A concise synthetic approach to the sorbicillactones: Total synthesis of sorbicillactone A and 9-epi-sorbicillactone A

Article abstract of DOI:10.1021/ol201211f

A concise (12 step) total synthesis of sorbicillactone A and 9-epi-sorbicillactone A is reported. Unlike typical routes to the sorbicillinoids, this strategy does not start from sorbicillin and allows for the production of the bicyclic core on a multigram scale. The intramolecular conjugate addition of a tethered malonate serves as an effective means of introducing the lactone ring and provides a synthetic handle for installing the amide nitrogen.

Full text of DOI:10.1021/ol201211f

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4486–4489
A Concise Synthetic Approach to
the Sorbicillactones: Total
Synthesis of Sorbicillactone A
and 9-epi-Sorbicillactone A
Kelly A. Volp, Diane M. Johnson, and Andrew M. Harned*
Department of Chemistry, University of Minnesota;Twin Cities, 207 Pleasant Street SE,
Minneapolis, Minnesota 55455, United States
harned@umn.edu
Received May 6, 2011
ABSTRACT
A concise (12 step) total synthesis of sorbicillactone A and 9-epi-sorbicillactone A is reported. Unlike typical routes to the sorbicillinoids, this
strategy does not start from sorbicillin and allows for the production of the bicyclic core on a multigram scale. The intramolecular conjugate
addition of a tethered malonate serves as an effective means of introducing the lactone ring and provides a synthetic handle for installing the
amide nitrogen.
The sorbicillinoid natural products are a family of
bioactive molecules that have been isolated from
fungal species found in both terrestrial and marine
environments.1 Various members of the family have de-
monstrated activity in radical scavenging, anticancer, and
tumor necrosis factor-R inhibition screens, among others.
Synthetic efforts toward these natural products have typi-
cally involved an initial oxidative dearomatization of
sorbicillin or a close derivative.2,3 This generates an
intermediate similar to sorbicillinol (1, Scheme 1) that is
poised for dimerization, conjugate addition, and other
diversification reactions.1 While these studies have con-
firmed many of the biosynthetic hypotheses4 concerning
these compounds, their reliance on sorbicillin as a starting
materiallimitsthenumberofanalogs thatcan be generated
for further structureꢀactivity relationship studies.
In 2003, Bringmann and co-workers reported the iso-
lation of sorbicillactones A (2) and B (3).5 Structurally,
these compounds are interesting as they are the first, and to
date only, sorbicillinoids containing an amino acid residue
(Scheme 1). This introduces synthetic challenges that are
not present in other members of the family. The biological
activity of these compounds is also quite interesting:
while 2 demonstrated selective antileukemia activity, the
(1) Review: Harned, A. M.; Volp, K. A. Manuscript submitted.
(2) (a) Barnes-Seeman, D.; Corey, E. J. Org. Lett. 1999, 1, 1503–1504.
(b) Pettus, L. H.; Van de Water, R. W.; Pettus, T. R. R. Org. Lett. 2001,
3, 905–908. (c) Nicolaou, K. C.; Jautelat, R.; Vassilikogiannakis, G.;
Baran, P. S.; Simonsen, K. B. Chem.;Eur. J. 1999, 5, 3651–3665. (d)
Nicolaou, K. C.; Vassilikogiannakis, G.; Simonsen, K. B.; Baran, P. S.;
Zhong, Y.-L.; Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. J. Am.
Chem. Soc. 2000, 122, 3071–3079. (e) Nicolaou, K. C.; Simonsen, K. B.;
Vassilikogiannakis, G.; Baran, P. S.; Vidali, V. P.; Pitsinos, E. N.;
Couladouros, E. A. Angew. Chem., Int. Ed. 1999, 38, 3555–3559. (f)
Hong, R.; Chen, Y.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 3478–
3481.
(4) (a) Abe, N.; Sugimoto, O.; Tanji, K.-i.; Hirota, A. J. Am. Chem.
Soc. 2000, 122, 12606–12607. (b) Abe, N.; Arakawa, T.; Yamamoto, K.;
Hirota, A. Biosci. Biotechnol. Biochem. 2002, 66, 2090–2099.
€
(5) (a) Bringmann, G.; Lang, G.; Muhlbacher, J.; Schaumann, K.;
€
€
Steffens, S.; Rytik, P. G.; Hentschel, U.; Morschhauser, J.; Muller,
W. E. G. Sorbicillactone A: A Structurally Unprecedented Bioactive
Novel-Type Alkaloid from a Sponge-Derived Fungus. In Sponges
(Porifera); M€uller, W. E. G., Ed.; Springer Verlag: Berlin, 2003; pp
231ꢀ253. (b) Bringmann, G.; Lang, G.; Gulder, T. A. M.; Tsuruta,
€
H.; Muhlbacher, J.; Maksimenka, K.; Steffens, S.; Schaumann, K.;
(3) For an alternative approach, see: Wood, J. L.; Thompson, B. D.;
€
€
Stohr, R.; Wiese, J.; Imhoff, J. F.; Perovic-Ottstadt, S.; Boreiko, O.;
€
Muller, W. E. G. Tetrahedron 2005, 61, 7252–7265.
Yusuff, N.; Pflum, D. A.; Matthaus, M. S. P. J. Am. Chem. Soc. 2001,
123, 2097–2098.
r
10.1021/ol201211f
Published on Web 07/29/2011
2011 American Chemical Society

seemingly minor change of removing the 20ꢀ30 double
bond was enough to render 3 inactive. Further investiga-
tions revealed that 2 also displayed activity in anti-HIV
and neuroprotection assays.5 We were intrigued by the bio-
logical properties displayed by 2 and set out to develop a
synthesis of this molecule that would allow for the facile
generation of analogs. In particular, we were interested in
further exploring the influence of the C10 and C100 side chain
structure on the biological activity. Herein, we report our
work on the total synthesis of sorbicillactone A. As will be
seen, this remarkably concise route can generate multigram
quantities of a key intermediate that will prove useful for
generating unnatural analogs for further biological studies.6
The synthesis of phenol 7 began with the formylation of
2-methylresorcinol (8, Scheme 3). Sequential selective
benzylation and methylation of the two hydroxyl groups
was followed by exhaustive hydrogenolysis to afford
phenol 7. Oxidative dearomatization proceeded smoothly
to give quinol 6. While the direct treatment of the phenol
with PhI(OAc)2 in aqueous acetonitrile could be used to
form the quinol, higher yields were realized by first con-
verting the phenol into the corresponding trimethylsilyl
ether.7
Scheme 3. Building the Sorbicillactone Corea
Scheme 1. Bringmann’s Proposed Biosynthetic Origin of the
Sorbicillactones5
In order to accomplish our goal, a route needed to be
devised that was not dependent on sorbicillin (Scheme 2).
Our plan was to install the C10 and C100 side chains at a late
stage through the use of a bicyclic intermediate similar to 4.
We envisioned forging the C6ꢀC9 bond through an intra-
molecular conjugate addition of dienone 5. Because of the
sensitivity of quinol derivatives to strong bases, the Michael
donor in 5 would need to be substituted in such a way as to
greatly increase the acidity of the R-carbon. Furthermore,
the activating substituent (“Z-group”) would also have to
function as a synthetic equivalent of an NH2 group. Based
on this strategy, phenol 7 was chosen as the starting material.
a For more details, see Supporting Information.
After investigating several options for acylating quinol
6, we determined that malonic acid monoesters were
uniquely suited to this task. A malonate side chain would
not only facilitate the construction of the C6ꢀC9 bond and
the installation of the C9 methyl group but also serve as a
masked amine that could be revealed through a Curtius
rearrangement sequence.
Scheme 2. Our Synthetic Strategy to Sorbicillactone A
To this end, the coupling of quinol 6 with mono-tert-
butyl malonate produced dienone 9. Initial work employed
conditions reported by Stork8 for coupling a tertiary
alcohol to a malonic ester using TFAA; however, we found
DCC/DMAP to be more practical for larger scale work.
Malonate 9 was then cyclized to bicyclic lactone 10 in the
presence of Cs2CO3.9 Although intermediate 10 could be
isolated, it was more convenient to add MeI to the reaction
mixture once the cyclization was complete. Initial work
with this sequence allowed us to isolate lactone 11a as a
single diastereomer directly from quinol 6 with only a
single purification.
(7) Felpin, F.-X. Tetrahedron Lett. 2007, 48, 409–412.
(8) Stork, G.; La Clair, J. J.; Spargo, P.; Nargund, R. P.; Totah, N.
J. Am. Chem. Soc. 1996, 118, 5304–5305.
(9) Nicolaou has reported a similar cyclization of an acetate with the
sorbyl chain present. See ref 2d.
(6) ForalargescalefermentationofsorbicillactoneA, see:Bringmann,
€
G.; Gulder, T. A. M.; Lang, G.; Schmitt, S.; Stohr, R.; Wiese, J.; Nagel,
K.; Imhoff, J. F. Mar. Drugs 2007, 5, 23–30.
Org. Lett., Vol. 13, No. 17, 2011
4487

Performing an NOE experiment allowed us to confirm
the cis-fused ring system. Unfortunately, we did not observe
an NOE between the C9 methyl group and the C5 methyl or
C6 proton, which would be expected with the desired diaste-
reomer (Figure 1). We then converted compound 11a into
amide 12,10 which afforded crystals suitable for X-ray anal-
ysis. This confirmed our suspicions that the C9 stereocenter in
11a was indeed epimeric to the natural material.
converted directly to the corresponding acyl azide.13 After
experimenting with several methods for effecting the Cur-
tius rearrangement, we determined that the optimal con-
ditions were to simply heat a THF solution of the azide in a
microwave reactor. Monitoring the reaction progress by
IR spectroscopy confirmed the disappearance of the azide
and the formation of the isocyanate. Hydrolysis was then
followed by in situ acylation with fumarate 14 to provide
amide 13.
Scheme 4. Synthesis of 9-epi-Sorbicillactone Aa
Figure 1. Observed NOEs (red lines) for the two diastereomers
of 11 and X-ray of 12.
Fortunately, when the conversion of 6 to 11 was run on a
larger scale, we were able to isolate a minor component that
we identified as diastereomer 11b.11 Gratifyingly, this
compound did reveal an NOE interaction between the C9
methyl and the C6 proton. Although the diastereomeric
ratio is unfavorable,12 the concise and high-yielding route
to this key intermediate has allowed us to perform the
conversion of 6 to 11 on a multigram scale. In doing so, we
have been able to isolate over 1 g of 11b. Additionally,
diastereomer 11a proved to be a useful intermediate for
developing the remaining synthetic steps and will provide
access to 9-epi-sorbicillactone analogs, allowing us to com-
pare their biological activity to the natural diastereomers.
The tert-butyl ester in 11a was cleaved with TFA
(Scheme 4), and the resulting carboxylic acid was
a For more details, see Supporting Information.
With amide 13 in hand, the remaining hurdle was the
installation of the C10 side chain. This task proved to be
more challenging than initially anticipated. Unfortunately,
employing standard reaction conditions (e.g., LDA or
LiHMDS, ꢀ78 °C; acid chloride, aldehyde, or cyanoacetate)
afforded only trace quantities of the desired product and
decomposition of the starting material. We were able to
remedythisproblemby formingand reacting the enolateat
ꢀ100 °C.14 To our delight, this approach worked well and
product 16 could be produced in an acceptable 45% yield
along with 45% of recovered starting material.
(10) See Supporting Information for details.
(11) We also tried to alkylate malonate 10 by using NaH and MeI.
Once again, diastereomer 11a was isolated as the major product along
with minor amounts of 11b. Likewise, performing a similar acylation/
cyclization with A also did not improve the diastereoselectivity.
With both side chains in place, all that remained was
the cleavage of the methyl ether and the tert-butyl ester.
Although treating 16 with NaI/TMSCl efficiently removed
the tert-butyl ester, the methyl ether proved to be quite
resistant to these conditions.15 Various other acidic, basic,
and nucleophilic conditions were attempted in order to
realize this deprotection. Ultimately, we found that heating
(12) Myers and co-workers have observed a similar endo preference
during the alkylation of bicyclic lactams. This was rationalized on
stereoelectronic grounds and may involve an interaction between the
developing σ* orbital of the newly formed CꢀC bond and the lone pair
of the lactam (in this case the lactone) in the transition state. See: (a)
Meyers, A. I.; Wallace, R. H. J. Org. Chem. 1989, 54, 2509–2510. (b)
Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F.; Williard, P. G.
J. Am. Chem. Soc. 1998, 120, 7429–7438 and references therein.
(13) Kim, J.-G.; Jang, D. O. Synthesis 2008, 2072–2074.
€
(14) Franck, G.; Brodner, K.; Helmchen, G. Org. Lett. 2010, 12,
3886–3889.
(15) When 13 was treated with 4 equiv of TMSI, both the tert-butyl
ester and the methyl ether were cleaved.
(16) (a) Tsukano, C.; Siegel, D. R.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2007, 46, 8840–8844. (b) Waizumi, N.; Stankovic, A. R.; Rawal,
V. H. J. Am. Chem. Soc. 2003, 125, 13022–13023.
4488
Org. Lett., Vol. 13, No. 17, 2011

a mixture of 16 and LiI in a microwave reactor cleanly
effected the cleavage of the vinylogous methyl ester.16
A
Scheme 5. Synthesis of Sorbicillactone Aa
one-pot deprotection of the tert-butyl esterwasachievedby
adding NaI and TMSCl. This afforded 9-epi-sorbicillac-
tione A (17) in 12 overall steps from 2-methylresorcinol.17
With a viable route to the complete sorbicillactone
skeleton, we turned our attention to the conversion
of lactone 11b into the original synthetic target, sorbicil-
lactone A (Scheme 5). Using similar conditions as those
described above, we were able to convert the tert-butyl
ester in 11b into the acyl azide 18. Curiously, attempts at
using the above Curtius rearrangement conditions (THF,
100 °C, μw) with 18 were unreliable and produced uni-
dentified polar reaction products that failed to react with
fumarate 14. Contrary to the exo isocyanate formed from
11a, the endo isocyanate formed from 18 would likely be in
close proximity to the vinylogous ester moiety. This may
allow undesired side reactions to occur at high temperature
in the absence of a suitable trap. To circumvent this
problem, we used modified conditions in which acyl azide
18 was heated in a THF/H2O mixture. This succeeded in
producing the desired amine. The acylation of this amine
to give amide 19 also proved to be much more sluggish
than with the epimeric substrate. We were able to over-
come this reactivity difference by extending the reaction
times and using multiple additions of fumarate 14.
The C-acylation of amide 19 proceeded smoothly to give
20. We experienced considerable difficulties when attempt-
ing to deprotect compound 20. Treating this compound
with TFA or NaI/TMSCl cleanly revealed the carboxylic
acid,10 but all attempts at cleaving the methoxy group were
accompanied by significant amounts of decomposition to
as yet unidentified compounds. We made repeated at-
tempts at purifying the product with both Sephadex LH-
20 and reverse-phase chromatography but were unable to
attainsyntheticsorbicillactone A (2) inour usualstandards
ofpurity.17 Incontrast, 9-epi-sorbicillactone A (17) and the
two protected compounds 16 and 20 proved to be stable
and survived chromatographic purification. At this time, it
is not clear why 2is unstable to removing the methoxy group,
but it may be related to the reactivity of the vinylogous acid
and the close proximity of the endocyclic amide.
a For more details, see Supporting Information.
cillactones and to probe their mechanism of action. In
addition to devising a solution to the diastereoselectivity
observed during installation of the C9 stereocenter, we are
also exploring methods to access enantiopure material.
These results will be reported in due course.
Acknowledgment. Financial support was provided by
the University of Minnesota and by the National Science
Foundation through a Graduate Research Fellowship to
K.A.V. Wethank Ms. LylienTan (U of MN) forassistance
in preparing phenol 7, and Dr. Robert McNair (Johnson-
Matthey) for helpful discussions and for providing us with
Pd/C. We also thank Profs. Thomas Hoye (U of MN) and
Chris Douglas (U of MN) for helpful discussions, Prof.
Mark Distefano (U of MN) and Mr. Joshua Ochocki (U of
MN) for HPLC assistance, and Prof. Gerhard Bringmann
€
(Universitat Wurzburg) for providing spectral data for
sorbicillactone A.
€
In conclusion, we havecompleted the first total synthesis
of sorbicillactone A and 9-epi-sorbicillactone A. This
concise 12-step route can produce gram quantities of the
key intermediate 11 and is highly amenable to the synthesis
of other analogs. We plan to use this strategy to further
explore the structureꢀactivity relationships of the sorbi-
Supporting Information Available. Experimental pro-
cedures and spectral information are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Note Added after ASAP Publication. This article was
published ASAP on July 29, 2011. A correction has been
made to the text in paragraph three. The corrected version
was posted on August 2, 2011.
(17) See Supporting Information for a comparison of the 1H NMR
spectra of natural sorbicillactone A (2), synthetic 2, and 9-epi-sorbicil-
lactone A (17).
Org. Lett., Vol. 13, No. 17, 2011
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