Pellasoren: Structure elucidation, biosynthesis, and total synthesis of a cytotoxic secondary metabolite from Sorangium cellulosum

Article abstract of DOI:10.1002/anie.201200327

Genetic analysis of biosynthetic gene clusters is becoming an accepted tool to predict the stereochemical outcome of a biosynthesis. However, in the case of pellasoren, one chiral center was not predicted correctly. The absolute configuration was verified by total synthesis, which also demonstrated that stereoselective protonations can be successfully applied to natural products synthesis. Copyright

Full text of DOI:10.1002/anie.201200327

Angewandte
Chemie
DOI: 10.1002/anie.201200327
Natural Products
Pellasoren: Structure Elucidation, Biosynthesis, and Total Synthesis of
a Cytotoxic Secondary Metabolite from Sorangium cellulosum**
Christine Jahns, Thomas Hoffmann, Stefan Mꢀller, Klaus Gerth, Peter Washausen,
Gerhard Hçfle, Hans Reichenbach, Markus Kalesse,* and Rolf Mꢀller*
Myxobacteria are efficient producers of numerous secondary
metabolites, and the genus Sorangium is frequently described
as an proficient source for new, biologically active natural
products.[1–3] We report here the discovery and complete
structure elucidation of pellasoren from the myxobacterium
Sorangium cellulosum. Identification of the corresponding pel
gene cluster from S. cellulosum So ce38 allowed us to
establish a model for pellasoren biosynthesis, providing
evidence for an unusual route to glycolate extender unit
generation. Moreover, we present the first total synthesis of
pellasoren and thereby confirm the absolute configuration of
this natural product.
Scheme 1. Structure of pellasoren A (1a) and B (1b).
Pellasoren (1; Scheme 1) was initially isolated from
S. cellulosum So ce35 in the course of an activity-guided
discovery program.[4] Additionally, we recently identified 1 in
relatively high amounts in extracts from the related strain
S. cellulosum So ce38 by using LC-MS analysis. Here we
determine its cytotoxicity against HCT-116 human colon
cancer cells at a concentration of 155 nm (IC50). Full
structural elucidation by NMR and ESI-MS analysis was
performed and confirmed the identity of pellasoren from both
sources (Figures S1–S3 and Table S1 in the Supporting
Information).
products, which was corroborated by specific HMBC corre-
lations between a methoxy signal and sp2-hybridized carbon
atoms (Figure S1 in the Supporting Information).[5–7] The
lactone moiety was identified through HMBC correlation
between C1 and C5 and characteristic shifts for H-5 and C5 of
d = 4.02 and 90.3 ppm, respectively. The position of the amide
bond was assigned on the basis of indicative fragments in CID
spectra. Efforts were made to establish the moleculeꢀs relative
configuration by using NOE spectroscopy: ROESY interac-
tions together with molecular modeling suggest an anti
configuration of the substituents at C4 and C5, as well as
a syn configuration of the methyl groups at C2 and C4
(Figure S2 in the Supporting Information). The stereocenter
at C14 maintains the configuration derived from the incor-
poration of an l-alanine building block during biosynthesis.
Stereochemical assignments that could initially not be vali-
dated by NOE analysis, such as the configuration at C6, were
later established following total synthesis. Additionally, two
isomeric pellasorens differing in the configuration of the C10–
C11 double bond were isolated from S. cellulosum extracts.
Pellasoren A (1a) represents the all-E configuration while
pellasoren B (1b) has a Z-configured double bond at C10–
C11 which can be rationalized by photochemical isomer-
ization.
Following the structural elucidation of pellasoren, we set
out to identify the underlying biosynthetic machinery using
fragmentary whole-genome sequence information for strain
S. cellulosum So ce38. Assuming that pellasoren is most likely
the product of a hybrid PKS/NRPS biosynthetic pathway,[8]
the full complement of putative PKR/NRPS-related domains
encoded in the So ce38 genome was annotated using
bioinformatic tools.[9] Using the presumed incorporation of
alanine into pellasoren as a guide, we identified a genomic
region roughly 57500 bp in size, containing seven character-
istic PKS modules organized as an apparent operon which
also encodes one adenylation (A) domain exhibiting the
The pellasoren scaffold features an unusual enol ether
moiety, also known from a small number of other natural
[*] C. Jahns,[+] Prof. Dr. M. Kalesse
Institut fꢀr Organische Chemie, Leibniz Universitꢁt Hannover
Schneiderberg 1B, 30167 Hannover
and
Helmholtz-Zentrum fꢀr Infektionsforschung (HZI)
Inhoffenstrasse 7, Braunschweig (Germany)
E-mail: markus.kalesse@oci.uni-hannover.de
T. Hoffmann,[+] S. Mꢀller, Prof. Dr. R. Mꢀller
Helmholtz-Institut fꢀr Pharmazeutische Forschung Saarland
(HIPS), Helmholtz-Zentrum fꢀr Infektionsforschung und Pharma-
zeutische Biotechnologie, Universitꢁt des Saarlandes
Campus, Gebꢁude C2.3, 66123 Saarbrꢀcken (Germany)
E-mail: rom@helmholtz-hzi.de
Dr. K. Gerth, Dr. P. Washausen, Prof. Dr. G. Hçfle,
Prof. Dr. H. Reichenbach
Helmholtz-Zentrum fꢀr Infektionsforschung (HZI)
Inhoffenstrasse 7, Braunschweig (Germany)
[+] These authors contributed equally to this work.
[**] We thank Daniel Krug for proofreading the manuscript, Jennifer
Herrmann for performing the bioactivity assays, and Susanne
Schneiker-Bekel for genome sequencing. Research in R.M’s labo-
ratory was funded by the Bundesministerium fꢀr Bildung und
Forschung and the Deutsche Forschungsgemeinschaft.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200327.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
required predicted substrate specificity for alanine (Sche-
me 2a). Insertion by single-crossover homologous recombi-
nation of a plasmid conferring hygromycin resistance into
module 7 led to the abolishment of pellasoren production and
thus ultimately confirmed involvement of the pel locus in
pellasoren biosynthesis (Figure S5 in the Supporting Infor-
mation).
of extender units agree well with the pellasoren scaffold.
Modules 2 and 7 encode seemingly superfluous ketoreductase
(PelA-KR2) and dehydratase domains (PelE-DH), respec-
tively; however, these domains are likely inactive as judged
on the basis of sequence analysis, which revealed deviations
inside otherwise highly conserved amino acid motifs
(Tables S4 and S6 in the Supporting Information).
In line with standard biosynthesis mechanisms for PKS-
and NRPS-derived natural products, we reasoned that
pellasoren formation starts with the condensation between
an ACP-bound propionate and a rare glycolate-derived
extender unit catalyzed by module 1, followed by extension
with alanine in module 2. Biosynthesis then continues by
means of elongation with two methylmalonyl-CoA units
(mM-CoA, modules 3 and 4), one malonyl-CoA (M-CoA,
module 5), and another three mM-CoA extender units
(modules 6 to 8). Finally the full-length intermediate under-
goes lactone ring formation and the ACP-bound product is
released by the terminal TE domain in module 8 (Sche-
me 2a). The order and function of domains encoded by genes
pelA to pelF corresponds to the proposed biosynthetic route.
Furthermore, both the predicted substrate specificities of
the AT and A domains (Table S5 and Figure S4 in the
Supporting Information) and the presence of KR, DH, and
ER domains necessary to achieve the appropriate reduction
Pellasoren (1) features several chiral centers (C2, C4, C5,
C6, C14), the configuration of which is set during the
biosynthesis. The absence of an epimerization domain
within the NRPS module 2 in PelA indicates an S configura-
tion at C14 for the l-alanine-derived building block. The
configuration at C4 and C5 results from extender-unit
reduction by PelE-KR in module 7, whereas stereocenters
at C2 and C6 are generated by the ER domains PelD-ER
(module 6) and PelF-ER (module 8, Scheme 2a). All active
KR domains are of B-type[10] which is in agreement with the
4R,5R configuration of pellasoren. Kwan et al. highlighted
several key amino acid residues in ER domains which appear
to exert a crucial influence on the stereochemical outcome of
the reduction resulting in either 2R or 2S configuration of the
intermediary building block.[11] A tryptophan residue at
position 52 has been shown to direct the conformation to
2S, whereas absence of Trp52 favors the 2R conformation. In
pellasoren biosynthesis, both ER domains should produce 2R
Scheme 2. A) The pel biosynthetic gene cluster in Sorangium cellulosum So ce38 and the proposed biosynthetic route to pellasoren. B) Putative
biosynthetic pathway to the glycolate extender unit, allowing for alternative loading of phosphoglycerate onto the PelG-ACP by PelK or PelG-AT.
A: adenylation domain, ACP: acyl carrier protein, AT: acyltransferase domain, C: condensation domain, DH: dehydratase domain, ER: enoylreduc-
tase domain, KR: ketoreductase domain, KS: ketosynthase domain, TE: thioesterase domain.
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
centers since they lack Trp52. Nevertheless, they appear to
establish converse stereogenic centers during biosynthesis: 2S
(by PelD-ER) and 2R (by PelF-ER). The conflict between the
bioinformatics prediction and the proposed NMR-based
configuration of pellasoren (1) could only be solved by total
synthesis of the NMR-based structure. We therefore decided
to approach the synthesis of pellasoren A (1a).
Our retrosynthetic analysis divides pellasoren into two
key building blocks (2 and 3) which are supposed to be
connected by a Wittig olefination reaction in order to install
the sensitive triene at a late stage during the synthesis
(Scheme 3). In the synthetic direction, the western fragment 2
Scheme 4. Synthesis of aldehyde 3 by stereoselective intramolecular
protonation. a) TiCl4, CH2Cl2, À788C to À308C, 18 h, 61% (two steps),
d.r. 17:1; b) LiBH4, THF, MeOH, 08C, 3 h, 90%; c) MnO2, CH2Cl2, RT,
2 h, quant.; d) Stryker’s reagent, benzene, RT, 15 h, 65%, d.r. 20:1;
e) TPAP, NMO, MS 4 ꢂ, CH2Cl2, RT, 14 h, 90%; f) O3, CH2Cl2, À788C,
10 min, then PPh3, RT, 1 h, quant. Stryker’s reagent=[{(PPh3)CuH}6],
TPAP[15] =tetrapropylammonium perruthenate, NMO=N-methylmor-
pholine-N-oxide, MS=molecular sieves.
Scheme 3. Retrosynthetic analysis of pellasoren A.
Scheme 5. Synthesis of fragment 2. Reagents and conditions:
a) (COCl)2, DMSO, Et3N, CH2Cl2, À788C to 08C, 2 h; b) Ph3P=
C(CH3)CHO, toluene, 908C, 14 h, 65% (two steps); c) Ph3P=
C(CH3)CO2Et, CH2Cl2, RT, 16 h, 85%, 80% ee (determined by GC on
a chiral stationary phase); d) TFA, CH2Cl2, 08C, 30 min; e) 12, EDC,
HOBt, CH2Cl2, 08C, RT, 14 h, 82% (two steps); f) DiBAlH, CH2Cl2,
À788C, 2 h, 87%; g) CBr4, PPh3, CH2Cl2, RT, 5 min, 76%; h) PBu3,
MeCN, RT, 3 h, quant. TFA=trifluoroacetic acid, EDC=1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride, HOBt=1-hydroxy-
benzotriazole, DiBAlH=Diisobutylaluminum hydride.
is accessible by a sequence of eight steps, starting from
l-alanine (9). The eastern fragment 3 contains the lactone
subunit and it was planned to be generated by an intra-
molecular stereoselective protonation of an aldehyde-derived
enolate as the key step. This particular transformation takes
advantage of conjugate reduction of an a,b-unsaturated
aldehyde by Strykerꢀs reagent[12] and the subsequent proto-
nation of the resulting enolate through the secondary
alcohol.[13] The required enal 4 is synthesized by a vinylogous
Mukaiyama aldol[14] reaction (VMAR) of the chiral vinyl-
ketene silyl N,O-acetal 5 and aldehyde 6 to afford the anti
aldol product 7 (Scheme 4).
The western fragment 2 could be synthesized starting from
Boc-protected amino alcohol 9 (Scheme 5). Swern[16] oxida-
tion established the aldehyde functionality required for the
following sequence of two olefination reactions. The first
olefination yielded aldehyde 10 which was used in the next
transformation to generate ester 11. The aldehydes were used
immediately in the next steps to avoid racemization, yielding
ester 11 in 80% ee. Liberating the amine with trifluoroacetic
acid(TFA) in CH2Cl2 at 08C and peptide coupling with acid 12
(generated from 2-oxovaleric acid in two steps)[17] gave access
to compound 13. The synthesis continued by reduction of the
ester functionality of 13 to the alcohol which was submitted to
an Appel reaction to provide corresponding bromide.[18]
Reaction with tributylphosphine provided phosphonium
bromide 2 and completed the synthesis of this key building
block.
two segments through an E-selective Wittig olefination
between C8 and C9 (Scheme 6). Comparison of the
1H NMR data of synthetic and authentic pellasoren con-
firmed the relative configuration of pellasoren as shown in
structure 1a (see the Supporting Information). Additionally,
since the two chromophores are joined at carbon C14, it
should be possible to establish the absolute configuration by
analyzing the CD data. In order to compare the two isomers,
the unnatural diastereomer (14R)-pellasoren was also syn-
With both building blocks in hand we were able to
complete the synthesis of pellasoren A (1a) by connecting the
Scheme 6. Completion of the total synthesis of pellasoren (1a).
Reagents and conditions: a) KOtBu, THF, À788C to RT, 15 h, 46%.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
thesized following the same strategy as that described for 1a.
Gratifyingly, comparison of the NMR and CD spectra of
pellasoren (1a), (14R)-pellasoren, and the authentic sample
verified the absolute and relative configuration of this natural
product as shown for 1a (Scheme 1).
Verification of the pellasoren configuration by total
synthesis confirms the above-described deviations from
bioinformatic analysis, and thus underpins the current limits
of ER sequence-based stereochemistry prediction. When
seeking to improve bioinformatic tools, the pellasoren ER
domains may provide a useful starting point for future
biochemical and structural studies, as they show 92.4%
identity spanning 315 aa residues where Arg43 from PelF-
ER is replaced by Leu43 in PelD-ER. We hypothesize here
that Arg43 could be another important amino acid to govern
the stereochemistry of the reduced extender unit.
The genes involved in biosynthesis of the rarely observed
“glycolate” extender unit are located upstream of pelA-F.
Specifically, we propose that PelG to PelK generate the
unusual glycolate extender unit believed to be incorporated
by module 2, because these proteins show high similarity to
proteins responsible for synthesis of glycolate precursors in
the soraphen, ansamitocin, and FK-520 pathways (Table 1).
Unfortunately and despite serious efforts, our attempts to
prove the hypothesis based on gene cluster analysis by
incorporation studies using isotopically labeled precursors
does not have a FkbH analogue but uses a PelG homologue
instead. Since PelG-AT is supposed to catalyze this loading
step during pellasoren biosynthesis, PelK seems to be
redundant. The pel gene cluster actually represents the first
finding with this specific gene arrangement. However, when
speculating about a hypothetical function for PelK in
pellasoren biosynthesis it has to be pointed out that the
precise mechanism for loading of phosphoglycerate has to
date not been experimentally proven for any of the known
biosynthetic pathways which employ glycolate extender units.
Thus, the presence of two proteins potentially able to catalyze
the same loading reaction in the pellasoren pathway raises
more questions concerning the biosynthesis of this extender
unit. The involvement of pelK in the latter using targeted
inactivation is not straightforward because of the pel operon
organization, but will be the subject of future studies.
Pellasoren A is cytotoxic against human colon cancer cells
of the HCT-116 cell line with an IC50 of 155 nm. Interestingly,
pellasoren B is around one magnitude less active against
HCT-116 with an IC50 of 2.35 mm, emphasizing the impor-
tance of the linear an all-(E) configuration. Furthermore,
both pellasorens show a strong effect on lysosomes. Upon
incubation with osteosarcoma cells (U-2 OS) using an
acridine orange assay, the pH of the lysosomes changed
from acidic to neutral values (Figure S10 in the Supporting
Information). This is related to an apoptotic mechanism that
remains elusive at the current state
of research.[19]
Table 1: Comparison of proteins involved in biosynthesis of glycolate extender units.
This report features a new cyto-
toxic compound from Sorangium
cellulosum. We present the first
total synthesis of pellasoren and
thereby validated the moleculeꢀs
stereochemistry. A Wittig reaction
in the last step of the synthesis was
used to install the sensitive polyene
system. Further key steps include
Non-NRPS/PKS proteins of the So ce38 pellasoren biosynthetic machinery
Protein aa[a] Proposed function of
the homologous protein
Identity/similarity to:
FK-520
soraphen
biosynthesis genes
biosynthesis genes
PelG
794 acyl transferase (28–355)
Ppant attachment site (427–480)
57/65% (SorC, AT part)
22/28% (SorC, ACP part) 21/29% (FkbJ)
18/26% (FkbH)
FkbM methyltransferase (589–744) 39/48% (SorC, OMT part)
8/15% (FkbG)
36/51% (FkbK)
27/44% (FkbJ)
33/48% (FkbI)
41/57% (FkbH)
PelH
PelI
PelJ
283 hydroxyacyl-CoA dehydrogenase
93 acyl carrier protein
384 acyl-CoA dehydrogenase
74/82% (SorD)
57/67% (SorX)
49/60% (SorE)
not present
a
vinylogous Mukaiyama aldol
reaction of a chiral vinylketene
silyl N,O-acetal and a stereoselec-
tive intramolecular protonation,
which was shown to be an efficient
and practical protocol in natural
PelK
376 HAD superfamily phosphatase
[a] Amino acid sequence length.
and employing MS/MS analysis were not conclusive owing to
thorough metabolism of the fed compounds (Figure S7 in the
Supporting Information).[7] However, the above-mentioned
similarity to known glycolate pathways strongly supports the
biosynthesis as shown in Scheme 2.
products total syntheses for the first time. Identification of the
biosynthetic machinery nicely complements this work by
enabling bioinformatics and chemical analyses including an
unusual pathway to the glycolate extender unit.
It is assumed that 1,3-bisphosphoglycerate is loaded to an
ACP, and according to soraphen biosynthesis, PelG-ACP
binds 1,3-phosphoglycerate loaded by the PelG-AT domain.
Methylation could then be catalyzed by the internal SAM-
dependent PelG-MT domain. These functions are usually
facilitated by discrete proteins rather than a multifunctional
protein. Indeed, it appears that a trifunctional enzyme is
present (Scheme 2b). Moreover, the presence of the pelK
gene is fairly unexpected. PelK shows homology to FkbH,
a protein that is assumed to load 1,3-bisphosphoglycerate to
FkbJ in the FK-520 pathway.[5] The soraphen biosynthesis
Experimental Section
The pellasoren gene cluster sequence was deposited in the EMBL
database with the accession number HE616533. Full experimental
details, including stucture elucidation procedures and bioinformatic
analysis, can be found in the Supporting Information.
Received: January 12, 2012
Revised: February 16, 2012
Published online: && &&, &&&&
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[11] D. H. Kwan, Y. Sun, F. Schulz, H. Hong, B. Popovic, J. C. Sim-
Keywords: biosynthesis · myxobacteria · natural products ·
Sorangium cellulosum · total synthesis
.
Stark, S. F. Haydock, P. F. Leadlay, Chem. Biol. 2008, 15, 1231 –
1240; Ref. [1].
[12] a) W. S. Mahoney, D. M. Brestensky, J. M. Stryker, J. Am. Chem.
Soc. 1988, 110, 291 – 293; b) B. H. Lipshutz, J. M. Serevesko,
B. R. Taft, J. Am. Chem. Soc. 2004, 126, 8352 – 8353.
[13] A. Kena Diba, C. Noll, M. Richter, M. T. Gieseler, M. Kalesse,
Angew. Chem. 2010, 122, 8545 – 8547; Angew. Chem. Int. Ed.
2010, 49, 8367 – 8369.
[1] K. Gerth, H. Steinmetz, G. Hçfle, R. Jansen, Angew. Chem. 2008,
120, 610 – 613; Angew. Chem. Int. Ed. 2008, 47, 600 – 602.
[2] S. C. Wenzel, R. Mꢁller, Curr. Opin. Drug Discovery Dev. 2009,
12, 220 – 230.
[3] H. Irschik, H. Reichenbach, G. Hçfle, R. Jansen, J. Antibiot.
2007, 60, 733 – 738.
[14] a) S. Shirokawa, M. Kamiyama, T. Nakamura, M. Okada, A.
Nakazaki, S. Hosokawa, S. Kobayashi, J. Am. Chem. Soc. 2004,
126, 13604 – 13605; b) for a general review see: G. Casiraghi, L.
Battistini, C. Curti, G. Rassu, F. Zanardi, Chem. Rev. 2011, 111,
3076 – 3154; c) S. Shirokawa, M. Shinoyama, I. Ooi, S. Hoso-
kawa, A. Nakazaki, S. Kobayashi, Org. Lett. 2007, 9, 849 – 852;
d) S. Hosokawa, K. Matsushita, S. Tokimatsu, T. Toriumi, Y.
Suzuki, K. Tatsuta, Tetrahedron Lett. 2010, 51, 5532 – 5536.
[15] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639 – 666.
[16] K. Omura, D. Swern, Tetrahedron 1978, 34, 1651 – 1660.
[17] A. Fꢁrstner, M. M. Domostoj, B. Scheiper, J. Am. Chem. Soc.
2005, 127, 11620 – 11621.
[18] R. Appel, Angew. Chem. 1975, 87, 863 – 874; Angew. Chem. Int.
Ed. Engl. 1975, 14, 801 – 811.
[4] H. Reichenbach, G. Hçfle in Drug Discovery from Nature (Eds.:
S. Grabley, R. Thiericke), Springer, Berlin, 1999, p. 173.
[5] B. J. Carroll, S. J. Moss, L. Q. Bai, Y. Kato, S. Toelzer, T. W. Yu,
H. G. Floss, J. Am. Chem. Soc. 2002, 124, 4176 – 4177.
[6] K. Wu, L. Chung, W. P. Revill, L. Katz, C. D. Reeves, Gene 2000,
251, 81 – 90.
[7] S. C. Wenzel, R. M. Williamson, C. Grꢁnanger, J. Xu, K. Gerth,
R. A. Martinez, S. J. Moss, B. J. Carroll, S. Grond, C. J. Unkefer,
R. Mꢁller, H. G. Floss, J. Am. Chem. Soc. 2006, 128, 14325 –
14336.
[8] S. C. Wenzel, R. Mꢁller, Nat. Prod. Rep. 2009, 26, 1385 – 1407.
[9] B. O. Bachmann, J. Ravel, Methods Enzymol. 2009, 458, 181 –
217.
[10] a) P. Caffrey, ChemBioChem 2003, 4, 654 – 657; b) R. Reid, M.
Piagentini, E. Rodriguez, G. Ashley, N. Viswanathan, J. Carney,
D. V. Santi, C. R. Hutchinson, R. McDaniel, Biochemistry 2003,
42, 72 – 79.
[19] a) K. Kꢂgedal, M. Zhao, I. Svensson, U. T. Brunk, Biochem. J.
2001, 359, 335 – 343; b) A. C. Johansson, H. Appelqvist, C.
Nilsson, K. Kagedal, K. Roberg, K. Ollinger, Apoptosis 2010, 15,
527 – 540.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Natural Products
Genetic analysis of biosynthetic gene
clusters is becoming an accepted tool to
predict the stereochemical outcome of
a biosynthesis. However, in the case of
pellasoren one chiral center was not
predicted correctly. The absolute config-
uration was verified by total synthesis
which also demonstrated that stereose-
lective protonations can be successfully
applied to natural products synthesis.
C. Jahns, T. Hoffmann, S. Mꢁller, K. Gerth,
P. Washausen, G. Hçfle, H. Reichenbach,
M. Kalesse,* R. Mꢁller*
&&&& — &&&&
Pellasoren: Structure Elucidation,
Biosynthesis, and Total Synthesis of
a Cytotoxic Secondary Metabolite from
Sorangium cellulosum
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!