat. Prod. 2006, 69, 425.
(9) Frank, B.; Wenzel, S. C.; Bode, H. B.; Scharfe, M.; Bl o€ cker, H.;
M u€ ller, R. J. Mol. Biol. 2007, 374, 24.
(
(
1) Weissman, K. J.; M u€ ller, R. Nat. Prod. Rep. 2010, 27, 1276.
2) (a) Niggemann, J.; Bedorf, N.; Fl o€ rke, U.; Steinmetz, H.; Gerth,
K.; Reichenbach, H.; H o€ fle, G. Eur. J. Org. Chem. 2005, 5013.
b) Lorenz, M.; Bluhm, N.; Kalesse, M. Synthesis 2009, 3061. (c) Lorenz,
M.; Kalesse, M. Org. Lett. 2008, 10, 4371. (d) Lorenz, M.; Kalesse, M.
Tetrahedron Lett. 2007, 48, 2905. (e) Paterson, I.; Findlay, A. D.; Noti,
C. Chem. Commun. 2008, 6408.
(
(
3) Kunze, B.; Reichenbach, H.; M u€ ller, R.; H o€ fle, G. J. Antibiot.
2
005, 58, 244.
1
0.1021/ol3011387 r 2012 American Chemical Society
Published on Web 05/25/2012

during the isolation procedure. With this state of knowl-
edge in mind, we were aware that incorporation of the
furanone through an aldol process would require special
attention in order to avoid elimination to the correspond-
ing tetraene.
iodide 5 (vide infra). As coupling yields were poor, 10 was
further functionalized in a stereoselective (7:1 E/Z) cross
1
metathesis using Grubbs’ second generation catalyst to
1
complete the synthesis of pinacol boronate 4.
Scheme 3. Synthesis of the C5ÀC9 Fragment 5
Scheme 1. Retrosynthetic Analysis
The synthesis of the central C5ÀC9 fragment 5 starts
from commercially available 3-butene-1-ol (11) which is
silylprotectedand ozonolyzedtogivealdehyde13(Scheme
3
). Attempts to enantioselectively add TMS acetylene
1
The retrosynthetic analysis of aurafuron A (1) sets in
from linear intermediate 3 (Scheme 1). Herein the C4ÀC5
bond was envisioned to be built up via an aldol reaction
between ethyl ketone 6 and an aldehyde generated at C5.
The C9ÀC10 connection on the other hand can be estab-
lished using a palladium catalyzed Suzuki reaction be-
tween vinyl iodide 5 and pinacol boronate 4.
2
using the method developed by Carreira resulted in poor
yields of about 15%, albeit in an enantiomeric excess of
92% (chiral GC). Alternatively, a sequence of lithium
TMS acetylide addition, Dess-Martin oxidation (Dess-
1
Martin periodinane, DMP), and Noyori reduction
was chosen to obtain the S-configured alcohol 14 in 68%
yield (three steps) and 98% ee. Several other methods for
enantioselective reduction appeared applicable but were
proven somewhat inferior with respect to conversion and
enantioselectivities. So, for example, Noyori’s BINAl-H
3
14
Scheme 2. Synthesis of Western Fragment 4
1
5
reduction shows no conversion, whereas Alpine borane
1
6
reduction yields 50% of the desired product with 84% ee.
Silyl ether protection and iododesilylation, followed by
selective primary TBS deprotection, furnishes iodoacetyl-
ene 17 in good yields.
The desired Z-configured vinyl iodide 5 is built up in a
diimide reduction utilizing ortho-nitrobenzene sulfonyl
1
hydrazide (NBSH) under basic conditions. As attempted
7
Heck reactions between terminal alkene 10 and vinyl
1
iodide 5 using Jeffery type conditions and variations
developed during our synthesis of ratjadon never ex-
ceeded yields of 31%, we changed the strategy to a Suzuki
reaction between pinacol boronate 4 and vinyl iodide 5.
8
Western fragment 4 is accessible in five steps from
commercially available propionaldehyde (7) (Scheme 2).
Aldol condensation via its piperidino enamine with iso-
valeraldehyde yields the E-configured R,β-unsaturated
aldehyde 8 in 60% yield. In this case the undesired
Z-isomer (7%) iseasilyseparatedbycolumnchromatogra-
phy. The key step in this route is the enantioselective
1
9
(12) (a) Sasaki, H.; Boyall, D.; Carreira, E. Helv. Chim. Acta 2001, 84,
64. (b) El-Sayed, E.; Anand, N.; Carreira, E. Org. Lett. 2001, 3, 3017.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
8
1
0
Brown crotyl boration to generate alcohol 9 in 55% yield
and higher than 95% dr and >95% ee, respectively
(
14) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285.
1
determined by H NMR and Mosher ester method).
(
15) Noyori, R. Pure Appl. Chem. 1981, 53, 2315.
(
Silylether protection furnishes the terminal alkene 10
which was subsequently used in Heck reactions with vinyl
(
16) Midland, M.; Graham, R. S. Org. Synth. Coll. Vol. 7 1990, 63,
5
7.
(17) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997,
2, 7507.
6
(18) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(19) (a) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.;
(
10) Brown, H. J.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(
11) For a similar example in the total synthesis of chlorotonil, see:
Kalesse, M. Angew. Chem., Int. Ed. 2000, 39, 4364. (b) Bhatt, U.;
Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem.
2001, 66, 1885.
Rahn, N.; Kalesse, M. Angew. Chem., Int. Ed. 2008, 47, 597 and
references therein.
Org. Lett., Vol. 14, No. 12, 2012
3065

Unfortunately, first attempts utilizing Pd(PPh ) (5 mol %)
3
those subsequent TES deprotection and oxidation at-
tempts proved to be fruitless in all orders due to stable
4
and diisopropylamine showed very low conversion and
isolated yields of only 17%. Motivated by reports from
Roush and co-workers during their synthesis of super-
2
hemiacetal formation and elimination issues.
2
As we were not able to circumvent these problems using
thisparticularroutewechangedtheC2protecting group to
one in the correct oxidation state and therefore chose to
2
0
11
stolide A and our synthesis of chlorotonil, we found
that also in this case the use of thallium salts was essential
to provide good yields of 68%. Subsequent Dess-
Martin oxidation sets the stage for further manipulations
2
3
introduce dithiane 6. Intensive optimization of the aldol
addition showed that already a slight surplus of base leads
to a considerable drop of conversion. Apparently, in those
cases the aldehyde is deprotonated by the excess of base
before it is able to react with the preformed lithium enolate
of ethyl ketone 6. Running the reaction accordingly and
employing a ratio of 2:2:1 (ketone/base/aldehyde), high
yields of 23 (85%) could be achieved (Scheme 5). Subse-
quent Dess-Martin oxidation proceeds slowly, but without
detectable formation of the corresponding sulfoxide.
(
Scheme 4).
Scheme 4. C9ÀC10 Bond Formation via Suzuki Coupling
Scheme 5. Completion of the Synthesis
With aldehyde 19 in hand, several endgame strategies
failed (Figure 2). First, attempts to utilize the C4 enolate of
ethyl ketone 20 in all cases led to C6ÀC7 elimination and
formation of a fully conjugated ketone.
The dithiane hydrolysis of 3 proved to be troublesome
and needed intensive elaboration. Several of the following
methods were tested and either led to decomposition
2
4
25
(buffered or unbuffered Stork’s reagent, NBS, visible
light/rose bengal ) or no conversion (Hg(ClO ) ,
2
6
27
2
31
4
2
8
29
30
HgCl2, DMP, IBX, benzene selenic anhydride ).
32
An attempted Pummerer type hydrolysis which employed
mCPBA, followed by Ac O and Et N, gave a complex
2
3
mixture. Finally, we were able to obtain the corresponding
furanone (24) under methylation conditions using large
(
22) Dunetz, J. R.; Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am.
Chem. Soc. 2008, 130, 16407.
23) Dithiane 6 is available in two steps from commercially available
-methyl 1,3-dithiane and propionic aldehyde. For details, see Support-
ing Information.
(
2
(24) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(25) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
(26) Epling, G. A.; Wang, Q. Synlett 1992, 335.
Figure 2. Endgame strategy.
(27) (a) Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull. 1978,
6, 3742. (b) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.;
McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama,
2
K.; Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191.
In a second approach we joined aldehyde 19 and lactate
(
28) Valiulin, R. A.; Halliburton, L. M.; Kutateladze, A. G. Org.
2
1
derived ethyl ketone 21 in an aldol addition. We envi-
sioned oxidizing the C2 and C5 alcohol functionalities at a
late stage to gain the desired triketone 22. Unfortunately,
Lett. 2007, 9, 4061.
(29) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575.
(
30) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077.
31) (a) Barton, D. H. R.; Cussans, N. J.; Ley, S. V. J. Chem. Soc.,
(
Chem. Comm 1977, 751. (b) Hanessian, S.; Focken, T.; Mi, X.; Oza, R.;
Chen, B.; Ritson, D.; Beaudegnies, R. J. Org. Chem. 2010, 75, 5601.
(32) Smith, A. B., III; Dorsey, B. D.; Visnick, M.; Maeda, T.;
Malamas, M. S. J. Am. Chem. Soc. 1986, 108, 3110.
(
20) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2008,
3, 9657.
21) For highly stereoselective aldol reactions with similar lactate
7
(
derived ethyl ketones, see: (a) Paterson, I.; Wallace, D. J.; Cowden, C. J.
Synthesis 1998, 639. (b) Denmark, S. E.; Pham, S. M. Org. Lett. 2001, 3,
(33) We could also obtain a corresponding furanone in a simplified
system which was generated by aldol reaction between dithiane 6 and
isovaleric aldehyde and subsequent DMP oxidation.
2201.
3
066
Org. Lett., Vol. 14, No. 12, 2012

35% on an 8 mg scale. As the yields dropped further upon
upscaling we decided to rely on the above-mentioned
methylation conditions. Global deprotection of 3 was
accomplished with a HFÀpyridine complex in THF with
extra pyridrine to furnish aurafuron A (1).
The spectroscopic data of synthetic aurafuron A match
3
those of the authentic material. Additionally, the optical
6
rotation of the synthetic material is in good agreement with
20
Figure 3. Comparison of spectroscopic data.
the authentic material (synthetic [R]
À36.7, c 0.06,
D
2
0
D
MeOH; authentic [R]
the structure as well as the proposed configurations of this
À40.5, MeOH) and thus confirms
3
3,34
excesses of methyl iodide
in refluxing aqueous aceto-
nitrile in 40% yield accompanied by some decomposition.
The open form of the lactol (22) was never observed. A
second mild method especially for the hydrolysis of double
bond containing dithianes such as 3 was found to be the
combination of silver nitrate and N-chlorosuccinimide
natural product (Figure 3).
Synthetic access to aurafuron A was established in a
longest linear sequence of 15 steps starting from commer-
cially available substances with a total yield of 2.3%.
Biological results will be reported in due course.
3
5
(
NCS). 24 could be isolated in a diminished yield of
Acknowledgment. Dr. Gerald Dr €a ger and Olena Mancuso
(Leibniz Universit €a t Hannover) are kindly acknowledged
for HPLC assistance.
(
34) (a) Kolb, H. C.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J.
J. Chem. Soc., Perkin Trans. 1 1992, 2735. (b) Kim, H.; Baker, J. B.; Lee,
S.-U.; Park, Y.; Bolduc, K. L.; Park, H.-B.; Dickens, M. G.; Lee, D.-S.;
Kim, Y.; Kim, S. H.; Hong, J. J. Am. Chem. Soc. 2009, 131, 3192.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
35) (a) Gr o€ bel, B.-T.; Seebach, D. Synthesis 1977, 357 and references
therein. (b) Trost, B. M.; Grese, T. A. J. Org. Chem. 1992, 57, 686.
36) In our case COSY experiments revealed the C8 proton to have
chemical shifts of 5.31/5.34 ppm, whereas the reported values are 6.36/
(
1
6.38 ppm and by that differ about 1 ppm. As an authentic H NMR
spectrum is in accordance with the spectrum of the synthetic material,
the typo was confirmed by G. H o€ fle (personal correspondence).
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
3067