Novel and efficient copper-catalysed synthesis of nitrogen-linked medium-ring biaryls

Article abstract of DOI:10.1002/chem.201002093

Herein, a new copper-catalysed strategy for the synthesis of rare nitrogen-linked seven-, eight- and nine-membered biaryl ring systems is described. It is proposed that the reaction proceeds through a highly activated intramolecularly co-ordinated copper

Full text of DOI:10.1002/chem.201002093

FULL PAPER
DOI: 10.1002/chem.201002093
Novel and Efficient Copper-Catalysed Synthesis of Nitrogen-Linked
Medium-Ring Biaryls
Jayne L. Kenwright,[a] Warren R. J. D. Galloway,[a] David T. Blackwell,[a]
Albert Isidro-Llobet,[a] James Hodgkinson,[a] Lars Wortmann,[b] Steven D. Bowden,[c]
Martin Welch,[c] and David R. Spring*[a]
Abstract: Herein, a new copper-cata-
lysed strategy for the synthesis of rare
nitrogen-linked seven-, eight- and nine-
membered biaryl ring systems is de-
scribed. It is proposed that the reaction
proceeds through a highly activated in-
tramolecularly co-ordinated copper
catalyst. The process is technically
simple, proceeds under relatively mild
conditions, displays a broad substrate
scope and forms biologically valuable
products that are difficult to synthesise
by other methods. We envisage that
this methodology will prove useful in a
wide synthetic context, with possible
applications in both target-oriented
and diversity-oriented synthesis.
Keywords: antibiotics
· biaryls ·
copper · medium-ring compounds ·
synthetic methods
Introduction
The importance of the N-aryl amine bond in organic and
medicinal chemistry is exemplified by its presence in a large
number of biologically active and pharmaceutically relevant
compounds.[1] One therapeutically pertinent class of mole-
cule incorporating this moiety is cyclic nitrogen-linked (N-
linked) biaryls. Numerous compounds based around seven-
membered N-linked biaryl scaffolds have been found to
demonstrate extraordinary biological properties; eight-mem-
bered-ring derivatives are also known, but are relatively
scarce (Figure 1). Indeed, there are very few reported exam-
ples of N-linked medium-ring biaryl compounds. This can be
primarily attributed to the difficulties associated with
medium-ring synthesis in general;[5] medium-ring biaryl scaf-
folds in particular are known to be especially challenging
synthetic targets.[6] As a result, compounds based around N-
linked medium-ring biaryls are currently under-represented
in small molecule libraries.
Figure 1. Some examples of biologically active compounds based around
N-linked medium-ring biaryl scaffolds (highlighted in bold). Oxcarbaze-
pine (1) is used in the treatment of epilepsy;[2] imipramine (2) and desipr-
amine (3) are commonly used as anti-depressants[3] and compound 4 has
been reported to have analgesic and anti-inflammatory effects.[4]
thus limited functional group tolerability), difficulties in sub-
strate preparation, low yields, unpredictability and limited
structural diversity in the resulting compounds.[7] Thus, there
is a need for the development of new and efficient method-
ology of broad utility for the synthesis of N-linked medium-
ring biaryls so that the biological usefulness of this structural
moiety can be investigated and exploited further. Herein,
we describe a novel strategy for the synthesis of seven-,
eight- and nine-membered N-linked biaryl ring systems
from acyclic precursors that is based around the ability of an
activated intramolecular copper species to facilitate C-
À
Typical approaches to these ring systems suffer from
drawbacks including a reliance on harsh conditions (and
[a] Dr. J. L. Kenwright, Dr. W. R. J. D. Galloway, Dr. D. T. Blackwell,
Dr. A. Isidro-Llobet, J. Hodgkinson, Dr. D. R. Spring
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge (UK)
AHCTUNGTREG(NNUN aryl) N bond formation and thus affect ring closure.
Fax : (+44)1223-336362
E-mail: spring@ch.cam.ac.uk
[b] Dr. L. Wortmann
Bayer Schering Pharma AG
Mꢀllerstraße 178, 13353 Berlin (Germany)
Results and Discussion
[c] Dr. S. D. Bowden, Dr. M. Welch
À
Palladium- and copper-mediated C
(aryl) N bond forming
Department of Biochemistry, University of Cambridge
Lensfiled Road, Cambridge (UK)
reactions are synthetically powerful processes that are used
routinely in both academic and industrial settings.[8] Intra-
molecular N-arylations mediated by these metals have been
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002093.
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reported, primarily for the generation of five-, six- and, to a
lesser extent, seven-membered rings.[9] Seven-membered N-
linked biaryl systems are also commonly accessed by meth-
ods involving the direct metal-mediated N-arylation of acy-
clic precursors;[7d–g] however, there is much less precedence
for the synthesis of eight- and nine-membered analogues by
this approach despite its arguably being the most syntheti-
cally versatile and conceptually straightforward route to-
wards such scaffolds. To this end we envisaged a new
copper-catalysed strategy for the direct N-arylation of acy-
clic precursors based around internal chelation and activa-
tion of the copper metal.
halide bond, which may facilitate the subsequent oxidative
addition step to generate intermediates of the form 8 (also
termed the copper(I)-mediated aryl halide activation step).
In analogous cyclisation substrates without an auxiliary ni-
trogen, oxidative addition across the aryl–halide bond re-
quires the formation of medium-to-large ring systems. How-
ever, in the case of internally chelated systems of the form
7, the oxidative addition step requires the formation of
smaller ring sizes (as bicyclo metallocyclic species are gener-
ated) and, as such, are expected to be more kinetically
facile.[11,12]
Initial optimisation studies focused upon the cyclisation of
aniline derivative 9 to generate eight-membered N-linked
biaryl 10 (Table 1). A variety of copper-catalysed amination
Buchwald et al. have proposed that copper-mediated C-
À
ACHTUNGTRENNUNG(aryl) N bond-forming reactions between amines and aryl
halides may proceed through
a copper(I)/copperCAHTUNTGNUER(NG III)
couple.[10] Co-ordination of the copper(I) species to the
amine is followed by oxidative addition to the aryl halide
and subsequent reductive elimination yields the coupled
product.[10] Based on this mechanism, we hypothesised that
the copper-catalysed synthesis of N-linked medium-ring
À
Table 1. Optimisation of reaction conditions for the intramolecular cycli-
sation reaction.[a]
biaryls of general form 5 by direct CACTHNUTRGNEUNG(aryl) N bond forma-
tion may be facilitated by the presence of an auxiliary nitro-
gen atom in the acyclic precursors 6 (Scheme 1). The lone
Ligand
Base
Copper
source
Solvent
Yield
[%][b]
1
2,4-pentanedione
Cs2CO3 CuI
Cs2CO3 CuI
DMF
DMF
DMF
ethanol
63
55
42
85
72
43
2[c] 2,4-pentanedione
3
2-acetylcyclohexanone Cs2CO3 CuI
4[d] 2,4-pentanedione
Cs2CO3 CuI
Cs2CO3 Cu
5
6
7
2,4-pentanedione
2,4-pentanedione
ethylene glycol
A
K3PO4 CuI
Cs2CO3 CuI
DMF
ethylene glycol 91
[a] Reactions were performed at a substrate concentration of 0.05m by
using catalyst (10 mol%), base (2 equiv), ligand (20 mol%; except in the
case of entry 7, in which the ligand is the solvent). For the synthesis of
substrate 9, see the Supporting Information. [b] Yield of isolated product.
[c] Reaction left for 24 h. [d] Reaction heated to 788C (reflux).
conditions based on those previously reported by Buchwald
et al. were examined.[13] In all cases, the desired product was
isolated. Pleasingly, an excellent yield of 10 was obtained by
use of a combination of copper(I) iodide, Cs2CO3 and ethyl-
ene glycol (as both solvent and ligand, Table 1, entry 7) at a
substrate concentration of 0.05m. Under these conditions
there was no evidence of competing intermolecular cou-
plings, despite the relatively high concentration employed.[14]
This implies that the intramolecular process is significantly
more favourable. Furthermore, preliminary investigations
established that two-component intermolecular coupling
was not significant under the optimised cyclisation condi-
tions.[15] These results highlight the importance of the auxili-
Scheme 1. Mechanistic blueprint for the copper(I)-catalysed N-linked
biaryl cyclisation strategy. Possible ancillary ligands omitted for clarity.
The auxiliary ꢀN atom allows internal chelation to form the active intra-
molecular copper species and its geometry may facilitate ring closure.
pair of electrons on this atom could be involved in co-ordi-
nation to any copper-based intermediates. Thus, in combina-
tion with the aniline nitrogen, an internal diamine species is
effectively present in the substrate. The use of chelating bi-
dentate ligands, in particular diamine ligands, in copper-
mediated cross-coupling reactions is known to be associated
with high levels of catalyst reactivity.[1a,8f,g,i] The internal co-
ordination of the diamine moiety of substrates of the form 6
to the copper(I) catalyst would thus be expected to yield a
highly activated intramolecular form of copper, in which the
À
ary nitrogen atom in facilitating C N bond formation under
these conditions, which lends some degree of support to the
mechanistic concept.
With optimised conditions in hand, the cyclisation of vari-
ous other acyclic precursors was examined in order to ex-
plore the substrate scope of the methodology (Table 2). A
range of electron donating and withdrawing substituents on
the aniline-based ring portion were tolerated, allowing
metal is incorporated in
Scheme 1).
a six-membered chelate (7,
In addition, such chelation would be expected to bring
the reactive copper metal into close proximity with the aryl
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Medium-Sized-Ring Biaryl Compounds
FULL PAPER
Table 2. Synthesis of seven-, eight- and nine-membered N-linked
biaryls.[a]
successfully incorporated into the product scaffolds, with no
evidence of competing intermolecular processes (Table 2,
entries 2 and 3).
Product
Yield
[%]
Significantly, the reaction can be carried out on substrates
bearing free hydroxyl and ester groups (Table 2, entries 6
and 7); these functionalities are valuable as they provide
possible synthetic handles for post-cyclisation structure elab-
oration around the biaryl core. In addition, we found that
the reaction conditions were tolerant of both allyl and
benzyl protecting groups on the auxiliary nitrogen (Table 2,
entry 1), and unprotected amine derivatives could also be
smoothly converted into the corresponding product
(Table 2, entries 1 and 2) providing an additional point for
further synthetic manipulation of the cyclised products (see
below). The methodology was also extended to the forma-
tion of seven- and nine-membered rings 18 and 19 from the
corresponding acyclic precursors in good-to-excellent yields
(Table 2, entries 8 and 9).
The modification of the central core of known bioactive
compounds in an attempt to discover structurally novel de-
rivatives (so-called scaffold hopping) plays a central role in
modern medicinal chemistry.[16] In this context, given the rel-
ative scarcity of eight-membered N-linked biaryls (see
above) a potentially valuable application of the new meth-
odology is to form eight-membered ring analogues of
known N-linked biaryl-based bioactive molecules and other
related nitrogen-containing ring systems. To this end, we ap-
plied the methodology in the concise synthesis of analogues
of compounds 20 (Lixivaptan or VPA-985) and 21
(Scheme 2).[17] These are both arginine vasopressin (AVP)
R=H, 11a
64
91
97
80
R=Me, 11b
R=allyl, 11c
R=benzyl, 11d
1
2
R=H, 12a
R=Me, 12b
53
86
3
4
13
14
84
77
5
15
96
6
7
16
17
62
45[b]
R=H, 18a
R=Me, 18b
82
94
8
9
R=H, 19a
R=Me, 19b
82
93
[a] Conditions in all cases: CuI (10 mol%), Cs2CO3 (2 equiv), ethylene
glycol (substrate concentration of 0.05m), 1008C, 3 h. The carbon–carbon
bond formed during the cyclisation process is highlighted in bold. The
syntheses of the acyclic precursors are described in the Supporting Infor-
mation. [b] A 30% yield of the ethylene glycol trans-esterified derivative
of the ring-closed product was also obtained.
access to a variety of eight-membered N-linked biaryl rings
Scheme 2. Synthesis of eight-membered-ring analogues of arginine vaso-
(11–17) in good-to-excellent yields. Halogen atoms could be
pressin (AVP) antagonists 20 and 21.
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D. R. Spring et al.
antagonists with potential applications in the treatment of
disorders characterised by excess renal reabsorption of free
water, such as congestive heart failure and liver cirrhosis.
Lixivaptan (20) is currently in clinical trials for the treat-
ment of congestive heart failure.[18] Two analogues of these
compounds 22 and 23 were synthesised; in both cases, the
key step involved the regioselective mono-acylation of
eight-membered N-linked biaryl 11a, thus demonstrating
the ability to conduct additional synthetic manipulations on
the biaryl core of such compounds.
The biological activities of the compounds disclosed in
this report are currently being evaluated and preliminary in-
vestigations have yielded some promising results. For exam-
ple, inhibition of proliferation phenotypic assays have identi-
fied compounds capable of modulating the growth of the
Gram-positive bacterium Staphylococcus aureus and the
Gram-negative bacterium Escherichia coli (Table 3). S.
strain CV026 at a concentration of 200 mm and compound
19a inhibited prodigiosin production in Serratia ATCC
39006 biosensor strain SP19 at a concentration of 50 mm.[21]
Several clinically relevant pathogens use quorum sensing
systems to regulate processes associated with virulence.[22]
Thus, the identification of small molecules that can antago-
nise quorum sensing pathways has attracted significant inter-
est in recent years.[23] A full account of the results of our
screening experiments will be reported in due course.
We hypothesise that the success of the copper-catalysed
N-linked medium-ring biaryl formation process is due to the
presence of an appropriately positioned auxiliary nitrogen
atom in the acyclic substrates (Scheme 1). It is believed that
the lone pair of electrons on this nitrogen is involved in co-
ordination to copper-based species generated during the re-
action process, thereby facilitating cyclisation. Attempts to
obtain a crystal structure of any of the copper-based inter-
mediates have thus far been unsuccessful. However, the in-
ability to cyclise substrates that are either lacking the auxili-
ary nitrogen (24, Figure 2) or have a carbonyl group incor-
Table 3. Some examples of compounds from this study which display
growth inhibitory activity against various bacterial strains. NS=no signif-
icant activity observed.
Growth inhibition [%][a]
Compounds
E. coli[b]
S. aureus[c]
1
2
13
NS
76
11d
54
40
Figure 2. Substrates that do not undergo cyclisation under the reaction
conditions. In 25–27 the auxiliary (benzylic) nitrogen atom forms part of
an amide or carbamate functionality. As such, the lone pair of electrons
of the auxiliary nitrogen can be delocalised into a carbonyl bond and
thus is not as available for co-ordination to a copper species.
3
4
19a
18a
30
NS
48
NS
porated adjacent to the auxiliary nitrogen (25–27, Figure 2)
provides indirect evidence for the importance of the free ni-
trogen lone pair on the auxiliary nitrogen and thus the pres-
ence of a copper-based intermediate species co-ordinated to
this atom.[24] The absence of any significant intermolecular
coupling under the cyclisation conditions provides additional
support for the important role played by the auxiliary nitro-
gen atom.[14]
[a] Percentage of growth inhibition at a compound concentration of
200 mm after 8 h of incubation at 378C. [b] E. coli. (strain ESS). [c] S.
aureus (MSSA strain H) incubated in the presence of an enhanced
oxygen atmosphere.
aureus is well documented as an opportunistic human patho-
gen that is responsible for several serious infections includ-
ing pneumonia, meningitis and scalded skin syndrome.[19]
Strains of E. coli are known to cause a range of infections
and diseases, including urinary tract infections, meningitis
and diarrheal disease.[19] Several of the compounds also
showed activity in phenotypic assays designed to identify
possible antagonists of bacterial quorum sensing.[20] For ex-
ample, compounds 11d, 12b, 13, 18a and 19a inhibited vio-
lacein production in Chromobacterium violaceum biosensor
Conclusion
In summary, we have developed a new strategy for the syn-
thesis of nitrogen-linked seven–nine-membered-ring biaryls,
based on the premise of generating a highly active intramo-
lecular form of copper. The process is technically simple,
proceeds under relatively mild conditions, displays a broad
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Medium-Sized-Ring Biaryl Compounds
FULL PAPER
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[5] The formation of medium rings from acyclic precursors is disfav-
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[6] a) X. B. Su, G. L. Thomas, W. R. J. D. Galloway, D. S. Surry, R. J.
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44, 1870.
substrate scope, uses inexpensive copper catalysts and forms
biologically valuable products that are difficult to synthesise
by other methods. Furthermore, the strategy outlined in this
report may conceivably be applied to the synthesis of a vari-
ety of other ring systems, including larger-sized cyclic N-
linked biaryls, N-linked biaryls incorporating heterocycles
and even ring systems involving different biaryl linking het-
eroatoms.[25] As such we envisage that this methodology will
prove useful in a wide synthetic context, with possible appli-
cations in both target-oriented and diversity-oriented syn-
thesis.[26]
Experimental Section
[7] Selected examples of the formation of seven-membered and
medium-sized N-linked biaryl ring systems: for intramolecular aryl–
General experimental procedure for medium-ring biaryl synthesis: Ethyl-
ene glycol (2 mL per mmol substrate) was added to a mixture of the acy-
clic precursor (1 equiv), Cs2CO3 (2 equiv) and CuI (0.1 equiv). The reac-
tion mixture was stirred at 1008C for 3 h, cooled to room temperature
and filtered through Celite. The solution was diluted with Et2O (4.0 mL
per mmol substrate) and the ethylene glycol was removed from the or-
ganic layer by washing with a large excess of water. The organic layer
was washed with brine, dried over Na2SO4 and concentrated under re-
duced pressure. The crude product was purified by using flash column
chromatography on silica.
À
aryl (C C bond) coupling (Ullmann-type chemistry) and intramo-
lecular amide bond formation followed by reduction to form the
amine, see: a) F.-W. Sum, J. Dusza, E. D. Santos, G. Grosu, M.
Reich, X. Du, J. D. Albright, P. Chan, J. Coupet, X. Ru, H. Mazan-
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À
ductive phenylation and cyclisation of nitroarenes (C N bond for-
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biaryl systems generated by methods involving the direct metal-
mediated N-arylation of acyclic precursors, see: d) M. Carril, R. San-
Martin, F. Churruca, I. Tellitu, E. Dominguez, Org. Lett. 2005, 7,
4787; e) N. Carril, R. SanMartin, E. Dominguez, I. Tellitu, Tetrahe-
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Synlett 2008, 1833; g) B. J. Margolis, J. J. Swidorski, B. N. Rogers, J.
Org. Chem. 2003, 68, 644.
Analytical data for 5,6,7,12-tetrahydrodibenzoACTHNUGRTENNU[G b,g]AHCTUNGTRNEN[UGN 1,5]diazocine (11a):
Rf =0.16 (SiO2; MeOH/CH2Cl2, 1:9); 1H NMR (500 MHz, CD3OD): d=
5.66–5.61 (m, 2H; aryl H), 5.57 (dd, J=7.5, 1.5 Hz, 2H; aryl H), 5.40 (dd,
J=8.0, 1.0 Hz, 2H; aryl H), 5.33 (apparent td, J=7.5, 1.0 Hz, 2H; aryl
H), 2.40 (s, 4H; CH2), 1.84–1.81 ppm (m, 2H; NH, CH2NH); 13C NMR
(125 MHz, CD3OD): d=143.80, 130.57, 126.98, 121.36, 118.74, 116.57,
À
À
43.92 ppm; IR: n˜max = 3384 (m; N H), 3288 (m; N H), 3195 (m; aromat-
À
À
À
À
ic C H), 3028 (m; aromatic C H), 2925 (m; C H), 2852 (m; C H), 1727
(m), 1606 (m; aromatic C=C), 1585 (m; aromatic C=C), 1470 (s), 1454
(m), 1332 (s), 1297 (m), 1253 cmÀ1 (m); HRMS (ESI+): m/z calcd for
C14H15N2+: 221.1235 [M+H]+; found: 221.1244 (D=4.3 ppm).
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Acknowledgements
The authors thank Bayer Schering and the EU, EPSRC, BBSRC, MRC,
Wellcome Trust and Newman Trust for funding.
[9] Selected examples of the formation of medium ring systems by
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[11] This may be a particularly relevant consideration as the CuI-mediat-
ed aryl halide activation step is known to be rate determining in the
copper-catalysed N-arylation of amides (see ref. [10]).
[12] Recently, Sperotto et al. have described the use of well-defined ami-
À
noarenethiolato-copper(I) (pre-)catalysts in C N coupling reactions,
in which a copper atom and a chelating amino ꢄarmꢅ are present
within the catalyst structure itself (cf. our work in which the chelat-
ing amino moiety is incorporated into the substrate), see: E. Sperot-
to, G. P. M. Van Klink, J. D. De Vries, G. Van Koten, Tetrahedron
2010, 66, 3478. The (pre-)catalysts of Sperotto et al. where found to
be soluble in common organic solvents. It may be the case that the
chelating nitrogen-type arrangement present in the acyclic substrates
used in our report helps to enhance the solubility of the copper(I)
catalyst, facilitating reactivity.
Chem. Eur. J. 2011, 17, 2981 – 2986
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2985

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the exogenous addition of the corresponding native acyl homoserine
lactone or a functional equivalent. Antagonists of quorum sensing
can be identified through the inhibition of pigment production
under these conditions. For more details see the Supporting Infor-
mation and S. Poulter, T. M. Carlton, X. Su, D. R. Spring, G. P. C.
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[14] Medium ring formations from acyclic precursors typically require
the use of dilute reaction conditions in order to maintain a low (ef-
fective) concentration of the reacting compound and thereby mini-
mise competing intermolecular reactions; see ref. [5] and a) P.
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94. Some preliminary experiments (using CuII (10 mol%), acetylace-
tone (20 mol%), Cs2CO3 (2 equiv), DMF, 1008C, 3 h) showed that
cyclisation could be carried out at higher concentrations without any
significant impact upon the isolated yield of the cyclised product:
i) 0.05m, 91%, ii) 0.1m, 85%, iii) 0.2m, 84%, iv) 0.5m, 71% and
v) 1m, 51%. Only at a concentration of 1m was any significant inter-
molecular coupling observed.
[15] Control experiments were carried out to see if intermolecular cou-
pling between aniline and 4-bromobiphenyl- or 4-methoxybromo-
benzene would occur under the optimised cyclisation conditions. At
a total substrate concentration of 0.05m (the substrate concentration
used for cyclisation), there was no evidence of any intermolecular
coupling after 3 h. The fact that cyclisation was observed at this con-
centration highlights the importance of the auxiliary nitrogen atom
[22] For example, in many bacterial species biofilm formation and the
production and secretion of virulence factors are regulated by
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À
in facilitating C N bond formation under these conditions and lends
[24] There was no evidence for the formation of any cyclised products
when substrates 24–28 were subjected to the standard cyclisation
conditions (by 1H NMR and LCMS or HRMS analysis). In addition
to the chelation argument discussed in the main text, another possi-
ble explanation as to why cyclisation was not possible by using sub-
strates with a carbonyl group incorporated adjacent to the auxiliary
nitrogen is that delocalisation of the nitrogen lone pair creates a
more rigid system which cannot adopt a conformation suitable for
ring closure. Whilst this possibility cannot be discounted outright, in
light of other observations, such as the result with compound 24, it
is likely that the auxiliary nitrogen lone pair plays an important role
in the progress of the cyclisation process.
some support to our mechanistic hypothesis outlined in Scheme 1.
No intermolecular coupling between aniline and 4-bromobiphenyl-
or 4-methoxybromobenzene was observed at a total substrate con-
centration of 0.15m.
[16] a) H.-J. Bçhm, A. Flohr, M. Stahl, Drug Discovery Today: Technol.
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[18] Study to evaluate the effects of oral administration of Lixivaptan in
patients with congestive heart failure: http://clinicaltrials.gov/ct2/
show/NCT01055912; accessed 4th April 2010.
[19] P. R. Murray, E. J. Baron, M. A. Pfaller, F. C. Tenover, R. H.
Yolken, Manual Of Clinical Microbiology, 7th ed., ASM Press
Washington, D. C., 1999.
[20] Quorum sensing is the intercellular signalling mechanism, mediated
by small molecules that numerous species of bacteria use to co-ordi-
nate their gene expression in a cell-density dependent manner;
a) W. C. Fuqua, S. C. Winans, E. P. Greenberg, J. Bacteriol. 1994,
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[25] Preliminary work has shown that under slightly modified reaction
conditions it is possible to form an O-linked biaryl ring system by
using a phenol derivative containing an auxiliary nitrogen atom; see
the Supporting Information for full details.
[26] For recent reviews on diversity-oriented synthesis (DOS), see:
a) S. L. Schreiber, Nature 2009, 457, 153; b) W. R. J. D. Galloway,
D. R. Spring, Expert Opin. Drug Discovery 2009, 4, 467; c) E. Niel-
sen, S. L. Schreiber, Angew. Chem. 2008, 120, 52; Angew. Chem. Int.
Ed. 2008, 47, 48; d) W. R. J. D. Galloway, A. Bender, M. Welch,
D. R. Spring, Chem. Commun. 2009, 2446; e) C. Cordier, D. Morton,
S. Murrison, A. Nelson, C. OꢅLeary-Steele, Nat. Prod. Rep. 2008, 25,
719.
Received: July 22, 2010
[21] The bacterial strains CV026 and SP19 are mutants in which the pro-
duction of the pigments violacein (purple) and prodigiosin (red), re-
Revised: October 21, 2010
Published online: February 2, 2011
2986
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