Combinatorial catalysis employing a visible enzymatic beacon in real time: Synthetically versatile (Pseudo)halometalation/carbocyclizations

Article abstract of DOI:10.1002/anie.201103365

For the big screen: An alcohol oxidase/peroxidase-based screen for combinatorial catalysis produces a signal in the visible region and in real time. A targeted high-throughput screen uncovered a bromometalation/ carbocyclization route to bicyclic terpenoid cores and a thiocyano palladation/carbocyclization for the ready installation of vinyl thiocyanates.

Full text of DOI:10.1002/anie.201103365

DOI: 10.1002/anie.201103365
Synthetic Methods
Combinatorial Catalysis Employing a Visible Enzymatic Beacon in
Real Time: Synthetically Versatile (Pseudo)Halometalation/
Carbocyclizations**
Jacob A. Friest, Sylvain Broussy, Woo Jin Chung, and David B. Berkowitz*
Combinatorial approaches to catalysis have made an impact
in targeted transformation development, including silver-
mediated carbene insertion,[1] scandium/pybox-based
(pybox = bis(oxazolinyl)pyridine) asymmetric cyclopropana-
tion,[2] and rhodium/iridium-based asymmetric hydrogena-
tion.[3] Useful design elements have emerged from these
studies, for example, the value of ligand self-assembly,[4] or of
the inclusion of peptide-like structural elements[5–7] in build-
ing ligand arrays. Efficient screening methods are of para-
mount importance for such efforts. Methods based on
fluorescence,[8] REMPI,[9] MS,[10] NMR,[11] and IR thermog-
raphy[12] have appeared. A chromophore may be installed into
the substrate[13] or product[14] of the reaction under study.
Alternatively, one can exploit chromophores inherent in
proteins[15] or enzyme-associated reactions,[16] and use these
sensors to report back on product formation and composition.
Our group has developed an in situ enzymatic screening
(ISES) approach whereby an organometallic reaction under
study is coupled to an enzymatic reporting reaction in real
time.[17] This screening method led to the discovery of the first
asymmetric allylic amination with nickel(0)[18] and to the
identification of novel salen [salen = N,N’-bis(salicylidene)-
ethylenediamine)] ligands with promise for asymmetric syn-
thesis.[19] Those approaches involved dehydrogenase
enzymes[20] as sensors, thus utilizing the inherent nicotinamide
cofactor to provide a UV signal.
envision this providing a rapid entry into the cores of
terpenoid natural products featuring exomethylene g-lac-
tones (Scheme 1). The 6-exo-trig substrate 6 would lead into
cores of xerophilusin and crassin, a specific modulator of
STAT phosphorylation.[22] The 5-exo-trig substrate 3 is
designed to give 5,7-sesquiterpenoid lactone cores.[23] Key
natural products (NPs) here include the guaianolide, ixerin Y
(1),[24] and xanthatin (2), which shows anti-MRSA (methicil-
lin-resistant Staphylococcus aureus),[25] antifungal,[26] and
antiulcer[27] activity.
Herein we describe an important new ISES mode in which
the reporting enzymes lead to a visible signal in real time. The
advantages of colorimetric approaches have been articu-
lated[13,21] and include the ability to screen a diverse array of
catalysts with the naked eye, without employing specialized
equipment, as well as increasing convenience and throughput.
Synthetically, this study was directed at developing formal
halometalation/carbocyclization transformations. One can
[*] J. A. Friest, S. Broussy, W. J. Chung, Prof. D. B. Berkowitz
Department of Chemistry, University of Nebraska
Lincoln, NE 68588 (USA)
E-mail: dbb@unlserve.unl.edu
Homepage: http://chem.unl.edu/dbb/site/welcome.html
[**] D.B.B. currently serves as a Program Director at the National
Science Foundation. This research was facilitated by the Individual
Research & Development (IR/D) program associated with that
appointment. The authors acknowledge the NSF-CHE-0911732 for
research support. We thank the NIH (SIG-1-510-RR-06307) and NSF
(CHE-0091975, MRI-0079750) for NMR instrumentation, and the
NIH (RR016544) for facilities renovation.
Scheme 1. Proposed halometalation/carbocyclization routes leading to
the core structures of terpenoid exomethylene lactone natural prod-
ucts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103365.
Angew. Chem. Int. Ed. 2011, 50, 8895 –8899
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8895

Communications
Related NP-derived a-methylene
butyrolactone moieties appear to undergo
Michael addition with Cys-38[28] of the
transcription factor NF-kB,[29] thereby
blocking DNA binding.[30] Our synthetic
approach is particularly attractive in light
of such structure–activity relationships
(SAR), as it would deliver the NP core
with
a b-halo a,b-unsaturated lactone
moiety, for potential target capture,
in vivo, and also to tap into cross-coupling
chemistry ex vivo for chain extension/
library elaboration. The drive toward
streamlined methods for the construction
of such NP cores is motivated by the
effectiveness of NP-core-based chemical
biology libraries in defining studies by
groups such as Schreiber,[31] Waldmann,[32]
Shair,[33] Arndt,[34] and Snapper.[35]
While the chemistry envisioned in
Scheme 1 remained largely unexplored,
there was some precedent from the work
of Lu and co-workers,[36a,b,c] who reported
primarily on acetoxy metalation/carbocy-
clization employing PdII catalysis in neat
acetic acid[37] as solvent. We set out to
examine a much broader spectrum of
metal, (pseudo)halide, and substrate
space combinatorially by using visual col-
orimetric ISES for higher throughput.
We demonstrate herein that the com-
bination of alcohol oxidase and peroxidase
Figure 1. a) Schematic of the in situ screen; b) UV spectrum for the formation of the ABTS
radical cation over time; c) the potential catalytic combinations screened.
serves as an effective reporting duo for the title transforma-
tion (Figures 1a and 1b). By utilizing 2,2-azino-bis(3-ethyl-
benzothiazoline-6-sulfonate) (ABTS), as a peroxidase cofac-
tor, one achieves particular sensitivity. This sensitivity arises
because each molecule of alcohol (by)product emanating
from the organic reaction of interest that is oxidized by the
alcohol oxidase reporter gives rise to two equivalents of the
ABTS radical cation, thus providing an intense (e405À414
(2 ABTS.+) ca. 70000mÀ1 cmÀ1)[38] colorimetric signal in the
visible range (jungle green). This allows first-pass scanning of
a large number of potential catalytic combinations with the
naked eye (Figure 2). A more quantitative ranking (relative
rates) may then be obtained by UV/visible spectrophoto-
metry on the first-pass hits (Figure 3).
A broad array of 64 metal catalyst candidates was chosen
and subdivided into four groups of 16 catalysts each, as
detailed in the Supporting Information. These were screened
against six (pseudo)halides (LiF, LiCl, LiBr, LiCN, LiOCN,
LiSCN) and three candidate substrates (3, 7, and 8), thereby
creating a 64 ꢀ 6 ꢀ 3 = 1152 combinatorial array (see Fig-
ure 1c). Figure 2 shows a 96 well tray for the metal set III
versus substrate 3. These were run in a convenient 300 mL
format (200 mL organic/100 mL aq. enzymatic layer). One sees
clear positive readouts for the combination of LiBr with both
RhII perfluorocarboxylates (in contrast to the RhII carboxyl-
ate catalyst), as well as with [PdII(acac)] (but not [NiII(acac)])
and [PdCl2(PhCN)2] (but not [PtCl2(PhCN)2]).
Figure 2. Example of a d9-d10 array for substrate 3. 16 Metal com-
plexes were screened across six (pseudo)halides with the propiolate
ester 3 (5-exo-trig substrate). acac=acetylacetonate.
8896 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8895 –8899

could be lowered to 2.5 mol% by using gentle heating or
sonication without compromising the yield (see the Support-
ing Information).
This reaction would appear to constitute a new reaction
mode for the RhII/LiX combination. Control experiments
established that this reactivity is not a function of stray
trifluoroacetic acid (see the Supporting Information). The
disparate reactivity of RhII perfluorocarboxylates versus RhII
carboxylates is reminiscent of the observations reported by
Padwa, Doyle, et al., that is, the tendency of only the RhII
perfluorocarboxylate to promote electrophilic aromatic sub-
stitution over carbene insertion.[39] Clearly this unusual and
valuable reactivity warrants further exploration.
Figure 3. a) Initial hits from visual colorimetric ISES are ranked
spectrophotometrically (Abs405 in mAbs minÀ1; A, B, and C are
substrates 3, 7, and 8, respectively; see the Supporting Information for
experimental details). b) An example of the cuvette ISES experiment.
The ABTS indicator shows turnover with RhII perfluorobutyrate,
whereas the highly colored RhIII catalyst fails.
Perhaps of equal significance is the combination of
[PdCl2(PhCN)2] with LiSCN, which yields an unprecedented
formal thiocyano palladation/carbocyclization transforma-
tion. As such, this reaction assembles a cyclic NP-core bearing
a terminal vinyl thiocyanate in one operation (the product
structure was verified both spectroscopically and chemically;
see the Supporting Information). Given the importance of the
thiocyanate functionality for elegant vibrational Stark-effect
studies to probe active-site environments carried out by
Boxer and co-workers,[40] this transformation will likely be of
real value to chemical biologists.
The most interesting hits in the colorimetric tray screen
were then “cherry-picked” visually, and then ranked more
quantitatively by spectrophotometric analysis in the cuvette
(Figure 3). As can be seen, for PdII the cyclization chemistry
proceeds efficiently with [PdCl2(PhCN)2] and LiBr for both
the 5-exo-trig ester and ether substrates. Acetic acid clearly is
not necessary for these cyclizations. Among the other PdII
catalysts screened, [Pd(acac)2], gave the next fastest rates.
However, the most generally effective catalytic combina-
tion found was LiBr with the RhII perfluorocarboxylates,
which provided efficient formal bromorhodiation/carbocycli-
zation across all three test substrates; this result was in stark
contrast to the RhII acetate dimer, and all RhI and RhIII
complexes examined. This reactivity was verified under
standard round bottom flask conditions, through which
product identity, stereochemistry, and yield were established
(Figure 4). Note that the cyclizations are highly diastereo-
selective, giving the 1,2-trans stereochemistry for the xantha-
tin core from 3, and the 1,3-cis stereochemistry for the crassin-
type core from 7. Also of interest is that the catalyst loading
We next utilized the new RhII perfluorocarboxylate
chemistry to fashion a library of small compounds based on
the xanthatin core, which was obtained through stereocon-
trolled synthesis and then tailoring chemistry (Scheme 2).
Figure 4. Chart showing the success of catalytic metal/(pseudo)halide
combinations as a function of substrate. Yields of the isolated
products for the homogeneous material after running the reactions
under standard round bottom flask conditions and purifying the
resulting products by chromatography on silica gel. [a] Reaction carried
out at 608C. [b] Yield determined by GC methods.
Scheme 2. Application of the new halometalation/carbocyclization
route to the stereocontrolled synthesis of the xanthatin core.
DIAD=diisopropylazodicarboxylate, pyr=pyridine, TBAF=tetra-n-
butylammonium fluoride, TBDPS=tert-butyldiphenylsilyl, 1,1,2-
TCE=1,1,2-trichloroethane, THF=tetrahydrofuran.
Angew. Chem. Int. Ed. 2011, 50, 8895 –8899
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8897

Communications
[4] a) M. Weis, C. Waloch, W. Seiche, B. Breit, J. Am. Chem. Soc.
2006, 128, 4188 – 4189; b) J. M. Takacs, K. Chaiseeda, S. A.
Moteki, D. S. Reddy, D. Wu, K. Chandra, Pure Appl. Chem.
2006, 78, 501 – 509.
[5] a) B. S. Fowler, P. J. Mikochik, S. J. Miller, J. Am. Chem. Soc.
2010, 132, 2870 – 2871; b) J. L. Gustafson, D. Lim, S. J. Miller,
Science 2010, 328, 1251 – 1255; c) P. A. Jordan, K. J. Kayser-
Bricker, S. J. Miller, Proc. Natl. Acad. Sci. USA 2010, 107,
20620 – 20624; d) A. Agarkov, S. Greenfield, D. Xie, R. Pawlick,
G. Starkey, S. R. Gilbertson, Biopolymers 2006, 84, 48 – 73.
[6] M. B. Francis, E. N. Jacobsen, Angew. Chem. 1999, 111, 987 – 991;
Angew. Chem. Int. Ed. 1999, 38, 937 – 941.
Alpine borane mediated ynone reduction establishes the
absolute stereochemistry[41] (see the Supporting Information)
and the bromometallation/carbocyclization sets the relative
stereochemistry. Finally, ring-closing metathesis yields the
desired xanthanolide core with the bromomethylene lactone
functionality 14, which undergoes palladium-mediated chain
extension reactions as shown in Scheme 3.
[7] L. C. Wieland, E. M. Vieira, M. L. Snapper, A. H. Hoveyda,
J. Am. Chem. Soc. 2009, 131, 570 – 576.
[8] a) R. Biswas, N. Maillard, J. Kofoed, J.-L. Reymond, Chem.
Commun. 2010, 46, 8746 – 8748; b) S. Becker, H. Hoebenreich,
A. Vogel, J. Knorr, S. Wilhelm, F. Rosenau, K.-E. Jaeger, M. T.
Reetz, H. Kolmar, Angew. Chem. 2008, 120, 5163 – 5166; Angew.
Chem. Int. Ed. 2008, 47, 5085 – 5088; c) W. G. Lewis, F. G.
Magallon, V. V. Fokin, M. G. Finn, J. Am. Chem. Soc. 2004, 126,
9152 – 9153; d) S. R. Stauffer, J. F. Hartwig, J. Am. Chem. Soc.
2003, 125, 6977 – 6985; e) E. R. Jarvo, C. A. Evans, G. T. Cope-
land, S. J. Miller, J. Org. Chem. 2001, 66, 5522 – 5527.
[9] S. M. Senkan, Nature 1998, 394, 350 – 353.
Scheme 3. Exploitation of the bromomethylene lactone functionality for
[10] a) P. A. Lichtor, S. J. Miller, ACS Combinatorial Sci. 2011, 13,
321 – 326; b) C. Ebner, C. A. Muller, C. Markert, A. Pfaltz,
J. Am. Chem. Soc. 2011, 133, 4710 – 4713; c) J. Wassenaar, E.
Jansen, W.-J. van Zeist, F. M. Bickelhaupt, M. A. Siegler, A. L.
Spek, J. N. H. Reek, Nat. Chem. 2010, 2, 417 – 421; d) C. A.
Mueller, A. Pfaltz, Angew. Chem. 2008, 120, 3411 – 3414; Angew.
Chem. Int. Ed. 2008, 47, 3363 – 3366; e) P. Chen, Angew. Chem.
2003, 115, 2938 – 2954; Angew. Chem. Int. Ed. 2003, 42, 2832 –
2847.
[11] a) M. T. Reetz, P. Tielmann, A. Eipper, A. Ross, G. Schlotter-
beck, Chem. Commun. 2004, 1366 – 1367; b) M. A. Evans, J. P.
Morken, J. Am. Chem. Soc. 2002, 124, 9020 – 9021.
[12] a) M. T. Reetz, M. H. Becker, M. Liebl, A. Furstner, Angew.
Chem. 2000, 112, 1294 – 1298; Angew. Chem. Int. Ed. 2000, 39,
1236 – 1239; b) S. J. Taylor, J. P. Morken, Science 1998, 280, 267 –
270.
[13] J. A. Loch, R. H. Crabtree, Pure Appl. Chem. 2001, 73, 119 – 128.
[14] a) O. Lavastre, J. P. Morken, Angew. Chem. 1999, 111, 3357 –
3359; Angew. Chem. Int. Ed. 1999, 38, 3163 – 3165; b) R.
Moreira, M. Havranek, D. Sames, J. Am. Chem. Soc. 2001, 123,
3927 – 3931.
[15] a) H. Matsushita, N. Yamamoto, M. M. Meijler, P. Wirsching,
R. A. Lerner, M. Matsushita, K. D. Janda, Mol. BioSyst. 2005, 1,
303 – 306; b) M. Matsushita, K. Yoshida, N. Yamamoto, P.
Wirsching, R. A. Lerner, K. D. Janda, Angew. Chem. 2003, 115,
6166 – 6169; Angew. Chem. Int. Ed. 2003, 42, 5984 – 5987; c) F.
Taran, C. Gauchet, B. Mohar, S. Meunier, A. Valleix, P. Y.
Renard, C. Creminon, J. Grassi, A. Wagner, C. Mioskowski,
Angew. Chem. 2002, 114, 132 – 135; Angew. Chem. Int. Ed. 2002,
41, 124 – 127.
[16] a) A. Hamberg, S. Lundgren, M. Penhoat, C. Moberg, K. Hult,
J. Am. Chem. Soc. 2006, 128, 2234 – 2235; b) C. M. Sprout, C. T.
Seto, Org. Lett. 2005, 7, 5099 – 5102; c) P. Abato, C. T. Seto,
J. Am. Chem. Soc. 2001, 123, 9206 – 9207.
[17] D. B. Berkowitz, M. Bose, S. Choi, Angew. Chem. 2002, 114,
1673 – 1677; Angew. Chem. Int. Ed. 2002, 41, 1603 – 1607.
[18] a) D. B. Berkowitz, W. Shen, G. Maiti, Tetrahedron: Asymmetry
2004, 15, 2845 – 2851; b) D. B. Berkowitz, G. Maiti, Org. Lett.
2004, 6, 2661 – 2664.
transition metal mediated tailoring chemistry upon the bicyclic xantha-
ꢀ À
ꢀ
nolide core: a) HC C SiMe3, Cui, [PdCl2(PPh3)2], Et2NH; b) Bu3SnC
À
=
C SiMe3, cat. [Pd2(dba)3], Pfur3, D; c) BrZnC(Ph)C CH2, [Pd(PPh3)4]
=
D; d) Bu3SnCH CH2, [Pd2(dba)3], Pfur3, D. dba=dibenzylideneace-
tone, fur=furyl.
Note that the standard Sonogashira coupling proceeds
with double-bond migration, thus yielding the bicyclic dien-
oate in 15. Use of modified Stille coupling conditions (i.e.,
stannylated acetylene) prevents this migration and gives
ynenoate 16 instead. All analogues feature more extended
Michael acceptors that are of potential interest, given the
mechanistic hypothesis that has been advanced (see above).
In summary, the first application of visible, colorimetric ISES
has uncovered both a generalizable RhII perfluorocarbox-
ylate/LiBr-mediated halometalation/carbocyclization and the
first formal thiocyanometalation/carbocyclization. Current
efforts are focused on exploring the scope of these new
tandem bond constructions, and the colorimetric screen that
led to their discovery.
Received: May 17, 2011
Published online: August 16, 2011
Keywords: carbocyclization · enzyme catalysis · heterocycles ·
.
stereoselective catalysis · synthetic methods
[1] K. Burgess, H.-J. Lim, A. M. Porte, G. A. Sulikowski, Angew.
Chem. 1996, 108, 192 – 194; Angew. Chem. Int. Ed. 1996, 35, 220 –
222.
[2] D. Moye-Sherman, M. B. Welch, J. Reibenspies, K. Burgess,
Chem. Commun. 1998, 2377 – 2378.
[3] a) D. J. Ager, L. Lefort, J. G. de Vries, ACS Symp. Ser. 2009,
1009, 239 – 250; b) M. T. Reetz, O. Bondarev, Angew. Chem.
2007, 119, 4607 – 4610; Angew. Chem. Int. Ed. 2007, 46, 4523 –
4526; c) J. G. de Vries, L. Lefort, Chem. Eur. J. 2006, 12, 4722 –
4734.
[19] a) S. Dey, D. R. Powell, C. Hu, D. B. Berkowitz, Angew. Chem.
2007, 119, 7140 – 7144; Angew. Chem. Int. Ed. 2007, 46, 7010 –
7014; b) S. Dey, K. R. Karukurichi, W. Shen, D. B. Berkowitz,
J. Am. Chem. Soc. 2005, 127, 8610 – 8611.
8898 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8895 –8899

[20] For complementary examples of alcohol dehydrogenases in
asymmetric synthesis, see: a) G. A. Applegate, R. W. Cheloha,
D. L. Nelson, D. B. Berkowitz, Chem. Commun. 2011, 47, 2420 –
2422; b) J. A. Friest, Y. Maezato, S. Broussy, P. Blum, D. B.
Berkowitz, J. Am. Chem. Soc. 2010, 132, 5930 – 5931; c) S.
Broussy, R. W. Cheloha, D. B. Berkowitz, Org. Lett. 2009, 11,
305 – 308.
[21] a) J. F. Folmer-Andersen, V. M. Lynch, E. V. Anslyn, J. Am.
Chem. Soc. 2005, 127, 7986 – 7987; b) M. Kawatsura, J. F.
Hartwig, Organometallics 2001, 20, 1960 – 1964.
[31] a) S. L. Schreiber, Nat. Chem. Biol. 2007, 3, 352; b) M. D. Burke,
E. M. Berger, S. L. Schreiber, J. Am. Chem. Soc. 2004, 126,
14095 – 14104.
[32] a) S. Basu, B. Ellinger, S. Rizzo, C. Deraeve, M. Schurmann, H.
Preut, H.-D. Arndt, H. Waldmann, Proc. Natl. Acad. Sci. USA
2011, 108, 6805 – 6810; b) H. Waldmann, Nat. Chem. Biol. 2009,
5, 76 – 77.
[33] a) H. E. Pelish, J. R. Peterson, S. B. Salvarezza, E. Rodriguez-
Boulan, J.-L. Chen, M. Stamnes, E. Macia, Y. Feng, M. D. Shair,
T. Kirchhausen, Nat. Chem. Biol. 2006, 2, 39 – 46; b) H. E. Pelish,
N. J. Westwood, Y. Feng, T. Kirchhausen, M. D. Shair, J. Am.
Chem. Soc. 2001, 123, 6740 – 6741.
[22] P. O. Krutzik, J. M. Crane, M. R. Clutter, G. P. Nolan, Nat. Chem.
Biol. 2008, 4, 132 – 142.
[34] a) C. P. R. Hackenberger, H.-D. Arndt, D. Schwarzer, Chem.
Unserer Zeit 2010, 44, 198 – 206; b) T. Walther, S. Renner, H.
Waldmann, H.-D. Arndt, ChemBioChem 2009, 10, 1153 – 1162.
[35] a) B. G. Kim, T. G. Chun, H.-Y. Lee, M. L. Snapper, Bioorg.
Med. Chem. 2009, 17, 6707 – 6714; b) H. S. Radeke, C. A. Digits,
S. D. Bruner, M. L. Snapper, J. Org. Chem. 1997, 62, 2823 – 2831.
[36] a) X. Xie, X. Lu, Y. Liu, W. Xu, J. Org. Chem. 2001, 66, 6545 –
6550; b) G. Zhu, X. Lu, Organometallics 1995, 14, 4899 – 4904;
c) G. R. Cook, R. Hayashi, Org. Lett. 2006, 8, 1045 – 1048.
[37] a) J. Song, Q. Shen, F. Xu, X. Lu, Tetrahedron 2007, 63, 5148 –
5153; b) Q. Zhang, X. Lu, J. Am. Chem. Soc. 2000, 122, 7604 –
7605.
[38] a) J. Kulys, I. Bratkovskaja, Talanta 2007, 72, 526 – 531; b) M.
Solis-Oba, V. M. Ugalde-Saldivar, I. Gonzalez, G. Viniegra-
Gonzalez, J. Electroanal. Chem. 2005, 579, 59 – 66; c) S. L. Scott,
W. J. Chen, A. Bakac, J. H. Espenson, J. Phys. Chem. 1993, 97,
6710 – 6714.
[39] A. Padwa, D. J. Austin, A. T. Price, M. A. Semones, M. P. Doyle,
M. N. Protopopova, W. R. Winchester, A. Tran, J. Am. Chem.
Soc. 1993, 115, 8669 – 8680.
[40] a) A. T. Fafarman, P. A. Sigala, D. Herschlag, S. G. Boxer, J. Am.
Chem. Soc. 2010, 132, 12811 – 12813; b) P. A. Sigala, A. T.
Fafarman, P. E. Bogard, S. G. Boxer, D. Herschlag, J. Am.
Chem. Soc. 2007, 129, 12104 – 12105.
[23] a) D. A. Kummer, J. B. Brenneman, S. F. Martin, Org. Lett. 2005,
7, 4621 – 4623; b) M. A. Evans, J. P. Morken, Org. Lett. 2005, 7,
3371 – 3373; c) B. Nosse, R. B. Chhor, W. B. Jeong, C. Boehm, O.
Reiser, Org. Lett. 2003, 5, 941 – 944.
[24] J.-Y. Ma, Z.-T. Wang, L.-S. Xu, G.-J. Xu, Phytochemistry 1999,
50, 113 – 115.
[25] Y. Sato, H. Oketani, T. Yamada, K.-I. Singyouchi, T. Ohtsubo, M.
Kihara, H. Shibata, T. Higuti, J. Pharm. Pharmacol. 1997, 49,
1042 – 1044.
[26] B. Pinel, A. Landreau, D. Seraphin, G. Larcher, J.-P. Bouchara, P.
Richomme, J. Enzyme Inhib. Med. Chem. 2005, 20, 575 – 579.
[27] L. S. Favier, A. O. M. Maria, G. H. Wendel, E. J. Borkowski,
O. S. Giordano, L. Pelzer, C. E. Tonn, J. Ethnopharmacol. 2005,
100, 260 – 267.
[28] S. Wagner, A. Hofmann, B. Siedle, L. Terfloth, I. Merfort, J.
Gasteiger, J. Med. Chem. 2006, 49, 2241 – 2252.
[29] M. L. Schmitz, I. Mattioli, H. Buss, M. Kracht, ChemBioChem
2004, 5, 1348 – 1358.
[30] a) N. Lopez-Anton, C. Hermann, R. Murillo, I. Merfort, G.
Wanner, A. M. Vollmar, V. M. Dirsch, Apoptosis 2007, 12, 41 –
153; b) B. Siedle, A. J. Garcia-Pineres, R. Murillo, J. Schulte-
Moenting, V. Castro, P. Ruengeler, C. A. Klaas, F. B. Da Costa,
W. Kisiel, I. Merfort, J. Med. Chem. 2004, 47, 6042 – 6054.
[41] M. M. Midland, Chem. Rev. 1989, 89, 1553 – 1561.
Angew. Chem. Int. Ed. 2011, 50, 8895 –8899
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8899